HUP0200403A2 - Pyrrolopyrimidines as protein kinase inhibitors, pharmaceutical compositions containing them and their use - Google Patents

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compounds of the general formula — where preferably

The optionally substituted benzene, naphthalene, pyridine or indole ring;

L is an oxygen atom, a group of the general formula -NHSO ₂ - or a group of the formula -NHC(O)O or -NHC(O)-;

R ¹ is, with certain restrictions, optionally substituted alkyl, cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ² is hydrogen; and

R ³ is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl group — and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use in the treatment of diseases associated with tyrosine kinases, especially inflammation, hyperproliferative diseases and immunological disorders.

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N prp7CtV.Ö71 c _? > ívklini Iroda uq/, b. Andrássy út US'. t i'f 14 11 950 Fax: Teleim- 341 ^CO 4 0 5. Pyrrolopyrimidines as protein kinase inhibitors

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The invention relates to pyrrolopyrimidines and their pharmaceutically acceptable salts, pharmaceutical compositions containing them and their use in the treatment of disorders associated with protein kinases.

At least 400 enzymes are known to be protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. Phosphorylation is usually achieved through a so-called transfer reaction, in which a phosphate group is transferred from the ATP molecule to the substrate protein. By determining the site in the substrate protein to which the phosphate group is transferred, it was found that this is a tyrosine, serine or threonine amino acid residue within the peptide chain. Since these amino acid residues in proteins correspond to the structural element on which phosphorylation takes place, the common name for protein kinase enzymes is tyrosine kinase or serine/threonine kinase.

Phosphorylation of tyrosine, serine, and threonine amino acid residues, and the opposite reaction, dephosphorylation catalyzed by phosphatases, are essential components of a variety of cellular responses to intracellular signals, typically mediated by cellular receptors, including the regulation of cellular functions and the initiation or cessation of cellular processes. Protein kinase cascades are often part of intracellular signal transduction and are essential for the execution of certain cellular processes. Since protein kinases are involved in almost all cellular processes, it follows that they are found both as integral parts of the plasma membrane or as cytoplasmic enzymes, and in the nucleus, often as components of enzyme complexes. In many cases, these protein kinases are essential components of enzyme and structural protein complexes that determine where and when a cellular process occurs in the cell.

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Posttranslational modification of these substrate proteins, which are often enzymes themselves, acts as molecular switches that regulate cell proliferation, activation, or differentiation [for a review, see Schlessinger and Ulrich: Neuron 9, 383-391 (1992)]. Aberrant or excessive PTK activity has been observed in a variety of pathological conditions, including benign and malignant proliferative diseases, as well as diseases associated with inappropriate activation of the immune system, such as autoimmune diseases, allograft rejection, and graft versus host disease. In addition, endothelial cell-specific receptor protein tyrosine kinases, such as KDR and Tie-2, are involved in the regulation of angiogenic processes, and therefore play a role in the progression of cancer processes or other diseases associated with inadequate vascularization (e.g. diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, childhood haemangioma).

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Tyrosine kinases can be of the receptor type, which have extracellular or transmembrane domains, or of the non-receptor type, which are entirely intracellular.

Receptor tyrosine kinases (RTKs) are a large family of transmembrane receptors with diverse biological activities, and at least 19 distinct RTK subfamilies have been described. Receptor tyrosine kinases include receptors that are crucial for the proliferation and differentiation of various cell types [see Yardén and Ullrich: Ann. Rev. Biochem. 57, 433-478 (1988); Ullrich and Schlessinger: Cell 61, 243-254 (1990)]. Receptor tyrosine kinases basically function by being activated upon ligand binding, resulting in phosphorylation of the receptor and its associated cellular substrates, followed by a variety of cellular responses [Ullrich and Schlessinger: Cell 61, 203-212 (1990)]. Signal transduction mediated by receptor tyrosine kinases is thus initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. The binding sites thus act as intracellular signaling molecules, their function triggering the production of a series of cytoplasmic signaling molecules that promote appropriate cellular responses (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) [see Sclessinger and Ullrich: Neuron 9, 1-20 (1992)] .

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Proteins that have an SH2 (src homolog 2) or phosphotyrosine-binding (PBT) domain bind with high affinity to activated tyrosine kinase receptors and their substrates, thereby transmitting signals into the cell. Both domains recognize phosphotyrosine [ Fantl et al.: Cell 69, 413-423 (1992); Songyang et al.: Mol. Cell. Biol. 14, 2777-2785 (1994); Songyang et al.: Cell 72, 767-778 (1993); Koch et al.: Science 252, 668-678 (1991); Shoelson: Curr. Opin. Chern. Biol. 1(2), 227-234 (1997) ; Cowburn: Curr. Opin. Struct. Biol. 7(6), 835-838 (1997)] . Several intracellular substrate proteins have been identified that interact with receptor tyrosine kinases (RTKs), and these can be divided into two main groups: 1) substrates that have catalytic domains; and 2) substrates that do not have catalytic domains but serve as adaptors and bind to catalytically active molecules [Songyang et al.: Cell 72, 767-778 (1993)] . The specificity of the interaction between receptors or proteins and the SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine. For example, differences in binding affinity between SH2 domains and the amino acid sequence surrounding phosphotyrosine in specific receptors correlate with differences in the phosphorylation profile observed in the substrate [Songyang et al.: Cell 72, 767-778 (1993)]. From these observations, we can conclude that the function of individual receptor tyrosine kinases is determined not only by the expression pattern and ligand availability, but also by the sequential signaling pathways activated by the specific receptor.

72.227/BE arrangement of full pathways, as well as the timing and duration of stimuli. Phosphorylation is therefore an important regulatory step that influences the specificity of signaling pathways designated by specific growth factor receptors, as well as the differentiation of factor receptors.

Several receptor tyrosine kinases, such as FGFR-1, PDGFR, TIE-2, and c-Met, and their associated growth factors are known to play a role in angiogenesis, although in some cases this role is only indirect [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 subgroup of receptor tyrosine kinases. Human FLK-1 is also known as kinase insert domain-containing receptor (KDR) [Termán et al.: Oncogene 6, 1677-1683 (1991)]. FLK-1/KDR is also known as vascular endothelial cell growth factor receptor 2 (VEGFR-2), because it binds VEGF with high affinity. The murine version of FLK-1/VEGFR-2 is also known as NYK [Oelrichs et al.: Oncogene 8(1), 11-15 (1993)]. DNAs encoding mouse, rat and human FLK-1 have been isolated and the nucleotide and encoded amino acid sequences have been described [Matthews et al.: Proc. Natl. Acad. Sci. USA 88, 9026-9030 (1991); Termán et al.: see above (1991); Termán et al.: Biochem. Biophys. Res. Comm. 187, 1579-1586 (1992); Sarzani et al.: see above; and Millauer et al.: Cell 72, 835-846 (1993)] . Several studies, including that published by Millauer et al. (see above), report that

72.227/BE ···· ·«·· ···· ···« ·· ··· ·· ·♦ · · *· be that VEGF and FLK-l/KDR/VEGFR-2 form a ligand-receptor pair that plays an important role in the proliferation of vascular endothelial cells and in the formation and repair of blood vessels, in other words, in vasculogenesis and angiogenesis.

Another type III subgroup of receptor tyrosine kinases is the fms-like tyrosine kinase 1 (Flt-1) [DeVries et al. : Science 255, 989-991 (1992); Shibuya et al. : Oncogene 5, 519-524 (1990)] tyrosine kinases, which are related to FLK-1/KDR. Another name for Flt-1 is vascular endothelial cell growth factor receptor 1 (VEGFR-1). It is currently known that members of the FLK-1/KDR/VEGFR-2 and FIt-1/VEGFR-1 subgroups are primarily expressed by endothelial cells. Kinases in these subgroups are specifically stimulated by members of the vascular endothelial growth factor (VEGF) ligand family [ Klagsburn and D'Amore: Cytokine and Growth Factor Reviews 7, 259-270 (1996)] . Vascular endothelial growth factor (VEGF) binds Flt-1 with greater affinity than FLK-1/KDR and exerts a mitogenic effect on vascular endothelial cells [ Termán et al.: supra (1992); Mustonen et al.: supra; DeVries et al.: supra]. It is believed that Flt-1 is essential for endothelial organization during vascular development. In the mouse embryo, Flt-1 expression has been associated with vascular formation and neovascularization during wound healing [ Mustonnen and Alitalio: supra]. Flt-1 expression in monocytes, osteoclasts and osteoblasts, as well as in

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··· · · · · ·· ·· ·· «· «· · ·· in tissues of the kidneys, such as the glomeruli of the kidney, suggests that this receptor has some other function that is not related to cell proliferation [Mustonen and Alitalio: see above] .

As previously explained, based on the data currently available, we can say that VEGE plays a role in stimulating both normal and pathological angiogenesis [ Jakeman et al.: Endocrinology 133, 848-859 (1993); Kolch et al.: Breast Cancer Research and Treatment 36, 139-155 (1995);

Ferrara et al.: Endocrine Reviews 18(1), 4-25 (1997); Ferrara et al.: in Regulation of Angiogenesis (ed. L.D. Goldberg and E.M. Rosen) 209-232 (1997)] . VEGF has also been implicated in the regulation and increase of vascular permeability [Connolly et al. : J. Biol. Chem. 264, 20017-20024 (1989); Brown et al.: in Regulation of Angiogenesis (ed. L.D. Goldberg and E.M. Rosen) (233-269 (1997)] . As is evident from the publications, different forms of VEGF are known due to the different splicing of the mRNA, and these include the 4 forms described by Ferrara et al. [Ferrara et al. : J. Cell. Biochem. 47, 211-218 (1991)] . Ferrara et al. (see above) identified both secreted and predominantly cell-bound forms of VEGF, and the protein is known to exist in the form of a disulfide-linked dimer.

Recently, several homologous relatives of VEGF have been described, but their roles in normal physiological and pathological processes have not yet been elucidated. Furthermore, members of the VEGF family are often co-expressed in many tissues, including

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VEGF, with which they are usually able to form heterodimers. This property is likely to alter the receptor specificity and the biological effects of the heterodimer, which creates further complications and thus makes it difficult to elucidate their specific functions, as illustrated by the following [Korpelainen and Alitalo: Curr. Opin. Cell Biol., 159-164 (1998) and references therein].

Placental growth factor (P1GF) contains an amino acid sequence that shows significant homology to that of VEGF [Park et al.: J. Biol. Chem. 269, 25646-25654 (1994)] ; Maglione et al.: Oncogene 8, 925-931 (1993)] . Similar to VEGF, different forms of P1GF are known due to different mRNA splicing, and the protein also exists in a dimeric form [Park et al.: see above] . P1GF-1 and P1GF-2 bind with high affinity to Flt-1, and P1GF-2 also binds readily to neuropilin 1 [Migdal et al.: J. Biol. Chem. 273(35), 22272-22278] , but none bind to FLK-1/KDR [ Park et al. : see above] . It has been reported [ Park et al. : see above] that when VEGF is present in low concentrations in endothelial cells (evidently due to heterodimer formation), it potentiates both the vascular permeability-influencing and mitogenic effects of VEGF.

VEGF-B is produced in two isoforms (167 and 185 amino acids) and appears to also bind to Flt-1/VEGFR-1. By modulating the expression and activity of urokinase-type plasminogen activator and plasminogen activator inhibitor 1, it may play a role in extracellular matrix degradation as well as cell adhesion and migration [Pepper et al.: Proc. Natl. Acad. Sci. USA 95(20), 11709-11714 (1998)].

VEGF-C was originally cloned as a ligand for VEGFR-3/F11-4, which are primarily expressed by lymphatic endothelial cells. In its fully processed form, VEGF-C also binds to KDR/VEGFR-2 and stimulates endothelial cell proliferation and migration in vitro and angiogenesis in in vivo models [ Lymboussaki et al. : Am. J. Pathol. 153(2), 395-403 (1998); Witzenbichler et al. : Am. J. Pathol. 153(2), 381-394 (1998)]. Transgenic overexpression of VEGF-C causes proliferation and enlargement of lymphatic vessels only, with no effect on blood vessels. Unlike VEGF, VEGF-C expression is not induced by hypoxia [ Ristimaki et al. : J. Biol. Chem. 273(14), 8413-8418 (1998)].

The recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D has been reported to bind to and activate at least two of the vascular endothelial cell growth factor receptors, VEGFR-3/Flt-4 and KDR/VEGFR-2. VEGF-D was originally cloned as a c-fos-inducible mitogen for fibroblasts and is most prominently expressed in mesenchymal cells of the lung and skin [Achen et al.: Proc. Natl. Acad. Sci. USA 95(2), 548-553 (1998) and references therein].

Regarding the use of VEGF, VEGF-C and VEGF-D, since they induce an increase in vascular permeability in vivo when injected into skin tissue in the so-called Miles test [Witzenbichler et al.: see above]

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• · · · « · ··· ·· · «· ·* ·· *· patent applications have been filed [see patent documents PCT/US97/14696 and WO98/07832]. However, the physiological role and importance of these ligands in modulating vascular hyperpermeability and endothelial cell responses in tissues expressing them has remained unclear.

Recently, a novel type of virally encoded vascular endothelial growth factor, designated VEGF-E or NZ-7 VEGF, has been reported to preferentially bind to the KDR/Flk-1 receptor and to have potent mitotic activity without a heparin-binding domain. [Meyer et al. EMBO J. 18(2), 363-374 (1999); Ogawa et al. J. Biol. Chem. 273(47), 31273-31282 (1998)] . VEGF-E has a 25% sequence homology to mammalian VEGF, and the virus encoding it is a parapoxvirus, Orf virus (OV). This parapoxvirus infects sheep and goats, and occasionally humans, and causes lesions through angiogenesis. VEGF-E is a dimer of approximately 20 kilodaltons that lacks a basic domain and has no affinity for heparin, but contains a characteristic cysteine-knot motif that is also present in all mammalian VEGFs. Surprisingly, it exhibits similar potency and biological activity to the heparin-binding isomorph VEGF165 of VEGF-A, i.e. both factors stimulate tissue factor (TF) release, proliferation, chemotaxis, and sprouting in cultured vascular endothelial cells in vitro, and angiogenesis in vivo. VEGF-E, like VEGF165, has been found to bind with high affinity to VEGF receptor 2 (KDR), which inhibits the autophosphorylation of the receptor.

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• · · · · · • · · · « · · · · and results in a biphasic increase in free intracellular calcium ion concentration, however, unlike VEGF165, VEGF-E does not bind to the VEGF-l receptor (Flt-1).

Based on the increasing number of additional VEGF and VEGFR homologues discovered and examples of ligand-receptor heterodimerization, it is believed that the effects of VEGF homologues may be related to the formation of VEGF-ligand heterodimers and/or heterodimerization of receptors or their binding to as yet undiscovered VEGFRs [ Witzenbichler et al.: see above]. Also recently, reports have emerged suggesting that neuropilin 1 [ Migdal et al.: see above] or VEGFR-3/Flt-4 [ Witzenbichler et al.: see above], as well as other receptors other than KDR/VEGFR-2, may play a role in the induction of vascular permeability [ S.A. Stacker, A. Vitali, T. Domagala, E. Nice and A.F. Wilks: Angiogenesis and Cancer Conference, Amer. Assoc. Cancer Res., Orlando, FL, 1998; Williams: Diabetologia 40, S118-120 (1997)].

Tie-2 (TEK) is a recently discovered family of endothelial cell-specific receptor tyrosine kinases involved in critical angiogenic processes (e.g., vessel branching, sprouting, remodeling, development, and stability). Tie-2 is the first mammalian receptor tyrosine kinase for which both agonist ligand(s)—such as Angiopoietin 1 (Ang1), which stimulates receptor autophosphorylation and signal transduction—and antagonist ligand(s)—such as Angiopoietin 2 (Ang2)—are known. Expression of Tie-2 and its ligands can be controlled by gene knockout or transgenic manipulation.

72.227/BE was stopped, demonstrating that tight spatial and temporal control of Tie-2 signaling is essential for the proper development of new vascular networks. The generally accepted model suggests that stimulation of Tie-2 kinase by the ligand Ang1 is directly linked to vessel branching, sprouting, and new vessel outgrowth, and that the presence and interaction of periendothelial skeletal cells are important elements in maintaining vascular integrity and inducing quiescence. In the absence of Ang1 stimulation of Tie-2 or inhibition of Tie-2 autophosphorylation by Ang2, which is produced in high amounts at sites of vascular regression, loss of vascular structure and matrix contact can result in endothelial cell death, especially in the absence of growth or survival-promoting stimuli. However, the situation is much more complicated, as recent findings have revealed at least two additional Tie-2 ligands (Ang3 and Ang4) and have shown that heterodimerization of different agonist and antagonist angiopoietins can alter their activity. Consequently, it seems less likely to consider Tie-2 ligand-receptor interactions as an angiogenic therapeutic target, and a strategy based on kinase inhibition is more advantageous.

The soluble extracellular domain (ExTek) of Tie-2 can disrupt tumor vasculature and tumor cell-mediated overt neovascularization in breast cancer xenograft and lung metastasis models. In vivo, mg/ml levels of ExTek production can be achieved in rodents after adenovirus infection for 7-10 days without any adverse effects. This is

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................ .. • · « * * · • · · · · · « * results suggest that disruption of the Tie-2 signaling pathway is well tolerated in normal, healthy animals. This ExTek-induced Tie-2 inhibitory cellular response may be a consequence of sequestration of the ligand(s) and/or the formation of an inactive heterodimer of full-length Tie-2.

Recently, significant upregulation of Tie-2 expression within the synovial membrane of human arthritic joints has been observed, consistent with a consequence of inappropriate neovascularization. These data suggest a role for Tie-2 in the progression of rheumatoid arthritis. Point mutations resulting in constitutively activated forms of Tie-2 have been associated with human venous malformations. Consequently, Tie-2 inhibitors may be useful in the treatment of these diseases as well as other pathological conditions resulting from inappropriate neovascularization.

Nonreceptor tyrosine kinases are cellular enzymes that lack extracellular or transmembrane sequences. More than 24 unique nonreceptor tyrosine kinases have been identified to date, and they can be classified into 11 subgroups (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK). Currently, the Src subgroup of nonreceptor tyrosine kinases contains the largest number of protein tyrosine kinases, including Src, Yes, Fyn, Lyn, Lek, Blk, Hck, Fgr, and Yrk. The Src subgroup of enzymes is closely associated with oncogenesis and immune responses. A more detailed discussion of nonreceptor tyrosine kinases can be found in Bohlen [Oncogen 8, 2025-2031 (1993)].

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The «4« *r«t .... ..

• ♦ · · · « « _ . ·«* *. * ^Λ ·*

Several tyrosine kinases, including receptor tyrosine kinases and non-receptor tyrosine kinases, have been found to play a role in cellular signaling mechanisms and are therefore implicated in the development of several pathogenic conditions, such as cancer, psoriasis and other hyperproliferative diseases, or in excessive immune responses.

Based on the assumption that protein tyrosine kinases are important links in the control, regulation and modulation of cell proliferation and the development of diseases associated with abnormal cell growth, many attempts have been made to inhibit the function of receptor and non-receptor tyrosine kinases. These attempts have sought different solutions, including the use of mutant ligands [U.S. Patent No. 4,966,849], the use of soluble receptors and antibodies [WO 94/10202; Kendall and Thomas: Proc. Natl. Acad. Sci. 90, 10705-709 (1994); Kim et al.: Nature 362, 841-844 (1993)], use of RNA ligands [Jelűnek et al.: Biochemistry 33, 10450-456; Takano et al., Mol. Bio. Cell 4, 358A (1993); Kinsella et al.: Exp. Cell Res. 199, 56-62 (1992); Wright et al.: J.

Cellular Phys. 152, 448-457 (1992)] and the use of tyrosine kinase inhibitors [ WO 94/03427, WO 92/21660, WO 91/15495, WO 94/14808 and U.S. Patent No. 5,330,992; Mariani et al.: Proc. Am. Assoc. Cancer Res. 35, 2268 (1994)].

Recently, attempts have been made to find small molecules that can be used as tyrosine kinase inhibitors, such as bismonocyclic, bicyclic, and heterocyclic aryl compounds [ PCT

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WO 92/20642] and vinylene azaindole derivatives have been described in general as tyrosine kinase inhibitors. Styryl compounds [U.S. Patent No. 5,217,999], styryl-substituted pyridine derivatives [U.S. [US Patent No. 5,302,606], certain quinazoline derivatives [EP 0 566 266], selenoindoles and selenides [WO 94/03427], tricyclic polyhydroxy compounds [PCT WO 92/21660], and benzylphosphonic acid derivatives [PCT WO 91/15495]. Anilinocinnolines [PCT WO 97/34876], and quinazoline derivatives [PCT WO 97/22596 and PCT WO 97/42187] have been reported to act as inhibitors of angiogenesis and vascular permeability.

In addition to the above, attempts have been made to find small molecules that are serine/threonine kinase inhibitors. For example, bis(indolylmaleimide) derivatives have been described as inhibitors of specific protein kinase C serine/threonine kinase isoforms that have been implicated in signaling function and altered vascular permeability in VEGF-related diseases [PCT WO 97/40830 and PCT WO 97/40831].

An important regulator of the cell cycle process is the serine/threonine kinase known as Plk-1, which plays a critical role in the assembly and function of the mitotic spindle. Plk-1 and related kinases have also been shown to be involved in the activation and secretion of other cell cycle regulators, such as cyclin-dependent kinases. High expression of Plk-1 is associated with cell proliferation activity and is frequently found in malignant tumors of various origins. Plk-1 inhibitors are therefore expected to block cancer cell proliferation by disrupting the process leading to mitotic spindle formation and by inappropriate activation of cyclin-dependent kinases.

Cdc2/cyclin B kinase (also known as cdc2 CDK1) is another serine/threonine kinase that belongs to the cyclin-dependent kinase (CDK) family. These enzymes are involved in critical transitions between different phases of the cell cycle. It is believed that uncontrolled cell proliferation, a major hallmark of cancer, is associated with increased CDK activity in these cells. Inhibition of increased CDK activity in cancer cells with cdc2/cyclin B kinase inhibitors may therefore suppress proliferation and restore normal cell cycle regulation.

The regulation of CDK activation is complex, but it requires the association of CDK with one of the regulatory subunits of the cyclin family [ 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)] . A further level of regulation is achieved through the activation or inactivation of the CDK subunit resulting in phosphorylation [ 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);

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Krek and Nigg: EMBO Journal 10, 3331-3341 (1991); Solomon et al.: Cell 63, 1013-1024 (1990)] . Coordinated activation and inactivation of different cyclin/CDK complexes are required for the normal progression of the cell cycle [ Pines: Trends in Biochemical Sciences 18, 195-197 (1993)] . The critical G ₁ -S and G ₂ -M transitions are controlled by the activation of different cyclin/CDK effects. According to our current knowledge, the initiation of S-phase in G^phase occurs through the mediation of cyclin D/CDK4 and cyclin E/CDK2 [ Matsushima et al.: Molecular and Cellular Biology 14, 2066-2076 (1994); Ohtsubo and Roberts: Science 259, 1908-1912 (1993);

Quelle et al.: Genes and Development 7, 1559-1571 (1993); Resnitzky et al.: Molecular and Cellular Biology 14, 1669-1679 (1994)] . S-phase progression requires the activity of the cyclin A/CDK2 complex [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 Mailer: Nature 354, 314-317 (1991); Zindy et al.: Biochemical and Biophysical Research Communications 182, 1144-1154 (1992)], but the initiation of metaphase requires the activation of the cyclin A/cdc2 (CDK1) and cyclin B/cdc2 complexes [ 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.: 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 Mailer: Nature 354, 314-317 (1991); Zindy et al.: Biochemical and Biophysical

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Research Communications 182, 1144-1154 (1992)] . It is therefore not surprising that dysregulation of CDK regulation is a common feature in hyperproliferative diseases and cancer. [ Pines: Current Opinion in Cell Biology 4, 144-148 (1992); Lees: Current Opinion in Cell Biology 7, 773-780 (1995); Hunter and Pines: Cell 79, 573-582 (1994)] .

Inhibitors of kinases involved in mediating and maintaining the pathological state represent a new approach to the treatment of such diseases. Without intending to be limiting, the following are some of the therapeutic options related to such kinases: (1) inhibition of c-Src [ Brickell: Critical Reviews in Oncogenesis 3, 401-406 (1992); Courtneidge: Seminars in Cancer Biology 5, 236-246 (1994)], raf [ Powis: Pharmacology and Therapeutics: 62, 57-95 (1994)] and cyclin-dependent kinases (CDk1, CDK2 and CDK4) [ 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)] in cancer; (2) CDK2 or PDGRF-R inhibition in restenosis [Buchdunger et al.: Proceedings of the National Academy of Science USA 92, 2258-2262 (1995)]; (3) CDK5 and GSK3 inhibition in Alzheimer's disease [Hosoi et al.: Journal of Biochemistry (Tokyo) 117, 741-749 (1995); Aplin et al.: Journal of Neurochemistry 67, 699-707 (1996)]; c-Src inhibition in osteoporosis [Tanaka et al.: Nature 383, 528-331 (1996)]; (5) GSK3 inhibition in type II diabetes [Borthwick et al.: Biochemical and Biophysical Research Communications 210, 738-745 (1955)]; (6) p38 inhibition in inflammation [Badger et al.: The Journal of Pharmacology and Experimental Therapeutics

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279, 1453-1461 (1996)] ; (7) inhibition of VEGFR-1, -2 and -3, and Tie-1 and -2 in diseases associated with angiogenesis [ Shawver et al. : Drug Discovery Today 2, 50-63 (1997)] ; (8) inhibition of UL97 in viral infection [ He et al.: Journal of Virology 71, 405-411 (1997)] ; (9) inhibition of CSF-1R kinase in bone and hematopoietic diseases [ Myers et al.: Bioorganic and Medicinal Chemistry Letters 7, 421-424 (1997)] ; and (10) inhibition of Lek in autoimmune diseases and transplant rejection [ Myers et al.: Bioorganic and Medicinal Chemistry Letters 7, 417-420 (1997)] .

In addition to the above, another possibility for the therapeutic use of kinase inhibitors is when the kinase is indispensable for the maintenance of the pathological state for other reasons than the defective regulatory mechanism. In such cases, inhibition of the kinase activity may result in either cure of the disease or relief of symptoms. For example, several viruses, including human papillomavirus, disrupt the normal cell cycle and cause the cell to enter the S phase of the cell cycle [Vousden: FASEB Journal 7, 8720879 (1993)]. If a mechanism essential for the initiation of the S phase, such as the activity of CDK2, is inhibited, we can prevent cells from starting DNA synthesis after viral infection, thus interrupting the viral life cycle by eliminating viral replication. The same principle can be applied to protect normal somatic cells from the toxicity of cycle-specific chemotherapeutic agents [Stone et al.: Cancer Research 56, 3199-3202 (1996); Kohn et al.: Journal of Cellular Biochemistry 54, 44-452 (1994)]. The

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Inhibition of CDK2 or CDK4 prevents cells from entering the normal cell cycle, thereby limiting the toxic effects of cytotoxic agents in S phase, _G2 phase, or mitosis. The regulatory effect of CDK2/cyclin E activity has also been shown to extend to NF-kB. Inhibition of CDK2 activity stimulates NF-kB-dependent gene expression, an event that occurs through interactions with the p300 coactivator [Perkins et al.: Science 275, 523-527 (1997)]. NF-kB regulates genes involved in inflammatory responses (e.g., hematopoietic growth factors, chemokines, and leukocyte adhesion molecules) [Baeuerle and Henkel: Annual Review of Immunology 12, 141-179 (1994)], and may play a role in suppressing apoptotic signals within the cell [Beg and Baltimore: Science 274, 782-784 (1996); Wang et al.: Science 274, 784-787 (1996); Van Antwerp et al.: Science 274, 787-789 (1966)] . Thus, inhibition of CDK2 may suppress apoptosis induced by cytotoxic agents through a mechanism that is related to NF-kB. These data suggest that inhibition of CDK2 activity may be useful in other cases, such as diseases in which NF-kB regulation is implicated. Another example is fungal infections. Aspergillosis, for example, is a common infection in immunocompromised patients [ Armstrong: Clinical Infectious Diseases 16, 1-7 (1993)]. The Cdc2/CDC28 or Nim A Aspergillus kinases [ Osmani et al.: EMBO Journal 10, 2669-2679 (1991); Osmani et al.: Cell 67, 283-291

72,227/BE (1991)] may suppress or kill fungi, resulting in improved therapeutic prospects for patients suffering from such infections.

Based on the above, it can be concluded that it would be desirable to find effective small molecule compounds that specifically inhibit signal transduction and cellular proliferation by modulating the activity of receptor and non-receptor tyrosine and serine/threonine kinases, so that they can be used to control or modify abnormal or inappropriate cell proliferation, cell differentiation or metabolism. It would be particularly important to have methods and active ingredients that specifically inhibit the function of tyrosine kinases, which play a pivotal role in angiogenesis and the development of vascular hyperpermeability, as well as in the development of edema, ascites, effusion and exudation, macromolecular extravasation and matrix deposition, and in diseases associated with these.

The subject of the invention is therefore primarily the

compounds of general formula — in which formula

A represents a 6-membered aromatic ring or a 5- or 6-membered heteroaromatic ring, optionally having one or more substituents.

72.227/BE carries a tituens, and the substituents may be selected from the following: substituted or unsubstituted aliphatic group, halogen atom, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroarylalkyl group, cyano or nitro group, group of the general formula -NR ⁴ R ^S , carboxy or hydroxy group, substituted or unsubstituted alkoxycarbonyl group, (haloalkoxy)carbonyl group, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylthio, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkylcarbonyl or (haloalkyl)carbonyl group, substituted or unsubstituted aliphatic ether group, substituted or unsubstituted aromatic ether group, substituted or unsubstituted carboxamido group, tetrazolyl, [ (trifluoromethyl)sulfonyl] -amino-, (trifluoroacetyl)-amino-, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamido-, substituted or unsubstituted arylamido, substituted or unsubstituted styryl and substituted or unsubstituted aralkylamido groups;

72.227/BE

..................

• · · · · · · ·· ft*

L is an oxygen or sulfur atom, a sulfinyl or sulfonyl group, -N(R)-, -N[C(O)OR]-, -N[C(O)R]- or -N(SO ₂ R)-, a group of the general formula, a group of the general formula -CH ₂ O- or -CH ₂ S-, -CH ₂ N(R)-, -CH(NR)-, -CH ₂ N[ C(O)R] -, -CH ₂ N[ C (0) OR] -, -CH ₂ N (SO ₂ R)-, -CH(NHR)-, -CH[ NHC (0) R] - , -CH(NHS0 ₂ R)-, CH[ NHC (0 ) OR] - , -CH[OC(O)R]~ or -CH[ OC (0) NHR] - group of the general formula, a vinylene group, -C (=N0R)- group of the general formula, a carbonyl group, -CH(OR)-, -C(0)N(R)-, -N(R)C(0)-, -N(R)S(O)-,

-N(R)S(0) ₂ -, -0C(0)N(R)-, -N(R)C(0)N(R)-, -NRC(0)0-, -S(O)N(R)-, -S(O) ₂ N(R)-, -N[ C (0) R] S (0)-, -N[ C (0) R] S (0) ₂ -, N (R) S (0) N (R)-, -N (R) S (0) ₂ N (R)-, -C (ON (R) C (0)-S (0) N (R) C (0)-, -S (0) ₂ N (R) C (0)-, -0S(0)N(R)-, -OS (0) ₂ N (R)-, -N(R)S(0)0-, -N (R) S (0) ₂ 0~,

- N (R) S (0) C (0)-N(R)S(O) ₂ C(O)-, -SON[ C (0) R] -, -SO ₂ N[ C (0) R] -, -N(R)SON (R)- or -N (R) SO ₂ N (R) - group, -0(0)0- group, -N (R) P (OR' ) 0-, -N (R) P (OR' ) - ,

- N (R) P (0) (OR' )0-, -N (R) P (0) (OR')-, -N[ C (0 ) R] P (OR' ) 0-,

- a group of the general formula N[ C (0) R] P (OR' ) -, -N[ C (0) R] P (0) (OR' )0- or -N[ C (O) R] P (O 'R), where in the general formulae R and R' independently represent a hydrogen atom, 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; or

L is a group of the general formula -R ^b N (R) S (0) ₂ -, -R ^h N (R) P (0) - or -R ^b N (R) P (0) 0-, in which R ^b represents an alkylene group, and together with the sulfonamide, phosphinamide or phosphonamide group to which it is attached, a 5- or 6-membered,

It forms a ring fused with the ring; or

or

one of the groups of the general formula, in which R ⁸⁵ is a group that leaves the given ring in a 5-, 6- or

It completes into a 7-membered aromatic, heteroaromatic, or heterocycloalkane ring;

R ¹ is a substituted aliphatic group, a substituted cycloalkyl, a substituted bicycloalkyl or a substituted cycloalkenyl group, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, an optionally substituted heteroarylalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterobicycloalkyl, an optionally substituted alkylamido, an optionally substituted arylamido, an optionally substituted alkylsulfonyl, an optionally substituted cycloalkylsulfonyl, an alkylcarbonyl or an optionally substituted alkylcarbonyl group; where R ¹ is

One or more substituents of groups corresponding to the 72.227/BE entry may preferably be selected from the following: substituted or unsubstituted aliphatic group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ether group, substituted or unsubstituted aliphatic ether group, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted (aryloxy)carbonyl group, hydroxy group, substituted or unsubstituted carbamoyl group, hydroxyimino group, substituted or unsubstituted azabicycloalkyl, heterocycloalkyl, oxo or formyl group, substituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, substituted or unsubstituted bicycloalkyl or substituted or unsubstituted heterobicycloalkyl group, cyano, amino, alkylamino, ureido or thioureido group or a group of the general formula -BE; provided, however, that in the case where R ¹ represents an aliphatic group or a cycloalkyl group, and these carry either one or more substituents

72.227/BE, the substituents must also include a group other than a hydroxy or lower alkoxy group; furthermore, the heterocycloalkyl group may only be a group other than a 2-phenyl-1,3-dioxan-5-yl group; and in the case of an aliphatic group, whether it carries one or more substituents, the substituents must also include a group other than an aliphatic group;

B represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, an alkylene, aminoalkyl, alkylenecarbonyl or (aminoalkyl)carbonyl group;

E means 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 heteroarylalkyl, 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 group;

R is a hydrogen atom, substituted or unsubstituted

72.227/BE

..................

·« · · · · · ♦ ·· « W · W* «* aliphatic group, substituted or unsubstituted cycloalkyl group, halogen atom, hydroxy or cyano group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroarylalkyl group, and a group of the general formula -NR ⁴ R ⁵ or -C(O)NR ⁴ R ⁵ ;

R ³ represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterocycloalkyl group;

R ⁴ and R ⁵ independently represent a hydrogen atom, azabicycloalkyl, heterocycloalkyl or a substituted or unsubstituted alkyl group or a group of the general formula -YZ; or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or substituted or unsubstituted heteroaryl group;

Y is a carbonyl group, a group of the general formula -(CH ₂ ) _p -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, -(CH ₂ ) _p O~, -(CH ₂ ) _p NH-, -(CH ₂ ) _p S-, -(CH ₂ ) _p S(O)- or

- (CH ₂ ) _p S (0) ₂ - group of general formula;

p is an integer from 0 to 6;

Z is substituted or unsubstituted alkyl,

72.227/BE • 4 · 4 · substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; and j is an integer from 0 to 6, with the proviso that when L is a group of the general formula -CH ₂ NR-, -C(O)NR- or -NRC(O)- and R ³ is an azacycloalkyl or azaheteroaryl group, j is 0; and when L is an oxygen atom and R ³ is a phenyl group, j is 0 — and pharmaceutically acceptable salts thereof.

The compounds of the invention are useful as inhibitors of serine/threonine and tyrosine kinases. More specifically, the compounds of the invention are useful as inhibitors of tyrosine kinases that are closely associated with hyperproliferative diseases, particularly cancer, and the process of angiogenesis. For example, some of these compounds are inhibitors of the KDR, Flt-1, FGFR, PDGFR, c-MET, Tie-2, and IGF-1-R receptor kinases. Since some of the compounds also have antiangiogenic activity, they are valuable agents and can be used to inhibit the progression of pathological conditions in which angiogenesis plays an important role. Some of the compounds of the invention are effective inhibitors of the following serine/threonine kinases: PKC family, erk, MAP kinase, MAP kinase kinase, MAP kinase kinase kinase, cdk family, Plk-1, and Raf-1. These compounds can be used to treat cancer and hyperproliferative diseases. In addition, some compounds effectively inhibit certain

72.227/BE

non-receptor kinases, such as the Src (e.g. lek, blk and lyn), Tec, Csk, Jak, Map, Nik and Syk kinase families, such that these compounds can be used to treat cancer, hyperproliferative diseases and immunological disorders.

Some of the compounds of the invention are selective Tie-2 kinase inhibitors and may be antiangiogenic (especially in combination with one or more VEGFR inhibitors) or proangiogenic when used in the presence or in conjunction with a VEGF-like stimulus. As such, these inhibitors are useful for promoting therapeutic angiogenesis, and thus for example in the treatment of ischemia, infarction or occlusion, and for accelerating wound healing.

The invention therefore further provides a method for inhibiting the enzymatic activity of tyrosine kinases and serine/threonine kinases, which comprises introducing a compound of general formula (I) into the environment of the kinase in question in a concentration sufficient to inhibit the enzymatic activity.

The invention also provides the use of these compounds as active ingredients in pharmaceutical compositions, which means that a therapeutically effective amount of the compounds described above is combined with a pharmaceutically acceptable carrier or pharmaceutical excipients. These pharmaceutical compositions are used to slow or stop the process of angiogenesis in diseases supported by angiogenesis, and to treat edema, effusion, exudation or ascites, and other conditions associated with vascular hyperpermeability.

- ··· V *·. ♦ can be used to treat diseases. Certain pharmaceutical compositions, administered to a patient and thus inhibiting the function of certain serine/threonine kinases, such as cdk, Plk-1, erk, etc., can be used to treat cancer and other hyperproliferative diseases.

In the first group of preferred compounds of general formula (I), the symbols have the following meanings:

L is preferably a group of the general formula -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O) or -C(O)N(R)- or an oxygen atom.

R ³ is preferably substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted dioxolanyl, substituted or unsubstituted quinolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted isoquinolyl, substituted or substituted72.227/BE

..................

··· · · · ·· • · · * · ·· · · ·· unsubstituted quinoxalinyl, substituted or unsubstituted indolyl or substituted or unsubstituted pyrazolyl. Furthermore, in the case where L is a group of the general formula -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 (0 ) N (R' ) - or -N(R) S (0 ) ₂ ) N (R ' ) -, R ³ may also be a substituted or unsubstituted aliphatic group or a substituted or unsubstituted alkenyl group. In a preferred embodiment of the invention, R ³ represents a substituted or unsubstituted phenyl group.

The group corresponding to the symbol R ³ may carry one or more substituents, and the following are preferred among the substituents: fluorine, chlorine, bromine and iodine atoms, methyl, nitro, trifluoromethoxy, methoxy, cyano, methoxycarbonyl, trifluoromethyl, tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted tetrazolyl or styryl, substituted or unsubstituted arylthio or substituted or unsubstituted heteroarylthio group, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl or alkynyl group, and a group of the general formula -C(O)NR ^f R ^g , -R ^c or -CH ₂ OR ^c .

R ^f and R ^g independently represent a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group; or R ^f and R ^g together with the nitrogen72.227/BE atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicycloalkyl group or a substituted or unsubstituted heteroaromatic group.

R ^c represents a hydrogen atom, a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl group, and a group of the general formula -W-(CH2)t-NR ^d R ^e , -W-(CH2) _t -O-alkyl, -W-( _CH2 ) _t -S-alkyl or -W-( _CH2 ) _t -OH.

The value of t is an integer from 0 to approximately 6.

W represents a valence line expressing a chemical bond, an oxygen or sulfur atom, a sulfinyl or sulfonyl group, and a group of the general formula -NR ^k .

R ^k represents a hydrogen atom or an alkyl group.

R ^d and R ^e independently represent a hydrogen atom, an alkyl or alkanoyl group, or a group of the general formula -KD; or R ^d and R ^e together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heterobicyclic group.

K represents a sulfonyl or carbonyl group, a group of the formula -C(O)NH- or —C(O) ₂ — or a valence line expressing a direct chemical bond.

D represents a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaromatic group, a substituted or

72.227/BE unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl or substituted or unsubstituted aminocycloalkyl, -COOR ¹ group or substituted or unsubstituted alkyl group.

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

Particularly preferred substituents of the group represented by the symbol R ³ may be selected from fluorine, chlorine, bromine and iodine atoms, as well as cyano, nitro, trifluoromethoxy, methyl and trifluoromethyl groups.

Ring A is preferably a substituted or unsubstituted benzene ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted pyridine ring, or a substituted or unsubstituted indole ring. In a preferred embodiment of the invention, ring A is a substituted or unsubstituted benzene ring.

Ring A may carry one or more substituents, and the following are preferred substituents on ring A: fluorine, chlorine, bromine and iodine, methyl, nitro, trifluoromethoxy, methoxy, cyano, methoxycarbonyl, trifluoromethyl, tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted

72.227/BE phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted tetrazolyl or styryl group, substituted or unsubstituted arylthio or substituted or unsubstituted heteroarylthio group, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl or alkynyl group, and a group of the general formula -C(O)NR ^f R ^g , -R ^c or -CH ₂ OR ^c , in which R ^f , R ⁹ and R ^c are as defined above.

Ring A is particularly preferably substituted with a fluorine or chlorine atom or a nitro group.

R ² is preferably hydrogen.

In one embodiment of the invention, R ¹ is

Qm < ^Ia >

a group of general formula wherein m is an integer from 0 to approximately 3.

In another embodiment, R ¹ is

7- ^<ib > (CH ₂ )t NR8R9 group, in which m and t have the meanings previously given, and R ⁸ and R ⁹ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted

72.227/BE means an unsubstituted heteroaromatic group or a substituted or unsubstituted heterobicycloalkyl group; or R ⁸ and R ⁹ are independently hydrogen, aza-bicycloalkyl or heterocycloalkyl, and a group of the general formula -Y ² -Z ² , in which Y ² is a carbonyl group, a group of the general formula -(CH ₂ ) _q - _, a sulfonyl group, a group of the general formula -C(0)0-, -SO ₂ NH- or -CONH- group, -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH 2 ) _q S(O)- or -(CH ₂ ) _q S (0) ₂ - group, where q is an integer from 1 to 6, and Z ² is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group.

In a further embodiment, R ¹ is

R77 is a group of the general formula NR8R9, in which m, t, ^R8 and ^R9 are as defined above, s is an integer from 0 to 6, q is an integer from 0 to about 6, and ^R77 is ^-OR78 or ^-NR79R80 , in which ^R78 is hydrogen or a substituted or unsubstituted aliphatic group, and ^R79 and ^R80 together with the nitrogen atom to which they are attached form ^a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted

72.227/BE or an unsubstituted heterobicycloalkyl group; or R ⁷⁹ and R ⁸⁰ independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ , in which Y ³ represents a carbonyl group, a group of the general formula ~(CH ₂ ) _q ~, a sulfonyl group, -C(0)0-,

-SO ₂ NH- or -CONH- group, -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-,

-(CH ₂ ) _q S-, -(CH ₂ ) _q S (O) - or -(CH ₂ ) _q S (0) ₂ - is a group of the general formula, and Z ³ is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group.

In yet another embodiment, R ¹ is

R10 is a group of the general formula ^{-Xo v} , wherein v is an integer from 1 to about 3, and ^R10 is hydrogen, azabicycloalkyl or heterocycloalkyl, or ^-Y2 - ^Z2 , wherein ^Y2 and ^Z2 are as defined above.

In yet another embodiment, R ¹ is ^R11 < ^Ie >

A group of general formula RIO, in which R ¹⁰ is as previously defined and R ¹¹ is one or more substituents which may independently be selected from the following:

72.227/BE hydrogen atom, hydroxy and oxo group, substituted or unsubstituted aliphatic group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl and substituted or unsubstituted aralkyl groups, with the proviso that the carbon atoms adjacent to the nitrogen atom may only bear a group other than a hydroxy group as a substituent.

In another embodiment, R ¹ is

I (If)

A group of general formula R10, in which ^R10 has the meaning defined above.

In another embodiment, R ¹ is a group of general formula (lg) wherein r is an integer from 1 to

72.227/BE up to approximately 6, and R ⁸ and R ⁹ have the meanings given previously.

In a further embodiment, R ¹ is

w R12O' ^x (CH ₂ )t (Ih)

A group of the general formula RS, wherein R ⁸ , R ⁹ and t are as defined above, w is an integer from 0 to about 4, t is 0 or 1, and R ¹² is hydrogen or a substituted or unsubstituted alkyl group.

In another embodiment, R ¹ is

RlÖO ^N

R12 is a group of general formula, in which aw, t, ^R10 and ^R12 are as defined above.

In a further embodiment, R ¹ is a group of formula (Ig) or (Ih) wherein

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a

R2O, r19' r18R17

R16 represents a heterocycloalkyl group of general formula, where u is as previously defined; ^R13 , ^R14 , ^R15 , ^R16 , ^R13 , ^R18 , ^R19 and ^R20 independently represent a lower alkyl group or a hydrogen atom; or at least one of the pairs ^R13 and ^R14 , ^R15 and ^R16 , ^R17 and ^R18 or ^R19 and ^R20 together represents an oxygen atom; or at least one of R ¹³ and R ¹⁵ is a cyano group or a group of the general formula -CONHR ²¹ , -COOR ²¹ , -CH2OR ²¹ or -CH2NR ²¹ (R ²² ), in which R ²¹ and R ²² together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterobicycloalkyl group, or R ²¹ and R ²² independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ , in which Y ³ and Z ³ have the meanings previously given; and X represents an oxygen or sulfur atom, a sulfinyl, sulfonyl or methylene group or a group of the general formula -CH(OR ₂₃ )- or -NR ²³ -, in which R ²³ represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, an amidino group or a group of the general formula -C(O)R ²⁴ or -C(O)OR ²⁴ (wherein R ²⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group).

In another embodiment, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a

(H2C ₎

Sun ^r22

R21

72.227/BE

forms a heterocycloalkyl group of the general formula wherein t, R ²¹ and R ²² are as previously defined, R ²⁵ and R ²⁶ are independently hydrogen or lower alkyl, or R ²⁵ and R ²⁶ together are oxo, and i is an integer from 1 to about 6.

In another embodiment, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a

IN (CH ₂ ) i

R27 forms a heterocycloalkyl group of the general formula, in which i is as defined above, and ^R27 is a hydroxymethyl group or a group ^of the general formula -C(O) ^NR24R28 or ^-COOR24 , in which ^R24 and ^R28 are as defined above.

In a further embodiment, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a heterocycloalkyl group of the general formula, in which R ²⁹ is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl group, carboxy or cyano group, --C(O)OR ³⁰ , -CH2OR ³⁰ , -CH2NR ²¹ R ²² or -C(O)NR ²¹ R ²² group, in which R ³⁰ is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl group, R ²¹ and R ²²

The meaning of 72.227/BE is as previously stated.

In a still further embodiment, at least one of R ⁸ and R ⁹ represents a group of the general formula -Y ³ -D, wherein Y ³ is as defined above and D is

a group of the general formula, where ax is 0, 1 or 2, and T may represent an oxygen atom, a carbonyl group, a sulfur atom, a sulfinyl·-, sulfonyl or methylene group, and a group of the general formula -CH(OR ²⁴ )- or -N(R ²⁴ )- (in the general formulas R ²⁴ has the meaning given above).

In yet another embodiment, at least one of R ⁸ and R ⁹ is a group of the general formula -Y ³ -N (R ³¹ ) R ³² , wherein Y ³ is as defined above, and R ³¹ and R ³² are independently a substituted or unsubstituted carboxyalkyl, substituted or unsubstituted (alkoxycarbonyl)alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted cyanoalkyl. R ³¹ and R ³² may also form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl group.

In another embodiment, where R ¹ is a group of formula (le), Z ² is a group of formula -N(R ³⁵ )R ³⁶ ,

72.227/BE in which R ³⁵ and R ³⁶ independently represent a hydrogen atom, an alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, carbamoyl, cyano, alkylcarbonyl or aralkyl group.

In a further embodiment, where R ¹ is a group of formula (le), Z ² is a

X1=X1 II ^X R37 represents a group of the general formula, in which X _x independently represents a methine group or a nitrogen atom, and R ³⁷ represents a substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl·, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl group.

In a still further embodiment, where R ¹ is a group of formula (le), Z ² is a

means a group of the general formula wherein g is an integer from 0 to about 3, T is as defined above, and R ³⁷ is hydrogen, as well as cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted carbamoyl, substituted

72.227/BE substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl group.

In a still further embodiment, wherein R ¹ is a group of the general formula (le)

means a group of the general formula wherein g is as defined above and R ³⁷ is an unsubstituted aralkyl group as defined above.

In a still further embodiment, where R ¹ is a group of formula (le), Z ² is a

means a group of general formula wherein T, g and R ³⁷ are as previously defined.

In a still further embodiment, where R ¹ is a group of formula (le), Z ² is a

r37

R38 represents a group of general formula in which ^R37 is as previously defined and ^R38 represents a hydrogen atom or a substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted carbamoyl, perhaloalkyl, substituted or unsubstituted alkenyl,

72.227/BE substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl group.

In another embodiment, R ¹ is

a group of the general formula, in which the value of u is as previously defined; R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ independently represent a methyl group or a hydrogen atom; or at least one of the pairs R ³⁹ and R ⁴⁰ , R ³⁶ and R ³⁷ or R ³⁸ and R ³⁹ , or R ⁴⁰ and R ⁴¹ together represent an oxygen atom; and R ⁴⁷ represents a hydrogen atom, an aza-bicycloalkyl or heterocycloalkyl group or a group of the general formula -Y ² -Z ² , in which Y ² and Z ² have the meanings defined above, or R ⁴⁷ is a

represents a group of the general formula, in which y is 0 or 1; R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ and R ⁵⁵ independently represent a methyl group or a hydrogen atom; or at least one of the pairs R ⁴⁸ and R ⁴⁹ , R ⁵⁰ and R ⁵¹ , R ⁵² and R ⁵³ or R ⁵⁴ and R ⁵⁵ together represents an oxygen atom; and R ⁵⁶ represents a hydrogen atom, an aza-bicycloalkyl or heterocycloalkyl group or a group of the general formula -Y ³ -Z ³ , in which Y ³ and Z ³ have the meanings previously defined.

In another embodiment, R ¹ is

72.227/BE

a group of the general formula, in which 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 independently methyl or hydrogen; or at least one of the pairs R ⁵⁷ and R ⁵⁸ , R ⁵⁹ and R ⁶⁰ , R ⁶¹ and R ⁶² or R ⁶³ and R ⁶⁴ together is oxygen; and R ⁶⁷ is hydrogen, aza-bicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -Z ² , in which Y ² and Z ² are as defined above, or R ⁶⁷ is a

represents a group of the general formula, in which d is 0 or 1; R ⁶⁸ , R ⁶⁹ , R ⁷⁰ , R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ and R ⁷⁵ independently represent a lower alkyl group or a hydrogen atom; or at least one of the pairs R ⁶⁸ and R ⁶⁹ , R ⁷⁰ and R ⁷¹ , R ⁷² and R ³³ or R ⁷⁴ and R ⁷⁵ together represents an oxygen atom; and R ⁵⁶ represents a hydrogen atom, an aza-bicycloalkyl or heterocycloalkyl group or a group of the general formula -Y ³ -Z ³ , in which Y ³ and Z ³ have the meanings previously defined.

The term aromatic group, as used herein, may refer to a group derived from carbocyclic ring systems.

72.227/BE aromatic groups, such as benzyl or cinnamyl, and groups derived from fused polycyclic ring systems, such as naphthyl or 1,2,3,4-tetrahydronaphthyl. Aromatic groups are also referred to herein as aryl groups.

Heteroaromatic groups, as used herein, may be heteroaryl groups (e.g., thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl, thiazolyl, isoxazolyl, isothiazolyl, tetrazolyl, or oxadiazolyl) or may be groups derived from fused ring systems in which one or more heteroaromatic rings are joined by a carbocyclic aromatic, a carbocyclic nonaromatic, or a heteroaromatic ring, such as: benzene [b] thienyl, benzimidazolyl, indolyl, tetrahydroindolyl, azaindolyl, indazolyl, quinolyl, imidazopyridyl, purinyl, pyrrolol 2,3-d]pyrimidinyl and pyrazolo[3,4-d]pyrimidinyl groups, as well as groups derived from the corresponding N-oxides.

We define an aralkyl group as an aromatic group that is attached to the rest of the molecule through an aliphatic group, and the aliphatic group contains an increasing number of carbon atoms from 1 to approximately 6.

A heteroarylalkyl group is defined as a heteroaromatic group that is linked to the rest of the molecule through an aliphatic group, and the aliphatic group contains an increasing number of carbon atoms from 1 to approximately 6.

The heterocycloalkyl group designation, as used herein, is

72.227/BE

7 ................. ..

• · · · · · · ··* *··* -*· ·* * β* is used to mean a group derived from a 3-8 atom non-aromatic ring system containing at least one heteroatom, such as nitrogen, oxygen or sulfur.

The term acyl group herein refers to a group of the general formula -C(O)NR ^X R ^Z , -C(O)OR ^X or C(O)R ^X , in which R ^x and R ^z independently represent a hydrogen atom, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.

In the specification, the term aliphatic group means — as used herein — a group derived from straight or branched chain or cyclic hydrocarbons having 1 to 8 carbon atoms, which is fully saturated or contains one or more unsaturated bonds. The term lower alkyl group refers to saturated aliphatic groups having 1 to 6 carbon atoms.

The compounds of formula (I) may exist in the form of salts with pharmaceutically acceptable acids, such as hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [such as (+)-tartrates, (-)-tartrates or mixtures thereof, e.g. racemic mixtures], succinates and benzoates, as well as salts with amino acids, e.g. glutamine. The salts are of course within the scope of the invention. The salts may be prepared by methods well known to those skilled in the art.

Some of the compounds of formula (I) which contain acidic substituents may exist in the form of salts with pharmaceutically acceptable bases, and these salts are also considered part of the invention. The salts with bases

72.227/BE salts include, for example, sodium salts, potassium salts, salts with lysine, and salts with arginine. These salts can also be prepared by methods well known to those skilled in the art.

Some of the compounds of formula (I) and their salts may exist in more than one crystalline form, and consequently all of the crystalline forms and mixtures thereof are included within the scope of the invention.

Some of the compounds of general formula (I) and their salts may also exist in the form of solvates, for example hydrates, and it is therefore considered necessary to note that all solvates and mixtures thereof are also within the scope of the invention.

Some of the compounds of formula (I) may contain one or more chiral centers and may exist in an optically active form. Compounds of formula (I) which contain one chiral center may exist in two enantiomeric forms, and of course both enantiomers and mixtures thereof, such as racemic mixtures, are also part of the invention. The enantiomers may be separated by methods well known to those skilled in the art. For example, diastereomeric salt pairs may be formed, which may then be separated, for example, by crystallization; diastereomeric derivatives or complexes may be formed, which may be separated, for example, by crystallization, gas chromatography or liquid chromatography; selective, enantiomer-specific reactions such as enzymatic esterification may be used; or the enantiomers may be separated by gas and liquid chromatography under chiral conditions.

............. ..

Λ · · · *· ··· · · · · • · · · · · 4* .«· «» * , for example, on a column containing a chiral ligand bound to silica gel or in the presence of a chiral solvent. It is easy to see that in cases where the desired enantiomer is converted into another chemical entity according to the resolution technique used, an additional step is required to obtain it in its original form. In addition to the above, the enantiomer of interest can also be prepared by asymmetric synthesis, using optically active reagents, substrates, catalysts or solvents, and by asymmetric transformation of the other enantiomer.

Compounds of formula (I) which contain more than one chiral center in their molecule may exist as diastereomers. The diastereomeric pairs may be separated by methods well known to those skilled in the art, such as chromatography or crystallization, and the separation of the individual enantiomers may be accomplished by any of the techniques described above. The invention naturally includes each diastereomer of the compounds of formula (I) as well as mixtures thereof.

Among the compounds of general formula (I), there are those which may have different tautomeric forms or geometric isomers, and it is understood that the invention also relates to these tautomeric forms and/or geometric isomers, as well as to mixtures thereof.

Certain compounds of formula (I) may exist in the form of stable conformers which can be separated. Hindered rotation of an asymmetric single bond, such as that caused by spherical inhibition or ring strain, may result in torsional asymmetry and allow the separation of different conformers. Naturally, these conformational isomers of compounds of formula (I) and mixtures thereof are also part of the invention.

Certain compounds of formula (I) may also exist in zwitterionic form, and the invention also relates to these zwitterionic modifications of compounds of formula (I), as well as mixtures thereof.

Preferred compounds of general formula (I) include, for example:

cis-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

trans-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride;

trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

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

cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride;

5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride;

72.227/BE cis-5-(4-phenoxyphenyl)-7-(4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

trans-5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

cis-5-(4-phenoxyphenyl)-7-{4-(4-(2-methoxyethyl)-piperazin-1-yl]-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

trans-5-(4-phenoxyphenyl)-7-{4-(4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

cis -7-[4-(4-ethylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

trans-7-[4-(4-ethylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

cis-5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxyphenyl)-7-(4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

cis-5-(4-phenoxyphenyl)-7-{4-(4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxyphenyl)-7-{4-(4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

cis-5-(4-phenoxyphenyl)-7-(4-{[3-(1H-imidazol-1-yl)propylamino]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxyphenyl)-7-(4-((3-(1H-imidazol-1-yl)-propylamino]-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminodimaleate;

cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate;

trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate;

72.227/BE «··· ‘ • » · · · · • · ® · * * ·»♦ * * · · »· * .. · »1» -w * w Ok trans-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate;

cis-5-(4-phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

5-(4-phenoxyphenyl)-7-[3-(4-methyl-piperazin-1-yl)-cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-aminotrimaleate;

trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride;

cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride;

trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

cis-benzyl {N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate}-trimaleate;

trans-benzyl {N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]carbamate}trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-benzamide;

72.227/BE .«»· ··*· · ·» · » '♦ ··£ » -.’* *-»* *«*.<' 4» trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-benzamide trimaleate;

cis-N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-3-phenyl-propionic acid amide;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3-phenylpropionic acid amide;

cis-N-[4-(4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3-phenylpropionic acid amide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-3-phenylpropionic acid amide trimaleate;

cis-2-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-phenoxy]-6-[(3-methoxy-propyl)-amino]-benzonitrile trimaleate;

trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy]-6-[(3-methoxypropyl)amino]benzonitrile trimaleate;

cis-2-amino-6-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy]benzonitrile trimaleate;

trans-2-amino-6-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]benzonitrile trimaleate;

72.227/ΒΞ cis-2-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-phenoxy]-6-[(4-tolyl)-thio]-benzonitrile trimaleate;

trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]-6-[(4-tolyl)thio]benzonitrile trimaleate;

cis-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]-6-[(2-pyridyl)thio]benzonitrile trimaleate;

trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]-6-[(2-pyridyl)thio]benzonitrile trimaleate;

cis-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate;

N-{4-[4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide;

N-{4-[4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide;

N-{4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide;

72.227/BE

N-{4-[4-amino-7-(1-formyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide;

N-{4-[4-amino-7-{1-[(1-methyl-1H-imidazol-4-yl)-sulfonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4fluorobenzenesulfonamide dimaleate;

N-{4-[4-amino-7-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4fluorobenzenesulfonamide;

N-{4-[4-amino-7-{1-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide;

N-{4-[4-amino-7-{1-[(2-pyridyl)carbonyl]-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide;

N-[4-{4-amino-7-[1-(1-methyl-piperidin-4-yl)-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimealate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-(trifluoromethoxy)benzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-chloro-2-thiophenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluoro-2-chlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]

72.227/BE

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluoro-2-chlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-difluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-difluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3,4-trifluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-nitrobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-fluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,4,6-trichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

..................

• ·· · · · ·· ·· · * · ·· ·· ··

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-dichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-chlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-3-fluorobenzenesulfonamide dimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-5-chloro-2-thiophene sulfonamide dimaleate;

cis-N-[4-(4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2,6-difluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluoro-3-chlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2-iodo-benzenesulfonamide trimaleate;

cis-N-[4-(4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-(trifluoromethoxy)benzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

..................

• · · · · · · · · · · · · · ·* ··

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-chloro-6-methylbenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-cyano-2-chlorobenzenesulfonamide trimalate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3,4-trifluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3,4-difluorobenzosulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2-fluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-5-bromo-2-thiophenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,4-dichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3,4-trichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-3-bromo-5-chloro-2-thiophenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

................ ..

• · · » · «·· ·· · «· ·· ·· ·»

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,1,3-benzoxadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dichloro-1-thiophenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-7-chloro-2,1,3-benzoxadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-7-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-chloro-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-3-chloro-2-methyl-benzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-bromobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

..................

··· ·· ·· ·· «£>

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dibromo-3,6-difluorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate;

cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-(2-nitrophenyl)methanesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-nitrobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-fluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,4,6-trichlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-dichlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-chlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-fluorobenzenesulfonamide dimaleate;

trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2,5-difluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluoro-3-chlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-iodobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-chloro-6-methylbenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-cyano-2-chlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3,4-difluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2-fluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-bromo-2-thiophenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

..................

• « · * · * ·♦ · · · ·* ·*

-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,4-dichlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3,4-trichlorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-bromo-5-chloro-2-thiophenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,1,3-benzoxadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dichloro-1-thiophenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-7-chloro-2,1,3-benzoxadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-7-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-5-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-chloro-2,1,3-benzothiadiazole-4-sulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] 72.227/BE

..................

• · · a · · · * · ·♦ · 9 9 ·· ·· «·

-7H-pyrrolo[2,3-d]pyrimidin-5-yl·}-2-fluorophenyl]-3-chloro-2-methylbenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-bromobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dibromo-3,6-difluorobenzenesulfonamide trimaleate;

trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-(2-nitrophenyl)methanesulfonamide trimaleate.

The compounds of the invention exhibit antiangiogenic activity, and this antiangiogenic activity is at least partly attributable to their inhibition of protein tyrosine kinases, which play an essential role in angiogenic processes. Consequently, these compounds can be used as active ingredients in pharmaceutical compositions for the treatment of the following pathological conditions: arthritis, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, collateral lesions of the coronary and cerebral vessels, ischemic limb angiogenesis, ischemic/reperfusion injuries, wound healing, peptic ulcers and Helicobacter-induced diseases, viral angiogenic disorders, fractures, Crow-Fucase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch disease (felinosis), rubeosis, neovascular glaucoma and retinopathies such as diabetic-associated retinopathy, retinopathy of prematurity, and aging.

•·· * · · ··· ·♦ · · · ·· *· associated macular degeneration. In addition to the above, some of the compounds may be useful as active agents in the treatment of solid tumors, malignant ascites, von Hippel-Lindau syndrome, hematopoietic cancers and hyperproliferative diseases such as thyroid hyperplasia (especially Graves' disease), cysts such as hypervascularization of the ovarian connective tissue, which is a characteristic feature of the polycystic ovary disorder known as Stein-Leventhal syndrome, and polycystic kidney disease, since proliferation of blood vessel cells is required for growth and/or metastasis.

Some of these compounds may also be useful as active ingredients in pharmaceutical compositions for the treatment of burns, chronic lung diseases, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, altitude sickness, trauma or hypoxia-induced cerebral or pulmonary edema, ocular or macular edema, ascites, glomerulonephritis and other diseases associated with vascular hyperpermeability, effusion, exudation, protein extravasation or edema. The compounds of the invention may also be useful in the treatment of diseases in which protein extravasation leads to fibrin or extracellular matrix deposition, promoting connective tissue proliferation (e.g., keloid fibrosis, cirrhosis, carpal tunnel syndrome). Increased VEGF production potentiates inflammatory processes, such as the proliferation and activation of monocytes, and consequently the compounds of the invention are useful in inflammatory diseases,

72.227/BE

........*.........

• · · · 4 9 • · ♦ · · « · * · for example, it can also be used to treat inflammatory bowel diseases (IBD) and Crohn's disease.

The vascular endothelial growth factors are unique in that they are the only known family of angiogenic growth factors that are responsible for vascular hyperpermeability and edema. Indeed, although vascular hyperpermeability and edema are associated with the expression or use of several other growth factors, their effects appear to be dependent on VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia induces a marked upregulation of VEGF production in many tissues, and it follows that in certain situations—such as infarction, occlusion, ischemia, anemia, or circulatory failure—typical VEGF/VPF-mediated responses are initiated. Vascular hyperpermeability and associated edema, altered transendothelial processes and macromolecular extravasation, as well as their frequent accompaniment, diapedesis, can cause excessive matrix deposition, aberrant connective tissue proliferation, fibrosis, etc. Consequently, VEGF-mediated hyperpermeability significantly contributes to the progression of diseases of this origin.

Since blastocyst implantation, placental development and embryogenesis are dependent on angiogenesis, some of the compounds of the invention may be useful as contraceptives and antifertility agents.

We can see that protein tyrosine kinases, such as

72.227/BE

The activity of the tyrosine kinases KDR/VEGFR-2 and/or Flt-1/VEGFR-1 and/or Tie-2. By inhibiting the function of these tyrosine kinases, the progression of the listed diseases can be prevented, since in the mentioned pathological conditions the angiogenic or vascular hyperpermeability-related component is significantly suppressed. The action of some of the compounds of the invention is selective for a specific tyrosine kinase, so they cause fewer side effects than would be expected if a less selective tyrosine kinase inhibitor were used. Some of the compounds of the invention are also effective inhibitors of FGFR, PDGFR, c-Met and IGF-1-R. These receptor kinases directly or indirectly enhance angiogenic and hyperproliferative reactions in various diseases, and consequently their inhibition can delay the deterioration of the pathological condition.

The compounds of the invention inhibit the function of protein kinases, i.e. modulate the signal transduction mediated by protein kinases. The compounds of the invention inhibit serine/threonine kinases and enzymes belonging to the tyrosine kinase family. More specifically, these compounds selectively inhibit the KDR/FLK-1/VEGFR-2 tyrosine kinases. Some of the compounds of the invention also inhibit the function of additional tyrosine kinases, for example the following: Flt-1//VEGFR-1, Tie-2, FGFR, PDGFR, IGF-1R and c-Met, as well as members of the Src subgroup, such as Lek, Src, fyn, yes, etc. Some of the compounds of the invention also significantly inhibit serine/threonine kinases, such as PKC, MAP kinases, erk, cyclin-dependent kinases, Plk-1 and

72.227/BE

Raf-1, which play a key role in cell proliferation and cell cycle progression. The potency and specificity of the compounds of the invention against a particular protein kinase can often be altered and optimized by varying the nature, number and arrangement of substituents (e.g. R ¹ , R ² , R ³ , and substituents on the A ring or other rings) and by conformational constraints. In addition, metabolites of certain compounds may also have significant protein kinase inhibitory activity.

The compounds of the invention, when administered to a subject in need of such treatment, inhibit vascular hyperpermeability and edema formation in such subjects. It is believed that these compounds exert their effect by inhibiting the function of KDR tyrosine kinase, an enzyme involved in the process of vascular hyperpermeability and edema formation. KDR tyrosine kinase is also known as FLK-1 tyrosine kinase, NYK tyrosine kinase, or VEGFR-2 tyrosine kinase. KDR tyrosine kinase is activated when vascular endothelial growth factor (VEGF) or another ligand (e.g., VEGF-C, VEGF-D, VEGF-E, or the Tat protein) binds to the KDR tyrosine kinase receptor located on the surface of vascular endothelial cells. The consequence of the above-mentioned activation of KDR tyrosine kinase is vascular hyperpermeability, which allows fluid from the bloodstream to leak through the vessel wall into the interstitial space, resulting in edema. The response triggered by activation is often accompanied by diapedesis. Similarly, excessive vascular hyperpermeability can disrupt the endothelium-mediated

72.227/BE f

«' · · ”** · ·* ♦·»· ‘f- ~« • * · · * 4 < · 5 normal molecular turnover in some critical tissues and organs (e.g. lung and kidney), resulting in macromolecular extravasation and deposition. When the acute cellular response to KDR stimulation, which is known to promote the subsequent angiogenic process, is followed by sustained KDR tyrosine kinase stimulation, this triggers proliferation and chemotaxis of vascular endothelial cells and the formation of new blood vessels. Inhibition of KDR tyrosine kinase function, either by blocking the production of the activating ligand, by inhibiting the binding of the activating ligand to the KDR tyrosine kinase receptor, by preventing receptor dimerization and transphosphorylation (by inhibiting the enzymatic activity of KDR tyrosine kinase, more specifically the phosphorylation function of the enzyme), or by some other mechanism, interrupts the further signaling cascade [D. Mukhopedhyay et al.: Cancer Res. 58, 1278-1284 (1998)], and thus the consequences, i.e. hyperpermeability and its accompanying phenomenon of extravasation, and then the formation of edema and matrix deposition, as well as angiogenic reactions, can be eliminated or minimized.

A preferred group of compounds of the invention are those which inhibit the function of KDR tyrosine kinases without significantly affecting the activity of Flt-1 tyrosine kinase (also known as VEGFR-1). VEGF can activate either the KDR tyrosine kinase receptor or the Flt-1 tyrosine kinase receptor by binding to it. However, among the compounds of the invention there are preferred active ingredients which are uniquely active only in one

72.227/BE ··♦♦ *4*· ·'··j />*, ··* ·* ♦ ♦ ·*· ^ · « * · 4 ο * *♦-· *’· · X .·

They inhibit the function of VEGF receptor tyrosine kinase (KDR) when it is activated by binding of the activating ligand, and do not inhibit the function of other receptor tyrosine kinases, such as Flt-1, which are also activated by certain activating ligands. Certain preferred compounds of the invention thus exhibit selectivity for tyrosine kinase inhibitory activity.

One embodiment of the invention is therefore a method of treating a pathological condition in a patient associated with a protein kinase, which comprises administering to the patient a therapeutically or prophylactically effective amount of one or more compounds of formula (I).

The term protein kinase-associated pathological condition is used in the medical sense to refer to a disease or undesirable physical condition whose development and progression depend, at least in part, on the activity of at least one protein kinase. The protein kinase may be, for example, a protein tyrosine kinase or a protein serine/threonine kinase.

The patient or patient to be treated may be an animal, preferably a mammal, such as a domestic animal or a farm animal. The term patient or patient is particularly preferably a human.

A therapeutically effective amount is an amount of a compound of formula (I) or a combination of two or more such compounds that completely or partially inhibits the progression of a pathological condition or at least partially alleviates one or more symptoms of the disease. A therapeutically effective amount may further be an amount of the active ingredient that is prophylactically effective. The therapeutically effective amount will depend on the size and sex of the patient, the pathological condition being treated, the severity of the condition, and the desired result. The therapeutically effective amount for a given patient can be determined by methods well known to those skilled in the art.

The method of the invention may be used to treat pathological conditions associated with protein kinases, such as those listed above. In one embodiment of the invention, the pathological condition associated with protein tyrosine kinase is characterized by undesirable angiogenesis, edema, and connective tissue deposition. Such diseases include ulcers caused by bacterial or fungal infections, such as Mooren's ulcers and ulcerative colitis, but also include, for example, the following: diseases caused by microbial infection, such as Lyme disease, sepsis, and septic shock; infections caused by herpes simplex, herpes zoster, human immunodeficiency virus, protozoan, toxoplasma, or parapoxvirus; angiogenic disorders, such as von Hippel-Lindau syndrome, polycystic kidney disease, pemphigus, Paget's disease, and psoriasis; diseases affecting the reproductive organs, such as endometriosis, ovarian hyperstimulation syndrome, preeclampsia or menometrorrhagia; fibrotic and edematous disorders, such as sarcoidosis, fibrosis, cirrhosis, thyroiditis, systemic hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic obstructive pulmonary disease, asthma, burns, trauma, radiation, stroke, hypoxia or ischemia-induced edema; and inflammatory/immunological diseases, such as systemic lupus, chronic inflammation, glomerulonephritis,

72.227/BE synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis and graft rejection. Diseases associated with protein kinases include sickle cell anemia, osteoporosis, osteopetrosis, tumor-induced hypercalcemia and bone metastases. Other diseases that can be treated according to the method of the invention include eye diseases, such as: retinopathy and macular degeneration, ocular and macular edema, neovascularization eye disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, orbital disease, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt syndrome and Eales syndrome.

The compounds of the invention may also find use in cardiovascular diseases, such as atherosclerosis, restenosis, vascular occlusion or carotid stenosis.

The compounds of the invention can also be used to treat cancer-related lesions, such as: solid tumors, sarcomas, especially Ewing's sarcoma and osteosarcoma, retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic disorders, such as leukemia and lymphoma, tumor-induced pleural and pericardial effusions, and malignant ascites.

The compounds of the invention are also indicated for use in Crow-Fukaz syndrome (POEMS) and diabetes-related conditions such as glaucoma, diabetic retinopathy and microangiopathy.

Kinases of the Src, Tec, Jak, Map, Csk, NF _K B and Syk families

72-227/BE members play a crucial role in the regulation of immune processes. The Src family currently includes the following: Fyn, Lek, Fgr, Fes, Lyn, Src, Yrk, Fyk, Yes, Hck, and Blk. The Syk family has recently been identified as including only Zap and Syk. The Tec family consists of Tec, Btk, Rlk, and Itk. Enzymes belonging to the Janus family of kinases are involved in the transduction of growth factor and proinflammatory cytokine signals mediated by a variety of receptors. Although the roles of Btk and Itk — members of the Tec kinase family — in immune biology are poorly understood, their modulation by inhibitors may prove therapeutically useful. The Csk kinase family currently includes Csk and Chk. A group of kinases, such as RIP, IRAK-1, IRAK-2, NIK, p38 MAP kinases, Jnk, IKK-1 and IKK-2 are the most important proinflammatory cytokines and are involved in the TNF and IL-1 signaling pathways. Due to their ability to inhibit the function of one or more of these kinases, the compounds of the invention can be used as immunomodulatory agents, for example, to prevent allograft rejection, to treat autoimmune diseases, and to treat sepsis and septic shock. Since the compounds of the invention are able to regulate the migration and activation of T cells, B cells, mast cells, monocytes and neutrophils, these agents can be used to treat autoimmune diseases and sepsis. The efficacy of treatment aimed at preventing transplant rejection, whether in the case of host versus graft reaction of solid organs or graft versus host reaction of bone marrow, is limited72.227/BE by the toxicity of currently known immunosuppressive agents, and it would therefore be particularly useful to have agents with a better therapeutic index than those known so far. The role of Src in the biology of osteoclasts — these cells are responsible for bone resorption — has been demonstrated by gene manipulation experiments. The compounds of general formula (I) can therefore be used in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor-induced hypercalcemia and bone metastases due to their role in the regulation of Src.

Several protein kinases have been shown to be proto-oncogenes. Chromosomal breakage (on chromosome 5, at the Itk kinase breakpoint), translocation, such as fusion of the abl gene with BCR (Philadelphia chromosome), truncation, such as c-Kit or EGER, or mutation (such as Met) can all generate aberrantly functioning proteins, converting proto-oncogenes into oncogenic products. In other tumors, autocrine or paracrine ligand/growth factor interactions are the driving forces behind oncogenesis. Kinases of the src family are typically involved in sequential signal transduction and their contribution promotes oncogenesis, and they themselves can become oncogenic through overexpression or mutation. Inhibition of the protein kinase activity of these proteins can disrupt the disease process.

Vascular restenosis is associated with smooth muscle and endothelial cell proliferation promoted by FGF and/or PDGF. Stimulation of FGFR, PDGFR, IGF1-R and c-Met by ligands in vivo is proangiogenic and contributes to angiogenesis-dependent diseases. FGFR, PDGFR, c-Met or

72.227/BE ·Ζ:

Inhibition of IGF1-R kinase activity, either individually or in combination, may be an effective strategy to prevent the onset of these symptoms. Consequently, compounds of formula (I) that inhibit the activity of normal or aberrant c-kit, c-met, c-fms, src family members, EGFR, erbB2, erbB4, BCR-Abl, PDGFR, FGFR and IGF1-R, as well as other receptor or cytoplasmic enzyme kinases, may be useful as valuable agents for the treatment of benign and neoplastic proliferative diseases.

In many pathological conditions (e.g., solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness resulting from inadequate ocular neovascularization, psoriasis, and atherosclerosis), disease progression is dependent on continued angiogenesis. Polypeptide growth factors are often produced in diseased tissues or associated inflammatory cells, and their corresponding endothelial cell-specific receptor kinases (e.g., KDR/VEGFR-2, Flt-1/VEGFR-1, Tie-2/Tek, and Tie) are essential for stimulating endothelial cell proliferation, migration, organization, and differentiation, and for the formation of the necessary new, functional vascular network. Due to the role of VEGF vascular permeability factor activity in mediating vascular hyperpermeability, VEGF stimulation of VGFR kinase is likely to be an important element in the development of the following pathological conditions: tumor, ascites, cerebral edema, pulmonary edema, pleural and pericardial effusions, delayed-type hypersensitivity reactions, trauma, burns, ischemia, diabetic complications, endometriosis, adult res

72.227/BE

5 ........ ..

respiratory distress syndrome (ARDS), tissue edema and organ dysfunction resulting from postcardiopulmonary bypass-associated hypotension and hyperpermeability, ocular edema leading to glaucoma, or blindness due to inadequate neovascularization. In addition to VEGF, the recently identified VEGF-C and VEGF-D, as well as the virally encoded VEGF-E or HIV-Tat protein, can also induce a cellular response characterized by hyperpermeability by stimulating the VEGFR kinase. The KDR/VEGFR-2 and/or Tie-2 kinases are also expressed by a distinct population of hematopoietic stem cells. Certain members of this population are pluripotent and, upon stimulation by growth factors, can differentiate into endothelial cells and participate in vasculogenetic angiogenic processes; therefore, these cells are called endothelial progenitor cells (EPCs) [ J. Clin. Invest. 103, 1230-1236 (1999)] . In some of the progenitors, Tie-2 is involved in the assembly, adhesion, regulation and differentiation of cells [Blood, 4317-4326 (1997)] . Certain compounds of general formula (I) are able to block the activity of endothelial cell-specific kinases, thus inhibiting the progression of diseases associated with the above situation.

Vascular destabilization by the antagonist ligand of Tie-2 (Ang2) is thought to create an unstable, so-called plastic state in the endothelium, which can induce a robust angiogenic response in the presence of high levels of VEGF, but in the absence of VEGF or VEGF-like stimuli, overt vessel regression and endothelial apoptosis can occur [ Genes and Devel. 13, 1055-1066 (1999)]. Analogously, a Tie-2 kinase

72.227/BE inhibitor can be proangiogenic or antiangiogenic in the presence or absence of VEGF-like stimuli. Consequently, Tie-2 inhibitors can be used in conjunction with appropriate proangiogenic stimulation (e.g. VEGF) to promote therapeutic angiogenesis, e.g. in wound healing, infarction or ischemia.

The compounds of formula (I) and their salts, as well as pharmaceutical compositions containing a therapeutically effective amount thereof, can be used to treat pathological conditions associated with protein kinases, for example, the benign and neoplastic proliferative diseases already discussed above, and disorders of the immune system. These diseases include, for example, the following: rheumatoid arthritis, thyroiditis, type I diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel diseases, Crohn's disease, myasthenia gravis, lupus erythematosus, psoriasis, transplant rejection (e.g., renal rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers, such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancers, and malignant hematopoietic disorders, such as leukemia and lymphoma. Furthermore, diseases associated with inadequate vascularization may be mentioned, such as: diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, and childhood hemangioma in humans. The inhibitors of the invention may also find use in the treatment of diseases in which edema, ascites, effusion, and exudate are associated with VEGF.

72.227/BE ation plays an important role, such as macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).

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

It can therefore be concluded that protein tyrosine kinases, including the activity of VEGF receptor tyrosine kinases (e.g. KDR, Flt-1 and/or Tie-2), play a significant role in the diseases listed above. By inhibiting the function of these tyrosine kinases, we can prevent the progression of the listed diseases, since in the aforementioned pathological conditions the angiogenic or vascular hyperpermeability-related component is significantly suppressed. The compounds of the invention, being selective for a specific tyrosine kinase, cause fewer side effects than would be expected if a less selective tyrosine kinase inhibitor were used.

The invention further relates to the use of the compounds of formula (I) as defined above as medicaments, in particular as inhibitors of protein kinases, for example as medicaments inhibiting the activity of tyrosine kinases, the activity of serine kinases and the activity of threonine kinases. The invention still further relates to the use of the compounds of formula (I) as defined above for the preparation of pharmaceutical compositions for inhibiting the activity of protein kinases.

In the following section, we provide the meanings of some of the technical terms used in this description.

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8 ..

The term physiologically acceptable salt refers to salts which retain the efficacy and biological properties of the free base and which can be prepared by reacting the base with an inorganic acid, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or an organic acid, such as a sulfonic or carboxylic acid, an organophosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid or the like.

By alkyl group we mean a straight or branched chain aliphatic or cyclic hydrocarbon group having 1-6 carbon atoms or 3-6 carbon atoms.

The term alkoxy group means an alkyl group, as defined above, attached to the rest of the molecule through an oxygen atom.

The compounds of the invention, alone or in combination with suitable carriers and/or pharmaceutical excipients, can be administered to humans in the form of pharmaceutical compositions in a dosage sufficient to treat vascular hyperpermeability and edema and diseases associated therewith. Mixtures of the compounds, either as simple mixtures or in the form of suitable pharmaceutical compositions, can also be used for such treatment. A therapeutically effective dose is hereinafter defined as an amount of one or more compounds sufficient to prevent or reduce pathological neovascularization, progression of hyperproliferative diseases, edema formation, VEGF-associated hyperpermeability and/or VEGF-associated hyperpermeability.

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Hypotension may be induced. Methodological descriptions for direct administration of the compounds, as well as for formulation and use of the compounds, can be found in the latest edition of Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).

The route of administration of the active ingredients may vary, including oral administration, eye drop administration, rectal administration, mucosal or intestinal absorption, but parenteral administration routes such as intramuscular, subcutaneous and intramedullary injection, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections are also suitable.

In addition to systemic administration, the compounds of the invention can also be administered topically, for example by injection directly into the site of edema, usually in the form of a depot preparation or a sustained-release preparation.

Another method of application of the active ingredients is targeted delivery, where the active ingredient is contained in liposomes coated with an endothelial cell-specific antibody.

The pharmaceutical compositions of the invention can be prepared in a manner known per se, using conventional technological operations, such as mixing, dissolving, granulating, dragee coating, powdering, emulsifying, encapsulating, microencapsulating or lyophilizing.

The pharmaceutical compositions for use according to the invention are therefore prepared in a conventional manner, in one or more physiologically acceptable

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7:

It can be produced using a suitable carrier, diluent or enhancer, as well as pharmaceutical excipients that facilitate the processing of the active ingredient into a suitable preparation. The formulation technology and the preparation to be produced must always be chosen depending on the method of application.

For injection purposes, aqueous solutions of the compound of the invention can be prepared, which are preferably prepared with physiologically acceptable buffer solutions, such as Hanks' solution, Ringer's solution or physiological sodium chloride solution. In the case of preparations absorbed through the mucous membrane, penetration-enhancing excipients are used during the formulation, which are generally known in the pharmaceutical arts.

The compounds of the invention can be prepared without any difficulty, using pharmaceutically acceptable carriers well known and generally used in pharmaceutical manufacture, into a pharmaceutical preparation for oral administration, such as tablets, pills, dragees, capsules, lozenges, jellies, syrups, pastes, suspensions or the like, i.e. those which are taken orally by the patient. Oral preparations of the compounds of the invention can be prepared, for example, by mixing the active ingredient with solid ingredients, optionally grinding and granulating the mixture, and then — if desired, after adding suitable excipients — pressing the granules or powder mixture into tablets or dragee seeds. The ingredients used can be selected from the following, for example: diluents, such as sugars, such as lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat72.227/BE sí t -. * *-** ’··*'~♦ starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, (hydroxypropyl) methyl cellulose, (carboxymethyl) cellulose sodium salt and/or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate may be used.

The dragee cores are then provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, as well as glazing solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may also be added to the tablet mass or the coating material, in this way preparations containing different doses of the active ingredient are easily recognizable.

Among the pharmaceutical forms intended for oral administration, we can mention the gelatin capsule consisting of two parts fitted together (hard gelatin capsule) and the so-called soft gelatin capsule, which is closed and made of gelatin with the use of plasticizers, such as glycerin or sorbitol. The hard gelatin capsule may contain the active ingredient mixed with diluents or fillers, such as lactose, binders, such as starch, and/or lubricants, such as talc or magnesium stearate, and optionally stabilizers. The soft gelatin capsule may contain a solution or suspension of the active ingredient in suitable liquids, such as unsaturated fatty acid oils, liquid paraffin or liquid polyethylene glycols, and stabilizers may also be added. All pharmaceutical forms intended for oral administration contain the active ingredient in a dosage appropriate for such use.

The pharmaceutical form of the preparation intended for buccal administration may be a tablet or lozenge, which can be prepared in conventional manner.

The inhalation composition suitable for use according to the invention may be administered to the body in the form of an aerosol spray filled in a pressure-resistant bottle or as a spray produced by a nebulizer, using a propellant such as difluorodichloromethane, fluorotrichloromethane, tetrafluorodichloroethane, carbon dioxide or other suitable gas. In the case of an aerosol filled in a pressure-resistant bottle, the administration of the appropriate dose may be ensured by a valve suitable for dispensing a metered amount. The capsule or cartridge (e.g. made of gelatin) which can be placed in an inhaler or insufflator may contain the active ingredient in the form of a powder mixture with a suitable powder base such as lactose or starch.

The compounds of the invention can be prepared as injectable preparations for parenteral administration, for example by bolus injection or continuous infusion. The injectable preparations can be presented, for example, in unit dose ampoules, or in multidose vials, with the addition of a preservative. The preparation itself is a suspension or solution in an oily or aqueous vehicle containing

72.227/BE may also contain additional excipients, such as a suspending agent, a stabilizing additive and/or a dispersant.

A pharmaceutical preparation suitable for parenteral administration is, for example, an aqueous solution of a water-soluble form of the active ingredient, but oily suspensions of the active ingredients can also be prepared, and for these, for example, lipophilic solvents, fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate, and triglycerides or liposomes can be used as carriers.

Aqueous suspensions for injection may contain viscosity-increasing agents, such as sodium carboxymethyl cellulose, sorbitol, or dextran, and, if appropriate, suitable stabilizers may be added to the suspension. Excipients may also be used to increase the solubility of the compounds, which may also enable the preparation of concentrated solutions.

Another injectable pharmaceutical form is the so-called dry ampoule, which contains the active ingredient in powder form, and from this, the injectable preparation is prepared with a suitable carrier, such as sterile, pyrogen-free water, immediately before administration.

The compounds of the invention may also be formulated into rectally administrable formulations, such as suppositories or enemas. Suppositories may be prepared using conventional suppository bases, such as cocoa butter or other glycerides.

In addition to those discussed so far, depot preparations can also be prepared from the compounds of the invention. These long-acting preparations are generally administered by implant, for example, subcutaneous or intramuscular, and intramuscular injection.

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··· e · · ··· • * * « · ·· · ·* tion. For such purposes, the active ingredient can be processed with suitable polymers or hydrophobic carriers (for example, a suspension made with a suitable oil), as well as ion exchange resins, but very poorly soluble derivatives of the active ingredient, such as almost insoluble salts, can also be used for depot preparations.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a solvent system comprising: benzyl alcohol, a non-polar surfactant, a water-soluble organic polymer and an aqueous phase. Such a solvent system is, for example, the so-called VDP solvent system, one of the components of which is an ethanol solution containing benzyl alcohol at a concentration of 3% by weight, polysorbate 80 at a concentration of 8% by weight as a non-polar surfactant and polyethylene glycol 300 at a concentration of 65% by weight. The VDP:50W solvent system is therefore the solution of the above composition diluted in a 1:1 ratio with 5% aqueous dextrose solution, in which hydrophobic compounds are well soluble, but the solvent itself is very slightly toxic when used systemically. Of course, the ratio of the components of the solvent system can be varied within quite wide limits without worsening the solvent effect or toxicity. In addition, the components of the solvent system can be replaced with other components, for example, instead of polysorbate 80, other less toxic, non-polar surfactants can be used; other fractions of polyethylene glycols can be used; polyethylene glycol can be replaced with other biocompatible polymers.

72.227/BE with polymers such as polyvinylpyrrolidone; finally, dextrose can also be replaced with other sugars or polysaccharides.

Hydrophobic active ingredients can also be administered in other ways than those discussed so far, such as liposomes and emulsions, which are well known in pharmaceuticals. Organic solvents, such as dimethyl sulfoxide, are also permitted, although the higher solubility is usually at the expense of higher toxicity. In addition, active ingredients can be administered in the form of a sustained-release formulation, in which the active ingredient is contained in a semipermeable encapsulating material, such as a solid hydrophobic polymer. A wide variety of materials are used in pharmaceuticals to produce sustained-release dosage forms, and these are well known to those skilled in the art. For example, sustained-release capsules, depending on the chemical properties of the capsule, allow the active ingredient to become available over a period of several weeks to up to 100 days. Depending on the chemical properties and biological stability of the therapeutic agent, additional strategies can be used to stabilize proteins.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or pharmaceutical diluents, such as, but not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers,

72.227/BE such as polyethylene glycols.

Many of the compounds of the invention form salts with pharmaceutically acceptable counterions. There are a number of acids that form pharmaceutically acceptable salts, including, but not limited to, hydrochloric acid, sulfuric acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts are generally more soluble in water or other protic solvents than the corresponding free bases.

Pharmaceutical compositions suitable for use according to the invention contain such amounts of the active ingredient that their effect allows the desired goal to be achieved. More specifically, a therapeutically effective amount means a dose of the active ingredient that prevents the development of symptoms or alleviates the symptoms already developed in the subject being treated. Determination of effective doses of the compounds of the invention is within the knowledge of the person skilled in the art of medicine.

The effective doses of the compounds used in accordance with the method of the invention can initially be determined on the basis of cellular studies. The active ingredients are formulated at doses that produce blood levels in animal studies that correspond to concentrations around the IC ₅₀ value determined in cellular studies (this is the concentration of the test substance that produces 50% of the maximum inhibition of a given protein kinase). In some cases, additional data can be obtained by determining the IC ₅₀ value in the presence of 3-5% serum albumin, since these studies

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··· β · · ··· ··· ··· <· ·* *· the result gives an approximate indication of the extent of the compound's binding to plasma proteins. This information is used to determine human doses more precisely. The most preferred compounds for systemic use effectively inhibit protein kinase signaling function in intact cells at a dose level that is safely available in plasma.

The therapeutically effective dose is therefore that amount of compound that results in amelioration of symptoms in a patient. The toxicity and therapeutic efficacy of compounds can be determined by standard pharmacological tests, cell culture or animal studies, for example by determining the maximum tolerated dose (MTD) or the dose required to achieve 50% of the maximum effect (ED ₅₀ ). The ratio between the toxic dose and the therapeutically effective dose is the therapeutic index, and this can be expressed as the ratio of the MTD to the ED ₅₀ . Compounds with a high therapeutic index are preferred. Cell culture and animal studies can be used to prepare formulations containing doses suitable for human use. The doses of compounds thus determined preferably correspond to an amount of active ingredient that achieves blood levels approaching the ED ₅₀ value, but is only slightly or not at all toxic. The dosages may vary within certain limits depending on the pharmaceutical form and route of administration. The appropriate pharmaceutical form, route of administration and dosage should be determined by the attending physician in the light of the patient's condition [see example

72.227/BE ul Fingl et al.: The Phramacological Basis of Therapeutics, Ch. 1, p. 1] . In a crisis, treatment may require an acute bolus injection or an infusion rate approaching the MTD to achieve an adequate outcome.

The dose and frequency of administration can be determined for each individual, with the aim of achieving plasma levels of the active ingredient sufficient to maintain the kinase-modulating effect or to reach the minimum effective concentration (MEC). The MEC value may vary for each compound, but can be estimated from in vitro data; for example, it corresponds to the concentration required to achieve 50-90% inhibition of protein kinase function in the assays described herein. The dose required to achieve the MEC depends on the individual characteristics and the route of administration, but high-performance liquid chromatography or biological measurement methods are available to determine plasma levels.

The dosage range can also be determined by taking into account the MEC value. The compounds should be administered according to a dosage regimen such that the plasma level is above the MEC value for 10-90% of the time, preferably 30-90% of the time, and more preferably 50-90% of the time, until the desired reduction in symptoms is achieved. In the case of topical application or selective absorption, the effective local concentration of the active substance is not related to the plasma concentration.

The amount of active ingredient to be delivered to the body with the pharmaceutical preparation naturally also depends on the patient to be treated, for example the patient's body weight, the severity of the condition, the method of administration72.227/BE

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·· · · · · · · · ·* and the judgment of the treating physician.

The pharmaceutical compositions are optionally presented to the user in suitable packaging or in a dispensing device, and these dosage forms may contain one or more doses of the active ingredient. The packaging material may be, for example, metal or plastic foil, for example, a so-called blister pack. The pharmaceutical package or dispensing device is usually provided with instructions for the method of administration. Compositions containing the compounds of the invention, formulated with compatible pharmaceutical carriers, may also be prepared in such a packaged form, suitably packaged and placed in containers, and the packaging is marked with indications for use.

For some pharmaceutical compositions, it is advantageous to use the compounds of the invention in a very small particle size form. Very finely divided powders can be produced, for example, in fluidized bed mills.

The following are examples illustrating the processing of the compounds of the invention into pharmaceutical compositions. In these examples, the active ingredient may be any of the compounds of the invention, however, the term primarily refers to the final products in the subsequent preparation examples.

a) Capsule production

To prepare capsules, 10 parts by weight of the active ingredient and 240 parts by weight of lactose are ground and mixed together. The powder mixture is then filled into hard gelatin capsules so that each capsule contains an amount of active ingredient corresponding to the unit dose or a certain fraction of the unit dose.

72.227/BE

b) Tablet production

A tablet can be prepared from the following ingredients:

Active ingredient 10 mass fraction Lactose 190 mass fraction Cornstarch 22 mass fraction Poly(vinylpyrrolidone) 10 mass fraction Magnesium stearate 3 mass fraction

The active ingredient, lactose and a portion of the corn starch are ground, mixed, and the powder mixture is granulated with an ethanolic solution of polyvinylpyrrolidone. The dry granulation is then mixed with magnesium stearate and the remainder of the starch, and the mass is compressed on a tabletting machine into tablets containing the active ingredient in the unit dose or a certain fraction of the unit dose.

c) Preparation of enteric-coated tablets

Tablets can be prepared as described in point b) above, and the resulting dragee cores are then coated in the usual manner using a solution containing 20% cellulose acetate phthalate and 3% diethyl phthalate, prepared in a 1:1 mixture of ethanol and methylene dichloride.

d) Preparation of rectal suppositories

To prepare a rectal suppository, 100 parts by weight of the active ingredient is dispersed in 1300 parts by weight of a triglyceride-based suppository base, and the mixture is then formed into suppositories, each containing a therapeutically effective amount of the active ingredient.

The pharmaceutical compositions of the invention may optionally contain the active ingredient in other compounds compatible with the compounds of the invention.

72.227/BE lis, may contain together with pharmaceutically active substances. For example, the compounds of the invention may be used in combination with one or more active substances that inhibit or prevent the production of VEGE or angiopoietins, attenuate the intracellular cellular response to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, suppress inflammation and inhibit or prevent the formation of edema or neovascularization. The compounds of the invention may be administered to the patient prior to, concurrently with, or following the administration of the other active substance, any suitable administration regimen being appropriate. Other therapeutic agents that can be combined with the compounds of the invention include, but are not limited to, anti-inflammatory and anti-edema steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF antagonists, COX-1 inhibitors, COX-2 inhibitors, nitric oxide synthase inhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, and PI3 kinase inhibitors. The combined effects of the compounds of the invention and other therapeutic agents may be additive or synergistic. Consequently, treatment with such a combination of agents aimed at inhibiting angiogenesis, inhibiting vascular hyperpermeability, and/or inhibiting edema formation may be more effective in preventing the adverse consequences of hyperproliferative diseases, angiogenesis, vascular hyperpermeability, or edema than either agent alone.

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In our opinion, in the treatment of malignant diseases, the compounds of the invention can be combined with antiproliferative or cytotoxic chemotherapeutic agents, as well as with hyperthermic, hyperoxia or irradiation treatment methods.

Based on the above, the use of the compounds of general formula (I) as medicaments also forms an object of the invention.

The invention further relates to the use of compounds of general formula (I) or their salts for the preparation of pharmaceutical compositions for the treatment of vascular hyperpermeability, angiogenesis-dependent diseases, proliferative diseases and/or diseases of the immune system in mammals, especially humans.

The invention also provides a method for treating vascular hyperpermeability, pathological neovascularization, and proliferative diseases and/or diseases of the immune system, which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I).

The in vitro activity of compounds as inhibitors of protein kinases can be determined by the methods described in the following section.

The potency of the compounds can be determined by determining the degree of inhibitory effect of the test substances on the phosphorylation of an exogenous substrate, e.g. a synthetic peptide [see Z. Songyang et al.: Nature 373, 536-539] relative to the control.

Production of KDR tyrosine kinase using a baculovirus system:

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The sequence encoding the intracellular domain of human KDR (aa789-1354) was constructed by polymerase chain reaction using cDNA isolated from human umbilical vein endothelial cells (HUVEC). A poly-His ₆ sequence was also inserted into the N-terminal part of the protein. This fragment was then cloned into the pVL1393 transfection vector at the Xba 1 and Not 1 sites. Recombinant baculovirus (BV) was generated by cotransfection using BaculoGold transfection reagent (PharMingen), which was then subjected to plaque purification and identified by Western blot analysis. To produce the protein, SF-9 cells (2 x 10 ⁶ /ml) were cultured in SF-900-II medium and infected at a multiplicity of infection (MOI) of 0.5. The cells were isolated 48 hours after infection.

Cleaning KDR:

The procedure is as follows: SF-9 cells expressing (His) ₆ KDR(aa789-1354) protein are lysed by adding 50 ml of Triton X-100 lysis buffer [20 mM Tris (pH = 8.0), 137 mM sodium chloride, 10% glycerol, 1% Triton X-100, 1 mM benzylsulfonyl fluoride (PMSF), 10 μg/ml aprotinin, 1 μg/ml leupeptin] to 1000 ml of cell culture cell mass, and then the cell lysate is centrifuged in a Sorval SS-34 rotor at 19,000 rpm for 30 minutes at 4 °C. The cell lysate is then applied to a 5 ml sepharose column equilibrated with 50 mM HEPES buffer (pH = 7.5) containing 0.3 M sodium chloride, chelated with nickel dichloride. The same buffer solution is used to elute KDR, but this time it also contains 0.25 M imidazole. The fractions eluted from the column are analyzed by polyacrylamide gel electrophoresis 72.227/BE (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA) (see later), i.e. the kinase activity is determined. The purified KDR is then transferred to another buffer solution [25 mM HEPES (pH = 7.5), 25 mM sodium chloride, 5 mM dithiothreitol (DTT)] and stored at -80 °C.

Production and purification of human Tie-2 kinase:

Using cDNA isolated from human placenta as a template, we generated the sequence encoding the intracellular domain of human Tie-2 (aa775-1124) by polymerase chain reaction. A poly-His ₆ sequence was also inserted into the N-terminal part of the protein, and this construct was then cloned into the pVL1939 transfection vector at the Xba 1 and Not 1 sites. Recombinant baculovirus (BV) was constructed by co-transfection using BaculoGold transfection reagent (PharMingen), then subjected to plaque purification and identified by Western analysis. For protein production, SF-9 cells (2 x 10 ⁶ /ml) were cultured in SF-900-II medium and infected at a multiplicity of infection (MOI) of 0.5 plaque-forming units per cell. The His-tagged kinase thus produced was purified in the same manner as described for KDR.

Production and purification of human Flt-1 tyrosine kinase:

The baculovirus pVL1393 expression vector (Phar Mingen, Los Angeles, CA) was used. The nucleotide sequence encoding poly-His ₆ was linked to the nucleotide region encoding the entire intracellular kinase domain of Flt-1 (amino acids 786-1338) at the 5' position. The nucleotide sequence encoding the kinase domain was constructed by polymerase chain reaction using a cDNA library isolated from HUVEC. The histidine tag allowed the protein to be affinity-expressed.

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Purify by chromatography, using a similar procedure as for KDR and ZAP70. SF-9 insect cells were infected at a multiplicity of 0.5 and the cells were isolated 48 hours later.

EGFR tyrosine kinase:

EGFR was purchased from Sigma (catalog # E-3641; 500 units/50 μΐ), and EGF ligand was purchased from Oncogen Research Products/Calbiochem (catalog # PF011-100).

ZAP70 expression:

The baculovirus pVL1393 expression vector (PharMingen, Los Angeles, CA) was used. The nucleotide sequence encoding the amino acid sequence M(H) ₆ LVPR ₉ S was fused to the entire ZAP70 coding region (amino acids 1-619) at the 5' position. The nucleotide sequence encoding ZAP70 was constructed by polymerase chain reaction using a cDNA library isolated from immortalized Jurkat T cells. The histidine tag allowed the protein to be purified by affinity chromatography (see later). The LVPR ₉ S-hid forms a so-called recognition sequence for proteolytic cleavage by thrombin, so that the affinity tag can be easily removed from the enzyme. SF-9 insect cells were infected at a multiplicity of 0.5, and the cells were isolated 48 hours later.

Extraction and purification of ZAP70:

The procedure is as follows: SF-9 cells are lysed in a buffer solution [composition: 20 mM Tris (pH = 8.0), 137 mM sodium chloride, 10% glycerol, 1% Triton X-100, 1 mM benzylsulfonyl fluoride (PMSF), 1 μg/ml leupeptin, 10 μg/ml aprotinin and 1 mM sodium orthovanadate], then the soluble lysate is applied to a 50 mM HEPES buffer containing 0.3 M sodium chloride.

72.227/BE onto a HiTrap sepharose column (Pharmacia) equilibrated with ferric solution (pH = 7.5). A 250 mM imidazole solution is used to elute the fusion protein. The enzyme is stored in a buffer solution [50 mM HEPES (pH = 7.5), 50 mM sodium chloride, 5 mM dithiothreitol (DTT)].

Protein kinases availability:

Lek, Fyn, Src, Blk, Csk, and Lyn, as well as truncated forms thereof, are commercially available [e.g., Upstate Biotechnology Inc. (Saranac Lake, N.Y.); and Santa Cruz Biotechnology Inc. (Santa Cruz, CA)], or can be obtained from known natural or recombinant sources and purified by conventional methods.

Determination of protein tyrosine kinase activity by enzyme-linked immunosorbent assay (ELISA):

Enzyme-linked immunosorbent assay (ELISA) was used to detect the presence of tyrosine kinases and to measure enzyme activity. ELISA determinations were performed following well-known literature descriptions [see, for example, Voller et al. : Enzyme-Linked Immunosorbent Assay, in: Manual of Clinical Immunology, 2nd ed., eds. Rose and Friedman, pp. 359-371 (Am. Soc. of Microbiology, Washington, D.C. 1980)].

The methods described in the literature have been adapted for the determination of the activity of specific protein tyrosine kinases. Preferred embodiments of ELISA assays are described below by way of example, but the adaptation of these procedures to the determination of the potency of compounds, other members of the receptor tyrosine kinase family, and non-receptor tyrosine kinases is within the skill of the art. Inhibitors

In studies to determine the selectivity of 72.227/BE, a universal PTK substrate [e.g., poly(Glu ₄ Tyr) random copolymer with a relative molecular mass between 20,000 and 50,000] was used together with ATP (typically 5 μΜ) at a concentration approximately twice the apparent K _m .

The inhibitory effect of the compounds of the invention on the activity of KDR, Flt-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1R, c-Met, Lek, Blk, Csk, Src, Lyn, Fyn and ZAP70 tyrosine kinases was determined as follows:

Buffers and solutions:

PGTPoly(Glu,Tyr) 4:1 is stored as a powder at -20 °C. The powder is dissolved in phosphate buffered saline (PBS) to prepare a 50 mg/ml solution. The solution is stored in 1 ml aliquots at -20 °C and diluted to a concentration of 250 μg/ml with Gibco PBS for the preparation of the experimental tray.

The reaction buffer composition is as follows: 100 mM HEPES, 20 mM magnesium chloride, 4 mM manganese dichloride, 5 mM dithiothreitol (DTT), 0.02% BSA, 200 μΜ NaV0 ₄ , pH = 7.10.

ATP: Store as a 100 mM solution at -20 °C, then dilute with water to a concentration of 20 μΜ.

Wash buffer: PBS, the solution contains 0.1% Tween 20 surfactant.

Antibody dilution buffer: 0.1% bovine serum albumin (BSA) in PBS. TMB substrate: immediately before use, mix the TMB substrate solution with peroxide solution in a ratio of 9:1, or use Neogen K-Blue substrate.

Stop solution: 1 M phosphoric acid solution.

72.227/BE _ζ τ· ν'·'<'

Measurement procedure:

1. Tray preparation:

PGT stock solution (50 mg/ml, frozen) was diluted with PBS to a concentration of 250 pg/ml and 125 μΙ of the solution was pipetted into each well of a Corning modified flat-bottom high affinity ELISA plate (Corning #25805-96). 125 μΐ PBS was simultaneously added to the wells reserved for the blank. The wells were then covered with sealing tape, incubated overnight at 37 °C, washed with 250 μΐ wash buffer, and dried in a dry incubator at 37 °C for 2 hours. The prepared plates were stored in a sealed foil bag at 4 °C until use.

2. Tyrosine kinase reaction

A four-fold (4x) solution of the inhibitor is prepared with a 20% dimethyl sulfoxide-water mixture, and the reaction buffer is prepared. An enzyme solution is prepared so that the desired unit volume is 50 μΐ, for example, in the case of KDR the concentration is 1 ng/μΙ, so 50 ng of enzyme is used per well for the enzyme reaction. The solution is stored on ice. A four-fold (4x) solution, i.e. 20 μΜ, is prepared with water from the 100 mM ATP stock solution, and the solution is kept on ice. Pipette 50-50 μΐ of enzyme solution (typically 5-50 ng of enzyme per well, depending on the specific activity of the kinase), then 25 μΐ of 4x inhibitor solution and 25 μΐ of 4x ATP solution (final concentrations in the reaction mixture: 5 μΜ ATP, 5% DMSO) into the wells of the prepared tray. The reaction mixtures are incubated for 10 minutes at room temperature, then the reaction is stopped by adding 50 μΐ of 0.05 M hydrochloric acid per well and the tray is washed.

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3. Antibody coupling:

A solution of 50 ng/ml of 100-fold and 200-fold dilutions of 100 mg/ml PY20-HRP (Pierce) antibody solution (phospho-tyrosine antibody) is prepared in two steps, first 100-fold and then 200-fold, with PBS containing 0.1% BSA, and 100 μΐ of the solution is pipetted into each well. The plate is incubated for 1 hour at room temperature and then for 1 hour at 4 °C, then washed four times.

4. Color reaction:

Prepare a TMB substrate solution and pipette 100 μΐ of the solution into each well. Measure the optical density (OD) at 650 nm until it reaches 0.6, then stop the reaction by adding 1 M phosphoric acid, shake the plate in a reader, and read the optical density at 450 nm.

The optimal incubation time and other conditions of the enzyme reaction can be empirically changed within certain limits depending on the enzyme preparation.

In the case of Lek, the reaction buffer composition is as follows: 100 mM 2-hydroxy-3-morpholinopropanesulfonic acid (MOPSO) (pH = 6.5), 4 mM manganese dichloride, 20 mM magnesium chloride, 5 mM DTT, 0.2% BSA, 200 mM NaVO ₄ . Other conditions are unchanged.

The compounds of general formula (I) can be used therapeutically in the treatment of all diseases associated with either already identified — including those not mentioned here — or as yet unidentified protein tyrosine kinases, the function of which is inhibited by the compounds of general formula (I). Each of the compounds exemplified herein is administered at 50 μΜ or less.

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At concentrations greater than 100, it exerts significant inhibitory effects on any of FGFR, PDGFR, KDR, Tie-2, Lek, Fyn, Blk, Lyn and Src. Some compounds also significantly inhibit the function of other tyrosine or serine/threonine kinases, such as cdc2 (cdkl), at concentrations of 50 μΜ or less.

Cdc2 accessibility:

The human recombinant enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA, USA), or the enzyme can be extracted from known natural or recombinant sources and purified by standard procedures.

Cdc2 assay:

The test was performed according to the specifications of the reagent supplier with minimal modification. The procedure is briefly as follows:

The reaction buffer solution consisted of 50 mM Tris (pH = 7.5), 100 mM sodium chloride, 1 mM ethylene bis[(oxyethylene) nitrilo] tetraacetic acid (EGTA), 2 mM dithiothreitol (DTT), 0.01% Brij, 5% dimethyl sulfoxide and 10 mM magnesium chloride (commercial buffer), supplemented with fresh ATP (300 μΜ; 31 μCi/ml) and histone type III-SS at a final concentration of 30 μg/ml. The reaction volume was 80 μΐ, which contained the appropriate amount of enzyme. The enzyme reaction was carried out at 25 °C with or without inhibitor, allowing a reaction time of 20 minutes, and then stopped by adding 120 μΐ of 10% acetic acid. The substrate is separated from its uniformly labeled environment by dropping the mixture onto a phosphocellulose paper and washing three times for 5 minutes with a 75 mM phosphoric acid solution.

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101 ..................

• · · · · · ··· · · · · ·· ··· · · e· · · ··

Radioactivity is determined in a beta counter in the presence of liquid scintillator.

Some of the compounds of the invention significantly inhibit cdc2 function at concentrations of 50 μΜ or less.

PKC looks like accessibility:

The catalytic subunit of PKC is commercially available (Calbiochem).

PKC kinase assay:

The radioactive measurement procedure reported in the literature [see I. Yasuda, A. Kirshimoto, S. Tanaka, M. Tominaga, A. Sakurai, Y. Nishizuka: Biochemical and Biophysical Research Communication 3 166, 1220-1227 (1990)] was used for the study. The procedure is briefly as follows:

The composition of the buffer solution used for the reaction is: 50 mM Tris-HCl (pH = 7.5), 10 mM magnesium chloride, 2 mM DTT 1 mM EGTA, 100 μΜ ATP, 8 μΜ peptide, 5% dimethyl sulfoxide and ³³ P-ATP (8 Ci/mM). The compound and enzyme are mixed in a reaction vessel, the reaction is started by adding ATP and substrate, and then stopped by adding 10 μΐ stop solution (5 mM ATP in 75 mM phosphoric acid solution). After that, a part of the mixture is dropped onto a phosphocellulose paper and washed three times for 5-15 minutes at room temperature with 75 mM phosphoric acid. The incorporated radioactivity is determined by liquid scintillation measurement.

Erk2 enzyme availability:

Recombinant mouse/rat enzyme and assay buffer are commercially available (New England Biolabs, Beverly MA.

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··· · · · · · · · · ·

USA), or the enzyme can be obtained from known natural or recombinant sources and purified by conventional methods.

Erk2 enzyme assay:

The composition of the buffer solution used for the reaction was: 50 mM Tris (pH = 7.5), 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% dimethyl sulfoxide and 10 mM magnesium chloride (commercial buffer), supplemented with fresh ATP (300 μΜ; 31 gCi/ml) and a concentration of 30 μΜ of myelin basic protein. The measurement was performed according to the recommendations of the reagent supplier. Regarding the volume of the reaction mixture and the determination of incorporated radioactivity, the information described under the heading PCK kinase assay (see above) should be taken into account.

In vitro T-cell activation models:

Mitogen- or antigen-induced activation of T cells induces IL-2 secretion. IL-2 is a growth factor that promotes the subsequent proliferative phase, and consequently we have the opportunity to measure either IL-2 production or the proliferation of primary T cells or appropriate T cell lines that can replace them. Both of these assays have been described in the literature, and a large database of assay parameters is available (see Current Protocols in Immunology, Vol 2, 7.10.1-7,11.2).

The procedure of the test is briefly as follows: T cells can be activated by co-culturing with allogeneic stimulator cells, a method known as the mixed lymphocyte reaction. Responder and stimulator peripheral blood mononuclear cells are collected in Ficoll-Hypaque

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Purification is performed using a 103 gradient (Pharmacia) following the manufacturer's instructions. Stimulator cells are mitotically inactivated by treatment with mitomycin C (Sigma) or gamma rays, and responder and stimulator cells are mixed in a 2:1 ratio and co-cultured with or without the test substance. Typically, 5 x ¹⁰⁴ stimulator cells are added to ¹⁰⁵ responder cells, resulting in a cell suspension volume of 200 μΐ, and plated in a round-bottomed microtiter plate (Costar Scientific). Cells are cultured in RPMI 1640 medium supplemented with heat-treated, inactivated fetal calf serum (Hyclone Laboratories) or pooled human AB serum from male donors, 5 x 10“ ⁵ M 2-mercaptoethanol and 0.5% dimethyl sulfoxide. On the penultimate day, typically after 3 days, 0.5 μθί [ ³ H] thymidine (Amersham) is added to the cultures, and the next day the cells are isolated with a Betapla cell harvester (Wallac) and the isotope uptake is measured by liquid scintillation counting (Betaple, Wallac).

The cells are cultured in the same way if the degree of T-cell activation is determined by IL-2 production. After 18-24 hours of cell culture setup, the supernatants are aspirated and the IL-2 concentration of the solution is measured by ELISA (R and D systems) following the manufacturer's instructions.

In vivo T-cell activation models:

The in vivo efficacy of compounds can be determined using known animal model assays, either by directly measuring T-cell activation or by injecting them into the bloodstream.

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104 cells are monitored in which T cells act as effectors. T cells can be activated in vivo by binding monoclonal anti-CD3 antibodies to the constant region of the T cell receptor. In this experimental model, BALB/c mice are administered 10 pg of anti-CD3 antibody intraperitoneally 2 hours before bleeding. Animals that also receive test material are pretreated with a single dose of the active substance 1 hour before the administration of the anti-CD3 antibody. Serum levels of proinflammatory cytokines, such as gamma-interferon (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which are considered indicators of T cell activation, are determined by ELISA. In a similar model, T cells are first activated in vivo with a specific antigen, keyhole limpet hemocyanin (KLH), and a secondary in vitro immune response is elicited by treating draining lymph node cells with the same antigen, and as in the previous case, cytokine production can be used to determine the activation status of the cultured cells. Briefly, the procedure is as follows: on day zero, C57BL/6 mice are immunized subcutaneously with 100 pg of KLH, emulsified in complete Freund's adjuvant (CFA). The animals are pretreated with the drug the day before immunization, and the treatment is repeated on the first, second, and third days after immunization. Draining lymph nodes were removed on day 4, and cell cultures were grown at a concentration of 6 x 10 ⁶ cells/ml in RPMI 1640 tissue culture medium supplemented with heat-treated, inactivated fetal calf serum (Hyclone Laboratories), 5 x 10 ⁵ M 2-mercaptoethanol, and 0.5% dimethyl sulfoxide (HO72.227/BE).

105 are created, the culture is continued for 24 or 48 hours, and finally the concentration of the autocrine T-cell growth factor, Interleukin-2 (IL-2) and/or IFN-γ is measured in the culture supernatant by ELISA.

The outstanding compounds can also be tested in animal experiments for human diseases. Examples of these include experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models, which mimic the condition that occurs in human multiple sclerosis, have been described in both mice and rats [for a review, see FASEB J. 5, 2560-2566 (1991); mouse/rat model: Lab. Invest. 4(3), 278 (1981); rodent model: J. Immunol. 164(4), 1163-1168 (1991)]. The procedure is briefly as follows: mice or rats are immunized with myelin basic protein (MBP) emulsion or neurogenic peptide derivatives and CFA. Bacterial toxins (e.g., Bordetella pertussis) can be used to induce the acute phase, while the relapsing/remitting phase disease can be induced by adoptive transfer of T cells from MBP/peptide-immunized animals.

CIA is modeled using DBA/1 mice immunized with type II collagen [J. Immunol. 142(7), 2237-2243]. In mice, arthritis symptoms appear within 10 days of immunization and can be observed for up to 90 days. The drug can be administered to animals in both EAE and CIA models prophylactically or post-disease. The active compounds have a beneficial effect on the severity and/or incidence of the condition.

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Some of the compounds of the invention that inhibit the function of one or more angiogenic receptor PTKs and/or protein kinases (e.g., lek) that are associated with inflammatory responses may reduce the severity and incidence of arthritis in these models.

Compounds can also be tested in mouse allograft models, either by skin transplantation [for review see Ann. Rev. Immunol. 10, 333-358 (1992); Transplantation 57(12), 17011706 (1994)] or by heart transplantation [Am. J. Anat. 113, 273 (1963)]. Briefly, the procedure is as follows: Full-thickness skin is transplanted from C57BL/6 mice to BALB/c mice. The transplanted skin is examined daily for signs of rejection starting on day 6. In the neonatal mouse heart transplantation model, hearts from newborn C57BL/6 mice are ectopically transplanted into the pinnae of adult CBA/J mice. The hearts are harvested 4-7 days after transplantation. It starts working on the 1st day, and rejection can be detected visually using a dissecting microscope by examining the cessation of the heartbeat.

Cellular receptor PTK assay:

The cellular experimental model described herein was used to determine the effect and efficacy of the compounds of the invention on KDR/VEGFR-2. Similarly, the effect of the compounds on other receptor protein tyrosine kinases can be tested using specific ligands, techniques well known to those skilled in the art.

VEGF-induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC) measured by western blot:

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1. Pooled HUVEC cells (Clonetics, San Diego, CA) from different donors were cultured according to the manufacturer's instructions. Cells were passaged only a few times, approximately 3-8 times, in this assay. Culture was performed in 100 mm diameter culture dishes (Falcon tissue culture dishes, Becton Dickinson; Plymouth, England) in complete EBM medium (Clonetics).

2. To evaluate the inhibitory effect of the compounds, cells were trypsinized and then plated at 0.5-1.0 x 10 ^s cells per well in a 6-well culture plate (Costar; Cambridge, MA).

3. On the 3rd or 4th day after cell plating, when the cell layer on the dishes is 90-100% confluent, the culture medium is removed from all wells, the wells are rinsed with 5-10 ml of phosphate-buffered saline (PBS), and the cells are then incubated with 5 ml of EBM-based culture medium without supplements (serum starvation) for 18-24 hours.

4. Prepare a dilution series of inhibitors and add the inhibitor to the cells at a final concentration of 25 μΜ, 5 μΜ and 1 μΜ in 1 ml of EBM. Incubate for 1 hour at 37 °C, then add human recombinant VEGF ₁₆₅ (R and D systems) in 2 ml of EBM to a final concentration of 50 ng/ml, and incubate for 10 minutes at 37 °C. Control cells are either treated with VEGF or not, and are used only to determine background phosphorylation and the induction of phosphorylation by VEGF.

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All wells were then rinsed with 5-10 ml of cold PBS containing 1 mM sodium orthovanadate (Sigma), and the cells were lysed and scraped in 200 μΐ of RIPA buffer containing protease inhibitors (1 mM PMSF, 1 μg/ml aprotinin, 1 μg/ml pepstatin, 1 μg/ml leupeptin, 1 mM sodium vanadate, 1 mM sodium fluoride) and 1 pg/ml DNase [50 mM Tris-HCl (pH = 7), 150 mM sodium chloride, 1% NP-40, 0.25% sodium deoxycholate, 1 mM ethylenediaminetetraacetic acid (EDTA)], and the lysate was centrifuged at 14,000 rpm for 30 min to remove the nuclei [note that all chemicals were purchased from Sigma Chemical Company (St Louis, MO) product supplied by] .

Equal amounts of protein are then precipitated from the solutions by adding two volumes of cold (-20 °C) ethanol, and the mixtures are left to stand for a minimum of 1 hour and a maximum of overnight. The pellet is taken up in Laemli buffer containing 5% 2-mercaptoethanol (BioRad; Hercules, CA), the mixture is boiled for 5 minutes, then the proteins are separated by polyacrylamide gel electrophoresis (6%, 1.5 mm Novex, San Diego, CA) and transferred to a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), the proteins are contacted with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) overnight at 4 °C. After washing and incubation with goat anti-rabbit or goat anti-mouse IgG HRP-conjugated F(ab) ₂ fragment for 1 hour, the bands were visualized using an emission chemiluminescence (ECL) system (Amersham Life Sciences, Arlington Height, IL) 72.227/BE

109 ....................

• ·· ·· ·* ·* * Some of the compounds of the invention significantly inhibit VEGF-induced KDR tyrosine kinase phosphorylation at concentrations of 50 μΜ or less.

In vivo uterine edema model:

This study aims to determine the extent to which compounds inhibit the increase in uterine mass within the first few hours after estrogen stimulation in mice. This early increase in uterine mass is thought to be due to edema resulting from increased permeability of the uterine vascular network. Cullinan-Bove and Koss [Endocrinology 133, 829-837 (1993)] have shown that there is a close temporal relationship between estrogen-stimulated uterine edema and increased expression of VEGF mRNA in the uterus. This result was confirmed by the fact that monoclonal antibodies neutralizing VEGF significantly reduced the acute increase in uterine weight following estrogen stimulation (WO 97/42187), and consequently this system can serve as an in vivo animal model for the inhibition of VEGF signaling function and the associated hyperpermeability and edema.

Materials:

All hormones were purchased from either Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared for use following the manufacturer's instructions.

The components used as vehicles (dimethyl sulfoxide, Cremafor EL) were supplied by Sigma (St Louis, MO).

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The 8-12 week old Balb/c mice used in the experiments were obtained from Laconic (Germantown, NY) and were housed under pathogen-free animal husbandry conditions in accordance with the relevant regulations (Institutional Animal Care and Use Committee Guidelines).

Method:

Day 1: Balb/c mice are given 12.5 units of pregnant mare serum gonadotropin (PMSG) by intraperitoneal (i.p.) injection.

Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) intraperitoneally.

Day 4: Mice are randomly assigned to groups of 5-10 animals and treated with doses of 1-100 mg/kg of the test substances, depending on solubility and vehicle, intraperitoneally (i.p.), intravenously (i.v.) or orally (p.o.). Animals in the vehicle control group receive only the vehicle, without active substance, and two groups are left untreated.

minutes later, the experimental animals, the animals in the control group, and the animals in one of the untreated groups are injected i.p. with 500 pg/kg of 17-estradiol, and after 2-3 hours the animals are killed by carbon dioxide inhalation. The animals are cut in the midline of the abdomen and the uterus is removed by making the cut directly below the cervix and at the junction of the uterus and the uterine horn. The fat and connective tissue are carefully removed, taking care to keep the bees intact until the wet weight is determined. The wet weight is measured

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After the procedure, the bees are pressed between two pieces of filter paper with a one-liter glass bottle filled with water, thus removing the liquid, and their weight is measured again, thus obtaining the so-called blotted weight. The difference between the wet weight and the blotted weight is taken as the fluid content of the uterus, and the average fluid content measured in the treated group is compared with the fluid content measured in the untreated and vehicle-treated groups. Significance is determined by the Student's t-test. An unstimulated control group is used to determine the response induced by estradiol.

The experimental results demonstrate that some of the compounds of the invention, when administered systemically to the body in various ways, inhibit the development of edema.

Compounds of the invention that are inhibitors of angiogenic receptor tyrosine kinases may also be active in the Matrigel implantation model of neovascularization. In the Matrigel neovascularization model, we investigate how the formation of new blood vessels in the pure marble material of the extracellular matrix implant implanted under the skin, induced by the presence of a proangiogenic factor produced by tumor cells, occurs [see, for example, A. Passaniti et al.: Leg. Investig. 67(4), 519-528 (1992); Anat. Rec. 249(1), 63-73 (1997); Int. J. Cancer 63(5), 694-701 (1995); Vase. Biol. 15(11), 1857-6 (1995)]. The experiment is preferably continued for 3-4 days, and at the end, visually observable macroscopic changes resulting from neovascularization are scored, which72.227/BE

112 ··«· ···· ** 4 4* 4 • 4 · · 4 ·* ·· ·* roscopically determine the density of microcapillaries, and quantify hemoglobin after removal of the implant, and compare the data obtained with those found in the control group of animals not treated with the inhibitor. In this model study, stimulation can be performed with bFGF or HGF.

Among the compounds of the invention, those that inhibit the function of one or more oncogenes, proto-oncogenes or proliferation-dependent protein kinases, or angiogenic receptor protein tyrosine kinases, also inhibit the growth of mouse, rat or human xenograft tumors in mice, or inhibit the formation of metastases in rodent model experiments.

The following describes processes for the preparation of compounds of formula (I), which also form a further essential part of the invention. The processes are preferably carried out at atmospheric pressure.

The compounds of general formula (I) can therefore be prepared by a

a compound of the general formula, in which R ¹ , R ² , R ³ , L and A are as defined above, is condensed with formamide at a temperature between 50 and 250 °C, optionally in the presence of a catalyst, for example 4-(dimethylamino)pyridine.

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113

Compounds of formula (I) can also be prepared by reacting a

a compound of the general formula, in which R ^x represents a bromine or iodine atom, is reacted with one of the following compounds of the general formula — in which R ³ represents the meaning given above — in the presence of a catalyst, for example a palladium(0) compound, such as [tetrakis(triphenylphosphine)palladium(0)]: R ³ B(OH)2, R ³ Sn(CH3) ₃ ,

R ³ —(H2C)j—L

B(OH)2 >

R3—(H ₂ C)j— L

Sn( _CH3 )3 -

Compounds of formula (I) in which R ¹ is an alkyl or aralkyl group can be prepared by reacting a

a compound of the general formula, in which R ² and R ³ are as defined above, with a R ³ X' of the general formula

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114

with a compound — in which R ¹ is an alkyl or aralkyl group and X' is a leaving group, for example halogen, (methylsulfonyl)oxy or [(4-tolyl)sulfonyl]oxy

- means group — we alkylate.

Compounds of formula (I) in which R ¹ is an optionally substituted cyclic ether derivative, such as tetrahydrofuranyl or tetrahydropyranyl, can be prepared by reacting a

a compound of the general formula, in which R ² and R ³ are as defined above, is alkylated with a compound of the general formula R 1', in which X' is as defined above and R ¹ is an optionally substituted cyclic ether derivative.

Compounds of formula (I) in which R ¹ is a group derived from a cyclic ether optionally substituted with a formyl group, for example a tetrahydrofuranyl or tetrahydropyranyl group, can be prepared by alkylating a compound of formula (VI) with a compound of formula R ¹ X' in which R ¹ is a group derived from a cyclic ether optionally substituted with a formyl group — the formyl group can be protected in a manner well known to those skilled in the art, for example in the form of an acetal [see, for example, Tet. Letts. 30(46), 6259-6262 (1989)] — and then removing the protective ring72.227/BE

115 ·*»· ***· ***· « **« ·* · -w ·*· port is removed from the molecule.

Compounds of formula (I) in which R ¹ is a group derived from a cyclic ether substituted with an (optionally substituted amino)methyl group, for example a tetrahydrofuranyl or tetrahydropyranyl group, can be prepared by reductive amination from compounds in which R ¹ is a group derived from a cyclic ether substituted with a formyl group.

The compounds of general formula (I), in which R ¹ is an optionally substituted furyl, thienyl or pyrrolyl group, can be prepared by reacting 5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine with the corresponding heteroaryl boronic acid at a temperature between 0 and 50 °C, preferably at room temperature, in the presence of a copper salt catalyst, for example copper (II) acetate, in a solvent suitable for the reactants, conveniently in a chlorinated hydrocarbon, for example methylene dichloride, a drying agent, for example 4Å molecular sieves, and in the presence of an organic base, for example triethylamine or pyridine [see Tet. Letts. 39, 2942-2944 (1998) and references therein]. These compounds can also be prepared by methods well known to those skilled in the art in the form of derivatives in which R ¹ is a furyl, thienyl or pyrrolyl group substituted with a formyl group, and the formyl groups of the compounds can also be aminated by methods well known to those skilled in the art to give compounds in which R ¹ is a furyl, thienyl or pyrrolyl group substituted with an aminomethyl group. According to another process variant, the intermediate 72.227/BE

116

From compounds in which R ¹ is a furyl, thienyl or pyrrolyl group, compounds in which R ¹ is a furyl, thienyl or pyrrolyl group substituted with an aminomethyl group can also be prepared by Mannich reaction.

Compounds of formula (I) can also be prepared by

A compound of the general formula, in which R ¹ , R ² , R ³ , L and A are as defined above and R _y is a leaving group, for example a halogen atom or a phenoxy group, can be reacted with ammonia or an ammonium salt, for example ammonium acetate, at a temperature between 15 and 250 °C, preferably in a pressure vessel.

The compounds of general formula (I) in which R ² represents a chlorine, bromine or iodine atom can be prepared by reacting a

a compound of the general formula, in which R ¹ , R ³ , L and A have the meanings given above, with a suitable halogenating agent, i.e. an iodizing agent, for example N-iodosuccinimide, or a 72.227/BE

117

with a brominating agent, such as N-bromosuccinimide, or with a chlorinating agent, such as N-chlorosuccinimide.

Compounds of formula (I) in which the group -LR ³ is equivalent to a group -NHC(O)R ³ can be prepared by reacting a

a compound of the general formula, in which R ¹ , R ² and A are as defined above and Y is a protected amino group, is reacted with a compound of the general formula R ³ COR ^X — in which R ^x is a leaving group, for example a chlorine atom —. According to another process variant, the compounds of the general formula (I) can also be prepared by reacting a compound of the general formula (IX) with a compound of the general formula R ³ COR ^X in which Y is a halogen atom, for example a chlorine atom, and reacting the product thus obtained with ammonia. The same procedure can be used for compounds of the general formula (I) in which the group of the general formula -LR ³ is equivalent to a group of the general formula -NRSO2R ³ . The same procedure can also be used to prepare compounds of formula (I) in which the group -LR ³ is replaced by a group -NRCO2-R ³ or -NRCONR', where R and R' are as defined above.

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118

The compounds of general formula (I) in which the formula

The group of general formula -LR ³ means a group of formula -OSO ₂ -, a

A compound of general formula (X) — in which R ¹ , R ² and A are as defined above — can be prepared by reacting it with a compound of general formula R ₄ SO ₂ R ^X .

Compounds of formula (I) can then be prepared from the appropriate intermediates by following the process illustrated in Scheme 2 or a variant thereof to be described later.

Compounds of formula (II) can be prepared by the process illustrated in Scheme 1, where IPA is isopropyl alcohol.

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Reaction scheme 1:

The

R ³ -(H ₂ C)j—L

Br

1) H2NRI, IPA or CH3CN

2) HCl/IPA

1)NaOCH2CH3/CH3CH2OH

2) NCCH2CN / NaOCH2CH3, CH3CH2OH, 50°C

It will be readily apparent to the skilled artisan that compounds of formula (I) can be converted into other compounds of formula (I) by known chemical reactions. For example, the alkoxy group can be cleaved to give a hydroxy derivative, the nitro group can be reduced to an amino group, the amines can be acylated or sulfonated, while the N-acyl

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120

-derivatives can be hydrolyzed to amines. Compounds of formula (I) in which L is a sulfur atom can be oxidized to compounds of formula (I) in which L is a sulfinyl or sulfonyl group by methods well known to those skilled in the art.

Compounds of formula (III) can be purchased commercially or prepared by methods well known to those skilled in the art.

Compounds of formula (V) in which R ^z is hydrogen can be prepared according to reaction scheme 2. The amino group can be protected by a method well known in organic synthetic chemistry before the last step, and the protecting group can be removed by well known methods after the last step in reaction scheme 2. Compounds of formula (V) in which R ² is other than hydrogen can be prepared by analogous methods [see J. Med. Chem. 33, 1984 (1990)].

Reaction scheme 2

θ' 1 NH3, CH3OH ^{pressure X} H Pd(O) _> NH ₂ 1 * ^TOTO ^{+ r3} — ^(CH2)j — ^L— Vx ^N \ ^B(OH) ₂ Π (AH—L—(CH2)jR ³ NH2 kV TO Rí

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121

A variant of the process shown in Scheme 2 is also possible in which the group of the general formula -(Ring A)-LR ³ is attached to the molecule prior to amination. Any variant of the process can also be carried out in the case where a substituent corresponding to the meaning of R ¹ is present in the molecule.

Compounds of formula (VII) in which R _y is chlorine can be prepared as illustrated in Scheme 3.

Reaction scheme 3:

Compounds lacking the side chain, i.e. the group of the general formula -(Ring A)-LR ³ , can be prepared according to Scheme 4 and as described in the literature [see J. Med. Chem. 31, 390 (1988) and references therein]. Compounds in which the group of the general formula -(Ring A)-LR ³ is other than hydrogen can also be prepared by analogous methods.

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122

Reaction scheme 4:

Compounds of general formula (VII) can be prepared by coupling the corresponding 5-iodo compound in the same manner as described for the synthesis of compounds of general formula (V).

The groups corresponding to R ¹ can be modified as shown in Schemes 5 and 6. In Schemes 5 and 6, P represents a protecting group.

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123

H

Y/N.

R R

Na(0Ac)3BH, HOAc

CICH2CH2CI

L—(CH2)j-R3

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124

Reaction scheme 6:

P

Na(0Ac)3BH, HOAc

CICH2CH2CI

P

It is readily apparent to the skilled person that in the cases where a reactant molecule in the processes discussed contains a substituent identical or similar to the functional group to be reacted, this substituent must be provided with a protecting group before carrying out the appropriate reaction step, and

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125 ..................

• · · * · * • · · « * φ ··· the protecting group can only be removed from the molecule after the reaction, otherwise competitive side reactions may occur. Another solution to the above problem may be to start from compounds whose substituents do not interfere with the reaction. Information on suitable protecting groups and their application or removal is abundant in the literature [see, for example, T.W. Green: Protective Grpups in Organic Chemistry, John Wiley and Sons, 1981]. Groups suitable for protecting amines include the formyl and acetyl groups.

In the following section, the general methods for preparing the compounds described above are illustrated by examples.

Example 1:

Benzyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

a) (Tetrahydro-2H-pyran-4-yl)-(trifluoromethanesulfonate) ml (20.97 mmol) tetrahydro-2H-pyran-4-ol is dissolved in 16 ml methylene dichloride, 1.7 ml (20.97 mmol) pyridine is added to the solution, then the flask is immersed in an ice-water bath and a solution of 3.6 ml (20.97 mmol) trifluoromethanesulfonic anhydride in 7 ml methylene dichloride is added dropwise over about 10 minutes. After 20 minutes, the reaction mixture is filtered and the filtered solid is washed with the smallest possible amount of methylene dichloride. The filtrate and washings are combined, shaken in sequence with water, 0.1 M hydrochloric acid, water again, and finally with saturated sodium chloride solution, then the organic phase is mag72.227/BE

126 is dried over sodium sulfate, filtered, and the solvent is evaporated. The product thus obtained is (tetrahydro-2H-pyran-4-yl)-(trifluoromethanesulfonate).

3-NMR spectrum (CDCl ₃ , δ): 1.99 (m, 2H); 2.11 (m, 2H); 3.58 (m, 2H); 3.96 (m, 2H); 5.17 (m, 1H).

b) 5-Iodo-4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 0.891 g (22.2 mmol) of sodium hydride and 40 ml of N,N-dimethylformamide at 0 °C was added 3.0 g (10.73 mmol) of 5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine in small portions. After the addition, the ice-water bath was removed and the mixture was allowed to stir for 30 minutes. (Tetrahydro-2H-pyran-4-yl)-(trifluoromethanesulfonate) was then added dropwise, the reaction mixture was stirred at room temperature for 24 hours, and then poured into 100 ml of ice-water. The separated solid was collected on a filter and purified by recrystallization to give 5-iodo-4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ^-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 2H) ; 3.63 (m, 2H) ; 4.16 (m, 2H) ; 5.00 (m, 1H) ; 7.45 (s, 1H); 8.61 (s, 1H) . Mass spectrum (LC-MS): MH ⁺ = 364.

c) (tert-Butyl)-[N-{4-[4-chloro-7-(tetrahydro-2H-pyran-4-yl)-

-7H-pyrrolo[2 _r 3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

An aqueous mixture of 1.66 g (4.75 mmol) of (tert-butyl)-{N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate} was sonicated under vacuum for 1 min to remove gases, then 1.1 g (3.17 mmol) of 5-iodo-4-chloro

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127

-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, 0.22 g (0.19 mmol) [tetrakis(triphenylphosphine)palladium(0)], 0.8 g (7.60 mmol) sodium carbonate and 30 ml 1,2-dimethoxyethane. The suspension thus obtained is first degassed again for 2 minutes, then heated to 85 ^° C and reacted at this temperature for 24 hours. The mixture is then cooled to room temperature, the solvent is evaporated off in vacuo, the evaporation residue is then redissolved in ethyl acetate, the solution is washed and dried over magnesium sulfate. The solid crude product was purified by flash chromatography on silica gel, eluting with a 7:3 mixture of heptane and ethyl acetate, to give (tert-butyl)-[N-{4-[4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate.

^x H-NMR spectrum (CDCl ₃ , δ): 1.55 (s, 9H); 2.10 (m, 4H); 3.66 (m, 2H); 3.92 (s, 3H); 4.16 (m, 2H); 5.05 (m, 1H); 7.06 (m, 2H); 7.14 (s, 1H); 7.32 (s, 1H); 8.13 (broad d, J = 8 Hz, 1H); 8.64 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 459.

d) 4-[4-Chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-2-methoxyaniline (tert-Butyl)-[ N-{4-[4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo 2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-carbamate] is added with 50 ml of a 10% trifluoroacetic acid solution prepared in methylene dichloride and cooled to 0 °C. After 20 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 4 hours. After the reaction is complete, the trifluoroacetic acid and methylene dichloride are evaporated in vacuo, then the evaporation mass is

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128 was redissolved in methylene chloride, shaken with saturated aqueous sodium bicarbonate, and the immiscible layers were separated. The aqueous portion was extracted with methylene chloride, and the combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated. The remaining solid was passed through a pad of silica gel, and the product was eluted with a 3:2 mixture of heptane and ethyl acetate to give 4-[4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyaniline.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.09 (m, 4H); 2.51 (broad s, NH ₂ ); 3.66 (m, 2H); 3.91 (s, 3H); 4.16 (m, 2H); 5.05 (m, 1H); 6.79 (d, J = 8 Hz, 1H); 6.93 (d, J = 8 Hz, 1H); 6.98 (s, 1H); 7.28 (s, 1H); 8.63 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 359.

e) 5-(4-Amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran~4-

-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of 0.73 g (2.03 mmol) of 4-[4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyaniline in 25 ml of dioxane was added 25 ml of concentrated ammonium hydroxide and the mixture was reacted in a sealed pressure tube at 122 °C for 2 days. The reaction mixture was then allowed to cool to room temperature, the solvent was evaporated, then ethyl acetate was added to the evaporation residue and the organic phase was washed, dried over magnesium sulfate, filtered and finally evaporated. The product thus obtained was 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

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129 3-NMR spectrum (DMSO-d ₆ , δ): 1.87 (m, 2H); 2.11 (m, 2H); 3.52 (m, 2H); 3.79 (s, 3H); 3.99 (m, 2H); 4.87 (m, 3H); 6.02 (broad s, NH ₂ ); 6.73 (d, J = 8 Hz, 2H); 6.77 (d, J = 8Hz, 1H); 6.88 (s, 1H); 7.33 (s, 1H); 8.10 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 340.

f? Benzyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.074 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 0.7 ml of methylene dichloride together with 0.7 ml of pyridine, then under nitrogen gas, at 0 °C, while stirring, 16 μΐ (0.110 mmol) of benzyl-(chloroformate) are added dropwise. After 10 minutes, the ice-water bath was removed, the reaction mixture was stirred for 4 hours, then the solvent was evaporated, and the residue was purified by preparative thin-layer chromatography, developing the chromatogram in a 95:5 mixture of methylene chloride and methanol. The product thus obtained was benzyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]. ¹ H-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 4H) ; 3.65 (m, 2H) ; 3.9 (s, 3H) ; 4.13 (m, 2H) ; 4.97 (m, 1H) ; 5.23 (s, 2H); 6.96 (s, 1H); 7.03 (s, 1H); 7.08 (d, J = 8 Hz, 1H); 7.42 (m, 6H); 8.20 (broad s, J = 8 Hz, 1H); 8.32 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 474.

Example 2:

Neopentyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

72.227/BE

130 mg (0.074 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in a mixture of 0.7 ml of pyridine and 0.7 ml of methylene dichloride, and then 13 μΐ (0.110 mmol) of neopentyl-(chloroformate) were added dropwise under nitrogen at 0 °C, while stirring. After 10 minutes, the ice-water bath was removed, the reaction mixture was stirred for 4 hours, then the solvent was evaporated, and the evaporation residue was purified by preparative thin-layer chromatography, developing the chromatogram in a 95:5 mixture of methylene dichloride and methanol. The product thus obtained is neopentyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate].

3-NMR spectrum (CDCl ₃ , δ): 1.00 (s, 3H); 2.07 (m, 4H); 3.65 (m, 2H); 3.91 (s, 2H); 3.94 (s, 3H); 4.13 (m, 2H); 4.97 (m, 1H); 5.18 (s, 2H); 6.97 (s, 1H); 7.03 (s, 1H); 7.07 (d, J = 8 Hz, 1H); 7.25 (s, 1H); 8.19 (broad s, J = 8 Hz, 1H); 8.33 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 454.

Example 3:

Phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

100 mg (0.294 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine are dissolved in 2 ml of methylene chloride, and first 2 ml of pyridine and then 44 μΐ (0.353 mmol) of phenyl-(chloroformate) are added to the solution. The reaction mixture is stirred for 3 hours, then another 44 μΐ of phenyl-(chloroformate) is added, and stirring is continued overnight. Other

72,227/IN

After 131 days, the solvent was evaporated and the residue was purified by preparative liquid chromatography coupled to mass spectrometry (LC-MS). The product thus obtained was phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate, mass 52 mg (0.113 mmol). ¹ H-NMR spectrum (CDCl ₃ , δ): 2.09 (m, 4H) ; 3.66 (m, 2H) ; 3.98 (s, 3H) ; 4.16 (m, 2H) ; 4.98 (m, 1H) ; 5.24 (s, 2H) ; 7.09 (m, 3H); 7.23 (m, 4H); 7.41 (m, 2H); 7.62 (s, 1H); 8.20 (broad d, J = 7.80 Hz, 1H); 8.33 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 4 60.

Example 4:

(Tetrahydro-2H-pyran-4-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

a) (4-Nitrophenyl)-(tetrahydro-2H-pyran-4-yl)carbonate

1.0 ml (10.5 mmol) of tetrahydro-2H-pyran-4-ol was dissolved together with 2.0 ml of N-methylmorpholine in 20 ml of methylene chloride, and 1.98 g (9.82 mmol) of (4-nitrophenyl)-(chloroformate) was added slowly to the solution. The reaction mixture was stirred for 5 h, then diluted with methylene chloride, and washed with water, 1.0 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, evaporated, and the remaining crude product was purified by flash chromatography on silica gel, eluting the column with a 4:1 mixture of ethyl acetate and heptane. The resulting (4-nitrophenyl)-(tetrahydro72.227/BE

132

(2H-pyran-4-yl)carbonate weight 1.5 g (5.62 mmol).

3-NMR spectrum (CDCl ₃ , δ): 1.87 (m, 2H); 2.06 (m, 2H); 3.58 (m, 2H); 3.98 (m, 2H); 4.97 (m, 1H); 7.40 (d, J = 9.0 Hz, 2H); 8.30 (d, J = 9.0 Hz, 2H).

b) (Tetrahydro-2H-pyran-4-yl) -[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] A mixture of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 90 mg (0.336 mmol) (4-nitrophenyl)-(tetrahydro-2H-pyran-4-yl)-carbonate and 1 ml of pyridine was stirred for 5 hours, then another 90 mg of (4-nitrophenyl)-(tetrahydro-2H-pyran-4-yl)-carbonate was added, and stirring was continued for 2 more days. The reaction mixture was then heated to 70 °C and kept at this temperature for 2 hours. Finally, the solvent was evaporated and the residue was purified by preparative thin layer chromatography. The product obtained was (tetrahydro-2H-pyran-4-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate, mass 30 mg (0.064 mmol). 1 H NMR spectrum (CDCl ₃ , δ): 1.78 (m, 4H); 2.08 (m, 4H); 3.60 (m, 4H); 3.94 (s, 3H); 3.97 (m, 2H); 4.15 (m, 2H); 4.98 (m, 2H); 5.23 (s, 2H); 6.78 (s, 1H); 7.04 (s, 1H); 7.07 (d, J = 8.3 Hz, 1H); 8.16 (broad d, J = 7.90 Hz, 1H); 8.33 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 468.

Example 5:

[ (3-Pyridyl)-methyl] - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

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133

a) (4-Nitrophenyl)-[(3-Pyridyl)methyl]carbonate

2.49 g (12.3 mmol) of (4-nitrophenyl)-(chloroformate) are dissolved in 20 ml of methylene chloride, the solution is immersed in an ice-water bath, then 1.0 ml (10.3 mmol) of (3-pyridyl)methanol and 2.0 ml (18.5 mmol) of N-methylmorpholine are added slowly. After the addition, the mixture is stirred cold for another 20 minutes, then allowed to warm to room temperature, then after 30 minutes ethyl acetate is added and filtered. The filtrate is washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered, evaporated, and the remaining dark brown solid is recrystallized from a mixture of ethyl acetate and heptane. The mass of [(3-pyridyl)methyl]-(tetrahydro-2H-pyran-4-yl)carbonate thus obtained was 1.52 g (5.54 mmol).

¹ H-NMR spectrum (CDCl ₃ , δ): 7.38 (m, 3H); 7.79 (m, IH) ; 8.28 (d, J = 9.09 Hz, 2H); 8.65 (m, IH) ; 8.72 (s, IH) .

b) [ (3-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.074 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 0.7 ml of methylene chloride, and to the solution is first added 0.7 ml of pyridine, then 30 mg (0.110 mmol) of (4-nitrophenyl)-[(3-pyridyl)-methyl] carbonate. The reaction mixture was reacted overnight at 100 °C, then the solvent was evaporated and the residue was purified by preparative liquid chromatography coupled to a mass spectrometer. The product thus obtained was [ (3

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134

-pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], weight 12 mg (0.025 mmol).

¹ H-NMR spectrum (CDCl ₃ , δ): 2.08 (m, 4H); 3.65 (m, 2H); 3.92 (s, 3H); 4.15 (m, 2H); 4.96 (m, 1H); 5.26 (s, 2H); 5.54 (broad s, 2H); 6.97 (s, 1H); 7.04 (s, 1H); 7.08 (d, J = 8.2 Hz, 1H); 7.35 (m, 2H); 7.79 (d, J = 7.8 Hz, 1H); 8.15 (m, 1H); 8.29 (s, 1H); 8.61 (s, 1H); 8.71 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 475.

c) [(3-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] hydrochloride mg (0.025 mmol) [ (3-pyridyl)-methyl]-[ N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-carbamate] is dissolved in 2.0 ml of ethyl acetate and 1 ml of 1.0 M diethyl ether hydrogen chloride solution is slowly added. The precipitate formed was filtered off under nitrogen gas to give 13 mg (0.025 mmol) of [(3-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate] hydrochloride.

¹ H-NMR spectrum (DMSO-d ₆ , δ): 1.91 (m, 2H); 2.17 (m, 2H); 3.54 (m, 2H); 3.87 (s, 3H); 4.03 (m, 2H); 4.97 (m, 1H); 5.23 (s, 2H); 7.05 (d, J = 8.2 Hz, 1H); 7.13 (s, 1H); 7.51 (m, 1H); 7.81 (d, J = 8.2 Hz, 1H); 7.84 (s, 1H); 7.95 (m, 1H); 8.42 (s, 1H); 8.60 (s, 1H); 8.71 (s, 1H); 8.82 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 475.

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135

Example 6:

(2-Morpholino-ethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]-hydrochloride A mixture of 1 mg (0.054 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.1 ml 2-morpholino-ethanol and 0.7 ml pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse-phase high-pressure liquid chromatography to give 24 mg (0.048 mmol) of (2-morpholinoethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate. The solid was dissolved in 2.0 mL of ethyl acetate, 0.2 mL of 1.0 M hydrogen chloride in diethyl ether was slowly added, and the precipitate was collected on a filter under nitrogen. The product thus obtained is (2-morpholino-ethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4~yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]-hydrochloride, the weight is 24 mg (0.045 mmol). ¹ H-NMR spectrum (DMSO-d ₆ , δ): 1.88 (m, 2H); 2.16 (m, 2H); 3.55 (m, 8H); 3.90 (s, 3H); 4.03 (m, 4H); 4.49 (m, 2H); 4.92 (m, 1H); 7.07 (m, 1H); 7.15 (s, 1H); 7.65 (broad s, 2H); 7.84 (s, 1H); 8.45 (s, 1H); 8.75 (s, 1H); 10.95 (broad s, 1H). Mass spectrum (LC-MS): MH ⁺ = 497.

Example 7:

[ (4-Bromo-1,3-thiazol-5-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

72.227/BE

136 *.·..... «... .... .· · · « 4 ♦

4·· 4 4 ♦ *♦?

a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde

A mixture of 3.52 g (30 mmol) of 1,3-thiazolidine-2,4-dione, 43 g (150 mmol) of phosphorus tribromide oxide and 2.56 ml (34 mmol) of N,N-dimethylformamide was reacted for 1 hour at 75 °C and then for 5 hours at 100 °C. The reaction mixture was then cooled to room temperature, poured into 500 ml of ice water and the aqueous mixture was extracted with methylene dichloride. The combined organic solvent extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated and the remaining brown solid was washed with petroleum ether. Evaporation of the solvent gave 1.74 g (6.42 mmol) of 2,4-dibromo-1,3-thiazole-5-carbaldehyde.

3-NMR spectrum (CDCl ₃ , δ): 9.90 (s, 1H).

b) (2,4-Dibromo-1,3-thiazol-5-yl)-methanol

1.74 g (6.42 mmol) of 2,4-dibromo-1,3-thiazole-5-carbaldehyde was dissolved in 70 ml of methanol and 0.244 g (6.42 mmol) of sodium [tetrahydridoborate] was added in small portions at 0 °C. After the addition, the mixture was stirred cold for another 10 minutes, then the ice-water bath was removed and stirring was continued at room temperature overnight. The next day, the solvent was evaporated, saturated ammonium chloride solution was added to the distillation residue, and the pH was adjusted to 10 with 1.0 M sodium hydroxide solution. The aqueous mixture was then extracted with ethyl acetate, and the combined organic solvent extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The remaining crude product was purified by flash chromatography to give 0.946 g (3.47 mmol) of (2,4-dibromo-1,3-thiazole72.227/BE

137 .... »**· ··«·

·.> <· \> >'

-5-yl)-methanol is obtained.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.11 (broad s, 1H); 4.79 (s, 2H).

c) (4-Bromo-1,3-thiazol-5-yl)-methanol

A mixture of 0.94 g (3.44 mmol) (2,4-dibromo-1,3-thiazol-5-yl)-methanol, 1.34 g sodium carbonate-water (1/3), 0.07 g 10% palladium-on-carbon catalyst and 33 ml methanol was hydrogenated at 4.15 bar for 2 days, then the catalyst was filtered off on a Celite filter bed. The filtrate was evaporated and the residue was purified by flash chromatography to give 0.32 g (2.78 mmol) (4-bromo-1,3-thiazol-5-yl)-methanol. ¹ H-NMR spectrum (CDCl ₃ , δ): 2.29 (broad s, 1H) ; 4.86 (s, 2H) ; 8.72 (s, 1H).

d) [(4-Bromo-1,3-thiazol-5-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 1 mg (0.061 mmol) of phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl)-carbamate], 50 mg (0.434 mmol) of (4-bromo-1,3-thiazol-5-yl)-methanol and 0.5 ml of pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give [(4-bromo-1,3-thiazol-5-yl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate].

3-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 4H); 3.65 (m, 2H); 3.92 (s, 3H); 4.13 (m, 2H); 4.98 (m, 1H); 5.35 (s, 1H); 5.40 (s, 2H);

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138

6.97 (s, 1H); 7.04 (s, 1H); 7.09

1H); 8.32 (s, 1H); 8.78 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 481.

(m, 1H); 7.35 (s, 1H); 8.17 (s

Example 8:

(3-Tetrahydrofuranyl) - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.05 ml tetrahydrofuran-3-ol and 0.5 ml pyridine are heated to 100 “C, kept at this temperature overnight, then the solvent is evaporated the next day. The evaporation residue is purified by preparative reverse phase high pressure liquid chromatography, which results in 14 mg (0.031 mmol) (3-tetrahydrofuranyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate] is obtained. 3-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 6H); 3.66 (m, 2H); 3.96 (m, 7H); 4.13 (m, 2H); 4.98 (m, 1H); 5.26 (s, 2H); 5.40 (m, 1H); 6.97 (s, 1H); 7.04 (s, 1H); 7.08 (d, J = 8.2 Hz, 1H); 7.26 (s, 1H); 8.30 (s, 1H); 8.32 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 455.

Examples 9 and 10:

(1,3-Dioxan-5-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

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139

[(1,3-Dioxolan-4-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 1 mg (0.065 mmol) of phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate], 0.05 ml of glycerol formate (a mixture of 1,3-dioxan-5-ol and 1,3-dioxolan-4-methanol) and 0.5 ml of pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue is purified by preparative reversed phase high pressure liquid chromatography to yield two products.

One of the products is (1,3-dioxan-5-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], the mass of which is 2 mg (0.004 mmol). ^-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 4H) ; 3.66 (m, 2H) ; 3.92 (m, 3H) ; 4.07 (m, 6H) ; 4.79 (m, 1H) ; 4.83 (d, J = 6.3 Hz, 1H) ; 4.96 (m, 1H) ; 5.04 (d, J = 6.3 Hz, 1H) ; 6.15 (very broad s, 2H); 6.96 (s, 1H); 7.05 (m, 2H); 7.53 (s, 1H); 8.15 (d, J = 8.2 Hz, 1H); 8.22 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 471.

The other product is [(1,3-Dioxolan-4-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], the mass of which is 6.0 mg (0.013 mmol). ¹ H-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 4H) ; 3.66 (m, 2H) ; 3.75 (m, 1H) ; 3.92 (m, 3H) ; 4.03 (m, 1H) ; 4.13 (m, 1H) ; 4.34 (m, 2H) ; 4.94 (s, 1H) ; 4.97 (m, 1H); 5.10 (s, 1H); 5.32 (broad s, 2H);

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PINK 4 03

6.97 (s, 1Η); 7.03 (m, 2H); 7.06 (d, J = 8.2 Hz, 1H); 7.38 (s, 1H); 8.15 (d, J = 7.9 Hz, 1H); 8.31 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 471.

11, example:

[ (2-Pyridyl) -methyl] -[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -2-methoxy-phenyl} -carbamate] -hydrochloride mg (0.065 mmol) phenyl-[ N-{ 4-( 4-amino-7-(tetrahydro-2H-pyran-4-yl) -7H-pyrrolo (2,3-d] pyrimidin-5-yl] -2-methoxy-phenyl} -carbamate] , 0.05 ml (2-pyridyl) -methanol and 0.5 ml pyridine are heated to 100 °C, kept at this temperature overnight, then the solvent is evaporated the next day. The evaporation residue is purified by preparative reverse phase liquid chromatography (LC-MS), resulting in 11 mg (0.023 mmol) [ (2-pyridyl)-methyl] -[ N-{4-[ 4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl] -2-methoxyphenyl} -carbamate] - is obtained. The solid is dissolved in 2 ml of ethyl acetate, 0.1 ml of 1.0 M diethyl ether hydrogen chloride solution is slowly added, then the precipitate is filtered off under nitrogen gas. The product thus obtained is [ (2-pyridyl)-methyl] -[ N-{4-[ 4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl] -2-methoxyphenyl} -carbamate] -hydrochloride, the mass of which is 12 mg (0.023 mmol).

¹ H-NMR spectrum (DMSO-d ₆ , δ): 1.92 (m, 2H); 2.16 (m, 2H); 3.55 (m, 2H); 3.89 (s, 3H); 4.02 (m, 2H); 4.91 (m, 1H); 5.23 (s, 2H); 7.05 (d, J = 8.2 Hz, 1H); 7.14 (s, 1H); 7.37 (m, 1H); 7.53 (d, J = 7.8 Hz, 1H); 7.87 (m, 3H); 8.42 (s, 1H); 8.57 (d, J = 4.2 Hz, 1H); 8.85 (s, 1H).

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Mass spectrum (LC-MS): MH ⁺ = 475.

Example 12:

[ (4-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] hydrochloride mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.05 ml (4-pyridyl)-methanol and 0.5 ml pyridine are heated to 100 °C, kept at this temperature overnight, then the solvent is evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 11 mg (0.023 mmol) of [(4-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]. The solid was dissolved in 2 mL of ethyl acetate, 0.1 mL of 1.0 M hydrogen chloride in diethyl ether was added slowly, and the precipitate was filtered off under nitrogen. The product thus obtained is [(4-pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]-hydrochloride, the weight is 12 mg (0.023 mmol). X-NMR spectrum (DMSO-d ₆ , δ): 1.91 (m, 2H); 2.16 (m, 2H); 3.55 (m, 2H); 3.90 (s, 3H); 4.03 (m, 2H); 4.92 (m, 1H); 5.34 (s, 2H);

7.06 (d, J = 8.2 Hz, 1H); 7.16 (s, 1H); 7.73 (m, 1H); 7.81 (m,

1H); 7.87 (s, 1H); 8.46 (s, 1H); 8.76 (d, J = 5.6 Hz, 1H); 9.05 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 475.

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Example 13:

[(5-Methyl-isoxazol-3-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 1 mg (0.065 mmol) of phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate], 0.05 ml of (5-methyl-isoxazol-3-yl)-methanol and 0.5 ml of pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 18 mg (0.038 mmol) of [(5-methylisoxazol-3-yl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate].

¹ H-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 2H); 2.44 (s, 3H); 3.64 (m, 2H); 3.91 (s, 3H); 4.13 (m, 2H); 4.96 (m, 1H); 5.26 (s, 2H); 6.12 (s, 1H); 6.95 (s, 1H); 7.06 (m, 2H); 7.39 (s, 1H); 8.17 (broad s, 1H); 8.21 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 479.

Example 14:

[(2S)-(5-oxo-pyrrolidin-2-yl)-methyl]-[N-(4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.05 ml (5S)-5-(hydroxymethyl)-2-pyrrolidinone and 0.5

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A mixture of 143 ml of pyridine was heated to 100 °C overnight and the solvent was evaporated the next day. The residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 10 mg (0.021 mmol) of [(2S)-(5-oxo-pyrrolidin-2-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate].

^X H-NMR spectrum (CDC1 ₃ , δ): 1.90 (m, 2H); 2.06 (m, 4H); 2.34 (m, 1H); 2.41 (m, 2H); 3.64 (m, 2H); 3.94 (s, 3H); 4.04 (m, 2H); 4.14 (m, 2H); 4.98 (m, 1H); 5.33 (m, 3H); 6.10 (s, 1H); 6.98 (s, 1H); 7.04 (s, 1H); 7.09 (m, 1H); 7.31 (s, 1H); 8.11 (broad s, 1H); 8.32 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 481.

Example 15:

(4-Aminobenzyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

a) (tert-Butyl)-{N-[4-(hydroxymethyl)-phenyl]-carbamate}

1.23 g (10 mmol) 4-aminobenzyl alcohol, 2.6 ml (15 mmol)

A mixture of N,N-diisopropylethylamine, 2.62 g (12 mmol) di(tert-butyl)dicarbonate and 50 ml methylene dichloride was stirred overnight at room temperature, then diluted with ethyl acetate the next day, washed with water, 1.0 M hydrochloric acid, saturated sodium carbonate solution, water again, and finally saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The remaining crude product was purified by flash chromatography, eluting the column with a 2:3 mixture of ethyl acetate and heptane, which gave

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144 resulted in 2.16 g (9.67 mmol) of (tert-butyl)-{N-[4-(hydroxymethyl)phenyl]carbamate}.

¹ H-NMR spectrum (CDCl ₃ , δ): 1.52 (s, 9H); 4.63 (s, 2H); 6.47 (broad s, 1H); 7.30 (d, J = 8.5 Hz, 2H); 7.36 (d, J = 8.5 Hz 2H).

b) A mixture of (4-Amino-benzyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] mg (0.111 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate], 119 mg (0.533 mmol) (tert-butyl)-{N-[4-(hydroxymethyl)-phenyl]-carbamate} and 0.8 ml pyridine is heated to 100 °C, kept at this temperature overnight, and the solvent is evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 9 mg (0.015 mmol) of (4-aminobenzyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate. H-NMR spectrum (CDCl ₃ , δ): 1.52 (s, 1H) ; 2.08 (m, 4H) ; 3.65 (m, 2H) ; 3.90 (s, 3H) ; 4.14 (m, 2H) ; 4.97 (m, 1H) ; 5.17 (s, 2H) ; 5.37 (broad s, 1H) ; 6.55 (s, 1H); 6.95 (s, 1H); 7.03 (s, 1H); 7.06 (m, 1H); 7.31 (s, 1H); 7.38 (m, 3H); 8.16 (broad s, 1H); 8.30 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 589.

Example 16:

N-f4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-benzamide

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145 mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in 2.0 ml of methylene chloride, then 2.0 ml of pyridine and then 41 μΐ (0.353 mmol) of benzoyl chloride were added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated, the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide, and 1 ml of methanol was added to the solution. The resulting precipitate was filtered off to give 64 mg (0.144 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}benzamide.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.12 (m, 4H); 3.67 (m, 2H); 3.99 (s, 3H); 4.17 (m, 2H); 4.99 (m, IH) ; 7.03 (s, IH) ; 7.04 (s, IH) ; 7.14 (d, J = 8.2 Hz, IH); 7.53 (m, 3H); 7.94 (d, J = 7.8 Hz, IH); 8.33 (s, IH) ; 8.58 (s, IH); 8.63 (d, J = 8.2 Hz, 1 H).

Mass spectrum (LC-MS): MH ⁺ = 444.

Example 17:

4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2-pyridinecarboxamide mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 2.0 ml of methylene chloride, and first 2.0 ml of pyridine and then 63 mg (0.353 mmol) of 2-pyridinecarbonyl chloride hydrochloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, yielding 84 mg (0.189 mmol)

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N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo-[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-2-pyridinecarboxamide is obtained.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.12 (m, 4H); 3.67 (m, 2H); 4.03 (s, 3H); 4.14 (m, 2H); 5.00 (m, 1H); 5.37 (s, 1H); 7.04 (s, 1H); 7.09 (s, 1H); 7.14 (d, J = 8.2 Hz, 1H); 7.50 (m, 1H); 7.92 (m, 1H); 8.33 (s, 1H); 8.70 (d, J = 8.2 Hz, 1H); 10.62 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 445.

Example 18:

N-[4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 2.0 ml of methylene chloride, and first 2.0 ml of pyridine and then 63 mg (0.353 mmol) of 2-pyridinecarbonyl chloride hydrochloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, yielding 30 mg (0.065 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide.

H-NMR spectrum (CDCl ₃ , δ): 2.11 (m, 4H); 2.32 (s, 3H); 3.66 (m, 2H); 3.99 (s, 3H); 4.13 (m, 2H); 4.17 (s, 3H); 4.99 (m, 1H); 5.22 (broad s, 2H); 6.46 (s, 1H); 7.03 (s, 1H); 7.07 (s, 1H); 7.12 (d, J = 8.2 Hz, 1H); 8.33 (2, 2H); 8.49 (d, J = 8.2 Hz, 1H). Mass spectrum (LC-MS): MH ⁺ = 462.

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Example 19:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2,2-dimethylpropionic acid amide mg (0.147 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine and then 31 mg (0.221 mmol) of 2,2-dimethylpropionyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated and the evaporation residue was dissolved in 1 ml of dimethylsulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, resulting in 27 mg (0.064 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2,2-dimethylpropionic acid amide.

3-NMR spectrum (CDCl ₃ , δ): 1.35 (s, 9H); 2.09 (m, 4H); 3.66 (m, 2H); 3.96 (s, 3H); 4.13 (m, 2H); 4.97 (m, 1H); 5.46 (wide s,

2H); 6.98 (s, 1H); 7.04 (s, 1H); 7.07 (d, J = 8.2 Hz, 1H); 8.15 (s, 1H); 8.29 (s, 1H); 8.49 (d, J = 8.2 Hz, 1H).

Mass spectrum (LC-MS): MH ⁺ = 424.

20, example:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-cyclopentanecarboxamide mg (0.147 mmol) 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine and then 31 mg (0.221 mmol) of cyclopentanecarbonyl chloride were added to the solution. The

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The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated and the residue was dissolved in 1 ml of dimethyl sulfoxide. To the solution was added 1 ml of methanol and the resulting precipitate was filtered off to give 33 mg (0.076 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-cyclopentanecarboxamide.

3-NMR spectrum (CDCl ₃ , δ): 1.66 (m, 2H); 1.81 (m, 2H); 1.95 (m,

4H); 2.06 (m, 4H); 2.77 (m, 1H); 3.65 (m, 2H); 3.94 (s, 3H);

4.15 (m, 2H); 4.96 (m, 1H); 5.37 (broad s, 2H); 6.98 (s, 1H);

7.03 (s, 1H); 7.07 (d, J = 8.2 Hz, 1H); 7.84 (s, 1H); 8.30 (s,

1H); 8.49 (d, J = 8.2 Hz, 1H).

Mass spectrum (LC-MS): MH ⁺ = 437.

Example 21:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropionic acid amide mg (0.147 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine and then 37 mg (0.221 mmol) of 3-phenylpropionyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated and the evaporation residue was dissolved in 1 ml of dimethylsulfoxide. 1 ml of methanol was added to the solution, and the resulting solid precipitate was filtered off, resulting in 7 mg (0.015 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-3-phenylpropionic acid72.227/BE

149 ....................

·4· · · « ··· · · · · · · · · · · · *· ·· ·* amide is obtained.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 4H); 2.75 (m, 2H); 3.09 (m, 2H); 3.65 (m, 2H); 3.88 (s, 3H); 4.13 (m, 2H); 4.96 (m, 1H); 5.97 (broad s, 2H); 6.93 (s, 1H); 7.05 (m, 2H); 7.26 (m, 5H); 7.70 (s, 1H); 8.24 (s, 1H); 8.46 (d, J = 8.2 Hz, 1H).

Mass spectrum (LC-MS): MH ⁺ = 472.

Example 22:

5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]~pyrimidin-4-amine

a) (3-Tetrahydrofuranyl)-(4-toluenesulfonate)

To a mixture of 5.0 g of 3-hydroxytetrahydrofuran and 100 ml of pyridine at 0 °C under nitrogen, 12.0 g of 4-toluenesulfonyl chloride were added in small portions while stirring. The reaction mixture was stirred at 0 °C for 2 hours, then allowed to warm to room temperature and stirred for a further 72 hours. After the reaction time, the mixture was cooled again to 0 °C, 200 ml of 5 M hydrochloric acid were added and the aqueous mixture was extracted with ethyl acetate. The combined organic solvent extracts were washed with 2 M hydrochloric acid and saturated sodium chloride solution, dried, filtered and evaporated to leave the title compound as an oil.

b) 5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo-

[2,3-d]pyrimidin-4-amine

906 mg of 4-amino-5-phenoxyphenyl-7H-pyrrolo[2,3-d]pyrimidine are dissolved in 30 ml of N,N-dimethylformamide, and 120 mg of 60% sodium hydride dispersed in mineral oil are added to the solution under nitrogen gas, while stirring. The reaction mixture is stirred for 30 minutes72.227/BE

150 ................ ...

·4· «· ♦* *4 ·* ni is allowed to stand, then a solution of 750 mg of (3-tetrahydrofuranyl)-(4-toluenesulfonate) in 30 ml of N,N-dimethylformamide is added. The mixture is then stirred for 18 hours at 95 °C, then concentrated in vacuo, and the residue is partitioned between ethyl acetate and water. The organic phase is separated, dried, the solvent is evaporated, and the sticky solid that remains is triturated with diethyl ether. The filtered product is 5-(4-phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point: 196-196.5 °C.

23, example:

5-(4-Phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as in Example 1, 4-amino-5-phenoxyphenyl-7H-pyrrolo[2,3-d]pyrimidine was reacted with (4-tetrahydropyranyl)-(4-toluenesulfonate). The crude product was purified by flash chromatography to give 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, m.p. 193-193.5 °C.

Example 24:

5-(4-Phenoxyphenyl)-7-{N-[(tert-butoxy)carbonyl]isoxazolidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

a) N-[(tert-Butoxy)carbonyl]-4-hydroxyisoxazolidine

2.4 g of 4-hydroxyisoxazolidine are dissolved together with 4.2 g of triethylamine in 100 ml of tetrahydrofuran, then 4.56 g of di(tert-butyl) is added under nitrogen at 0 °C while stirring.

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151

-dicarbonate. The reaction mixture was stirred at room temperature for 72 hours, then filtered and the filtrate was concentrated in vacuo. The residual oil was the title compound, which was used directly in the next reaction step without purification bj {N-[(tert-butoxy)carbonyl]isoxazolidin-4-yl}-(4-toluenesulfonate)

To 3.6 g of the product obtained as described in point a) above, 50 ml of pyridine are added, and 3.62 g of 4-toluenesulfonyl chloride are added in small portions at 0 °C, while stirring, under nitrogen. The reaction mixture is allowed to stir for another 1 hour at 0 °C, then stirring is continued at room temperature for a further 18 hours. After the reaction time, the pyridine is evaporated in vacuo, the evaporation residue is partitioned between 50 ml of ethyl acetate and 50 ml of 1 M aqueous citric acid solution, then the organic phase is separated, washed with 1 M citric acid solution and saturated sodium chloride solution, dried, filtered and evaporated. The residual oil was purified by flash chromatography, eluting the column with a solvent mixture of petroleum ether (bp 40-60 °C) and 20-30% ethyl acetate. The appropriate fractions were combined to give the title compound, mp 63-65 °C.

c) 5-(4-Phenoxyphenyl)-7-{N-[(tert-butoxy)carbonyl]-isoxazolidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

0.145 g of 60% sodium hydride dispersed in mineral oil is suspended in 60 ml of N,N-dimethylformamide, then at 0 °C, under nitrogen gas, 1.0 g is added dropwise while stirring.

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152 ,......

• · · « · * ♦·* • · · · ·· · * • •7- ·· r* «♦ **

A solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine in 40 ml of N,N-dimethylformamide was prepared. The reaction mixture was stirred at 0 °C for 1 hour, then 1.25 g of the compound prepared as described in b) was added and stirring was continued at 100 °C for a further 3 hours. The reaction mixture was then cooled to room temperature, quenched with water and the aqueous mixture was extracted with ethyl acetate. The resulting oil was triturated with ethyl acetate and the solid was collected on a filter to give the title compound. The product had a melting point of 162-163 °C.

Example 25:

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

0.29 g of the compound prepared as described in Example 3 was dissolved in 8 ml of methylene chloride, the solution was cooled to 0 °C and 2.0 ml of trifluoroacetic acid were added with stirring. The mixture was allowed to warm to room temperature, stirred for 2 hours, basified with sodium bicarbonate solution and the aqueous mixture was extracted with methylene chloride. The resulting oil was purified by flash chromatography, eluting with a 9:1 mixture of ethyl acetate and methanol, and the appropriate fractions were combined and evaporated. The remaining solid was dissolved in ethyl acetate, 3.0 ml of 1 M diethyl ether hydrogen chloride solution was added, then the precipitate was filtered off, washed with diethyl ether, and finally dried in vacuo at 45 °C for 2 hours. The product thus obtained was 5-(4-phenoxyphenyl)-772.227/BE

153 ................ ..

• l· * J «

-(4-isoxazolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride, melting at 208 °C with decomposition.

Example 6:

5-Iodo-4-chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine

a) 5-Iodo-4-chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidine

0.79 g of 60% sodium hydride dispersed in mineral oil and 100 ml of N,N-dimethylformamide are weighed out, and 5.0 g of 5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine are added at 0 °C with stirring. The mixture is allowed to stir until effervescence ceases, then 4.65 g of (3-tetrahydrofuranyl)-(4-toluenesulfonate) are added at 0 °C. The reaction mixture is then heated to 90 °C, stirred at this temperature for 2 hours, then at room temperature overnight, then 100 ml of water are carefully added. The aqueous mixture was extracted with ethyl acetate to give 5-iodo-4-chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine, mp 184-186°C.

b) 2-(4-Iodophenoxy)benzaldehyde

A mixture of 25.0 g of 4-iodophenol, 14.14 g of 2-fluorobenzaldehyde, 31.5 g of potassium carbonate and 50 ml of N,N-dimethylformamide was stirred under nitrogen at 120 °C for 15 hours, then cooled to room temperature and filtered. 500 ml of water was added to the filtrate and the aqueous mixture was extracted with ethyl acetate. The solid thus obtained was triturated with hot hexane and filtered, this product being 2-(4-iodophenoxy)benzaldehyde, melting point: 84.5-86 °C.

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154

Γ'· ···: ’·· .··.

· . · * * · ' · . h · 44'

c) 2-[4-(Trimethylstannyl)-phenoxy]-benzaldehyde

250 ml of toluene were purged with nitrogen gas for 30 minutes to remove traces of oxygen gas, then 6.46 g of 2-(4-iodophenoxy)benzaldehyde, 10.0 g of hexamethyldistannane and 1.4 g of [tetrakis(triphenylphosphine)palladium(0)] were added. The reaction mixture was refluxed under nitrogen for 7 hours, then cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting with a solvent mixture containing 3% ethyl acetate and petroleum ether boiling at 40-60 °C. The oil thus obtained was the title compound.

d) 2-{4-[4-Chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzaldehyde

A mixture of 1.80 g of the compound prepared as described in point c), 1.76 g of the compound obtained as described in point a), 228 mg of [tris(dibenzylideneacetone)dipalladium(0)], 383 mg of triphenylarsane and 75 ml of N,N-dimethylformamide was stirred under nitrogen at 65 °C for 70 hours. The reaction mixture was then cooled to room temperature, quenched with water and the aqueous mixture was extracted with ethyl acetate. The organic solvent extract was evaporated and the evaporation residue was purified by flash chromatography on silica gel, eluting the column with a solvent mixture containing ethyl acetate in increasing amounts from 30% to 50% and petroleum ether boiling at 40-60 °C. The solid thus obtained was triturated with more diethyl ether and the product, the title compound, was filtered off.

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155

e) 2-{4-[4-Chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzyl alcohol

360 mg of the compound prepared as described in d) above were dissolved in 5 ml of methanol and 65 mg of sodium [tetrahydridoborate] were added to the solution at 0 °C with stirring. The reaction mixture was then allowed to warm to room temperature, stirred for 1 hour, quenched with dilute sodium hydroxide solution and concentrated in vacuo. The residue was extracted with ethyl acetate to give the title compound.

f) 2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzyl alcohol

A mixture of 280 mg of the compound prepared as described in e) above, 15 ml of 1,4-dioxane and 15 ml of concentrated aqueous ammonia solution with a density of 0.88 is heated to 120 °C in a pressure-resistant reaction vessel, kept at this temperature for 20 hours, then cooled to room temperature and the solvent is evaporated in vacuo. The evaporation residue is taken up in ethyl acetate, washed with water, dried, filtered and evaporated, then the residual oil is purified by flash chromatography on silica gel, eluting the column with a 9:1 mixture of ethyl acetate and methanol. The glassy solid obtained, melting at 92-96 °C, is the title compound.

Example 27:

2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-N,N-diethylbenzylamine

a) N,N-Diethyl-2-{4-[4-chloro-7-(3-tetrahydrofuranyl)-7H-

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156 ................ ..

·«· · · * ··· • · · · · ♦· ·· ··

-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzylamine

In a 5 ml septum-sealed vial, 330 mg of 2-{4-[4-chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzaldehyde, 121 mg of diethylamine and ethylene dichloride are weighed, 264 mg of sodium triacetoxyhydridoborate are added to the mixture, then the vial is sealed. The reaction mixture is stirred at room temperature for 20 hours, then quenched with 5 ml of saturated aqueous sodium bicarbonate solution, and the aqueous mixture is extracted with ethyl acetate. The product thus obtained is the title compound.

b) 2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-N,N-diethylbenzylamine

A mixture of 280 mg of the compound prepared as described in point a) above, 15 ml of concentrated aqueous ammonia solution with a density of 0.88 and 10 ml of 1,4-dioxane is heated to 120 °C in a pressure-resistant reaction vessel, kept at this temperature for 16 hours, then cooled to room temperature and the solvent is evaporated in vacuo. The evaporation residue is taken up in ethyl acetate, washed with water, dried, filtered and evaporated, then the residual oil is purified by flash chromatography on silica gel, eluting the column with a mixture of ethyl acetate and methanol. The product thus obtained is the title compound, melting point: 107-110 °C.

Example 28:

2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzonitrile

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157 ..................

··« · · · · · · • « · · · · · «* ·*

a) 2-(4-Bromophenoxy)benzonitrile

A mixture of 28.8 g of 2-fluorobenzonitrile, 36.9 g of 4-bromophenol, 58.9 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred under nitrogen at 120 °C for 5 hours, then allowed to stand overnight at room temperature and partitioned between ethyl acetate and water. The organic phase was separated, washed, dried and evaporated to leave an oil which solidified on standing. This solid residue was triturated with petroleum ether boiling at 40-60 °C and the product was filtered off to give the title compound.

b) 2-[4-(Trimethylstannyl)phenoxy]benzonitrile

A mixture of 5.57 g of the compound prepared as described in a) above, 10.0 g of hexamethyldistannane, 1.4 g of [tetrakis(triphenylphosphine)palladium(0)] and 250 ml of degassed toluene is stirred under nitrogen at 110 °C for 4.5 hours, then cooled to room temperature and filtered through a filter bed made of silica gel. The filter is washed with ethyl acetate, then the filtrate and washings are combined, evaporated to dryness and the distillation residue is purified by flash chromatography on silica gel, eluting the column with a solvent mixture containing petroleum ether boiling at 40-60 °C and diethyl ether in increasing proportions from 2% to 5%. The appropriate fractions were combined and evaporated to give the title compound.

c) 2-{4-[4-Chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzonitrile

1.8 g of 5-iodo-4-chloro-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine prepared as described in Example 5 and 1.23 g of

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Compound 158 prepared as described in b) above was reacted as described in d) of Example 5. The reaction mixture was worked up to give the title compound.

d) 2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzonitrile

A mixture of 470 mg of the compound prepared as described in point c) above, 33 ml of concentrated aqueous ammonia solution with a density of 0.88 and 33 ml of 1,4-dioxane is heated to 120 °C in a pressure-resistant reaction vessel and maintained at this temperature for 18 hours. The reaction mixture is then worked up as described in Example 5 to give the title compound. The product has a melting point of 201-203 °C.

Example 29:

2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzaldehyde

a) 5-[4-(Benzyloxy)phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In a similar manner to Example 2, 1.84 g of (3-tetrahydrofuranyl·)-(4-toluenesulfonate) was reacted with 2.9 g of 5-[4-(benzyloxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in 40 ml of N,N-dimethylformamide in the presence of 0.30 g of 60% sodium hydride dispersed in mineral oil, but the reaction time was 4.5 hours at 90 °C. The title compound was thus obtained as a solid.

b) 4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenol

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159 ..................

• · · * · · • · · · · · · · ·

A mixture of 6.0 g of the compound prepared as described in a) above, 3.0 g of 10% palladium-on-carbon catalyst, 4.9 g of ammonium formate and 500 ml of ethanol was heated on a steam bath and stirred under nitrogen for 2 hours, then cooled to room temperature and filtered. The filtrate was evaporated to half its original volume to give the title compound as a solid. The product had a melting point of 257-259 °C.

c) 2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzaldehyde

A mixture of 2.55 g of 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol, 1.07 g of 2-fluorobenzaldehyde, 2.13 g of potassium carbonate and 80 ml of N,N-dimethylformamide was stirred under nitrogen at 120 °C for 5 hours, then cooled to room temperature and quenched with water. The aqueous mixture was extracted with ethyl acetate to give the title compound. The product had a melting point of 185-187 °C.

Example 30:

4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7yl]tetrahydrofuran-3-ol

902 mg of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine are dissolved in 30 ml of N,N-dimethylformamide, and 120 mg of 60% sodium hydride dispersed in mineral oil are added to the solution under nitrogen gas while stirring. The reaction mixture is allowed to stir for 30 minutes, then 300 mg of 3,6-dioxa-bicyclo[3.1.0]hexane are added, and the reaction is continued at 80 °C for a further 64 hours. The mixture is then evaporated in vacuo, the evaporation residue

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160 ..................

• ♦ · ♦ · · ··» « · · · · ·* · · ·* ·· *· is triturated with water, and diethyl ether is added to the oily gum thus obtained. The diethyl ether mixture is stirred rapidly for 30 min, as a result of which a solid precipitate is formed, which is filtered off, washed with methanol, and then set aside. The solid material recovered from the filtrate as a second generation product is recrystallized from ethanol. The melting point of the 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrofuran-3-ol thus obtained: 234.5-235.5 °C.

Example 31:

5-{4-[2-(Morpholinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of 0.15 g of 2-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzaldehyde, 64 mg of morpholine, 117 mg of sodium}triacetoxyhydridoborate] and 5 ml of ethylene dichloride was stirred at room temperature for 18 hours, then saturated aqueous sodium bicarbonate solution was added and filtered through an EMPORE® filter cartridge. The filtrate was evaporated, the evaporation residue was dissolved in 5 ml of methylene dichloride, 0.3 g of polymer-bound tris(2-aminoethyl)amine and 2 drops of concentrated anhydrous acetic acid were added to the solution, and the mixture was stirred at room temperature overnight. The next day, the polymer was filtered off, washed with methylene chloride and methanol, the filtrate and washings were combined, and the solvent was evaporated. The residual oil was triturated in a mixture of diethyl ether and ethyl acetate, the mixture was heated, so that the solid material went into solution, then the solution was cooled with ice, and the precipitate was collected.

72.227/BE

Collected on a filter 161. The thus obtained 5-{4-[2-(morpholinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine has a melting point of 169-171°C.

Example 32:

5-{4-[2-(Piperidinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as in Example 10, 0.15 g of 2-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenoxy]-benzaldehyde was reacted with 63 mg of piperidine. The glassy foam thus obtained was 5-{4-[2-(piperidinomethyl)-phenoxy]-phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The melting point of the product was 76-78 °C.

Example 33:

5-{4-[2-{[(2-Methoxyethyl)amino]methyl]phenoxy]phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as in Example 10, 0.15 g of 2-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]benzaldehyde was reacted with 56 mg of 2-methoxyethylamine. The resulting 5-{4-[2-{[(2-methoxyethyl)amino]methyl]phenoxy]phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was a glassy foam, melting point 66-68°C.

Example 34:

4-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzyl alcohol

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a) 4-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzaldehyde

The procedure is the same as that given in Example 9, but here 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine is reacted with 4-fluorobenzaldehyde to give the title compound.

b) 4-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo [2,3-d]-pyrimidin-5-yl]-phenoxy}-benzyl alcohol

0.35 g of the compound prepared as described in point a) above is dissolved in 10 ml of methanol, and 32 mg of sodium [tetrahydridoborate] is added to the solution at 0 °C. The reaction mixture is stirred for 10 minutes at constant temperature, then 4 ml of ethylene dichloride is added to increase the solubility, stirring is continued at room temperature for a further 18 hours, then 1 ml of concentrated, anhydrous acetic acid is added. The mixture is then evaporated in vacuo, the evaporation residue is partitioned between ethyl acetate and saturated aqueous sodium carbonate solution, then the organic phase is separated, dried, filtered and the solvent is evaporated. The thus obtained 4-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzyl alcohol has a melting point of 92-95°C.

Example 35:

5-[4-(4-Fluorophenoxy)phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

0.59 g 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol, 0.56 g 4-fluoroboric acid, 0.36 g copper (II)72.227/BE

163

-acetate, 1.01 g· triethylamine, 20 ml methylene dichloride and 0.5 g activated, ground 4Å molecular sieves are stirred under nitrogen gas atmosphere with the exclusion of moisture for 64 hours, then filtered through a short column filled with pretreated silica gel, and the column is eluted first with 200 ml methylene dichloride, then with 250 ml ethyl acetate, and finally with 250 ml of a 9:1 ethyl acetate-methanol mixture. The methylene dichloride and ethyl acetate fractions are combined and the crude product is purified by flash chromatography on silica gel, eluting the column with a mixture of ethyl acetate and methanol. In this way, 5-[4-(4-fluorophenoxy)phenyl]-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is obtained, melting point: 198-199°C.

Example 36:

5-{4-[4-(Morpholinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as in Example 10, 336 mg of 4-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenoxy}-benzaldehyde were reacted with 146 mg of morpholine. The product thus obtained was 5-{4-[4-(morpholinomethyl)-phenoxy]-phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point 142-144°C.

Example 37:

5-{4-[3-(Morpholinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

a) 3-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-phenoxy}-benzaldehyde

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164

In the same manner as in Example 14, 0.297 g of 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol was reacted with 3-formylphenylboronic acid. The product thus obtained was 3-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzaldehyde.

b) 5-{4-[3-(Morpholino-methyl)-phenoxy]-phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

100 mg of the compound prepared as described in a) above and 44 mg of morpholine were reacted using the reagents and conditions given in Example 10 to prepare 5-{4-[3-(morpholinomethyl)phenoxy]phenyl}-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point 83-85 °C.

Example 38:

2-(4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-{[2-(4-pyridyl)ethyl]amino}-benzonitrile

A mixture of 0.517 g of 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol, 0.42 g of 2-fluoro-6-{[2-(4-pyridyl)-ethyl]-amino}-benzonitrile, 0.48 g of potassium carbonate and 20 ml of N,N-dimethylformamide is heated to 120 °C under nitrogen gas, kept at this temperature for 8 hours, then allowed to cool and diluted with water. The aqueous mixture is extracted with ethyl acetate, then the solid residue thus obtained is recrystallized from ethyl acetate, and finally purified by flash chromatography on silica gel, eluting the column with a mixture of ethyl acetate and methanol in the ratio of 9:1, 8:1 and 4:1. The product is 2-{4-[4-amino-7-(372.227/BE

165

-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]-6-{[2-(4-pyridyl)ethyl]amino}benzonitrile, melting point: 212-213 °C.

Example 39:

2-{4-[4-Amino~7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-{[3-(1-imidazolyl)-propyl]amino}-benzonitrile

A mixture of 0.49 g of 4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol, 2-fluoro-6-{[3-(1-imidazolyl)propyl]amino}benzonitrile, 0.45 g of potassium carbonate and N,N-dimethylformamide was reacted in the same manner as in Example 17. The glassy foam thus obtained melting at 110°C was 2-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-{[2-(1-imidazolyl)propyl]amino}benzonitrile.

Example 40:

4-Amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine

a) 4-Amino - 6-bromo-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine

302 mg of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine were dissolved in 10 ml of N,N-dimethylacetamide and 50 ml of methylene chloride, and a solution of 178 mg of N-bromosuccinimide in 10 ml of methylene chloride was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo, the residue was triturated with water, and the solid was filtered off and dried. The product thus obtained was 4-amino-6-bromo

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166

-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, melting point: 282-283 °C.

b) 4-Amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuranyl)-

-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 1.14 g of the compound prepared as described in a) above and 30 ml of anhydrous N,N-dimethylformamide is stirred under nitrogen while 120 mg of 60% sodium hydride dispersed in mineral oil is added. A solution of 0.8 g of (3-tetrahydrofuranyl)-(4-toluenesulfonate) in 10 ml of N,N-dimethylformamide is then added, the reaction mixture is stirred overnight at 90 °C, then cooled and evaporated in vacuo. The evaporation residue is triturated with water, the solid is filtered off and dried, then dissolved in ethanol, and water is added to the solution until it becomes cloudy. The solution is then filtered, the filtrate is evaporated in vacuo, and the evaporation residue is purified by flash chromatography on silica gel. The melting point of the 4-amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidine thus obtained is 205-206°C.

Example 41:

2-{4-[4-Amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-[(3-methoxypropyl)amino]benzonitrile

A mixture of 0.65 g of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, 0.46 g of 2-fluoro-6-[(3-methoxypropyl)amino]benzonitrile, 0.61 g of potassium carbonate and 40 ml of N,N-dimethylformamide was reacted as described in Example 17 at 120 °C under nitrogen for 8 hours, and the reaction mixture was then worked up. The thus obtained

72.227/BE

Product 167 is 2-{4-[4-amino-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]phenoxy]-6-[(3-methoxypropyl)amino]benzonitrile, melting point: 183-184 °C.

Example 42:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-benzonitrile

a) 4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol

A mixture of 2.83 g of 5-[4-(benzyloxy)phenyl]-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 1.41 g of 10% palladium-on-carbon catalyst, 2.31 g of ammonium formate and 250 ml of ethanol was refluxed under nitrogen for 1.5 hours, cooled to room temperature and filtered. The filtrate was evaporated to give the title compound as a solid.

b) 2-(4-[4-Amino-7-(3-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}benzonitrile

In a vial, to a warm solution of 0.082 g of 4-[4-amino-7-(3-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol in 3.4 ml of N,N-dimethylformamide, 80 mg of 2-fluorobenzonitrile and 76 mg of potassium carbonate were added, the vial was flushed with nitrogen and sealed. The reaction mixture was shaken at 120 °C for 6 h, then allowed to cool to room temperature over 16 h and then diluted with 11 ml of water. The aqueous mixture was extracted with ethyl acetate to give 2-{4-[4-amino-7-(3-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy]benzonitrile,

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168 whose melting point is 125 °C (shrinks).

Examples 43-48:

The compounds of Examples 43-48 are prepared by treating 4-[4-amino-7-(3-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol with the appropriate nitrile in the same manner as described in Example 42, but shaking the reaction mixture for up to 48 hours if necessary. Heating is continued to monitor the progress of the reaction until the starting compound has been reacted.

9, example:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-{[3-(1-imidazolyl)propyl]amino}-benzonitrile The title compound was prepared from 2-fluoro-6-{[3-(1-imidazolyl)propyl]amino]benzonitrile.

Example 50:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-(2-morpholinoethoxy)benzonitrile

The title compound is prepared from 2-fluorobenzonitrile, the melting point of the glassy product is 110 °C.

Example 51:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-{[2-(4-pyridyl)ethyl]amino}-benzonitrile

The title compound was identified as 2-fluoro-6-{[2-(4-pyridyl)72.227/BE

169 ,.,, .... ........ ..

• · « ♦ * · ··· · · · * · ♦

-ethyl]-amino}-benzonitrile, the melting point of the glassy product: 120-123 °C.

Example 52:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-6-[(3-methoxypropyl)amino]benzonitrile

The compound named in the title is prepared from 2-fluoro-6-[((3-methoxypropyl)amino]benzonitrile, the melting point of the product: 205-207 °C.

Example 53:

2-{4-[4-Amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenoxy}-5-fluorobenzonitrile

The title compound is prepared from 2,5-difluorobenzonitrile, melting point of the product: 216-217 °C.

Examples 54-101:

General procedure

Quantities corresponding to 9 molar equivalents of the ester of the amines listed in Table 1 (47.5-184.5 mg) and 1 ml of methanol are weighed into each vial, and then 1 molar equivalent of ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] acetate] in 4 ml of a 23.2:1 methanol-triethylamine mixture is added to each. The reaction mixtures are shaken at 60-65 °C for 36 hours, then the methanol and triethylamine are evaporated at 50 °C under vacuum for 3 hours. Subsequently, 3 ml of water and 3 ml of methylene chloride are added to each vial.72.227/BE

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-dichloride is pipetted, the contents of the vials are stirred for 15 seconds, allowed to stand for 18 hours, then poured onto an EMPORE extraction disc insert (10 mm/6 ml), the methylene dichloride phases are separated, and the solutions are evaporated at 50 °C over 3 hours. During the processing, we experienced that a solid precipitate forms in the vials during the 18-hour standing time, therefore the aqueous layers were pressed out of the extraction inserts with compressed air, the extraction inserts were washed with 4 ml of methylene dichloride, and finally the filtrates were evaporated at 50 °C under vacuum over 3 hours. From what has been said, it follows that the desired product is either found in the original methylene dichloride extract, i.e. it is present in the liquid phase (this is denoted by the word liquid in the table), or it is encountered as a solid during repeated processing, in which case the table states as a note that the product is found in the solid phase, or for some compounds both of the above statements are true, i.e. they are present in both the liquid phase and the solid phase, and in such cases the table states the note both.

All of the compounds prepared in the above manner were subjected to mass spectrometry (LC-MS) analysis, which was performed under the following experimental conditions:

Column: 5 μΐ Hypersil BDS C18 (100 x 2.1 mm).

Mobile phase: a mixture of 0.1 M ammonium acetate buffer solution (pH = 4.55) and acetonitrile.

Elution: gradient elution as follows: 10-100% acetonitrile over 8 minutes; 100% acetonitrile over 1 minute; 100-10% acetonitrile over 2 minutes; total time 11 minutes.

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Flow rate: 1 ml/min (without gap in the mass spectrometer).

Wavelength: 250-320 nm.

Injected volume: 20 μΐ.

Mass spectrum: method: APCI11H; ionization: APCI +ve/-ve; mass range: 100-700 m/z; cone voltage: 20.

The molecular ion corresponding to the target compound was detected in all cases. The retention times (RT) of the products in minutes are also given in Table 1.

Table 1

Example number Name of the amine Phase RT 54 2-aminoethanol solid 3, 44 55 dl-2-amino-propan-1-ol liquid 3.58 56 l-amino-propan-2-ol solid 3.56 57 2-methoxyethylamine solid 3.78 58 3-amino-propan-1-ol all 3, 50 59 (S)-(+)-2-amino-propan-1-ol all 3.58 60 (R)-(-)-1-Aminopropan-2-ol all 3.56 61 N,N-Dimethylethylenediamine all 3.31 62 (±)-2-aminobutan-1-ol solid 3.77 63 l-aminobutan-2-ol all 3.77 64 3-aminopropane-1,2-diol solid 3.32 65 (S)-3-aminopropane-1,2-diol solid 3.32 66 (R)-3-aminopropane-1,2-diol solid 3.32 67 1-methylpiperazine all 3.28

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68 N,N-Dimethyltrimethylenediamine liquid 3.29 69 2-(Dimethylamino)propylamine all 3.37 70 2-(Dimethylamino)-1-methylethylamine liquid 3.44 71 dl-2-amino-3-methyl-butan-1-ol solid 3, 98 72 N-(2-morpholino-2-oxoethyl)piperazine liquid 3.56 73 2-amino-2-methyl-propan-1-ol all 3, 86 74 2-amino-2-methylpropane-1,3-diol all 3.49 75 2-(2-aminoethoxy)ethanol all 3.47 76 1-(2-aminoethyl)pyrrolidine liquid 3.40 77 N-methyl homopiperazine liquid 3.32 78 1-aminocyclopentane-1-methanol all 4.16 79 2-aminocyclohexanol solid 3, 98 80 N,N-Diethylethylenediamine liquid 3, 44 81 N-(3-hydroxypropyl)ethylenediamine all 3.24 82 2-[(2-aminoethyl)thio]ethanol all 3, 69 83 2-(2-aminoethyl)pyridine liquid 3.89 84 3-(2-aminoethyl)pyridine liquid 3.79 85 N-(3-aminopropyl)imidazole liquid 3.37 86 1-(2-morpholinoethyl)piperazine liquid 3.39 87 2-(Aminomethyl)-1-ethylpyrrolidine all 3.48 88 1-(2-aminoethyl)piperidine all 3.49 89 3-(1-pyrrolidinyl)propylamine liquid 3.37 90 (R)-( + )-2-(aminomethyl)-1-ethylpyrrolidine all 3.48 91 4-(2-aminoethyl)morpholine all 3.39 92 3-(diethylamino)propylamine all 3.43 93 3-(dimethylamino)-2,2-dimethylpropylamine all 3.47

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94 ethyl-(1-piperazinecarboxylate) liquid 4.34 95 2-(aminomethyl)-2-ethylpropane-1,3-diol all 3, 69 96 1-(3-Aminopropyl)-2-pyrrolidinone all 3.68 97 3-piperidinopropylamine liquid 3.46 98 4-(3-aminopropyl)morpholine liquid 3.33 99 N,N-diisopropylethylenediamine liquid 3.59 100 Ν,Ν-bis(3-aminopropyl)methylamine liquid 3, 03 101 tris(2-aminoethyl)amine liquid 3, 01

The compounds produced, listed by name, are as follows:

Example 54:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxyethyl)acetamide

Example 55:

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

Example 56:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxypropyl)acetamide

Example 57:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-methoxyethyl)acetamide

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Example 58:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(3-hydroxypropyl)acetamide

Example 59:

(S)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxy-1-methylethyl)acetamide

Example 60:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxypropyl)-acetamide

Example 61:

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

Example 62:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[1-(hydroxymethyl)propyl]-acetamide

Example 63:

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

Example 64:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2,3-dihydroxypropyl)acetamide

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Example 65:

(S)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-N-(2,3-dihydroxypropyl)acetamide

Example 66:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-N-(2,3-dihydroxypropyl)acetamide

67, example:

1-{2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetyl}-4-methylpiperazine

Example 68:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(dimethylamino)propyl]acetamide

Example 69:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)propyl]-acetamide

Example 70:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)-1-methylethyl]acetamide

Example 71:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[1-(hydroxymethyl)-2-methylpropyl]acetamide

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Example 72:

5-(4-Phenoxyphenyl)-7-{2-[4-(2-morpholino-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Example 73:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxy-1,1-dimethylethyl)acetamide

Example 74:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1,1-bis(hydroxymethyl)ethyl]acetamide

Example 75:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(2-hydroxyethoxy)ethyl]acetamide

Example 6:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(1-pyrrolidinyl)ethyl]acetamide

Example 77:

1-{2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetyl}-4-methylhomopiperazine

Example 78:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1-(hydroxymethyl)cyclopentyl]acetamide

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• · · « * · · <

• · · · * · · · *a

Example 79:

2-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxycyclohexyl)acetamide

Example 80:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(diethylamino)ethyl]acetamide

81, example:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-{2-[(3-hydroxypropyl)amino]ethyl}acetamide

Example 82:

2-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-{2-[(2-hydroxyethyl)thio]ethyl}acetamide

Example 83:

2-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo(2,3-d]pyrimidin-7-yl)-N-(2-(2-pyridyl)ethyl]acetamide

Example 84:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-(3-pyridyl)ethyl]acetamide

Example 85:

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

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Example 86:

5-(4-Phenoxyphenyl)-7-{2-[4-(2-morpholino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Example 87:

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

Example 88:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-piperidinoethyl)acetamide

Example 89:

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

Example 90:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[(N-ethylpyrrolidin-2-yl)methyl]acetamide

Example 91:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholinoethyl)acetamide

Example 92:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(diethylamino)propyl]acetamide

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Example 93:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(dimethylamino)-2,2-dimethylpropyl]acetamide

Example 94:

7-{2-[4-(Ethoxycarbonyl)piperazin-1-yl]-2-oxoethyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Example 95:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2,2-bis(hydroxymethyl)butyl]acetamide

Example 96:

2-[4-Amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-acetamide

Example 97:

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

Example 98:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(3-morpholinopropyl)acetamide

Example 99:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(diisopropylamino)ethyl]acetamide

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Example 100:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-{3-[N-(3-aminopropyl)-N-methylamino]propyl}acetamide

Example 101:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d pyrimidin-7-yl]-N-{2-[bis(2-aminoethyl)amino]ethyl}acetamide

Examples 102-146:

Following the general procedure given in connection with Examples 54-101, the amines listed in Table 2 can be reacted with ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl acetate}. The workup and analysis conditions of the reaction mixtures were the same as those described for Examples 54-101, and the molecular ion corresponding to the target compound was detected in each case.

In Table 2, the data reported under the headings phase and RT have the same meaning as in Table 1.

Table 2

Example number Name of the amine Phase RT 102 2-aminoethanol all 3.68 103 dl-2-amino-propan-1-ol all 3.78 104 l-amino-propan-2-ol all 3.81 105 2-methoxyethylamine all 4.08 106 3-amino-propan-1-ol all 3.73

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107 (S) — ( + )-2-amino-propan-1-ol all 3.78 108 (R)-(-)-1-Aminopropan-2-ol liquid 3, 81 109 N,N-Dimethylethylenediamine liquid 3.50 110 (+)-2-aminobutan-1-ol all 3, 96 111 l-aminobutan-2-ol all 4.06 112 3-aminopropane-1,2-diol all 3.52 113 (S)-3-aminopropane-1,2-diol all 3.53 114 (R)-3-Aminopropane-1,2-diol all 3.53 115 N,N-Dimethyltrimethylenediamine liquid 3, 47 116 2-(Dimethylamino)propylamine liquid 3.57 117 2-(Dimethylamino)-1-methylethylamine liquid 3, 67 118 dl-2-amino-3-methyl-butan-1-ol all 4.15 119 2-[(2-aminoethyl)amino]-ethanol liquid 3, 40 120 2-amino-2-methyl-propan-1-ol all 4.17 121 2-amino-2-methylpropane-1,3-diol liquid 3.76 122 2-(2-aminoethoxy)ethanol all 3.71 123 1-(2-aminoethyl)pyrrolidine all 3, 61 124 1-aminocyclopentane-1-methanol all 4.48 125 2-aminocyclohexanol all 4.19 126 N,N-Diethylethylenediamine all 3, 68 127 N-(3-hydroxypropyl)ethylenediamine all 3.42 128 2-[(2-aminoethyl)thio]ethanol liquid 3.94 129 2-(2-aminoethyl)pyridine liquid 4.13 130 3-(2-aminoethyl)pyridine all 4.05 131 N-(3-aminopropyl)imidazole liquid 3.58 132 2-[(2-aminoethyl)amino]-1-methylpyrrolidine all 3.56

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133 2-(Aminomethyl)-1-ethylpyrrolidine all 3, 70 134 1-(2-aminoethyl)piperidine all 3.70 135 3-(1-pyrrolidinyl)propylamine all 3, 60 136 (R)-(+)-2-(aminomethyl)-1-ethylpyrrolidine all 3.70 137 4-(2-aminoethyl)morpholine all 3, 63 138 3-(diethylamino)propylamine all 3, 64 139 3-(dimethylamino)-2,2-dimethylpropylamine all 3, 68 140 2-(aminomethyl)-2-ethylpropane-1,3-diol all 3, 94 141 1-(3-Aminopropyl)-2-pyrrolidinone liquid 3, 91 142 3-piperidinopropylamine all 3.70 143 4-(3-aminopropyl)morpholine liquid 3, 53 144 N,N-diisopropylethylenediamine liquid 3, 86 145 N,N-bis(3-aminopropyl)methylamine solid 3.21 146 tris(2-aminoethyl)amine all 3, 17

The compounds produced, listed by name, are as follows:

Example 102:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-hydroxyethyl)-propionic acid amide

Example 103:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-hydroxy-1-methylethyl)propionic acid amide

Example 104:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-hydroxypropyl)-propionic acid amide

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Example 105:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-methoxyethyl)propionic acid amide

Example 106:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(3-hydroxypropyl)-propionic acid amide

Example 107:

(S)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxy-1-methylethyl)-propionic acid

Example 108:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-N-(2-hydroxypropyl)-propionic acid amide

Example 109:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[2-(dimethylamino)ethyl]-propionic acid amide

Example 110:

2-[4-Amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[2 _r 3-d]pyrimidin-7-yl]-N-[1-(hydroxymethyl)-propyl]-propionic acid

Example 111:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxybutyl)propionic acid

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Example 112:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2,3-dihydroxypropyl)-propionic acid

Example 113:

(S)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2,3-dihydroxypropyl)-propionic acid

Example 114:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2,3-dihydroxypropyl)-propionic acid

Example 115:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(dimethylamino)propyl]-propionic acid

Example 116:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-dJpyrimidin-7-yl]-N-[2-(dimethylamino)propyl]-propionic acid

Example 117:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)-1-methylethyl]-propionic acid

Example 118:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1-(hydroxymethyl)-2-methylpropyl]-propionic acid

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Example 119:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-{2-[(2-hydroxyethyl)amino]ethyl}-propionic acid amide

Example 120:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-hydroxy-1,1-dimethylethyl)-propionic acid amide

Example 121:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1,1-bis(hydroxymethyl)ethyl]-propionic acid

Example 122:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(2-hydroxyethoxy)ethyl]-propionic acid

Example 123:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(1-pyrrolidinyl)ethyl]-propionic acid

Example 124:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1-(hydroxymethyl)cyclopentyl]propionic acid

Example 125:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxycyclohexyl)-propionic acid

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Example 126:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[2-(diethylamino)ethyl]-propionic acid amide

Example 127:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-{2-[(3-hydroxypropyl)-amino]-ethyl}-propionic acid amide

Example 128:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(2-[(2-hydroxyethyl)thio]ethyl}-propionic acid amide

Example 129:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[2-(2-pyridyl)ethyl]-propionic acid

Example 130:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(3-pyridyl)ethyl]-propionic acid

Example 131:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(1-imidazolyl)propyl]-propionic acid

Example 132:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[2-(N-methylpyrrolidin-2-yl)ethyl]-propionic acid amide

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133, example:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[(N-ethylpyrrolidin-2-yl)-methyl]-propionic acid amide

Example 134:

2-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-piperidinoethyl)-propionic acid

Example 135:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(1-pyrrolidinyl)propyl]-propionic acid

Example 136:

(R)-2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-N-[(N-ethylpyrrolidin-2-yl)methyl]-propionic acid

Example 137:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholinoethyl)-propionic acid

138, example:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[3-(dimethylamino)propyl]-propionic acid amide

139, example:

2-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[3-(dimethylamino)-2,2-dimethylpropyl]-propionic acid amide

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188 .... ........ ..

• · · * * ♦ ♦ *· · _ · ♦ '*·

-·* Λ -« Μ *»' w·

Example 140:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2,2-bis(hydroxymethyl)butyl]-propionic acid

Example 141:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-propionic acid

Example 142:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(3-piperidinopropyl)-propionic acid amide

Example 143:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-(3-morpholinopropyl)-propionic acid amide

Example 144:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[2-(diisopropylamino)ethyl]-propionic acid amide

Example 145:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-{3-[N-(3-aminopropyl)-N-methylamino]-propyl}-propionic acid

Example 146:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-{2-[bis(2-aminoethyl)amino]ethyl}-propionic acid amide

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9 ................ ,.

« * · ♦ * ·«« · _ν «·* ' * * * * *·< * *♦ *

Example 147:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]butyrolactone

a) 2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-butyrolactone

To a mixture of 0.158 g of 60% sodium hydride dispersed in mineral oil and 70 ml of N,N-dimethylformamide under nitrogen at 0 °C, 1.0 g of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine was added with stirring. The reaction mixture was stirred for 1 hour at 0 °C, then a solution of 0.60 g of α-bromo-γ-butyrolactone in 6 ml of N,N-dimethylformamide was added dropwise, and stirring was continued at room temperature for a further 18 hours. The reaction mixture was then quenched with water, the aqueous mixture was extracted with ethyl acetate, and the combined organic solvent extracts were dried and evaporated. The thus obtained 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]butyrolactone, which is an oil, is used directly for the next reaction step.

b) 2-[4-Amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-N-[2-(dimethylamino)ethyl]butyric acid amide

To a mixture of 1.2 g of the compound prepared as described in a) above, 50 mg of 2-pyridinone and 100 ml of toluene was added 5 ml of N,N-dimethylethylenediamine. The reaction mixture was heated to 100 °C, maintained at this temperature for 2 hours, and then evaporated to dryness in vacuo. The evaporation residue was partitioned between ethyl acetate and water, and the organic phase was extracted three times with 50 ml of 5 M hydrochloric acid. The combined acidic extracts were washed with ethyl acetate.

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The mixture was washed with 190 ml of acetate, basified with 6 M sodium hydroxide solution at 0 °C, and the product was back-extracted with ethyl acetate and methylene chloride. The combined organic solvent extracts were dried, filtered, the solvent was evaporated, and the residual oil was recrystallized from a mixture of ethyl acetate and diethyl ether. The 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3d]-pyrimidin-7-yl]-N-[2-(dimethylamino)ethyl]-butyric acid amide thus obtained had a melting point* of 178-179 °C.

Example 148:

Ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin7-yl]propionate)

To a mixture of 906 mg of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine and 30 ml of anhydrous N,N-dimethylformamide under a nitrogen atmosphere was added 120 mg of 60% sodium hydride dispersed in mineral oil. The reaction mixture was stirred at room temperature for 30 minutes, then 543 mg of ethyl-(2-bromopropionate) (10 ml) was added dropwise via a syringe over 10 minutes.

N,N-dimethylformamide solution. Stirring is then continued for 2 hours at room temperature, then the mixture is left to stand for 18 hours, then evaporated in vacuo, the evaporation residue is washed with water, and the solid is triturated with diethyl ether. The ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate] thus obtained has a melting point of 139-140 °C.

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191

Example 149:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)ethyl]-propionic acid

A mixture of 425 mg of ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate], 2 ml of N,N-dimethylethylenediamine and 20 ml of methanol is refluxed for 18 hours in the absence of carbon dioxide, then cooled, filtered, the filtrate is diluted with 50 ml of water and mixed with diethyl ether. The aqueous mixture is left to stand for 18 hours, then the solid precipitate that has separated is filtered off, washed with water and diethyl ether and finally dried. The thus obtained 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-dimethylamino)ethyl]propionic acid amide has a melting point of 163-164°C.

150, example:

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

To a mixture of 906 mg of 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine and 30 ml of anhydrous N,N-dimethylformamide under a nitrogen atmosphere was added 120 mg of 60% sodium hydride dispersed in mineral oil. The reaction mixture was stirred for 30 minutes at room temperature, then a solution of 0.5 ml of ethyl (bromoacetate) in 10 ml of N,N-dimethylformamide was added over 5 minutes at 0-5 °C while stirring. Stirring was then continued for 30 minutes at room temperature, the mixture was left to stand for 18 hours, then evaporated in vacuo, and the evaporation residue was triturated with water and diethyl ether. The solid was filtered off,

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192 is washed with water and diethyl ether to give ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate], melting point: 161-161.3 ^° C.

Examples 151-156:

General procedure

194 mg of ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate) was reacted with 10 molar equivalents of the appropriate amine in 12 ml of methanol at 62°C for 18 hours, and the reaction mixture was worked up. Thus, the compounds of Examples 151-156 were prepared.

Example 151:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]acetamide

The title compound was prepared from 1,1-bis(hydroxymethyl)-2-(hydroxyethyl)ethylamine. The product melted at 222-223°C with decomposition.

Example 152:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(1-piperazinyl)ethyl]acetamide

The title compound is prepared from 2-(1-piperazinyl)ethylamine, melting point of the product: 138-140 °C.

Example 153:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholinoethyl)acetamide

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193 :.................

··· · · ·* e · ··

The title compound is prepared from 2-morpholinoethylamine, melting point of the product: 164-165 °C.

Example 154:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-

-yl]-N-[3-(1-imidazolyl)propyl]-acetamide

The title compound was prepared from 3-(1-imidazolyl)propylamine, melting point of the product: 170-171 °C.

Example 155:

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

The title compound is prepared from (N-ethylpyrrolidin-2-yl)methylamine, melting point of the product: 122-122.5 °C.

Example 156:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(2-hydroxyethoxy)ethyl]acetamide

The title compound is prepared from 2-(2-hydroxyethoxy)ethylamine, melting point of the product: 145-147 °C.

Example 157:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionic acid

A mixture of 201 mg of ethyl {2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate}, 4 ml of 2 M aqueous sodium hydroxide solution and 20 ml of methanol was refluxed for 1 hour.

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194 and then concentrated in vacuo to a volume of approximately 5 ml. The distillation residue is diluted with 30 ml of water, the mixture is filtered hot, the filtrate is cooled and dilute acetic acid is added until no more precipitate forms. The acidified mixture is then heated on a hotplate until the resulting gel turns into a finely divided solid, which is finally filtered off. The 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid thus obtained has a melting point of 239.5-241 °C.

Example 158:

Ethyl {4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl] butyrate)

1.5 g of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine are dissolved in 30 ml of N,N-dimethylformamide, then 0.22 g of 60% sodium hydride dispersed in mineral oil is added to the solution, then 1.08 g of ethyl-(4-bromobutyrate) dissolved in 15 ml of N,N-dimethylformamide is added. By carrying out the reaction and working up the reaction mixture as described in Example 95, ethyl-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-butyrate] is obtained, the melting point of which is: 104-104.5 °C.

Example 159:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetamide

In the same manner as in Example 97, 1.0 g of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added to 50 ml of N,N-dimethylformamide with 1.032 g of 60%, dispersed in mineral oil.

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195 g of sodium hydride and 0.5 g of 2-bromoacetamide can be reacted. After working up the reaction mixture, the solid crude product is recrystallized from isopropyl alcohol. The thus obtained 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-acetamide has a melting point of 232-233 °C.

Example 160:

2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropionic acid

200 mg of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine are dissolved in 1.5 ml of 3,4,5,6-tetrahydro-1,3-dimethyl-2(1H)-pyrimidinone while stirring, 0.158 g of sodium hydroxide are added to the solution at room temperature, the mixture is allowed to stir for another 15 minutes, then 0.5 g of 2-bromo-2-methylpropionic acid amide is added. The reaction mixture is then stirred vigorously for 18 hours in the absence of moisture, then another 0.15 g of 2-bromo-2-methylpropionic acid amide is added, and stirring is continued for another 24 hours. After the reaction time, the mixture is diluted with 3 ml of water and the pH is adjusted to 0 with 5 M hydrochloric acid. 60 ml of water are added to the resulting suspension, the mixture is then left to stand for 18 hours, then the solid precipitate is filtered off, washed thoroughly with water and finally dried in a high vacuum at 50 °C. The product is purified by preparative reverse phase high pressure liquid chromatography, the appropriate fractions are combined, extracted with methylene dichloride and the organic solvent extract is evaporated. The melting point of the 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropionic acid amide thus obtained is: 227-228 °C.

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196

Example 161:

4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)ethyl]butyric acid

A mixture of 100 mg of ethyl-{2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-butyrate], 30 ml of methanol and 0.6 ml of 2-(dimethylamino)ethylamine was refluxed for 18 hours and then evaporated in vacuo. 10 ml of 2-(dimethylamino)ethylamine was added to the evaporation residue, the mixture was heated on a steam bath for 18 hours, then the excess amine was evaporated in vacuo. Water was added to the remaining crude product and the 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[2-(dimethylamino)ethyl]-butyric acid amide was filtered off.

Examples 162-164:

Examples 162, 163 and 164 were prepared by reacting the same ester with the appropriate amine as described in Example 108.

Example 165:

4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-[3-(1-imidazolyl)propyl]butyric acid amide

The title compound was prepared from 3-(1-imidazolyl)propylamine.

Example 166:

4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholinoethyl)butyric acid amide

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197

The title compound is prepared from 2-morpholinoethylamine.

Example 167:

4-[4-Amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(3-morpholinopropyl)-butyric acid

The title compound is prepared from 3-morpholinopropylamine.

Preparation of starting compounds:

a) 1-(tert-Butyl)-3-cyano-4-(4-phenoxyphenyl)-2-pyrrolamine

2.7 g of 2-bromo-4'-phenoxyacetophenone prepared by bromination of 4'-phenoxyacetophenone as described in the literature [Tetrahedron Letters 34, 3177 (1993)] were dissolved in isopropyl alcohol, and 15 ml of tert-butylamine were added with stirring. The mixture was heated to 80 °C, kept at this temperature for 3 hours, then cooled to 0 °C and 10 ml of concentrated hydrochloric acid were added. The suspension was stirred at room temperature for 18 hours, and the solid was filtered off to give 3.75 g of 2-[(tert-butyl)amino]-4'-phenoxyacetophenone hydrochloride. The product had a melting point of 210-212 °C.

93 mg of sodium metal are dissolved in 100 ml of ethanol, 3.75 g of 2-[(tert-butyl)-amino]-4'-phenoxyacetophenone hydrochloride are added in a single portion, and the mixture is stirred under nitrogen at 40 °C for 30 minutes. Meanwhile, in another flask, 331 mg of sodium metal are dissolved in 50 ml of ethanol, then 858 mg of malononitrile are added, and the mixture is left to stir for 5 minutes. After that, the

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198 without the precipitated sodium chloride, the ethanolic solution of 2-[(tert-butyl)-amino]-4'-phenoxyacetophenone obtained as described above is added in one portion, the reaction mixture is stirred for 3 hours at 50 °C, then for 2 hours at 80 °C, then the solvent is evaporated in vacuo. The evaporation residue is partitioned between water and ethyl acetate, then the organic phase is separated, dried and evaporated. The remaining black solid is dissolved in hot ethanol, then triturated with water, filtered and dried. The product thus obtained is the title compound.

b) 7-(tert-Butyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine

A mixture of 1.9 g of 1-(tert-butyl)-3-cyano-4-(4-phenoxyphenyl)-2-pyrrolamine, 30 ml of formamide and 10 mg of 4-(dimethylamino)pyridine was reacted at 180 °C for 6 hours, then cooled to room temperature and mixed with water. The dark solid that separated was filtered off, washed with water, then ethanol was added, the mixture was boiled and filtered hot. The filtered crude product was purified by preparative high-pressure liquid chromatography on a silica gel column using a 98:1:1 mixture of methylene chloride, isopropyl alcohol and ethanol as the mobile phase. The product thus obtained is 7-(tert-butyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine, or as used herein, 4-amino-7-(tert-butyl)-5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, with a melting point of 157-158 °C. ^x H-NMR spectrum (DMSO-d ₆ , δ): 8.15 (1H, s) ; 7.50-7.35 (4H, m) ; 7.30 (1H, s) ; 7.15 (1H, t) ; 7.10 (4H, m) ; 6.05 (2H, broad s) ; 1.75 (9H, s).

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199 :.................

* · · · · » ··· ·· ·

c) 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 5.8 g of 7-(tert-butyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 55 ml of concentrated anhydrous acetic acid and 55 ml of 48% aqueous hydrogen bromide solution was refluxed under nitrogen for 18 hours and then allowed to cool to room temperature. The solid was filtered off, washed with methanol and diethyl ether to give 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine hydrobromide, m.p. 288-292 °C. The hydrobromide salt is converted to the free base by stirring in a mixture of 100 ml of 5% w/w sodium hydroxide solution and 60 ml of ethanol with warm stirring, then the ethanol is evaporated and the aqueous residue is cooled. The solid product is filtered off and washed thoroughly with water to give 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point: 272 °C.

Example 168:

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

1.0 g of 5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 30 ml of anhydrous N,N-dimethylformamide, and 0.132 g of 60% sodium hydride dispersed in mineral oil was added to the solution under nitrogen gas with stirring. The reaction mixture was stirred for 30 minutes, and then a solution of 0.558 g of cyclopentanesulfonyl chloride prepared as described in the literature [see J.O.C. 17, 1529-1533 (1952)] in 5 ml of anhydrous N,N-dimethylformamide was added dropwise. The reaction mixture was stirred for 72 hours.

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The mixture is allowed to stand for 200 minutes, then evaporated in vacuo and the residue is triturated with water. The solid is filtered off, washed thoroughly with water, then stirred with ethyl acetate and the suspension is filtered. The filtrate is purified by flash chromatography on silica gel, eluting the column with ethyl acetate, then the appropriate fractions are combined and the solvent is evaporated. The 7-(cyclopentylsulfonyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine thus obtained has a melting point of 188-188.5 °C.

Example 169:

5-(4-Phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

906 mg of 5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in 30 ml of anhydrous N,N-dimethylformamide and 120 mg of 60% sodium hydride dispersed in mineral oil were added to the solution under nitrogen gas, while stirring. The reaction mixture was stirred for 30 minutes under nitrogen gas atmosphere, then a solution of 1.4 g of N-(8-bromooctyl)phthalimide in 5 ml of anhydrous N,N-dimethylformamide was added. The reaction mixture was stirred at room temperature under nitrogen gas for 18 hours, then partitioned between water and ethyl acetate. The organic phase was separated and the crude product was purified by flash chromatography on silica gel, eluting the column with ethyl acetate. The melting point of the thus obtained 5-(4-phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is 85-86°C.

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201

Example 170:

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

A mixture of 1.0 g of 5-(4-phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 1.0 ml of hydrazine hydrate and 40 ml of ethanol was refluxed for 2 hours in the absence of carbon dioxide and then cooled for 18 hours. The solid that separated was filtered off and set aside, the filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was dried and then concentrated hydrochloric acid in isopropyl alcohol was added dropwise until a precipitate was observed. The mixture was then left to stand overnight, the next day the supernatant was decanted and the semi-solid residue was triturated with ethyl acetate. The product thus obtained is 7-(8-aminooctyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride dihydrate, melting point: 120°C.

Example 171:

N-{2-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin7-yl]ethyl)phthalimide

In a similar manner to Example 468, but without the additional 3 hours of post-reaction at 90°C, 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was reacted with N-(2-bromoethyl)phthalimide. The resulting N-{2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]phthalimide had a melting point of 111-112°C.

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202

Example 172:

7-(2-Aminoethyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride

In a manner similar to that given in Example 469, the compound obtained as described in Example 171 was reacted with hydrazine hydrate. The thus prepared 7-(2-aminoethyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride had a melting point of 284-285 °C.

173, example:

5-(4-Phenoxyphenyl)-7-isobutyryl-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride

4.32 g of 5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine are dissolved together with 2 ml of anhydrous pyridine in 200 ml of anhydrous N,N-dimethylformamide, and 1.8 g of isobutyryl chloride are added dropwise to the solution under nitrogen gas, while stirring, at 20 °C. The reaction mixture is stirred for 1 hour at room temperature, then evaporated in vacuo, and the evaporation residue is partitioned between water and ethyl acetate. The organic phase is separated, dried, the solvent is evaporated, and the remaining crude product is recrystallized from toluene. The thus obtained 5-(4-phenoxyphenyl)-7-isobutyryl-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride has a melting point of 160.5-161°C.

Example 174:

7-(1,4-Dioxa-spiro[4.5]decan-8-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

1.94 g of 5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

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203 ..................

• · · « « · •·· · · ·»· ·· ·· · ♦ t * • * · · · ο* *« is dissolved in 50 ml of N,N-dimethylformamide, and 0.26 g of 60% sodium hydride dispersed in mineral oil is added to the solution at room temperature while stirring. The reaction mixture is stirred until the evolution of hydrogen gas ceases, then 2.0 g of U.S. (1, 4-dioxa-spiro[4.5] decan-8-yl)-(4-toluenesulfonate) prepared from 1,4-dioxa-spiro[4.5] decan-8-one [for preparation see J. Med. Chem. 1992, 2246] is added, and stirring is continued at 120 °C under nitrogen for a further 5 hours. The reaction mixture is then cooled to room temperature, quenched with water, and the aqueous mixture is extracted with ethyl acetate. The resulting evaporation residue is purified by flash chromatography on silica gel, eluting the column with ethyl acetate containing methanol in increasing proportions from 0% to 6%. The product is 7-(1,4-dioxa-spiro[4.5]decan-8-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point: 193-194 °C.

Example 175:

4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone

A mixture of 500 mg of the compound prepared as described in Example 174, 20 ml of acetone and 10 ml of 3 M hydrochloric acid was stirred under nitrogen for 20 minutes at room temperature and then for 1 hour at 60 °C. The acetone was then evaporated in vacuo and the evaporation residue was basified with 5 M aqueous sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate and the solid residue thus obtained was triturated with diethyl ether. The product

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204 is filtered off to give 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone, melting point 252-254°C.

Examples 176 and 177:

cis-5-(4-Phenoxyphenyl)-7-(4-morpholinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-(4-morpholinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a mixture of 120 mg of the compound prepared as described in Example 175, 31 mg of morpholine and ethylene dichloride were added 42 mg of sodium [triacetoxyhydridoborate] and 18 mg of concentrated anhydrous acetic acid. The mixture was stirred at 40 °C for 2 hours, then another 0.15 g of morpholine and 0.21 g of sodium [triacetoxyhydridoborate] were added. The reaction mixture was allowed to stir at room temperature for 20 hours, then quenched with saturated aqueous sodium bicarbonate solution and filtered through an EMPORE® filter pad. The filtrate was extracted with 3M hydrochloric acid, then the acidic extract was basified with 5M sodium hydroxide solution and the product was extracted with methylene dichloride. The distillation residue of the extract is purified by chromatography on silica gel, resulting in the products cis-5-(4-phenoxyphenyl)-7-(4-morpholinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-phenoxyphenyl)-7-(4-morpholinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

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205

Examples 178 and 179:

cis-7-{4-[4-(Ethoxycarbonyl)piperazin-1-yl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-7-{4-[4-(Ethoxycarbonyl)piperazin-1-yl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as described in Examples 176 and 177, 0.4 g (1.0 g of 40% pure material) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone was reacted with 158 mg of 1-(ethoxycarbonyl)piperazine in the presence of 296 mg of sodium [triacetoxyhydridoborate] in 15 ml of methylene chloride containing 60 mg of concentrated anhydrous acetic acid. After working up the reaction mixture, the crude product was purified by chromatography to give cis-7-{4-[4-(ethoxycarbonyl)piperazin-1-yl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-7-{4-[4-(ethoxycarbonyl)piperazin-1-yl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

Example 180:

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

906 mg of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine in 30 ml of N,N-dimethylformamide, in the presence of 150 mg of sodium hydride, at 100 °C, for 5 hours, are reacted with 510 mg of 2-chloronicotinonitrile, thus working up the reaction mixture, 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-pyridine-3-carbonitrile is obtained. The melting point of the product: 242-242.5 °C.

72.227/BE

206 ;.....-...... ..

·· * · · * · ·<** *♦/ ·«·* *'*

181, example:

7-[3-(Aminomethyl)pyridin-2-yl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminodimaleate

468 mg of the compound prepared as described in Example 180, 200 ml of ammonia-saturated ethanol and 2 ml of Raney®-nickel are weighed out, and the mixture is shaken under a hydrogen atmosphere of 26 bar at 80 °C for 6 hours. The mixture is then left to stand at room temperature for 68 hours, then filtered and the filter is thoroughly washed with ethanol. The filtrate is evaporated in vacuo, the distillation residue is taken up in ethyl acetate, filtered and a solution of 135 mg of maleic acid in 20 ml of ethyl acetate is added to the filtrate in small portions until no more precipitate forms. The mixture is then heated, the liquid is decanted from the small amount of residual gum, and the gum is extracted hot with another portion of ethyl acetate and the solution is decanted again. The combined organic solvent extracts were cooled and the solid precipitated from the solution was collected on a filter. The resulting 7-[3-(aminomethyl)pyridin-2-yl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate had a melting point of 131-134 °C.

Example 182:

3-[4-Amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-aza-bicyclo[3.2.1]octane

To a mixture of 770 mg of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 30 ml of Ν,Ν-dimethylformamide, 268 mg of 60% sodium hydroxide dispersed in mineral oil were first added under a nitrogen atmosphere.

72.227/BE

207 »·»'»·-«·»*«·*., «« ··· . . J

-hydrate, then 900 mg of 3-[(methylsulfonyl)-oxy]-8-methyl-1-8-aza-bicyclo[3.2.1]octane prepared as described in the literature [see J.A.C.S. 80, 4679 (1958)] are added. The reaction mixture is stirred for 5 hours at 75 °C, then left to stand at room temperature for 7 days. The solvent is then evaporated in vacuo, water is added to the evaporation residue, and the aqueous mixture is extracted with ethyl acetate. The residue thus obtained is purified by flash chromatography on silica gel, eluting the column with a 1:1 mixture of ethyl acetate and methanol to remove the starting compound, then with a 5:1:1 mixture of ethyl acetate, methanol and triethylamine. The appropriate fractions were evaporated, the remaining solid was triturated with diethyl ether and filtered to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane, m.p. 238-250 °C.

Examples 183 and 184:

cis-5-(4-Phenoxyphenyl)-7-[4-(N-methylhomopiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-[4-(N-methylhomopiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In the same manner as described in Examples 176 and 177, 0.4 g (1.0 g of 40% purity) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone was reacted with 114 mg of N-methylhomopiperazine in the presence of 296 mg of sodium [triacetoxyhydridoborate] in 15 ml of methylene chloride containing 60 mg of concentrated anhydrous acetic acid. The reaction mixture was filtered72,227/BE

208 ·>»*··*··»·· w·»» ·_ · * * * · • · * _ · · »p w , * ♦ · * ♦ * ·'- <*r »» * are added, the filtrate is evaporated, and the distillation residue is purified by chromatography on silica gel, as a result of which cis-5- (4-phenoxyphenyl)-7-[4-(N-methyl-homopiperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5- (4-phenoxyphenyl)-7-[4-(N-methyl-homopiperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]-pyrimidin-4-amine are obtained as products.

Examples 185 and 186:

cis-5-(4-Phenoxyphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The same amounts of reagents and cyclohexanone derivative as those given in Examples 183 and 184 were reacted with 100 mg of 1-methylpiperazine according to the procedure described therein to give cis-5-(4-phenoxyphenyl)-7-[4-(N-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-phenoxyphenyl)-7-[4-(N-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine as products.

Example 187:

3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanone

A mixture of 100 mg of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol, 500 mg of activated manganese dioxide and 100 ml of methylene dichloride was stirred at room temperature for 18 hours, then filtered, and the filtrate, which contained 3-[4-amino-5-

72,227/IN

9 ·»·»········ »^| ·**. . · · · »·· • · · * 9 4 _<W * _L> *

- A solution containing (4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanone is used directly for the reaction step described in the following example.

Example 188:

cis-5-(4-Phenoxyphenyl)-7-(3-morpholinocyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-(3-morpholinocyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To the solution obtained as described in Example 187, 45 mg of morpholine, 151 mg of sodium triacetoxyhydridoborate and 47 mg of concentrated anhydrous acetic acid were added. The mixture was stirred under nitrogen at room temperature for 18 hours, then the methylene chloride was evaporated. 100 ml of tetrahydrofuran was added to the evaporation residue, stirring was continued for a further 8 hours, and the reaction mixture was worked up. The products thus obtained were cis-5-(4-phenoxyphenyl)-7-(3-morpholinocyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-phenoxyphenyl)-7-(3-morpholinocyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

Example 189:

{3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[N-(2-morpholinoethyl)-carbamate]-hydrochloride mg 3-} 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentanol is dissolved in 1 ml of methylene chloride, 7 ml of N-methylmorpholine is added to the solution at 0 °C, and the mixture is allowed to stir for 20 minutes. The cooling bath is then removed.72.227/BE

210

P02 405, is removed, 12.5 mg of (4-nitrophenyl)-(chloroformate) is added to the mixture, then stirring is continued overnight at room temperature. The next day, the reaction mixture is diluted with methylene chloride, washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, then the organic phase is dried over magnesium sulfate and evaporated.

To the above crude product, 2 ml of methylene chloride and 0.2 ml of 2-morpholinoethylamine were added, and the mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, and the organic phase was dried, filtered and evaporated. The remaining crude product was purified by preparative high-pressure liquid chromatography to give {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-[N-(2-morpholinoethyl)carbamate].

The product obtained in the above manner was dissolved in 2 ml of ethyl acetate, hydrogen chloride gas was bubbled through the solution for 2 minutes, and the precipitated mixture was allowed to stir for a further 10 minutes. The solvent was then evaporated and the remaining solid was dissolved in water. The aqueous solution was lyophilized to give {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-[N-(2-morpholinoethyl)carbamate] as a solid product.

Example 190:

{3-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl}-(2-aminoacetate) hydrochloride

a) {3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]-cyclopentyl}-[2-{[(tert-butoxy)-carbonyl]-amino]-acetate]

72.227/BE

To a mixture of 211 mg (0.129 mmol) of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol, 34 mg (0.194 mmol) of N-[(tert-butoxy)carbonyl]glycine and 1 ml of N,N-dimethylformamide were added 31 mg (0.155 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 16 mg (0.129 mmol) of 4-(dimethylamino)pyridine. The reaction mixture was stirred under nitrogen at room temperature for 24 hours, then poured into ice water and the aqueous mixture was extracted with ethyl acetate. The organic solvent extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The solid residue was purified by chromatography on silica gel, eluting with ethyl acetate, to give the title compound, the structure of which was confirmed by ¹ H-NMR spectrum.

b) {3-[4-Amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]-cyclopentyl}-(2-aminoacetate) hydrochloride mg (0.072 mmol) {3-[4-amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[2-{[(tert-butoxy)carbonyl]-amino}-acetate] was dissolved in 2.5 ml of ethyl acetate and hydrogen chloride gas was bubbled through the solution for 1 min. The flask was then sealed, the solution was allowed to stir for a further 30 min, and diethyl ether was added, resulting in a precipitate. The solid was filtered off to give {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo}2,3-d]pyrimidin-7-yl]cyclopentyl}-(2-aminoacetate) hydrochloride, the structure of which was confirmed by ¹ H-NMR spectrum. Mass spectrum (LC-MS): MH ⁺ = 444. 72.227/BE

212

Example 191:

{3-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl}-[(2S)-2-amino-3-methylbutyrate] hydrochloride

a) To a solution of {3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl)-[(2S)-2-{[(tert-butoxy)carbonyl]-amino)-butyrate] mg (0.171 mmol) of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentanol in 1 ml of methylene chloride, 114 mg (0.362 mmol) of [(2S)—2—{[(tert-butoxy)carbonyl]-amino}-2-methylbutyric acid—2,5-dihydro-2,5-dioxo-1H-1-pyrrolecarboxylic acid] anhydride was added, and the mixture was stirred for 24 hours under nitrogen at room temperature, then with ethyl acetate diluted, washed, dried over magnesium sulfate, filtered and evaporated. The solid residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, to give the title compound, the structure of which was confirmed by ¹ H-NMR. Mass spectrum (LC-MS): MH ⁺ = 586.

b) 3-[4-Amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]-cyclopentyl}-[(2S)-2-amino-3-methyl-butyrate]-hydrochloride mg (0.060 mmol) {3-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2, 3-d]pyrimidin-7-yl]-cyclopentyl}-[(2S)-2-{[(tert-butoxy)-carbonyl]-amino}-butyrate]- was dissolved in 2.5 ml of ethyl acetate and hydrogen chloride gas was bubbled through the solution for 5 min. The flask was then sealed, the solution was allowed to stir for a further 30 min, and diethyl ether was added, resulting in a precipitate. The solid was filtered off,

72.227/BE

213 ..................

··· · · · · · · *·· · · ·* ·· «« we obtain {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-[(2S)-2-amino-3-methylbutyrate) hydrochloride, the structure of which is confirmed by the ^-NMR spectrum.

Mass spectrum (LC-MS): MH ⁺ = 486.

Example 192:

{3-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl)-[N-(2-morpholinoethyl)carbamate] hydrochloride

a) (3-[4-Amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]cyclopentyl}-(4-nitrophenyl)carbonate

12.5 g (0.062 mmol) of (4-nitrophenyl)-(chloroformate) were dissolved in 1 ml of methylene chloride and 0.007 ml (0.062 mmol) of N-methylmorpholine were added dropwise with stirring at 0 °C under nitrogen. After 20 min, the ice-water bath was removed, the reaction mixture was allowed to warm to room temperature, 20 mg (0.052 mmol) of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol were added and stirring was continued for another 24 h. The mixture was then diluted with methylene chloride, washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound, the structure of which was confirmed by ¹ H-NMR.

b) (3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-[N-(2-morpholinoethyl)carbamate]

0.052 g {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-(4-nitrophenyl)carbonate and 1 ml methylene72.227/BE

214

-dichloride mixture was added with 0.2 ml of 2-morpholinoethylamine, then the mixture was stirred for 24 hours under nitrogen at room temperature. The reaction mixture was then diluted with ethyl acetate, washed, and the organic phase was dried over magnesium sulfate, filtered and evaporated. The remaining crude product was purified by preparative high-pressure liquid chromatography, the product thus obtained was {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl}-[N-(2-morpholinoethyl)carbamate]. The structure was confirmed by the ^-NMR spectrum. Mass spectrum (LC-MS): MH ⁺ = 543.

c) {3-[4-Amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]-cyclopentyl}-[N-(2-morpholinoethyl)-carbamate]-hydrochloride mg {3-[4-amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[N-(2-morpholinoethyl)-carbamate]-hydrochloride was dissolved in 2.5 ml of ethyl acetate, hydrogen chloride gas was bubbled through the solution for 2 minutes, and the precipitated mixture was allowed to stir for a further 10 minutes. The solid product was then filtered off to give {3-[4-amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[N-(2-morpholinoethyl)-carbamate]-hydrochloride. The structure was confirmed by the ¹ H-NMR spectrum. Mass spectrum (LC-MS): MH ⁺ = 543.

Preparation of starting compounds:

a) 12.7 g of 1-(tert-Butyl)-3-cyano-4-(4-phenoxyphenyl)-2-pyrrolamine, prepared by bromination of 4'-phenoxyacetophenone as described in the literature [Tetrahedron Letters 34, 3177 (1993)], is dissolved in isopropyl alcohol,

72.227/BE

215 then 15 ml of tert-butylamine are added with stirring. The mixture is heated to 80 °C and kept at this temperature for 3 hours, then cooled to 0 °C and 10 ml of concentrated hydrochloric acid are added. The suspension is stirred at room temperature for 18 hours, then the solid is filtered off, thus obtaining 3.75 g of 2-[(tert-butyl)-amino]-4'-phenoxyacetophenone hydrochloride. The melting point of the product: 210-212 °C.

93 mg of sodium metal is dissolved in 100 ml of ethanol, 3.75 g of 2-[(tert-butyl)-amino]-4'-phenoxyacetophenone hydrochloride is added in a single portion, and the mixture is stirred under nitrogen at 40 °C for 30 minutes. Meanwhile, in another flask, 331 mg of sodium metal is dissolved in 50 ml of ethanol, then 858 mg of malononitrile is added, and the mixture is left to stir for 5 minutes. After that, the ethanolic 2-[(tert-butyl)-amino]-4'-phenoxyacetophenone solution obtained as described above is added in a single portion, without the separated sodium chloride, the reaction mixture is stirred for 3 hours at 50 °C, then for 2 hours at 80 °C, and then the solvent is evaporated in vacuo. The residue was partitioned between water and ethyl acetate, the organic phase was separated, dried and evaporated. The remaining black solid was dissolved in hot ethanol, triturated with water, filtered and dried to give the title compound.

b) 7-(tert-Butyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of 1.9 g of 1-(tert-butyl)-3-cyano-4-(4-phenoxyphenyl)-2-pyrrolamine, 30 ml of formamide and 10 mg of 4-(dimethylamino)pyridine was reacted at 180 °C for 6 hours, then cooled to room temperature.

72.227/BE

216 is cooled and mixed with water. The separated dark solid is filtered off, washed with water, then ethanol is added, the mixture is boiled and filtered hot. The filtered crude product is purified by preparative high-pressure liquid chromatography on a column packed with silica gel, using a 98:1:1 mixture of methylene dichloride, isopropyl alcohol and ethanol as the mobile phase. The product thus obtained is 7-(tert-butyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3d]-pyrimidin-4-amine, or as used herein, 4-amino-7-(tert-butyl)-5-(phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, whose melting point is: 157-158 °C.

H-NMR spectrum (DMSO-d ₆ , δ): 8.15 (1H, s); 7.50-7.35 (4H, m); 7.30 (1H, s); 7.15 (1H, t); 7.10 (4H, m); 6.05 (2H, broad s); 1.75 (9H, s).

c) 5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of 5.8 g of 7-(tert-butyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 55 ml of concentrated anhydrous acetic acid and 55 ml of 48% aqueous hydrogen bromide solution was refluxed under nitrogen for 18 hours and then allowed to cool to room temperature. The solid was filtered off, washed with methanol and diethyl ether to give 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine hydrobromide, m.p. 288-292 °C. The hydrobromide salt is converted to the free base by stirring in a mixture of 100 ml of 5% w/w sodium hydroxide solution and 60 ml of ethanol with warm stirring, then the ethanol is evaporated and the aqueous residue is cooled. The solid product is filtered off and washed thoroughly with water to give 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

72.227/BE

217

d) 4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-cyclopentenol

A mixture of 600 mg of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 40 ml of [tetrakis(triphenylphosphine)palladium(0)] and 30 ml of anhydrous dimethyl sulfoxide is stirred under nitrogen gas, immersed in an ice-water bath, and a solution of 200 mg of cyclopentadiene monoepoxide in 10 ml of tetrahydrofuran is added using a syringe, while maintaining the temperature at 0 °C. The reaction mixture is then allowed to stir at room temperature for a further 66 hours, protected from light, and the tetrahydrofuran is then evaporated in vacuo. Water is added to the evaporation residue, the aqueous mixture is allowed to stand for 18 hours, and then extracted with ethyl acetate. The crude product was purified by flash chromatography on silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol-denatured industrial ethanol. The oil thus obtained was the title compound, the structure confirmed by ¹ H-NMR and mass spectra.

e) 4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol

110 mg of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-cyclopentenol in 20 ml of ethanol were hydrogenated in the presence of 50 mg of 10% palladium-on-carbon catalyst at atmospheric pressure, the catalyst was filtered off and the filtrate was evaporated. In this way, the title compound was obtained, the structure of which was confirmed by the 1 H NMR spectrum and the mass spectrum.

72.227/BE

218

Example 193:

cis-5-(4-Phenoxyphenyl)-7-[4-(1-pyrrolidinyl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-[4-(1-pyrrolidinyl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2.34 g (5.9 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone were suspended in 250 ml of ethylene dichloride, 1.25 g (17.6 mmol) of pyrrolidine and 1.00 ml (17.6 mmol) of concentrated anhydrous acetic acid were added to the suspension under nitrogen gas atmosphere, and the mixture was stirred for 30 minutes at room temperature. Then, 1.87 g (8.8 mmol) of sodium [triacetoxyhydridoborate] was added in a single portion to the mixture, and stirring was continued for 70 hours. After the reaction time, the mixture was extracted twice with 200 ml of 2 M aqueous hydrochloric acid, the combined acidic extract was washed with 300 ml of methylene chloride, basified with 12.5 M aqueous sodium hydroxide solution, and the product was extracted again with 3 times 200 ml of methylene chloride. The combined organic solvent extract was dried over sodium sulfate, and the crude product was purified by chromatography on a Biotage 40S column, eluting with a mixture of ethyl acetate and triethylamine (95:5) and ethyl acetate, triethylamine and methanol (85:10:5), to give two products.

Cis-5-(4-phenoxyphenyl)-7-[4-(l-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine is an off-white solid, weight 0.65 g (1.4 mmol), melting point: 101-104 °C, liquid chromatography (LC-MS) retention time 3.56 min 72.227/BE

219 • •4 r * »*-* * · w 9 * * ·· • * · 7 ·-·. 7·· (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution— —acetonitrile, 10%-100% acetonitrile over 8 min).

Mass spectrum (LC-MS): MH ⁺ = 454.

Trans-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine is an off-white solid, mass 0.93 g (2.1 mmol), melting point 183-185 °C, liquid chromatography (LC-MS) retention time 3.68 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution—acetonitrile, 10%-100% acetonitrile over 8 min). Mass spectrum (LC-MS): MH ⁺ = 454.

Example 194:

cis-5-(4-Phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and trans-5-(4-Phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2.34 g (5.9 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone were suspended in 250 ml of ethylene dichloride, 1.50 g (17.6 mmol) of piperidine and 1.00 ml (17.6 mmol) of concentrated, anhydrous acetic acid were added to the suspension under nitrogen gas atmosphere, and the mixture was stirred for 30 minutes at room temperature. Then 1.87 g (8.8 mmol) of sodium [triacetoxyhydridoborate] was added in a single portion to the mixture, and stirring was continued for 70 hours. After the reaction, the mixture was extracted twice with 200 ml of 2 M aqueous hydrochloric acid, then the combined acid extract was washed with 300 ml of methylene chloride, dried with 12.5 M aqueous sodium hydroxide solution, and dried over 1000 ml of water.

220

The mixture was basified and the product was re-extracted with three 200 mL portions of methylene chloride. The combined organic extracts were dried over sodium sulfate and the crude product was purified by chromatography on a Biotage 40S column, eluting with a 95:5 mixture of ethyl acetate and triethylamine, to give the two title products.

Cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is a water-clear oil, weighing 0.23 g, with a liquid chromatography (LC-MS) retention time of 3.67 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution—acetonitrile, 10%-100% acetonitrile over 8 min). Mass spectrum (LC-MS): MH ⁺ = 468.

Trans-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is an off-white solid, mass 193 mg (0.4 mmol), melting point 192-195 °C, liquid chromatography (LC-MS) retention time 3.71 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution—acetonitrile, 10%-100% over 8 min). Mass spectrum (LC-MS): MH ⁺ = 468.

Example 195:

cis-5-(4-Phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride cis-5-(4-Phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7Hpyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 50 ml of ethyl acetate, the solution is diluted with 50 ml of diethyl ether, then 1 M diethyl ether hydrogen chloride solution is added until no more

72.227/BE

221 several precipitates are formed. The resulting solid is filtered off and recrystallized from anhydrous ethanol. 75 mg (0.2 mmol) of cis-5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride is thus obtained, melting point: 185-189 °C.

Example 196:

trans-7-[4-(Dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-

- 7H-pyrrolo[2,3-d]pyrimidine-4-amine cis-7-[4-(Dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3.24 g (8.1 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone were dissolved in 1000 ml of methylene chloride, 1.20 g (12.0 mmol) of N-methylpiperazine and 0.69 ml (12.0 mmol) of concentrated, anhydrous acetic acid were added to the solution under stirring under nitrogen, and the mixture was stirred for 10 minutes at room temperature. Then 1.70 g (8.0 mmol) of sodium [triacetoxyhydridoborate] was added in a single portion to the mixture, and stirring was continued for 6 hours. After that, the addition of the reagents was repeated in the same amounts, and the reaction mixture was stirred for another 70 hours. After the reaction, the mixture was extracted twice with 300 ml of 2 M aqueous hydrochloric acid, then the combined acidic extract was washed with 300 ml of methylene dichloride, then alkalized with 0.880 aqueous ammonia solution, and the product was extracted three times with 250 ml of methylene dichloride. The combined organic solvent extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate

72.227/BE

222 and the crude product was purified by chromatography on a Biotage 40M column, eluting with a 95:5 mixture of ethyl acetate and triethylamine, to give cis-7-[(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as an off-white solid, 220 mg (0.5 mmol), mp 180-182 °C, LC-MS retention time 3.43 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate-acetonitrile,

10%-100% acetonitrile in 8 minutes).

Mass spectrum (LC-MS): MH ⁺ = 428.

The column was then washed with a 4:1:1 mixture of ethyl acetate, methanol and triethylamine (500 ml) and the solution was evaporated in vacuo. The residue was dissolved in 200 ml of methylene chloride and purified by chromatography on a Biotage 40M column, starting with a 9:1 mixture of methylene chloride and methanol and ending with a 7:3 mixture. The resulting trans-7-[(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is an off-white solid, weighing 320 mg (0.75 mmol), melting point: 207.5-210 °C, liquid chromatography (LC-MS) retention time 3.48 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution—acetonitrile, 10%-100% acetonitrile over 8 min). Mass spectrum (LC-MS): MH ⁺ = 428.

Example 197:

(R)-(+)-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

72.227/BE

223 a? (S)-(3-Tetrahydrofuranyl)-(4-toluenesulfonate)

2.0 g (23 mmol) of (S)-3-hydroxytetrahydrofuran were dissolved in 40 ml of pyridine and 4.8 g (25 mmol) of 4-toluenesulfonyl chloride were added in small portions at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and then overnight at room temperature, and the pyridine was evaporated in vacuo. The evaporation residue was partitioned between 200 ml of ethyl acetate and 200 ml of saturated aqueous citric acid solution, the aqueous portion was extracted twice with 200 ml of ethyl acetate, then the combined organic solvent extracts were dried over sodium sulfate, filtered and evaporated. The title compound was obtained as an oil (4.5 g), yield 85%. 3-NMR spectrum (CDCl ₃ , 250 MHz, δ): 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).

b) (R)-(+)-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7R-pyrrolo[2,3-d]pyrimidin-4-amine

4.83 g (16 mmol) of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine are suspended in 80 ml of N,N-dimethylformamide under nitrogen gas, 0.75 g of 60% sodium hydride dispersed in mineral oil are added to the suspension while stirring, then the reaction mixture is allowed to stir for 30 minutes at room temperature. Subsequently, a solution of 4.20 g (18 mmol) of (S)-(3-tetrahydrofuranyl)-(4-toluenesulfonate) in 20 ml of N,N-dimethylformamide is added in 2 ml portions to the resulting dark solution, and the reaction mixture is stirred for 30 minutes at room temperature and then for 18 hours at 95 °C. After the reaction time, the mixture was allowed to cool to room temperature, then poured into 200 ml of ice water, and the aqueous portion was extracted three times with 200 ml of ethyl acetate. The combined

72.227/BE

224 ....................

··· · · · · ·· · ·· · ·* ·· ·♦ The organic solvent extract is washed four times with 150 ml of water, dried over sodium sulfate, and finally the solvent is evaporated in vacuo. The evaporation residue is heated with 1000 ml of methylene chloride until a solution is formed, then cooled to room temperature and purified by chromatography on a Biotage 40M column, eluting the column first with a 95:5 mixture of ethyl acetate and triethylamine, then with a 90:5:5 mixture of ethyl acetate, triethylamine and methanol. The thus obtained 4.35 g (12 mmol) of off-white solid is (R)-(+)-5-(4-phenoxyphenyl)-7-(3-tetrahydrofuranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, melting point: 165-166 °C, liquid chromatography (LC-MS) retention time 4.44 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution—acetonitrile, 10%-100% acetonitrile over 8 min).

Mass spectrum (LC-MS): MH ⁺ = 373.

Hd ² ' ^{6 =} +20.5° ± 0.6° (methylene dichloride).

Example 198:

N-[(tert-Butoxy)carbonyl]piperidinol

10.0 g (50 mmol) of N-[(tert-butoxy)carbonyl]-piperidinone are dissolved in 100 ml of methanol and 1.9 g (50 mmol) of sodium [tetrahydridoborate] are added in small portions at 0 °C. The reaction mixture is stirred for 1 hour at 0 °C and then for 20 hours at room temperature, then quenched with 20 ml of 2 M sodium hydroxide solution and the solvent is evaporated. The evaporation residue is partitioned between 100 ml of ethyl acetate and 100 ml of water, then the aqueous phase is extracted three more times with 100 ml of ethyl acetate. The same72.227/BE

225 The combined organic solvent extract was washed with 100 ml of saturated sodium chloride solution and water, then dried over sodium sulfate, filtered and evaporated. The remaining 10.5 g of colorless oil was N-[(tert-butoxy)carbonyl]piperidinol, yield 100%. The product had a thin layer chromatography R _f value of 0.05 (20% ethyl acetate in hexane; KMnOJ .

Infrared spectrum (film): 3428, 2939, 1693 cm ^-1 .

Example 199:

(tert-Butyl)- [4-{[(4-tolyl)sulfonyl]oxy}-1-piperidinecarboxylate]

10.5 g (0.052 mol) of N-[(tert-butoxy)carbonyl]-piperidinol are dissolved in 150 ml of pyridine and 9.94 g (0.052 mol) of 4-toluenesulfonyl chloride are added in small portions at 0 °C under nitrogen. The reaction mixture is stirred at 0 °C for 2 hours, then allowed to warm to room temperature and stirred overnight. The next day the solvent is evaporated, the evaporation residue is partitioned between 100 ml of 1 M citric acid solution and 200 ml of ethyl acetate, then the aqueous phase is extracted with another 100 ml of ethyl acetate. The combined organic solvent extracts were washed twice with 100 ml of 1 M citric acid solution, 100 ml of saturated sodium chloride solution and 100 ml of water, then dried over sodium sulfate, filtered and evaporated. The residual oil was purified by flash chromatography on silica gel, eluting the column with a solvent mixture containing first 10% ethyl acetate and cyclohexane, then 15% ethyl acetate and cyclohexane. The resulting 11.0 g of white solid was (tert-butyl) -[ 4-{ [ (4-tolyl)72.227/BE

226

-sulfonyl]oxy}-1-piperidinecarboxylate] (F30-68), yield 60%. TLC R _f of the product: 0.17 (20% ethyl acetate in cyclohexane).

3-NMR spectrum (CDCl ₃ , 250 MHz, δ): 7.79 (2H, d); 7.34 (2H, d); 4.67 (1H, m); 3.58 (2H, m); 3.27 (2H, m); 2.45 (3H, s); 1.59-1.83 (4H, m); 1.43 (9H, s).

Example 200:

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

2.0 g (6.6 mmol) of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine were dissolved in 100 ml of N,N-dimethylformamide at 0 °C under nitrogen. 0.264 g (6.6 mmol) of 60% sodium hydride dispersed in mineral oil were added to the solution, the mixture was allowed to warm to room temperature. Stirring was continued for 1 hour, then 2.34 g (6.6 mmol) of (tert-butyl)-[4-{[(4-tolyl)sulfonyl]oxy}-1-piperidinecarboxylate] was added to the mixture, and stirring was continued at 95 °C for 72 hours. After the reaction time, 150 ml of water is carefully added, and the aqueous mixture is extracted three times with 100 ml of ethyl acetate. The combined organic solvent extracts are washed four times with 100 ml of water and twice with 100 ml of saturated sodium chloride solution, and finally the organic phase is dried over sodium sulfate, filtered and evaporated. The remaining solid is adsorbed onto silica gel and then purified by flash chromatography on silica gel, eluting the column first with ethyl acetate and then with a solvent mixture containing 5% methanol and ethyl acetate. 1.0 g of white,

72.227/BE

227 solid (tert-butyl)-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate] (F 13-22) , yield 31%. The product had a melting point of 168.5-169.5 °C, and a thin layer chromatography R _f value of 0.4 (10% ethyl acetate in methanol).

3-NMR spectrum (DMSO-d ₆ , 250 MHz, δ): 8.14 (1H, s); 7.38-7.49 (5H, m); 7.07-7.23 (5H, m); 6.14 (2H, broad s); 4.76 (1H, m); 4.11 (2H, m); 2.93 (2H, m); 1.92-2.02 (4H, m); 1.43 (9H, s).

Mass spectrum: _{C28H31O3N5 ( 485} , ₂₄₃₀ ).

Infrared spectrum (KBr): 3059, 1695, 1588, 1235 cm ^-1 .

Example 201:

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

To a solution of 0.069 g (1.4 mmol) of (tert-butyl)-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate} in 25 ml of anhydrous methylene chloride and cooled to 0 °C, 5 ml of trifluoroacetic acid were added. The mixture was allowed to stir at room temperature for 20 hours, then the solvent was evaporated and the evaporation residue was taken up in 10 ml of 5 M sodium hydroxide solution. The suspension thus obtained was extracted three times with 50 ml of ethyl acetate, and the organic solvent extract was washed with 50 ml of saturated sodium chloride solution, dried, filtered and evaporated. The remaining solid was triturated with diethyl ether and the product, 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (433258), was isolated by filtration. The white solid, melting at 209-211 °C, weighed 500 mg and had a thin layer chromatography R _f value of 0.1 (ethyl acetate:methanol =

72.227/BE

228

1:1), the yield is 91%.

¹ H-NMR spectrum (DMSO-d ₆ , 250 MHz, δ): 8.13 (1H, s); 7.36-7.48 (4H, m); 7.29 (1H, s); 7.04-7.16 (5H, m); 5.80 (2H, broad s); 4.64 (1H, m); 3.10 (2H, m); 2.80 (1H, broad s); 2.67 (2H, m); 1.94 (4H, m).

Mass spectrum: C ₂₃ H ₂₃ ON ₅ (385, 1902).

Infrared spectrum (KBr): 3278, 1620, 1585, 1490, 1245 cm ¹ .

Example 202:

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

200 mg of 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (433258) were dissolved in a 1:1 mixture of ethyl acetate and methanol (15 ml), and 3 ml of 1.0 M hydrogen chloride in diethyl ether were added. The precipitate was filtered off under a stream of nitrogen and then dried under vacuum for 6 hours. The resulting white solid, melting at 304 °C with decomposition, was 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (120 mg), containing 1.4 mol of bound water. 3-NMR spectrum (D ₂ O, 250 MHz, δ): 8.48 (1H, s); 7.69 (1H, s); 7.50-7.58 (4H, m); 7.18-7.34 (5H, m); 5.16 (1H, m); 3.81 (2H, d); 3.46 (2H, m); 2.49 (4H, m). Infrared spectrum (KBr): 3937, 1657, 1231 cm ¹ .

Example 203:

N-[(tert-Butoxy)carbonyl]pyrrolidin-3-ol

10.0 g (0.11 mol) of 3-pyrrolidinol is dissolved in 200 ml of methylene72.227/BE

229 ....................

* · 4 · *· ·· ··

-dichloride, and at 0 °C first 22.2 g (30.5 ml; 0.22 mol) of triethylamine are added to the solution, then 28.8 g (0.13 mol) of di (tert-butyl) dicarbonate are added. The reaction mixture is allowed to warm to room temperature, stirred overnight, then quenched with 150 ml of saturated, aqueous citric acid solution. The organic phase is washed with 100 ml of water, saturated sodium chloride solution and again with water, then dried over sodium sulfate, filtered and evaporated. The remaining 20.0 g of golden yellow oil is the crude product N-[(tert-butoxy)-carbonyl]-pyrrolidin-3-ol, the yield is 93%.

Example 204:

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

a) (tert-Butyl)-[4-{[(4-tolyl)sulfonyl]oxy)-1-pyrrolidinecarboxylate]

19.8 g (0.106 mol) of N-[(tert-butoxy)carbonyl]-pyrrolidin-3-ol are dissolved in 200 ml of pyridine and 22.3 g (0.117 mol) of 4-toluenesulfonyl chloride are added in small portions at 0 °C under nitrogen. The reaction mixture is stirred at 0 °C for 2 hours, then allowed to warm to room temperature and stirred overnight. The next day the pyridine is evaporated in vacuo, the evaporation residue is partitioned between 200 ml of 1 M citric acid solution and 200 ml of ethyl acetate, then the aqueous phase is extracted twice more with 200 ml of ethyl acetate. The combined organic solvent extracts were dried over sodium sulfate, filtered and evaporated, and the residual oil was purified by flash chromatography on silica gel, eluting with 10% ethyl acetate and cyclo72,227/BE.

The column was eluted with a solvent mixture containing 230 hexanes. The purified compound F40-85 was an oil, which was dissolved in a 5:1 mixture of cyclohexane and diethyl ether (50 ml), then crystallization was initiated by scraping, and the solid was then filtered off to give (tert-butyl)-[4-{[(4-tolyl)sulfonyl]oxy}-1-pyrrolidinecarboxylate]. The white solid product weighed 10.5 g, and the thin layer chromatography R _f value was 0.13 (ethyl acetate:cyclohexane), yield 29%.

¹ H-NMR spectrum (CDCl ₃ , 250 MHz, δ): 7.79 (2H, d); 7.35 (2H, d); 5.04 (1H, m); 3.43 (4H, m); 2.46 (3H, s); 2.03-2.20 (2H, wide m); 1.43 (9H, s).

b) (tert-Butyl)-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate}

2.0 g (6.6 mmol) of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine are dissolved in 120 ml of N,N-dimethylformamide at 0 °C under nitrogen. 0.264 g (6.6 mmol) of 60% sodium hydride dispersed in mineral oil are added to the solution, and the mixture is first allowed to warm to room temperature, then stirred for 1 hour. 2.25 g (6.6 mmol) of (tert-butyl)-[4-{[(4-tolyl)sulfonyl]oxy}-1-pyrrolidinecarboxylate] are then added in small portions, and stirring is continued at 95 °C for 72 hours. After the reaction time, the reaction mixture is carefully quenched with 150 ml of water, and the aqueous mixture is extracted four times with 100 ml of ethyl acetate. The combined organic solvent extracts are washed four times with 100 ml of water and twice with 100 ml of saturated sodium chloride solution, then the organic phase is washed with sodium ba. 227/BE

231

-sulfate, filtered and evaporated. The remaining solid was dissolved in a mixture of ethyl acetate and methanol, the solution was adsorbed onto silica gel, and then purified by flash chromatography on silica gel, eluting the column with a solvent mixture containing 5% methanol and ethyl acetate. The resulting 1.0 g white solid was (tert-butyl) -{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate} (F17-25), yield 32%. The melting point of the product: 168-170 °C, thin layer chromatography R _f value: 0.46 (ethyl acetate:methanol = 9:1). ¹ H-NMR spectrum (DMSO-d ₆ , 250 MHz, δ): 8.17 (1H, s); 7.38-7.50 (5H, m); 6.19 (2H, wide s) 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 (Ο ₂₇ Η ₂₉ Ο ₃ Ν ₅ ) .

Infrared spectrum (KBr): 3130, 1683, 1585, 1404, 1245 cm ^-1 .

Example 205:

5-(4-Phenoxyphenyl)-7-(3-pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of 0.8 g (1.7 mmol) of (tert-butyl)-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate} in 25 ml of anhydrous methylene chloride and cooled to 0 °C, 5 ml of trifluoroacetic acid were added. The mixture was allowed to stir at room temperature for 20 hours, then the solvent was evaporated and the evaporation residue was taken up in 10 ml of 5 M sodium hydroxide solution. The solution thus obtained was extracted three times with 50 ml of ethyl acetate, and the organic solvent extract was washed with 75 ml of saturated sodium chloride solution, dried over sodium sulfate.

72.227/BE

232 dried, filtered and evaporated in vacuo. The remaining 0.5 g of white solid is 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl)-7H-pyrrolo}2, 3-d]pyrimidin-4-amine, yield 79%. The melting point of the product: 182-184 °C, thin layer chromatography R _f value: 0.15 (ethyl acetate:methanol = 1:1).

¹ H-NMR spectrum (DMSO-d ₆ , 250 MHz, δ): 8.14 (1H, s); 7.37-7.50 (5H, m); 7.05-7.18 (5H, m); 6.14 (2H, broad s); 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 ( _{C22H21ON5 )} .

Infrared spectrum (KBr): 3106, 1585, 1489, 1232 cm ¹ .

Example 206:

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

200 mg of 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in a 2:1 mixture of ethyl acetate and methanol (20 ml), then 3 ml of 1.0 M diethyl ether hydrogen chloride solution was added, and the precipitate was filtered off under nitrogen. The resulting 190 mg of white, solid material was 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride, which contained 0.4 mol of water of hydration. The melting point of the product was 298 °C (decomposed). Infrared spectrum (KBr): 2909, 1658, 1249 cm ¹ .

Example 207:

5-(4-Phenoxyphenyl)-7-(1-pyrrolizidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

72.227/BE

233

a) 1-Pyrrolisidinol

The title compound is prepared as described in the literature [see J. Schnekenburger, E. Briet: Arch. Pharm. (Wienheim) 310, 152-160 (1977)].

b) (1-Pyrrolisidinyl) methanesulfonate

To a mixture of 0.5 g (3.94 mmol) of 1-pyrrolizidinol, 0.60 g (5.91 mmol) of triethylamine and 10 ml of methylene chloride under nitrogen at 0 °C, while stirring, 0.68 g (5.91 mmol) of methanesulfonyl chloride was added, then the mixture was allowed to warm to room temperature and stirring was continued for a further 8 hours. Then 10 ml of saturated aqueous ammonium chloride solution, 25 ml of methylene chloride and 10 ml of saturated aqueous sodium bicarbonate solution were added, then the organic phase was separated, dried over magnesium sulphate, filtered and the filtrate was evaporated in vacuo. The distillation residue was purified by flash chromatography on silica gel, eluting with a 1:3 mixture of heptane and ethyl acetate, to give 0.54 g of (1-pyrrolizidinyl)methanesulfonate.

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 4.96 (m, 1H); 3.61 (m,

1H); 2.9-3.3 (m, 6H); 2.35 (m, 1H); 1.55-2.25 (m, 6H).

c) 5-(4-Phenoxyphenyl)-Ί-(1-pyrrolizidinyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine dihydrochloride

A mixture of 0.49 g (1.62 mmol) of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 100 mg (2.43 mmol) of 60% sodium hydride dispersed in oil and Ν,Ν-dimethylformamide was stirred under nitrogen at room temperature for 15 minutes and then at 100 °C for 18 hours. The reaction mixture was then cooled to room temperature, and another

72.227/BE

234 Uri ...» .... ·

100 mg of 60% sodium hydride dispersed in oil are added and stirring is continued at 100 °C for a further 2 hours. The mixture is cooled again to room temperature, the solvent is evaporated in vacuo, then the evaporation residue is partitioned between 10 ml of water and 30 ml of methylene chloride. The organic phase is dried over magnesium sulphate, filtered, the filtrate is evaporated in vacuo and the remaining crude product is purified by high pressure liquid chromatography on a reverse phase C18 preparative column. The 150 mg of white solid thus isolated was dissolved in 10 ml of ethyl acetate and 1 M diethyl ethereal hydrochloric acid solution was added to give 5-(4-phenoxyphenyl)-7-(1-pyrrolizidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride. The white solid had a HPLC retention time of 7.62 min (Hypersil HS C18, 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 min, 1 ml/min).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.52 (s, 1H); 7.95 (s, 1H); 7.02-7.58 (m, 1H); 5.38 (m, 10H); 4.40 (m, 1H); 1.9-3.9 (m, 10H). Mass spectrum: MH ⁺ = 412.

Example 208:

5-(4-Phenoxy-phen±l)-Ί-(2-methyl-perhydrocyclopenta[c]pyrrole-5-11)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

a) 2-Methylperhydrocyclopenta[c]pyrrol-5-ol

The title compound is prepared as described in the literature [see H. Bohme, G. Setiz: Arch. Pharm. (Wienheim) 301, 341 (1968)].

72.227/BE

235 ......... ..

* * ⁴ * · « ·

J'i ’

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

To a mixture of 0.38 g (1.36 mmol) of 5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 0.23 g (1.63 mmol) of 2-methylperhydrocyclopenta[c]pyrrol-5-ol, 0.71 g (2.72 mmol) of triphenylphosphine and 20 ml of tetrahydrofuran was added 0.474 g (2.72 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated in vacuo, and the evaporation residue was partitioned between 30 ml of methylene chloride and 10 ml of water. The organic phase was washed with 10 ml of saturated sodium chloride solution, then dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The remaining crude product was purified by flash chromatography on silica gel, eluting with a mixture of methylene chloride and methanol (8:2), to give 0.25 g of 5-iodo-4-chloro-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine. The product had a thin layer chromatography R _f value of 0.29 (methylene chloride:methanol = 8:2), and a high-pressure liquid chromatography retention time of 6.50 min (reversed phase, Hypersil HS C18, 5 gm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 min, 1 ml/min). ¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.62 (s, 1H); 7.44 (s, 1H); 7.26 (s, 2H); 5.36 (m, 1H); 2.88 (m, 2H); 2.68 (m, 2H); 2.43 (m, 2H); 2.36 (s, 3H); 2.06-2.02 (m, 4H). Mass spectrum: MH ⁺ = 403.

c) 5-(4-Phenoxyphenyl)-7-(2-methylperhydrocyclopenta[c]pyrrole-

-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

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236

A mixture of 0.25 g (0.622 mmol) of 5-iodo-4-chloro-7-(2-methyl-perhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine, 0.16 g (0.746 mmol) of 4-phenoxyphenylboronic acid, 0.043 g (0.037 mmol) of [tetrakis(triphenylphosphine)palladium(0)], 0.172 g (1.62 mmol) of sodium carbonate, 8 ml of ethylene glycol dimethyl ether and 4 ml of water was reacted under nitrogen at 90 °C for 18 hours, then allowed to cool to room temperature and the solvent was evaporated in vacuo. The distillation residue was partitioned between 10 ml of water and 30 ml of methylene chloride, then the organic phase was dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. To the remaining 0.354 g of intermediate product, 10 ml of 1,4-dioxane and 10 ml of concentrated 28% ammonium hydroxide were added, and the mixture was heated to 120 °C in a sealed tube, held at this temperature for 20 hours, then cooled to room temperature. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel, eluting the column with a 7:3 mixture of methylene chloride and methanol. The product thus obtained is 5-(4-phenoxyphenyl)-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (PH 454098), weight 0.05 g, high-pressure liquid chromatography retention time: 7.53 min (reversed phase, Hypersil HS C18, 5 pm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): (double peaks are due to the presence of cis-trans isomers) 10.6-10.8 (broad s, 1H); 8.49 (s, 1H); 6.99-7.98 (m, 11H); 5.39 and 5.48 (m, 1H); 2-3.8 (m, 10H)

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Mass spectrum: MH ⁺ = 426.

5-(4-Phenoxyphenyl)-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride was prepared by dissolving the free base in 10 ml of 1 M hydrochloric acid and then lyophilizing the solution.

Example 209:

cis- and trans-7-[4-{ (IS,4S)-2-[(tert-Butoxy)-carbonyl]-2,5-diaza-bicyclo[2.2.1]cycloheptanyl}-cyclohexyl]-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

0.67 g (1.68 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone is suspended in 40 ml of methylene chloride, 1.0 g (5.04 mmol) of (tert-butyl)-[(1S,4S)-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate] and 0.30 g (5.04 mmol) of concentrated, anhydrous acetic acid are added to the suspension, then the mixture is stirred for 1 hour at room temperature. After that, 0.46 g (2.17 mmol) of sodium [triacetoxyhydridoborate] is added, and stirring is continued at 80 °C for 8 days. The reaction mixture was then cooled and a solution of 0.377 g (10.08 mmol) of sodium bicarbonate in 15 ml of water was added and allowed to stir for 15 minutes. The immiscible layers were separated, the organic phase was washed with 300 ml of water and saturated sodium chloride solution, and the aqueous phase was extracted with methylene chloride. The combined organic solvent extracts were dried over magnesium sulfate, filtered, concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 2000 ml of 6% methanol and methylene chloride.

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The column was eluted with a solvent mixture of 238 and 2000 ml of a solvent mixture containing 10% methanol, 5% ammonium hydroxide and methylene chloride to give the compounds of Examples 210 and 211.

Example 210:

cis-7-[4-{(IS,4S)-2-[(tert-Butoxy)-carbonyl]-2,5-diaza-bicyclo[2.2.1]cycloheptanyl}-cyclohexyl]-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mass of the cis isomer obtained as described in Example 209 was 605 mg, yield 64%.

Mass spectrum (HPLC-MS; Perkin Elmer Pecosphere C18, 3 pm, 33 x 4.6, 3.5 mL/min, 100%-100% 50 mM ammonium acetate solution—acetonitrile over 4.5 min): C ₃₆ H ₄₄ N ₆ O ₃ (581.2), 95%.

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (1H, s); 7.39-7.49 (4H, m); 7.32 (1H, m); 7.07-7.17 (5H, m); 6.09 (2H, broad s); 4.63 (1H, m); 4.15 (1H, m); 3.30-3.70 (2H, m); 3.03-3.08 (2H, m); 2.80-2.90 (1H, m); 2.70-2.75 (1H, m); 2.29-2.35 (1H, m); 2.09-2.21 (1H, m); 1.81-1.93 (4H, m); 1.60-1.80 (4H, m); 1.39 (9H, m).

Example 211:

trans-7-[4-{ (1S,4S)-2-[(tert-Butoxy)-carbonyl]-2,5-diaza-bicyclo[2.2.1]cycloheptanyl}-cyclohexyl]-5- (4-phenoxy-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mass of the trans isomer obtained as described in Example 209 was 183 mg, yield 20%.

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239 ..................

··· ·· ·* ·» ··

Mass spectrum (HPLC-MS; Perkin Elmer Pecosphere C18, 3 pm, 33 x 4.6, 3.5 ml/min, 100%-100% 50 mM ammonium acetate solution—acetonitrile over 4.5 min): C ₃₆ H ₄₄ N ₆ O ₃ (581.2), 99%.

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (1H, s); 7.39-7.47 (5H, m); 7.15-7.17 (1H, m); 7.07-7.11 (4H, m); 6.10 (2H, broad s); 4.62 (IH, m); 4.1-4.2 (IH, m); 3.71 (IH, wide s); 3.03 (2H, m); 2.35 (2H, m); 1.93-2.01 (6H, m); 1.60-1.68 (2H, m); 1.40 (9H, m).

Example 212:

cis-N-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-N,N',N'-trimethylethylenediaminetrimaleate and trans-N-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-N,N',N'-trimethylethylenediaminetrimaleate

A mixture of 1.0 g (2.51 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone, 0.77 g (7.54 mmol) of Ν,Ν,Ν'-trimethylethylenediamine, 0.45 g (7.54 mmol) of acetic acid and 50 ml of ethylene dichloride was stirred under nitrogen at room temperature for 30 minutes. Then 0.69 g (3.26 mmol) of sodium [triacetoxyhydridoborate] was added, stirring was continued at room temperature for another 18 hours, then 20 ml of water and 1.26 g (15.1 mmol) of sodium bicarbonate were added to the mixture. The mixture was stirred for another 1 hour, then filtered through a Celite filter pad and washed with 75 ml of methylene chloride. The filtrate was transferred to a separatory funnel.

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240 funnel, the immiscible layers are separated, then the organic phase is dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The cis- and trans-isomer were purified by flash chromatography on silica gel, eluting the column with a 7:3 mixture of methylene chloride and methanol, to give 0.442 g of cis-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-N,N',N'-trimethylethylenediamine and 0.336 g of trans-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-N,N',N'-trimethylethylenediamine.

0.44 g (0.909 mmol) of cis-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl]-N,N’,N’-trimethylethylenediamine is dissolved in 100 ml of warm ethyl acetate, then a solution of 0.32 g (2.73 mmol) of maleic acid in 30 ml of ethyl acetate is added. The salt formed collects as an oil at the bottom of the flask and on the walls of the flask, so the liquid is poured off, the oily residue is dissolved in water, and the solution is then lyophilized. The mass of the thus obtained cis-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl]-N,N',N'-trimethylethylenediaminetrimaleate is 0.55 g, and the high-pressure liquid chromatography retention time is 9.27 minutes (reversed phase, Hypersil CPS, 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.22 (s, 1H); 7.41-7.50 (m, 5H); 7.08-7.19 (m, 5H); 6.5 (broad s, 2H); 6.15 (s, 6H); 4.78 (m, 1H); 3.28 (m, 2H); 3.00 (m, 2H); 2.80 (m, 1H); 2.79 (s, 6H); 2.50 (s, 3H); 2.19 (m, 2H); 1.99 (m, 2H); 1.78 (m, 4H). Mass spectrum: MH ⁺ = 485.

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241 ..................

··* «· ·· *« «4

In a similar manner, trans-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl]-N, N', N'-trimethylethylenediaminetrimaleate is prepared from the free base, the high-pressure liquid chromatography retention time of which is: 8.17 minutes (reversed phase, Hypersil CPS, 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute). ^-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.20 (s, 1H); 7.41-7.48 (m, 5H); 7.08-7.19 (m, 5H); 6.45 (broad s, 2H); 6.15 (s, 6H); 4.62 (m, 1H); 2.9-3.3 (m, 5H); 2.74 (s, 6H); 2.56 (s, 3H); 1.9-2.2 (m, 6H); 1.73 (m, 2H). Mass spectrum: MH ⁺ = 485.

The following compounds were prepared following the procedure described for cis-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-N,N',N'-trimethylethylenediamine.

Example 214:

cis-5-(4-Phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a high-performance liquid chromatography retention time of 7.817 min (Hypersil HS C18, 5 μm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min), 99%; TLC R _f value: 0.30 (90% methylene dichloride—methanol mixture, UV). ¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (1H, s) ; 7.39-7.50 (4H, m) ; 7.28 (1H, s); 7.07-7.16 (5H, m) ; 6.08 (2H, broad s) ;

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4.67 (1H, m); 2.49-2.67 (9H, m); 2.06-2.16 (5H, m); 1.70-1.72 (2H, m); 1.53-1.59 (2H, m); 0.97 (d, J = 6.5 Hz, 6H). Mass spectrum: C ₃₁ H ₃₈ N ₆ O (511.2).

Example 215:

trans-5-(4-Phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a HPLC retention time of 7.367 min (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 min, 1 ml/min), 91%; TLC R _f value: 0.21 (90% methylene chloride-methanol mixture, UV).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (1H, s); 7.40-7.47 (5H, m); 7.08-7.18 (5H, m); 6.08 (2H, broad s); 4.53 (1H, m); 2.45-2.55 (9H, m); 2.17-2.20 (1H, m); 1.86-1.96 (6H, m); 1.44-1.49 (2H, m); 0.97 (d, J = 5.5 Hz, 6H).

Mass spectrum: _{C31H38N6O ( 511.2} ).

Example 216:

cis-5-(4-Phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)-piperazin-1-yl]-cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a HPLC retention time of 7.317 min (Hypersil HS C18, 5 pm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 min, 1 ml/min), 95%; TLC R _f value: 0.22 (90% methylene chloride-methanol mixture, UV).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (1H, s); 7.39-7.50

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243 ................ ..

·· ·· ··*· · *1 ··· ··*·· «· (4H, m) ; 7.27 (1H, s); 7.07-7.11 (5H, m); 6.09 (2H, broad s); 4.68 (1H, m); 3.42 (2H, t, J = 5.9 Hz); 3.22 (3H, s); 2.43-2.55 (9H, m); 2.03-2.16 (6H, m); 1.60-1.71 (2H, m); 1.52-1.59 (2H, m). Mass spectrum: C ₃₁ H ₃₈ N ₆ O ₂ (527.2).

Example 217:

trans-5-(4-Phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a HPLC retention time of 7.200 min (Hypersil HS C18, 5 gm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 min, 1 ml/min), 99%; TLC R _f value: 0.31 (90% methylene chloride-methanol mixture, UV).

3-NMR spectrum (DMSO-d _s , 400 MHz, δ): 8.13 (1H, s); 7.39-7.47 (5H, m); 7.07-7.16 (5H, m); 6.09 (2H, broad s); 4.55 (1H, m); 3.36-3.42 (2H, m); 3.23 (3H, s); 2.33-2.55 (UH, m); 1.90-1.96 (6H, m); 1.44-1.47 (2H, m).

Mass spectrum: _{C31H38N6O2 ( 527.2} ) _.

Example 218:

cis-7-[4-(4-Ethyl-piperazin-1-yl)-cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a high-performance liquid chromatography retention time of 13.851 min (Waters delta pack C18, 150 x 3.9 mm; 5%-95% acetonitrile-0.1 M ammonium acetate solution over 30 min, 1 ml/min), 100%.

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.23 (1H, s); 7.41-7.47

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244 (4H, m); 7.07-7.17 (6H, m); 6.57 (2H, broad s); 6.20 (5H, s); 4.77 (1H, m); 2.04-2.13 (8H, m); 1.62-1.77 (5H, m); 1.21 (3H, t).

trans-7-[4-(4-Ethyl-piperazin-1-yl)-cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The product has a HPLC retention time of 13.701 min (Waters delta pack C18, 150 x 3.9 mm; 5%-95% acetonitrile-0.1 M ammonium acetate solution over 30 min, 1 ml/min), 96%.

¹ H-NMR spectrum (DMSO~d ₆ , 400 MHz, δ): 8.19 (1H, s); 7.40-7.47 (4H, m); 7.19 (1H, m); 7.08-7.19 (5H, m); 6.40 (2H, broad s); 6.18 (6H, s); 4.95 (1H, m); 3.17 (2H, broad s); 2.98 (2H, broad s); 2.69 (2H, broad s); 1.94-2.01 (8H, m); 1.54-1.57 (2H, d, J = 7.5 Hz); 1.17 (3H, t).

The following compounds were prepared following the procedure given for cis-N-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-N,N',N'-trimethylethylenediaminetrimaleate.

Example 219:

cis-5-(4-Phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

The product has a high-performance liquid chromatography retention time of 7.967 min (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min), 99%.

^x H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.23 (1H, s); 7.40-7.49

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245 (5H, m); 7.07-7.19 (5H, m); . 6.55 (2H, broad s); 6.16 (6H, s); 4.74 (1H, m); 3.26 (6H, broad s); 2.04-2.49 (13H, m); 1.63-1.75 (5H, m); 1.25 (d, J = 6.6 Hz, 6H).

Mass spectrum: _{C31H38N6O ( 511.1} ).

Example 220:

trans-5-(4-Phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

The product has a high-performance liquid chromatography retention time of 7.733 min (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min), 90%.

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.20 (1H, s); 7.40-7.65 (5H, m); 7.08-7.19 (5H, m); 6.46 (2H, broad s); 6.14 (6H, s); 4.60 (1H, m); 2.50-3.45 (17H, m); 1.95-2.02 (5H, m); 1.56-1.59 (2H, m); 1.20 (d, J = 6.5 Hz, 6H).

Mass spectrum: _{C31H3BN6O ( 511.2} ).

Example 221:

cis-5-(4-Phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

The product has a high-performance liquid chromatography retention time of 7.750 min (Hypersil HS C18, 5 µm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min), 99%.

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.23 (1H, s); 7.41-7.49 (5H, m); 7.07-7.19 (5H, m); 6.55 (2H, broad s); 6.16 (6H, s);

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246

4.75 (1H, m); 3.62 (2H, m); 3.30 (3H, s); 3.17 (6H, broad s); 2.50 (9H, m); 2.02-2.16 (5H, m); 1.74 (5H, m). Mass spectrum: C ₃₁ H ₃₈ N ₆ O ₂ (527.2).

Example 222:

trans-5-(4-Phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)piperazin-1-yl]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

The product has a high-performance liquid chromatography retention time of 7.383 min (Hypersil HS C18, 5 pm, 254 nm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min), 99%. ^-NMR spectrum (DMSO~d ₆ , 400 MHz, δ): 8.21 (1H, s) ; 7.41-7.48 (5H, m) ; 7.08-7.17 (5H, m) ; 6.53 (2H, broad s) ; 6.17 (6H, s) ; 4.61 (1H, m) ; 3.45 (3H, s) ; 2.50-3.56 (19H, m) ; 1.99-2.08 (6H, m); 1.64 (2H, m). _Mass spectrum: _C31H38N6O2 ( _{527.2 )} .

Example 223:

cis-N-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-N',N'-dimethylethylenediaminetrimaleate

The product has a high-performance liquid chromatography retention time of 8.90 minutes (reversed phase, Hypersil CPS, 5 µm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.19 (s, 1H); 7.40-7.49 (m, 5H); 7.08-7.19 (m, 5H); 6.35 (broad s, 2H); 6.13 (s, 6H);

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247 ..................

·· ·· ·· · * ·** ·* ** <·

4.78 (m, 1H); 3.15-3.45 (m, 5H); 2.74 (s, 6H); 1.8-2.25 (m, 8H). Mass spectrum: MH ⁺ = 471.

Example 224:

trans-N-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-N',N'-dimethylethylenediamine monomaleate

The product has a high-performance liquid chromatography retention time of 8.6 minutes (reversed phase, Hypersil CPS, 5 gm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 9.5 (broad s, 1H); 8.26 (s, 1H); 7.41-7.55 (m, 5H); 7.08-7.19 (m, 5H); 6.7 (broad s, 2H); 6.16 (s, 2H); 4.63 (m, 1H); 3.12-3.55 (m, 5H); 2.85 (s, 3H); 2.27 (m, 2H); 1.99-2.05 (m, 4H); 1.67-1.75 (m, 2H).

Mass spectrum: MH ⁺ = 471.

Example 225:

cis-5-(4-Phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)-propyl]-amino}-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate and trans-5-(4-Phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)-propyl]-amino}-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate

Example 227:

cis-5-(4-Phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)propyl]amino}-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

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248

The product has a high-performance liquid chromatography retention time of 9.07 minutes (reversed phase, Hypersil CPS, 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.78 (broad s, 1H); 8.48 (broad s, 2H); 8.18 (s, 1H); 7.66 (s, 1H); 7.55 (s, 1H); 7.41-7.49 (m, 5H); 7.08-7.19 (m, 5H); 6.33 (broad s, 2H); 6.12 (s, 6H); 4.78 (m, 1H); 4.27 (t, 2H); 2.99 (m, 3H); 1.8-2.25 (m, 10H). Mass spectrum: MH ⁺ = 508.

Example 228:

trans-5-(4-Phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)propyl]amino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate

High-performance liquid chromatography retention time of the product: 8.72 min (reversed phase, Hypersil CPS, 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min). ^-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.76 (broad s, 1H) ; 8.51 (broad s, 2H) ; 8.18 (s, 1H) ; 7.66 (s, 1H) ; 7.55 (s, 1H) ; 7.40-

-7.47 (m, 5H); 7.08-7.21 (m, 5H); 6.3 (broad s, 2H); 6.11 (s,

4H); 4.60 (m, 1H); 4.26 (t, 2H); 3.14 (m, 1H); 2.97 (m, 2H);

1.9-2.25 (m, 8H); 1.53-1.61 (m, 2H). Mass spectrum: MH ⁺ = 508.

Example 229:

cis-7-[4-(Dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate

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249 ..................

·· ·· ··*· * · * ·♦· ·· ·* *·

The product has a high-performance liquid chromatography retention time of 7.38 minutes (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 9.06 (broad s, 1H); 8.2 (s, 1H); 7.41-7.50 (m, 5H); 7.08-7.19 (m, 5H); 6.4 (broad s, 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).

Mass spectrum: MH ⁺ = 428.

Example 230:

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

The product has a high-performance liquid chromatography retention time of 7.98 minutes (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.92 (broad s, 1H); 8.18 (s, 1H); 7.4-7.5 (m, 5H); 7.08-7.19 (m, 5H); 6.3 (broad s, 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).

Mass spectrum: MH ⁺ = 468.

trans-5-(4-Phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate

High-performance liquid chromatography retention time of the product:

7.82 min (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x

72.227/BE

250 ......

···· ··** ««*» «··· «* • ·

4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 9.54 (broad s, 1H); 8.18 (s, 1H); 7.40-7.47 (m, 5H); 7.08-7.18 (m, 5H); 6.3 (broad s, 1H); 6.12 (s, 4H); 4.63 (m, 1H); 3.1-3.55 (m, 5H); 2.24 (m, 2H); 2.00 (m, 6H); 1.86 (m, 2H); 1.67 (m, 2H).

Mass spectrum: MH ⁺ = 454.

Example 231:

cis-5-(4-Phenoxyphenyl)-7-[4-(4-methyl-1,4-diazepan-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

The product has a high-performance liquid chromatography retention time of 7.67 min (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min). ^-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 11.7 (d, 1H) ; 11.38 (d, 1H) ; 8.57 (s, 1H) ; 8.34 (d, 1H) ; 7.42-7.51 (m, 4H) ; 7.03-7.20 (m, 5H); 4.93 (m, 1H); 4.7 (broad s, 2H); 3.4-3.99 (m, 9H); 2.8 (s, 3H); 1.86-2.57 (10H). Mass spectrum: MH ⁺ = 4 97.

trans-5-(4-Phenoxyphenyl)-7-[4-(4-methyl-1,4-diazepan-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

The product has a high-performance liquid chromatography retention time of 7.42 minutes (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 11.94 (d, 1H); 11.52 (d, 1H);

72.227/BE

251 ..

• « · · · · • · · ♦ · « · · ·<· ···«*· *«

8.56 (s, 1H); 7.8 (s, 1H); 7.42-7.51 (m, 4H); 7.10-7.20 (m, 5H); 4.76 (1H, m); <3.2-4.0 (m, 9H); 2.80 (s, 3H); 1.78-2.4 (m, 10H). Mass spectrum: MH ⁺ = 497.

Example 232:

cis-5-(4-Phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate and trans-5-(4-Phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

a) cis- and trans-(tert-Butyl)-[4-(4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl)-1-piperazinecarboxylate]

Example 233:

cis-(tert-Butyl)- [4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate]

High-performance liquid chromatography retention time of the product: 13.60 minutes (reversed phase, Hypersil HS, C18 5 pm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.14 (s, 1H); 7.3-7.5 (m, 6H); 7.07-7.16 (m, 5H); 6.1 (broad s, 2H); 4.69 (m, 1H); 3.2-3.4 (m, 4H); 2.38 (m, 4H); 2.0-2.25 (m, 5H); 1.5-1.8 (m, 4H); 1.41 (s, 9H).

trans-(tert-Butyl)-[4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate]

High-performance liquid chromatography retention time of the product:

72.227/BE

252 ......

♦ *··· ««·· ·»«* ·« • · ·· ·« « « *<* ·4 ·* *4 «·

10.40 min (reversed phase, Hypersil HS, C18 5 μη, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 min, 1 ml/min).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (s, 1H); 7.40-7.47 (m, 6H); 7.08-7.16 (m, 5H); 6.1 (broad s, 2H); 4.55 (m, 1H); 3.34 (m, 4H); 2.35-2.51 (m, 3H); 1.89-1.99 (m, 6H); 1.38-1.49 (m, 4H); 1.39 (s, 9H).

b) cis-5-(4-Phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-

-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

To 1.85 g (3.27 mmol) of cis-(tert-butyl)-[4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-1-piperazinecarboxylate], 60 ml of a 20% solution of trifluoroacetic acid in methylene dichloride were added, the mixture was stirred for 30 minutes at room temperature, then the solvent was evaporated in vacuo. The evaporation residue was partitioned between 200 ml of methylene dichloride and 30 ml of saturated aqueous sodium bicarbonate solution, then the organic phase was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The remaining crude product weighed 1.55 g, a portion of which (1.0 g, 2.15 mmol) was dissolved in 220 ml of warm ethyl acetate, and a solution of 0.75 g (0.44 mmol) of maleic acid in 75 ml of warm ethyl acetate was added. The mixture was allowed to cool to room temperature, and the separated crystals were filtered off and dried. The resulting 1.15 g white solid is cis-5-(4-phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate, the product has a high-pressure liquid chromatography retention time of 8.63 min (reversed phase, Hypersil CPS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M

72.227/BE

253 ammonium acetate solution over 10 minutes, 1 ml/minute).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.5 (broad s, 1H); 8.23 (s, 1H); 7.41-7.51 (m, 5H); 7.08-7.19 (m, 5H); 6.65 (broad s, 2H); 6.16 (s, 6H); 4.74 (m, 1H); 1.16-3.2 (m, 17H).

Mass spectrum: MH ⁺ = 469.

c) trans-5-(4-Phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

The product has a high-performance liquid chromatography retention time of 8.08 minutes (reversed phase, Hypersil HS, C18 5 μm, 100 A, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 10 minutes, 1 ml/minute).

^X H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.22 (s, 1H); 7.41-7.51 (m, 5H); 7.08-7.19 (m, 5H); 6.6 (broad s, 2H); 6.16 (s, 6H); 4.58 (m, 1H); 1.4-3.2 (m, 17H).

Mass spectrum: MH ⁺ = 4 69.

Example 234:

5-(4-Phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

To 2.14 g (0.0055 mol) of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol, 1000 ml of methylene dichloride and 12 g of active manganese dioxide were added, the mixture was stirred for 5 hours, then filtered, and 8 g of fresh manganese dioxide were added to the filtrate. Stirring was continued for a further 17 hours, then the reaction mixture was filtered, and the solution, which according to high-pressure liquid chromatography (HPLC-MS) analysis contained 62.7% of 3-[4-amino-5-(472.227/BE

254 ·*·* ·♦<(· • · « Μ 4 Μ ♦ · ♦ 4 · « * * <

·« 4« ♦' -* «*

-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanone (retention time: 4.38 min), was used directly for the next reaction step.

To the above methylene chloride solution, 1.0 g (0.01 mol) of N-methylpiperazine and 0.6 g (0.01 mol) of acetic acid were first added, followed after 15 minutes by 0.89 g (0.0042 mol) of sodium [triacetoxyhydridoborate]. The reaction mixture was stirred for 2 hours, then another 1.0 g of N-methylpiperazine, 0.6 g of acetic acid and 0.89 g of sodium [triacetoxyhydridoborate] were added, and stirring was continued for 17 hours. Subsequently, a further 2.0 g of N-methylpiperazine, 1.2 g of acetic acid and 1.2 g of sodium [triacetoxyhydridoborate] were added, and this time the mixture was allowed to stir for 3 days, then evaporated in vacuo. The distillation residue is mixed with a mixture of 200 ml of water and 50 ml of 6 M hydrochloric acid, the aqueous mixture is washed with ethyl acetate, the organic phase is set aside, the aqueous phase is basified with excess ammonium hydroxide and then extracted with ethyl acetate. The organic solvent extract is dried over sodium sulfate and the crude product is purified by flash chromatography on silica gel, first eluting the column with a 9:1 mixture of ethyl acetate and ethanol to remove impurities, then with a 8:1:1 mixture of ethyl acetate, ethanol and triethylamine. The appropriate fractions are combined, the solvent is evaporated in vacuo, the residue is dissolved in ethyl acetate, maleic acid is added to the ethyl acetate solution, and the salt is then dried at 80 °C in vacuo. The thus obtained 5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate (444395) 1.4 mol 72.227/BE

255 ·*** ·**} 4-·4« ·**· ·· · ΜΙ *···

Κ* contains saturated ethyl acetate, its mass is 0.95 g (0.001 mol), its melting point: 168-170 °C (decomposes).

Example 235:

4-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-α-phenylbenzyl alcohol

0.1 g (0.00026 mol) of [4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]phenyl ketone was dissolved in 4 ml of tetrahydrofuran, and 0.052 g (0.0013 mol) of sodium tetrahydridoborate and then Amberlist-15 resin of hydrogen ion phase were added to the solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 15 min, then filtered through a Celite pad and the solvent was evaporated in vacuo. The distillation residue was purified by reverse-phase preparative high-pressure liquid chromatography (Rainin, Hypersil C18, 8 μm, 100 A, 25 cm; 5%-85% acetonitrile-0.1% ammonium acetate solution over 20 min, 21 ml/min) to give 0.005 g (0.000013 mol) of 4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-α-phenylbenzyl alcohol. The product had a high-pressure liquid chromatography retention time of 16.74 min (reverse-phase, Delta Pák C18 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1% ammonium acetate solution over 20 min, 1 ml/min). 3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.12 (s, 1H); 7.31 (m, 10H); 6.01 (broad, 2H); 5.91 (d, 1H); 5.75 (d, 1H); 5.06 (m, 1H); 2.10 (broad, 2H); 1.88 (broad, 4H); 1.67 (wide, 2H) . Mass spectrum: MH ⁺ = 385.

72.227/BE

256

Example 236:

trans-5-(4-Phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

1.30 g (0.0027 mol) of trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine are dissolved in 300 ml of warm ethyl acetate, a solution of 0.94 g (0.0081 mol) of maleic acid in 100 ml of warm ethyl acetate is added, and the mixture is allowed to cool. The colorless crystals are filtered off, washed with ethyl acetate, and dried in vacuo at 3 mbar and 90 °C until constant weight. The 1.85 g (0.0022 mol) of trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate solvate obtained in this way contains 0.18 mol of bound ethyl acetate, melting point: 189 °C (decomposes).

Example 237:

trans-5-(4-Phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride

0.36 g (0.00075 mol) of trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 25 ml of warm isopropyl alcohol, a mixture of 0.225 ml (0.0027 mol) of 12 M hydrochloric acid and 2 ml of isopropyl alcohol is added, then the resulting suspension is rapidly heated to boiling, then evaporated in vacuo, and the remaining colorless solid is dried in vacuo at 5 mbar and 84 °C to constant weight. The thus obtained 0.25 g (0.0004 mol) of trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,372.227/BE

257

d] pyrimidine 4 amine trihydrochloride (444626) contains 1 mol of bound water and 0.25 mol of bound isopropyl alcohol, melting point: 304-306 °C (decomposes).

238, example:

cis-5-(4-Phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

1.45 g (0.0030 mol) of cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in ethyl acetate was reacted with 1.05 g (0.0091 mol) of maleic acid, and the colorless crystals were dried in vacuo at 3 mbar at 90 °C until constant weight. The resulting 2.15 g (0.0025 mol) of cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)-

-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate is the solvated form of the compound, which contains 0.14 mol of bound ethyl acetate and 0.5 mol of bound water, melting point: 186 °C (decomposes).

Example 239:

cis-5-(4-Phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride

0.80 g (0.0017 mol) of cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in isopropyl alcohol can be reacted with 0.5 ml (0.006 mol) of 12 M hydrochloric acid, then the resulting solid is filtered off, then dried in vacuo at 3 mbar at 80 °C until constant weight. The resulting 0.75 g (0.0011 mol) of cis-5-(4-phenoxyphenyl)-7-[3-(472.227/BE

258

-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride has hygroscopic properties, melting point: 224.5-226.5 °C (decomposes).

Example 240:

trans-5-(4-Phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

a) (4-Bromo-3-methylphenyl)phenyl ether

A mixture of 2.5 g (0.0136 mol) of 3-phenoxytoluene, 2.54 g (0.0142 mol) of N-bromosuccinimide and 20 ml of acetonitrile was stirred under nitrogen for 25 h, and the solvent was evaporated in vacuo. Carbon tetrachloride was added to the residue and the insoluble solid was filtered off. The filtrate was evaporated to give 3.5 g (0.0133 mol) of the title compound as a yellow oil, with a high-pressure liquid chromatography retention time of 14.72 min (reversed phase, Hypersil C18, 5 pm, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 23 min, 1 ml/min).

3-NMR spectrum (CDCl ₃ , 400 MHz, δ): 7.45 (d, 1H); 7.33 (m, 2H); 7.12 (t, 1H); 7.00 (d, 2H); 6.89 (s, 1H); 6.71 (d, 1H); 2.34 (s, 3H).

b) Phenyl-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-

-2-yl)-phenyl] ether

A mixture of 1/7 g (0.00646 mol) of (4-bromo-3-methylphenyl)phenyl ether, 2.0 g (0.00775 mol) of diboron pinacol ester, 0.16 g (0.00019 mol) of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride—methylene dichloride (1:1) complex, 1.9 g (0.01938 mol) of potassium acetate and 65 ml of N,N-dimethylformamide was heated to 80 °C under nitrogen.

72.227/BE

259, kept at this temperature for 22 hours, then cooled to room temperature and the solvent evaporated in vacuo. To the distillation residue is added methylene chloride, the solid is filtered off on a filter bed made of Celite, then the filtrate is evaporated and the black residue is purified by flash chromatography on silica gel, eluting the column with a mixture of ethyl acetate and heptane in a ratio of 3:97. The product thus obtained is the title compound, weight 1.05 g (0.00338 mol), thin layer chromatography R _f value: 0.28 (ethyl acetate:heptane = 3:97).

3-NMR spectrum (CDCl ₃ , 400 MHz, δ): 7.73 (d, 1H); 7.33 (m, 2H); 7.08 (t, 1H); 7.01 (d, 2H); 6.79 (d, 2H); 2.51 (s, 3H); 1.34 (s, 12H).

4-(5-Iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanone g (47.7 mmol) 7-(1,4-dioxa-spiro[4.5]decan-8-yl)-5-iodo-4-chloro-pyrrolo[2,3-d]pyrimidine, 60 ml (360 mmol) 6 M aqueous hydrochloric acid, 120 ml tetrahydrofuran and 600 ml acetone were stirred under nitrogen at room temperature for 17 hours, then the solvent was evaporated in vacuo. To the distillation residue were added 20 ml of 6 M aqueous hydrochloric acid, 60 ml of tetrahydrofuran and 300 ml of acetone, stirring was continued under nitrogen at room temperature for another 4.5 hours, then the mixture was concentrated in vacuo and the yellow residue was washed with water. The product thus obtained was the title compound, weight 12.3 g (32.7 mmol), high-pressure liquid chromatography retention time: 10.20 minutes (reversed phase, Hypersil C18, 5 μm, 250 x 4.6 mm; 25%-100% acetonitrile-0.1 M ammonium acetate solution over 15 minutes, 1 ml/minute).

d) trans-5-Iodo-4-chloro-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d] pyrimidine

72.227/BE

260 :................

···*· * * · ♦ * ♦·

A mixture of 5.6 g (14.9 mmol) of 4-(5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone, 3.3 ml (29.8 mmol) of N-methylpiperazine, 2.6 ml (44.7 mmol) of acetic acid, 9.9 ml (89.4 mmol) of trimethyl orthoformate and 100 ml of methylene chloride is stirred under nitrogen at room temperature for 1 hour, then 14.2 g (67.05 mmol) of sodium triacetoxyhydridoborate is added. Stirring is continued at room temperature under nitrogen for a further 18 hours, then the solvent is evaporated in vacuo, and the evaporation residue is partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted with a further portion of ethyl acetate and the combined organic solvent extracts were dried over sodium sulfate and evaporated in vacuo. The remaining crude product was purified by flash chromatography on silica gel, eluting with triethylamine:methylene dichloride (2:98) and methanol:triethylamine:methylene dichloride (2:3:95) to give the title compound. The product was weighed 1.7 g (3.7 mmol), HPLC retention time 6.17 min (reversed phase, Hypersil C18, 5 pm, 250 x 4.6 mm; 25%-100% acetonitrile-0.05 M ammonium acetate solution over 15 min, 1 ml/min).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.63 (s, 1H); 8.12 (s, 1H); 4.63 (br, 1H); 2.15 (s, 3H); 1.94 (br, 6H); 1.45 (br, 2H).

e) trans-5-Iodo-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-

-7H-pyrrolo[2,3-d]pyrimidin-4-amine

0.89 g trans-5-iodo-4-chloro-7-[4-(4-methylpiperazin-1-yl)]72.227/BE

61 :·.....

• · · · · ·* <· * > *

-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine, 40 ml of concentrated ammonium hydroxide and 40 ml of dioxane are heated to 120 C in a pressure-resistant reaction vessel, kept at this temperature for 18 hours, then allowed to cool to room temperature and the solvent is evaporated in vacuo. The evaporation residue is partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate, the aqueous part is extracted with further ethyl acetate, then the combined organic solvent extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and finally evaporated in vacuo. The product thus obtained is the title compound, weight 0.35 g (0.8 mmol), high-pressure liquid chromatography retention time: 4.01 min (reversed phase, Hypersil C18, 5 pm, 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 15 min, 1 ml/min).

Mass spectrum: MH ⁺ = 441.

f) trans-5-(4-Phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-4-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

A mixture of 0.347 g (0.000788 mol) trans-5-iodo-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 0.27 g (0.000867 mmol) phenyl-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-ether, 0.054 g (0.00047 mol) [tetrakis(triphenylphosphine)palladium(0)], 0.209 g (0.00197 mol) sodium carbonate, 15 ml N,N-dimethylformamide and 10 ml water is heated to 80 °C under nitrogen gas, kept at this temperature for 16 hours, then left Cool to room temperature and evaporate the solvent in vacuo. The evaporation residue is washed with saturated aqueous sodium bicarbonate solution and ethyl acetate.

262 is partitioned, the aqueous phase is extracted with further ethyl acetate, then the combined organic solvent extracts are dried over sodium sulfate, evaporated in vacuo, and the remaining crude product is purified by flash chromatography on silica gel, eluting the column first with a 5:95 mixture of triethylamine and methylene dichloride and then with a 3:5:92 mixture of methanol, triethylamine and methylene dichloride. The mass of trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine thus obtained is 0.376 g (0.000757 mol).

0.376 g (0.000757 mol) of trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 10 ml of ethanol under reflux, then a solution of 0.264 g (0.00227 mol) of maleic acid in 5 ml of hot ethanol is added. The mixture was refluxed for another 15 minutes, then cooled to room temperature, and finally the precipitate was filtered off, washed with cold ethanol and dried to give 0.153 g (0.000181 mol) of trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3d]pyrimidin-4-amine trimaleate. The product had a high-pressure liquid chromatography retention time of 7.30 minutes (reversed phase, Hypersil C18, 5 μπι, 250 x 4.6 mm; 25%-100% acetonitrile in 0.1 M ammonium acetate solution over 23 minutes, 1 ml/min). 3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.22 (s, 1H); 7.42 (m, 3H); 7.25 (d, 1H); 7.17 (t, 1H); 7.09 (d, 2H); 7.02 (s, 1H); 6.89 (d, 1H); 6.16 (s, 6H); 4.58 (m, 1H); 3.3 (broad 9H); 2.68 (s, 3H); 2.22 (s, 3H); 2.01 (broad, 6H); 1.57 (wide, 2H) . Mass spectrum: MH ⁺ = 4 97.

72.227/BE

263 G.....

Example 241:

{3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]-(2-aminoacetate) hydrochloride

a) (3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl] -cyclopentyl}-[2-( [ (tert-butoxy) -carbonyl] -amino}-acetate] mg (0.129 mmol) 3-[4-amino-5-(4-phenoxy-phenyl)-7H-pyrrolo[ 2,3-d] pyrimidin-7-yl]-cyclopentanol, 34 mg (0.194 mmol) 2-{ [ (tert-butoxy)-carbonyl]-amino] -acetic acid, 31 mg (0.155 mmol) 1-[ 3-(dimethyl-amino)-propyl]-3-ethyl-carbodiimide hydrochloride, 16 mg (0.129 mmol) 4-(dimethyl-amino)-pyridine and 1 ml N, N-dimethylformamide were stirred under nitrogen gas for 24 hours, then poured into ice-water. The aqueous mixture was extracted three times with ethyl acetate, then the combined organic solvent extracts were saturated The mixture was washed with brine, dried over magnesium sulfate, filtered, concentrated, and the residue was purified by flash chromatography, eluting with ethyl acetate to give the title compound, 39 mg (0.072 mmol), HPLC retention time: 19.22 min (Delta-Pack, C18, 5 μm, 300 A, 3.9 x 150 mm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 min, 1 ml/min).

b) 13-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-

-7-yl]-cyclopentyl}- (2-aminoacetate)-hydrochloride mg (0.072 mmol) {3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[2-{[(tert-butoxy)carbonyl]-amino}-acetate] - was dissolved in 2.5 ml of ethyl acetate, then hydrogen chloride gas was bubbled through the solution for 3 minutes72.227/BE

264 tons. The reaction mixture was then allowed to stir for a further 30 minutes, then diethyl ether was added and the precipitate was filtered off under nitrogen. The resulting white solid was {3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin ^- 7-yl]cyclopentyl}-(2-aminoacetate) hydrochloride (39 mg), which had a liquid chromatography retention time of 2.25 minutes (LC-MS, Pecospher, 3C-18, 3 μm, 4.6 x 33 mm; 0%-100% acetonitrile—0.1 M ammonium acetate solution over 5 minutes, 3.5 ml/min).

^X H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 2.20 (m, 5H); 2.67 (m,

1H); 3.83 (s, 2H); 5.25 (m, 1H); 5.31 (m, 1H); 7.14 (m, 2H); 7.43 (m, 1H); 7.50 (m, 1H); 7.68 (m, 1H); 8.26 (broad s, 2H); 8.40 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 444.

Example 242:

{3-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl}-[N-(2-morpholinoethyl)carbamate] hydrochloride

a) {3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl]cyclopentyl}-[N-(2-morpholinoethyl)carbamate]

12.5 mg (0.062 mmol) of (4-nitrophenyl)-(chloroformate) were dissolved in 1 ml of methylene chloride, the solution was cooled in an ice-water bath, and 7 μΐ (0.062 mmol) of N-methylmorpholine were slowly added. After 20 min, the cooling bath was removed, the reaction mixture was allowed to warm to room temperature, then 20 mg (0.052 mmol) of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentanol were added, and stirring was continued for 4 days. The mixture was then washed with methylene chloride72.227/BE

265 ml, the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate and evaporated. The remaining yellow solid is dissolved in 1 ml of methylene chloride, 0.2 ml of 2-morpholinoethylamine is added and the mixture is stirred overnight at room temperature. The next day, the reaction mixture is diluted with ethyl acetate, shaken three times with water and once with saturated sodium chloride solution, then the organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated. The crude product is purified by high-pressure liquid chromatography, which results in 17 mg (0.031 mmol) of the title compound. The product has a liquid chromatography retention time of 2.13 minutes (Pecospher, 3C-18, 3 gm, 4.6 x 33 mm; 0%-100% acetonitrile-0.1 M ammonium acetate solution over 5 minutes, 3.5 ml/minute).

1 H NMR spectrum (CDCl ₃ , δ): 2.08 (m, 4H); 2.43 (m, 7H); 2.73 (m, 1H); 3.29 (m, 2H); 3.67 (m, 4H); 5.28 (m, 5H); 7.09 (m, 6H); 7.40 (m, 4H); 8.30 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 543.

b) {3-[4-Amino-5-(4-phenoxyphenyl)-pyrrolo[2,3-d]pyrimidine-

-7-yl] -cyclopentyl} - [N- (2-morpholino-ethyl) -carbamate] -hydrochloride mg (0.0184 mmol) {3-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl] -cyclopentyl} - [N- (2-morpholino-ethyl) -carbamate] - is dissolved in 2.5 ml of ethyl acetate, hydrogen chloride gas is bubbled through the solution for 3 minutes, the precipitated mixture is allowed to stir for another 10 minutes, then the solid is filtered off under nitrogen gas. The white solid obtained is 72.227/BE

266 {3-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentyl}-[N-(2-morpholinoethyl)carbamate]-hydrochloride, liquid chromatography retention time of the product: 2.16 min (Pecospher, 3C-18, 3 μm, 4.6 x 33 mm; 0%-100% acetonitrile—0.1 M ammonium acetate solution over 5 min, 3.5 ml/min).

3-NMR spectrum (DMSO-d ₆ , δ): 1.99 (m, 4H); 2.55 (m, 2H); 3.32 (m, 12H); 5.08 (m, 0.5H); 5.19 (m, 0.5H); 7.16 (m, 5H); 7.45 (m, 5H); 8.26 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 543.

Example 243:

4-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanol

780 mg (2.0 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone were dissolved in 500 ml of methanol, and 500 mg (13 mmol) of sodium tetrahydridoborate were added in a single portion while stirring. The reaction mixture was then stirred under nitrogen for 1 hour, left to stand overnight, and the solvent was evaporated in vacuo the next day. The evaporation residue was partitioned between 100 ml of 2 M aqueous sodium hydroxide solution and 100 ml of methylene chloride, and the organic phase was separated and extracted twice more with 100 ml of methylene chloride. The combined organic solvent extracts were washed with 150 ml of water, dried over potassium carbonate, and the crude product was purified by chromatography on a Biotag 40S column, starting with a 98:2 mixture of ethyl acetate and triethylamine, continuing with a 95:5 mixture, and finally with ethyl72.227/BE

267 J............... ..

·· · · · · · · · ··

-acetate and ethanol 95:5 mixture. The resulting 4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanol was a white solid, weight 750 mg (1.9 mmol), melting point: 199-200 °C, and liquid chromatography retention time (LC-MS): 4.12 min (Hypersil BDS C18, 100 x 2.1 mm; 0.1 M ammonium acetate solution-acetonitrile, 10%-100% acetonitrile over 8 min).

Mass spectrum (LC-MS): MH ⁺ = 401.

Example 244:

Phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

100 mg (0.294 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in 2 ml of methylene chloride, and 2 ml of pyridine and then 44 μΐ (0.353 mmol) of phenyl-(chloroformate) were added to the solution. The reaction mixture was stirred for 3 hours, then another 44 μΐ of phenyl-(chloroformate) was added, and stirring was continued overnight. The next day, the solvent was evaporated, and the residue was purified by preparative liquid chromatography coupled to a mass spectrometer (LC-MS). The product thus obtained was phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate, weight 52 mg (0.113 mmol).

3-NMR spectrum (CDCl ₃ , δ): 2.09 (m, 4H); 3.66 (m, 2H); 3.98 (s, 3H); 4.16 (m, 2H); 4.98 (m, 1H); 5.24 (s, 2H); 7.09 (m, 3H); 7.23 (m, 4H); 7.41 (m, 2H); 7.62 (s, 1H); 8.20 (wide d, J =

72.227/BE

268 :·· ·.............

-· .· .· ♦ · · · · · « · ··· ·· W * A Ml

7, 80 Hz, 1H); 8.33 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 460.

245, example:

(Tetrahydro-2H-pyran-4-yl) - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

a) (4-Nitrophenyl)-(tetrahydro-2H-pyran-4-yl)carbonate

1.0 ml (10.5 mmol) of tetrahydro-2H-pyran-4-ol was dissolved together with 2.0 ml of N-methylmorpholine in 20 ml of methylene chloride, and 1.98 g (9.82 mmol) of (4-nitrophenyl)-(chloroformate) was added slowly to the solution. The reaction mixture was stirred for 5 h, then diluted with methylene chloride, and washed with water, 1.0 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, evaporated, and the remaining crude product was purified by flash chromatography on silica gel, eluting the column with a 4:1 mixture of ethyl acetate and heptane. The mass of (4-nitrophenyl)-(tetrahydro-2H-pyran-4-yl)carbonate thus obtained was 1.5 g (5.62 mmol).

3-NMR spectrum (CDCl ₃ , δ): 1.87 (m, 2H); 2.06 (m, 2H); 3.58 (m, 2H); 3.98 (m, 2H); 4.97 (m, IH) ; 7.40 (d, J = 9.0 Hz, 2H); 8.30 (d, J = 9.0 Hz, 2H).

b) (Tetrahydro-2H-pyran-4-yl)-[N-{4-[4-amino-7-(tetrahydro-

-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate] mg (0.168 mmol) 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro72.227/BE

269 :......

• * * _ ♦ ♦ * ··· ·· ·· ·· · · * · · · ·

-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 90 mg (0.336 mmol) (4-nitrophenyl)-(tetrahydro-2H-pyran-4-yl)-carbonate and 1 ml of pyridine are stirred for 5 hours, then another 90 mg of (4-nitrophenyl)-(tetrahydro-2H-pyran-4-yl)-carbonate are added, and stirring is continued for 2 days. Then the reaction mixture is heated to 70 °C, kept at this temperature for 2 hours, finally the solvent is evaporated, and the evaporation residue is purified by preparative thin layer chromatography. The product thus obtained was (tetrahydro-2H-pyran-4-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate, mass 30 mg (0.064 mmol).

3-NMR spectrum (CDCl ₃ , δ): 1.78 (m, 4H); 2.08 (m, 4H); 3.60 (m, 4H); 3.94 (s, 3H); 3.97 (m, 2H); 4.15 (m, 2H); 4.98 (m, 2H); 5.23 (s, 2H); 6.78 (s, 1H); 7.04 (s, 1H); 7.07 (d, J = 8.3 Hz, 1H); 8.16 (broad d, J = 7.90 Hz, 1H); 8.33 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 468.

Example 246:

[ (3-Pyridyl)-methyl] - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

a) (4-Nitrophenyl)-[(3-Pyridyl)methyl]carbonate

2.49 g (12.3 mmol) of (4-nitrophenyl)-(chloroformate) were dissolved in 20 ml of methylene chloride, the solution was immersed in an ice-water bath, then 1.0 ml (10.3 mmol) of (3-pyridyl)methanol and 2.0 ml (18.5 mmol) of N-methylmorpholine were added slowly. After the addition, the mixture was stirred cold for another 20 minutes, then allowed to warm to room temperature, and after 30 minutes

72.227/BE

270 :·..................

** · «« -Μ* «· * ethyl acetate is added and filtered. The filtrate is washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered, evaporated, and the remaining dark brown solid is recrystallized from a mixture of ethyl acetate and heptane. The mass of [ (3-pyridyl)-methyl] -(tetrahydro-2H-pyran-4-yl)-carbonate thus obtained is 1.52 g (5.54 mmol).

¹ H-NMR spectrum (CDCl ₃ , δ): 7.38 (m, 3H); 7.79 (m, 1H); 8.28 (d, J = 9.09 Hz, 2H); 8.65 (m, 1H); 8.72 (s, 1H).

b) [(3-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.074 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is dissolved in 0.7 ml of methylene chloride, and to the solution is first added 0.7 ml of pyridine, then 30 mg (0.110 mmol) of (4-nitrophenyl)-[(3-pyridyl)-methyl]-carbonate. The reaction mixture was stirred at 100 °C overnight, then the solvent was evaporated and the residue was purified by preparative liquid chromatography coupled to a mass spectrometer. The product thus obtained was [(3-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl)carbamate], mass 12 mg (0.025 mmol).

^x H-NMR spectrum (CDCl ₃ , δ): 2.08 (m, 4H); 3.65 (m, 2H); 3.92 (s, 3H); 4.15 (m, 2H); 4.96 (m, 1H); 5.26 (s, 2H); 5.54 (broad s, 2H); 6.97 (s, 1H); 7.04 (s, 1H); 7.08 (d, J = 8.2 Hz, 1H); 7.35 (m, 2H); 7.79 (d, J = 7.8 Hz, 1H); 8.15 (m, 1H); 8.29 (s, 1H);

72.227/BE

271

8.61 (s, 1H); 8.71 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 475.

c) [(3-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]-hydrochloride mg (0.025 mmol) [(3-pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl)-carbamate]- is dissolved in 2.0 ml of ethyl acetate and 1 ml of 1.0 M diethyl ether hydrogen chloride solution is slowly added. The precipitate formed was filtered off under nitrogen gas, yielding 13 mg (0.25 mmol) of [(3-pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]-hydrochloride. ^-NMR spectrum (DMSO-d ₆ , δ): 1.91 (m, 2H) ; 2.17 (m, 2H) ; 3.54 (m, 2H) ; 3.87 (s, 3H) ; 4.03 (m, 2H) ; 4.97 (m, 1H) ; 5.23 (s, 2H) ; 7.05 (d, J = 8.2 Hz, 1H) ; 7.13 (s, 1H); 7.51 (m, 1H); 7.81 (d, J = 8.2 Hz, 1H); 7.84 (s, 1H); 7.95 (m, 1H); 8.42 (s, 1H); 8.60 (s, 1H); 8.71 (s, 1H); 8.82 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 475.

Example 247:

(2-Morpholine-ethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] hydrochloride mg (0.054 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.1 ml 2-morpholinoethanol and 0.7 ml pyridine

72.227/BE

272

The mixture was heated to 100 °C overnight and the solvent was evaporated the next day. The residue was purified by preparative reverse-phase high-pressure liquid chromatography to give 24 mg (0.048 mmol) of (2-morpholinoethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate. The solid was dissolved in 2.0 ml of ethyl acetate, 0.2 ml of 1.0 M hydrogen chloride in diethyl ether was slowly added and the precipitate was collected on a filter under nitrogen. The product thus obtained was (2-morpholinoethyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl)carbamate] hydrochloride, weight 24 mg (0.045 mmol).

¹ H-NMR spectrum (DMSO-d ₆ , δ): 1.88 (m, 2H); 2.16 (m, 2H); 3.55 (m, 8H); 3.90 (s, 3H); 4.03 (m, 2H); 4.49 (m, 2H); 4.92 (m, 1H); 7.07 (m, 1H); 7.15 (s, 1H); 7.65 (broad s, 2H); 7.84 (s, 1H); 8.45 (s, 1H); 8.75 (s, 1H); 10.95 (wide s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 497.

Example 248:

[(4-Bromo-1,3-thiazol-5-yl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde

A mixture of 3.52 g (30 mmol) of 1,3-thiazolidine-2,4-dione, 43 g (150 mmol) of phosphorus tribromide oxide and 2.56 ml (34 mmol) of N,N-dimethylformamide can be reacted for 1 hour at 75 °C and then for 5 hours at 100 °C. The reaction mixture is then cooled to room temperature.

72.227/BE

273 g, poured into 500 ml of ice water and the aqueous mixture extracted with methylene chloride. The combined organic solvent extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated and the remaining brown solid was washed with petroleum ether. The solvent was evaporated to give 1.74 g (6.42 mmol) of 2,4-dibromo-1,3-thiazole-5-carbaldehyde.

3-NMR spectrum (CDCl ₃ , δ): 9.90 (s, 1H).

b) (2,4-Dibromo-1,3-thiazol-5-yl)-methanol

1.74 g (6.42 mmol) of 2,4-dibromo-1,3-thiazole-5-carbaldehyde were dissolved in 70 ml of methanol and 0.244 g (6.42 mmol) of sodium tetrahydridoborate were added in small portions at 0 °C. After the addition, the mixture was stirred for another 10 minutes in the cold, then the ice-water bath was removed and stirring was continued at room temperature overnight. The next day, the solvent was evaporated, saturated ammonium chloride solution was added to the distillation residue, and the pH was adjusted to 10 with 1.0 M sodium hydroxide solution. The aqueous mixture was then extracted with ethyl acetate, and the combined organic solvent extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The remaining crude product was purified by flash chromatography to give 0.946 g (3.47 mmol) of (2,4-dibromo-1,3-thiazol-5-yl)methanol.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.11 (broad s, 1H); 4.79 (s, 2H).

c) (4-Bromo-1,3-thiazol-5-yl)-methanol

0.94 g (3.44 mmol) (2,4-dibromo-1,3-thiazol-5-yl)-methanol, 1.34 g sodium carbonate-water (1/3), 0.07 g 10% bone charcoal

72.227/BE

274

A mixture of palladium catalyst and 33 ml methanol was hydrogenated at 4.15 bar for 2 days, then the catalyst was filtered off through a Celite filter bed. The filtrate was evaporated and the residue was purified by flash chromatography to give 0.32 g (2.78 mmol) of (4-bromo-1,3-thiazol-5-yl)-methanol.

1 H NMR spectrum ( _CDCl3 , δ): 2.29 (broad s, 1H); 4.86 (s, 2H); 8.72 (s, 1H).

d) [(4-Bromo-1,3-thiazol-5-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 1 mg (0.061 mmol) of phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl]-carbamate], 50 mg (0.434 mmol) of (4-bromo-1,3-thiazol-5-yl)-methanol and 0.5 ml of pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give [(4-bromo-1,3-thiazol-5-yl)methyl]-[N-(4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate]. ¹ H-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 4H) ; 3.65 (m, 2H) ; 3.92 (s, 3H) ; 4.13 (m, 2H) ; 4.98 (m, 1H) ; 5.35 (s, 1H) ; 5.40 (s, 2H) ; 6.97 (s, 1H); 7.04 (s, 1H); 7.09 (m, 1H); 7.35 (s, 1H); 8.17 (s, 1H); 8.32 (s, 1H); 8.78 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 481.

72.227/BE

275

Example 249:

(3-Tetrahydrofuranyl) - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl} -carbamate] mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl} -carbamate], 0.05 ml tetrahydrofuran-3-ol and 0.5 ml pyridine are heated to 100 °C, kept at this temperature overnight, and then the solvent is evaporated the next day. The distillation residue was purified by preparative reverse-phase high-pressure liquid chromatography to give 14 mg (0.031 mmol) of (3-tetrahydrofuranyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate.

3-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 6H); 3.66 (m, 2H); 3.96 (m, 7H); 4.13 (m, 2H); 4.98 (m, 1H); 5.26 (s, 2H); 5.40 (m, 1H); 6.97 (s, 1H); 7.04 (s, 1H); 7.08 (d, J = 8.2 Hz, 1H); 7.26 (s, 1H); 8.30 (s, 1H); 8.32 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 455.

250, example:

(1,3-Dioxan-5-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-H)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]

[(1,3-Dioxolan-4-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.065 mmol) phenyl-[N-{ 4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2H-carbamate]

276

-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate], 0.05 ml of glycerol formal (a mixture of 1,3-dioxan-5-ol and 1,3-dioxolane-4-methanol) and 0.5 ml of pyridine are heated to 100 °C, kept at this temperature overnight, and the solvent is evaporated the next day. The evaporation residue is purified by preparative reverse phase high pressure liquid chromatography, which results in two products.

One of the products is (1,3-dioxan-5-yl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-carbamate], the mass of which is 2 mg (0.004 mmol). ¹ H-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 4H) ; 3.66 (m, 2H) ; 3.92 (m, 3H) ; 4.07 (m, 6H) ; 4.79 (m, 1H) ; 4.83 (d, J = 6.3 Hz, 1H) ; 4.96 (m, 1H) ; 5.04 (d, J = 6.3 Hz, 1H) ; 6.15 (very broad s, 2H); 6.96 (s, 1H); 7.05 (m, 2H); 7.53 (s, 1H); 8.15 (d, J = 8.2 Hz, 1H); 8.22 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 471.

The other product is [(1,3-Dioxolan-4-yl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate], the mass of which is 6.0 mg (0.013 mmol).

3-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 4H); 3.66 (m, 2H); 3.75 (m, 1H); 3.92 (m, 3H); 4.03 (m, 1H); 4.13 (m, 1H); 4.34 (m, 2H);

4.94 (s, 1H); 4.97 (m, 1H); 5.10 (s, 1H); 5.32 (broad s, 2H); 6.97 (s, 1H); 7.03 (m, 2H); 7.06 (d, J = 8.2 Hz, 1H); 7.38 (s, 1H); 8.15 (d, J = 7.9 Hz, 1H); 8.31 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 471.

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277 ··** *·*· * * 4< *· »«·

Example 251:

[ (2-Pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)~7H-pyrrolo[2, 3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate]-hydrochloride A mixture of 1 mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.05 ml (2-pyridyl)-methanol and 0.5 ml pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 11 mg (0.023 mmol) of [(2-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]. The solid was dissolved in 2 mL of ethyl acetate, 0.1 mL of 1.0 M hydrogen chloride in diethyl ether was added slowly, and the precipitate was filtered off under nitrogen. The product thus obtained is [(2-pyridyl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]-hydrochloride, the weight is 12 mg (0.023 mmol). ^x H-NMR spectrum (DMSO-d ₆ , δ): 1.92 (m, 2H); 2.16 (m, 2H); 3.55 (m, 2H); 3.89 (s, 3H); 4.02 (m, 2H); 4.91 (m, 1H); 5.23 (s, 2H); 7.05 (d, J = 8.2 Hz, 1H); 7.14 (s, 1H); 7.37 (m, 1H); 7.53 (d, J = 7.8 Hz, 1H); 7.87 (m, 3H); 8.42 (s, 1H); 8.57 (d, J = 4.2 Hz, 1H); 8.85 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 475.

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278 ••“•ο ··»··.·· ·ν.$ .»

Λ· ;·

Example 252:

[ (4-Pyridyl) -methyl] - [Ν- {4-[4-amino-7-(tetrahydro-2H-pyran-4-yl) -7H-pyrrolo[2,3-d]pyrimidin-5-yl] -2-methoxyphenyl} -carbamate] -hydrochloride A mixture of mg (0.065 mmol) phenyl-[ N- {4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl] -2-methoxyphenyl) -carbamate] , 0.05 ml (4-pyridyl)-methanol and 0.5 ml pyridine is heated to 100 °C, kept at this temperature overnight, and the solvent is evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 11 mg (0.023 mmol) of [(4-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]carbamate. The solid was dissolved in 2 mL of ethyl acetate, 0.1 mL of 1.0 M hydrogen chloride in diethyl ether was added slowly, and the precipitate was filtered off under nitrogen. The product thus obtained is [(2-pyridyl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl)carbamate]-hydrochloride, the weight is 12 mg (0.023 mmol). ¹ H-NMR spectrum (DMSO-d ₆ , δ): 1.91 (m, 2H); 2.16 (m, 2H); 3.55 (m, 2H); 3.90 (s, 3H); 4.03 (m, 2H); 4.92 (m, 1H); 5.34 (s, 2H);

7.06 (d, J = 8.2 Hz, 1H); 7.16 (s, 1H); 7.73 (m, 1H); 7.81 (m,

1H); 7.87 (s, 1H); 8.46 (s, 1H); 8.76 (d, J = 5.6 Hz, 1H); 9.05 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 475.

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Example 253:

[ (5-Methyl-isoxazol-3-yl)-methyl]-[N-{4-[4-amino-7- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 1 mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate], 0.05 ml (5-methyl-isoxazol-3-yl)-methanol and 0.5 ml pyridine was heated to 100 °C, kept at this temperature overnight, and the solvent was evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 18 mg (0.038 mmol) of [(5-methylisoxazol-3-yl)methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate].

¹ H-NMR spectrum (CDCl ₃ , δ): 2.06 (m, 2H); 2.44 (s, 3H); 3.64 (m, 2H); 3.91 (s, 3H); 4.13 (m, 2H); 4.96 (m, 1H); 5.26 (s, 2H); 6.12 (s, 1H); 6.95 (s, 1H); 7.06 (m, 2H); 7.39 (s, 1H); 8.17 (broad s, 1H); 8.21 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 479.

Example 254:

[(2S)~(5-oxo-pyrrolidin-2-yl)-methyl]-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate] mg (0.065 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-carbamate], 0.05 ml (5S)-5-(hydroxymethyl)-2-pyrrolidinone and 0.5

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P02 405. ml pyridine mixture was heated to 100 °C, kept at this temperature overnight, then the solvent was evaporated the next day. The evaporation residue was purified by preparative reverse phase liquid chromatography (LC-MS), resulting in 10 mg (0.021 mmol) of [ (2S) - (5-oxo-pyrrolidin-2-yl)-methyl] -[ N -{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl] -2-methoxy-phenyl}-carbamate].

3-NMR spectrum (CDCl ₃ , δ): 1.90 (m, 2H); 2.06 (m, 4H); 2.34 (m, 1H); 2.41 (m, 2H); 3.64 (m, 2H); 3.94 (s, 3H); 4.04 (m, 2H);

4.14 (m, 2H); 4.98 (m, 1H); 5.33 (m, 3H); 6.10 (s, 1H); 6.98 (s, 1H); 7.04 (s, 1H); 7.09 (m, 1H); 7.31 (s, 1H); 8.11 (broad s, 1H); 8.32 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 481.

Example 255:

(4-Aminobenzyl) - [N-{4-[4-amino-7-(tetrahydro-2H-pyran-4~H)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

a) (tert-Butyl) -{N- [4-(hydroxymethyl)-phenyl] -carbamate]

1.23 g (10 mmol) 4-aminobenzyl alcohol, 2.6 ml (15 mmol)

A mixture of N,N-diisopropylethylamine, 2.62 g di(tert-butyl)dicarbonate and 50 ml methylene dichloride was stirred overnight at room temperature, then diluted with ethyl acetate the next day, washed with water, 1.0 M hydrochloric acid, saturated sodium carbonate solution, water again, and finally saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The remaining crude product was purified by flash chromatography, eluting the column with a 2:3 mixture of ethyl acetate and heptane, which resulted in

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Sun

281 gives 2.16 g (9.67 mmol) of (tert-butyl)-{N-[4-(hydroxymethyl)phenyl]carbamate}.

3-NMR spectrum (CDCl ₃ , δ): 1.52 (s, 9H); 4.63 (s, 2H); 6.47 (broad s, 1H); 7.30 (d, J = 8.5 Hz, 2H); 7.36 (d, J = 8.5 Hz 2H).

b) (4-Amino-benzyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate] A mixture of 100 mg (0.111 mmol) phenyl-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-carbamate], 119 mg (0.533 mmol) (tert-butyl)-{N-[4-(hydroxymethyl)-phenyl]-carbamate} and 0.8 ml pyridine is heated to 100 °C, kept at this temperature overnight, and the solvent is evaporated the next day. The distillation residue was purified by preparative reverse phase liquid chromatography (LC-MS) to give 9 mg (0.015 mmol) of (4-aminobenzyl)-[N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate.

3-NMR spectrum (CDCl ₃ , δ): 1.52 (s, 1H); 2.08 (m, 4H); 3.65 (m, 2H); 3.90 (s, 3H); 4.14 (m, 2H); 4.97 (m, 1H); 5.17 (s, 2H); 5.37 (broad s, 1H); 6.55 (s, 1H); 6.95 (s, 1H); 7.03 (s, 1H); 7.06 (m, 1H); 7.31 (s, 1H); 7.38 (m, 3H); 8.16 (broad s, 1H); 8.30 (s, 1H).

Mass spectrum (LC-MS): MH ⁺ = 589.

Example 256:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-benzamide

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282 mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine were dissolved in 2.0 ml of methylene chloride, then 2.0 ml of pyridine and then 41 μΐ (0.353 mmol) of benzoyl chloride were added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated, the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide, and 1 ml of methanol was added to the solution. The resulting precipitate was filtered off to give 64 mg (0.144 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}benzamide.

1 H-NMR spectrum ( _CDCl3 , H): 2.12 (m, 4H); 3.67 (m, 2H); 3.99 (s, 3H); 4.17 (m, 2H); 4.99 (m, 1H); 7.03 (s, 1H); 7.04 (s, 1H); 7.14 (d, J = 8.2 Hz, 1H); 7.53 (m, 3H); 7.94 (d, J = 7.8 Hz, 1H); 8.33 (s, 1H); 8.58 (s, 1H); 8.63 (d, J = 8.2 Hz, 1H). Mass spectrum (LC-MS): MH ⁺ = 444.

Example 257:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2-pyridinecarboxamide mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 2.0 ml of methylene chloride, and 2.0 ml of pyridine and then 63 mg (0.353 mmol) of 2-pyridinecarbonyl chloride hydrochloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide. 1 ml of methanol is added to the solution, then the resulting precipitate is filtered off, yielding 84 mg

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283 V (0.189 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2-pyridinecarboxamide is obtained.

^Χ Η-ΝΜΚ-spectrum (CDC1 ₃ , δ): 2.12 (m, 4H); 3.67 (m, 2H); 4.03 (s, 3H); 4.14 (m, 2H); 5.00 (m, 1H); 5.37 (s, 1H); 7.04 (s, 1H);

7.09 (s, 1H); 7.14 (d, J = 8.2 Hz, 1H); 7.50 (m, 1H); 7.92 (m, 1H); 8.33 (s, 1H); 8.70 (d, J = 8.2 Hz, 1H); 10.62 (s, 1H). Mass spectrum (LC-MS): MH ⁺ = 445.

Example 258:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide mg (0.236 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 2.0 ml of methylene chloride, and first 2.0 ml of pyridine and then 63 mg (0.353 mmol) of 2-pyridinecarbonyl chloride hydrochloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, yielding 30 mg (0.065 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.

3-NMR spectrum (CDCl ₃ , δ): 2.11 (m, 4H); 2.32 (s, 3H); 3.66 (m, 2H); 3.99 (s, 3H); 4.13 (m, 2H); 4.17 (s, 3H); 4.99 (m, 1H); 5.22 (broad s, 2H); 6.46 (s, 1H); 7.03 (s, 1H); 7.07 (s, 1H);

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7.12 (d, J = 8.2 Hz, 1H); 8.33 (2, 2H); 8.49 (d, J = 8.2 Hz, 1H). Mass spectrum (LC-MS): MH ⁺ = 462.

Example 259:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-2,2-dimethylpropionic acid amide mg (0.147 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine and then 31 mg (0.221 mmol) of 2,2-dimethylpropionyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethylsulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, resulting in 27 mg (0.064 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-2,2-dimethylpropionic acid amide.

² H-NMR spectrum (CDCl ₃ , δ): 1.35 (s, 9H); 2.09 (m, 4H); 3.66 (m, 2H); 3.96 (s, 3H); 4.13 (m, 2H); 4.97 (m, 1H); 5.46 (broad s, 2H); 6.98 (s, 1H); 7.04 (s, 1H); 7.07 (d, J = 8.2 Hz, 1H); 8.15 (s, 1H); 8.29 (s, 1H); 8.49 (d, J = 8.2 Hz, 1H).

Mass spectrum (LC-MS): MH ⁺ = 424.

Example 260:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}cyclopentanecarboxamide mg (0.147 mmol) 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro72.227/BE

285 :......:

-J-7:

-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine was added, followed by 31 mg (0.221 mmol) of cyclopentanecarbonyl chloride. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethyl sulfoxide. 1 ml of methanol was added to the solution, and the resulting precipitate was filtered off, resulting in 33 mg (0.076 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-cyclopentanecarboxamide.

¹ H-NMR spectrum (CDCl ₃ , δ): 1.66 (m, 2H); 1.81 (m, 2H); 1.95 (m,

4H); 2.06 (m, 4H); 2.77 (m, 1H); 3.65 (m, 2H); 3.94 (s, 3H);

4.15 (m, 2H); 4.96 (m, 1H); 5.37 (broad s, 2H); 6.98 (s, 1H);

7.03 (s, 1H); 7.07 (d, J = 8.2 Hz, 1H); 7.84 (s, 1H); 8.30 (s,

1H); 8.49 (d, J = 8.2 Hz, 1H).

Mass spectrum (LC-MS): MH ⁺ = 437.

Example 261:

N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropionic acid amide mg (0.147 mmol) of 5-(4-amino-3-methoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was dissolved in 1.5 ml of methylene chloride, and first 1.5 ml of pyridine and then 37 mg (0.221 mmol) of 3-phenylpropionyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was evaporated, and the evaporation residue was dissolved in 1 ml of dimethylsulfoxide. 1 ml of methanol was added to the solution, followed by the

72.227/BE r

' y 286 :......

V .*“· ·.? -J- 7:

The resulting solid precipitate was filtered off to give 7 mg (0.015 mmol) of N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl]-3-phenylpropionic acid amide.

¹ H-NMR spectrum (CDCl ₃ , δ): 2.07 (m, 4H); 2.75 (m, 2H); 3.09 (m, 2H); 3.65 (m, 2H); 3.88 (s, 3H); 4.13 (m, 2H); 4.96 (m, 1H); Γ

5.97 (broad s, 2H); 6.93 (s, 1H); 7.05 (m, 2H); 7.26 (m, 5H);

7.70 (s, 1H); 8.24 (s, 1H); 8.46 (d, J = 8.2 Hz, 1H). Mass spectrum (LC-MS): MH ⁺ = 472.

262-267, examples:

The compounds of Examples 262-267 were synthesized following the following procedure:

To a mixture of 0.25 g (0.575 mmol) of cis-5-(4-amino-3-methoxyphenyl)-7-[4Γ - (4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2.5 ml of pyridine and 2.5 ml of methylene chloride was added the appropriate acid chloride (0.862 mmol), and the reaction mixture was stirred under nitrogen at room temperature for 1 hour. The solvent was then evaporated in vacuo and the residue was purified by reverse phase preparative chromatography.

280 mg (0.460 mmol) of the compound obtained as described above were dissolved in 25 ml of hot ethyl acetate, and then a solution of 160 mg (1.38 mmol) of maleic acid in 10 ml of ethyl acetate was added. The mixture was allowed to cool to room temperature, stirred for 1 hour, then the solid was filtered off and dried. The product obtained was 370 mg of the trimaleate salt.

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287

The experimental conditions for determining the high-performance liquid chromatography retention times (RT) of the compounds indicated under the structural formulae are as follows: a reversed-phase analytical column (Hypersil HS C18, 4 pm, 100 A, 250 x 4.6 mm) is used, and the elution is performed by forming a linear gradient, during which the proportion of acetonitrile in the mixture of acetonitrile-0.1 M ammonium acetate solution is increased from 25 to 100% over 10 minutes at a flow rate of 1 ml/min. The molecular weight (MH ⁺ ) determined by mass spectrometry is also given under the formulas.

Example 262

RT :6.62

MH+: 576.3 Gradient a

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288

Example 263

RT:7.7 MH+: 608.2 Gradient a

Example 264

RT : 14.23

MH+: 588.3 Gradient b

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289

RT :6.85

MH+: 540.2 Gradient a

Example 266

RT :8.15

MH+: 608.2 Gradient a

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Example 267

RT: 8.15 MH+: 642.3

General procedure for salt formation: Dissolve trans-Benzyl-{N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate in ethyl acetate, and add 280 mg of a solution of maleic acid in ethyl acetate. The resulting solid precipitate is filtered off under a stream of nitrogen and dried under vacuum for 4 hours. The resulting 580 mg of cream-colored solid is cis-benzyl-{N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate}-trimaleate. The melting point of the product: 158 °C (decomposes), high-pressure liquid chromatography retention time: 13.30 minutes (acetonitrile—0.1 M ammonium acetate solution, 5%-95% acetonitrile over 20 minutes), 94%.

The following compounds are prepared in the same way, which

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The given liquid chromatography (LC-MS) retention times (RT) were determined on a Perkin Elmer column (Pecosphere C18, 3 gm, 33 x 4.6 mm; 3.5 ml/min, 0%-100% acetonitrile—50 mM ammonium acetate solution over 4.5 min). The molecular weight (MH ⁺ ) is also reported with the formulas.

Time MH+

Structure

2.92 497.1

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292

3.02 497.2

2.64 481.2

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293

2.7 481.2

Example 268:

cis- and trans-N-{4-(4-Amino-7- [4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-3-phenylpropionic acid amide

Weigh out 0.8 g (2.3 mmol) of 4-[4-amino-5-(4-amino-3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 45 ml of a 1:2 mixture of pyridine——methylene dichloride, then add a solution of 0.57 g (3.4 mmol) of 3-phenylpropyl chloride in 2 ml of methylene dichloride under nitrogen at 0 °C. The reaction mixture is stirred for 2 hours at 0 °C, then quenched with 50 ml of saturated, aqueous citric acid solution. The organic phase is washed twice with 50 ml of saturated, aqueous citric acid solution, dried, filtered, evaporated, and the remaining 1.0 g of brown foam is dissolved in 100 ml of methylene dichloride. To the solution were first added 0.63 g (6.3 mmol) of N-methylpiperazine and 0.38 g (6.3 mmol) of acetic acid, then in small portions 0.67 g

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294 μl (3.15 mmol) of sodium-[triacetoxyhydridoborate] are added, then the reaction mixture is stirred overnight at room temperature, the next day it is decomposed with 50 ml of saturated aqueous sodium bicarbonate solution, and the aqueous mixture is extracted three times with 100 ml of methylene chloride. The combined organic solvent extracts are dried over sodium sulfate, filtered, the solvent is evaporated, and the muddy residue is purified by flash chromatography on silica gel, eluting with a mixture of methylene chloride and methanol, gradually increasing the proportion of methanol from 0% to 50% in 5% steps. The fractions containing the faster moving isomer are combined and evaporated to give 0.26 g of cis-N-{4-(4-amino-7-[ 4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3-phenyl-propionic acid amide. This was dissolved in 5 ml of ethyl acetate, a solution of 160 mg of maleic acid in 2 ml of ethyl acetate was added, and the resulting solid precipitate was filtered off. The resulting 260 mg of white solid was cis-N-{4-(4-amino-7-[4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3-phenyl-propionic acid amide trimaleate, the product liquid chromatography (analytical LC-MS) retention time: 2.86 min (Pecosphere C18 column, 3 pm, 33 x 4.6 mm;), starting with 0% B:A mixture, and 3.5 at a flow rate of 100 ml/min, eluting with 100% B:A over 4.5 min (B = acetonitrile; A = 50 mM ammonium acetate solution, pH 4.5). Mass spectrum (MH ⁺ ): 568.4.

The fractions containing the slower moving isomer were combined and evaporated, yielding 0.11 g of trans-N-{ 4-(472.227/BE

295

.... .... --j ♦ ♦·*· ♦ · * * * *·

-amino-7-[4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-3-phenyl-propionic acid amide is obtained, which is dissolved in 5 ml of ethyl acetate and a solution of 68 mg of maleic acid in 2 ml of ^ethyl acetate is added. The solid precipitate that separates is filtered off, thus obtaining cis-N-{4-(4-amino-7-[4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3-phenyl-propionic acid amide trimaleate. The product is a white solid, weight 94 mg, liquid chromatography (analytical LC-MS) retention time: 2.68 min (Pecosphere C18 column, 3 pm, 33 x 4.6 mm;), starting with 0% B:A and eluting at a flow rate of 3.5 ml/min, ending with 100% B:A over 4.5 min (B = acetonitrile; A = 50 mM ammonium acetate solution at pH 4.5). Mass spectrum (MH ⁺ ): 568.2.

2.25 g (6.5 mmol) 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.17 g (19.5 mmol) acetic acid, 1.95 g

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296

To a mixture of N-methylpiperazine (19.5 mmol) and 200 ml of methylene chloride was added in small portions 2.07 g (9.75 mmol) of sodium [triacetoxyhydridoborate], and the reaction mixture was stirred overnight at room temperature. The next day, 150 ml of saturated aqueous sodium bicarbonate solution was added to the mixture, and the aqueous mixture was extracted three times with 100 ml of methylene chloride. The combined organic solvent extracts were dried over sodium sulfate, filtered, the solvent was evaporated, and the semi-solid residue was purified by flash chromatography on silica gel, eluting with a mixture of methylene chloride and methanol, gradually increasing the proportion of methanol from 0% to 50% in 5% increments. The fractions containing the faster moving isomer were combined and evaporated to give cis-5-(4-amino-3-methoxyphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-4-amine as a cream solid. The product weight was 1.2 g, the HPLC retention time was 11.2 min (97.6%), the yield was 43%.

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.1 (1H, s); 7.11 (1H, s); 6.87 (1H, s); 6.79 (1H, d); 6.05 (2H, broad s); 4.80 (2H, broad s); 4.64 (1H, m); 4.08 (1H, m); 3.82 (3H, s); 3.17 (2H, m); 2.37 (6H, m); 2.21 (3H, s); 2.08 (4H, m); 1.70 (2H, m); 1.53 (2H, m).

The fractions containing the slower moving isomer were combined and evaporated to give 0.4 g of trans-5-(4-amino-3-methoxyphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-4-amine. The product was a white solid, HPLC retention time: 10.13 min (97.9%), yield: 14%.

72.227/BE

297 r...... ’·*: ·’ .j» ./.. %

H-NMR spectrum (DMSO~d _s , 400 MHz, δ): 8.10 (1H, s); 7.26 (1H, s); 6.87 (1H, s); 6.77 (1H, d); 6.71 (1H, d); 6.05 (2H, broad s); 4.79 (2H, s); 4.52 (1H, m); 3.81 (3H, s); 3.35 (1H, m); 2.50 (5H, m); 2.31 (5H, m); 2.14 (1H, m); 1.97 (6H, m); 1.45 (2H, m).

mg (0.069 mmol) of cis-5-(4-amino-3-methoxyphenyl)-7-(4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-amine was dissolved in 0.5 ml of pyridine, and 2 equivalents (0.138 mmol) of the corresponding acid chloride were added to the solution. The vial was sealed, shaken on an orbital shaker overnight, and the next day, two additional portions of 1 equivalent each, for a total of 0.138 mmol, of acid chloride were added to the mixture. The reaction mixture is shaken again overnight and then subjected to liquid chromatography coupled to a mass spectrometer (LC-MS Micromass; column: Pecosphhere, C18, 3 pm, 33 x 4.6 mm; eluent: starting with 0% B:A and changing the ratios to 100% B:A over 4.5 minutes at a flow rate of 3.5 ml/min; B = acetonitrile; A = 50 mM ammonium acetate solution at pH 4.5) to detect the presence of the expected product in each case. The solutions are then evaporated to dryness and the evaporation residues are purified by reverse-phase preparative high-pressure liquid chromatography.

Examples 269-293:

Following the procedures outlined in Example 268, the compounds of Examples 269-293 were prepared, the structures and liquid chromatography/mass spectrometry (LC-MS) data of which are reported below.

72.227/BE

298

RT :2.61

MH+: 576.3

RT :3.02

MH+: 570.3

RT :2.61

MH+: 600.3

Example 272

RT: 3.26 MH+: 608.3

72.227/BE

299

Example 273

Example 274. ci

RT :2.78

MH+: 558.4

RT :2.74

MH+: 570.3

Example 275

Example 276

RT :3.00

MH+: 574.3

RT :2.76

MH+: 570.3

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300

Example 277

RT :3.26

MH+: 608.3

Example 278

RT :2.94

MH+: 570.3

Example 279

RT :3.16

MH+: 580.3

RT :3.13

MH+; 604.3

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301

RT :2.68

MH+: 565.3

RT :2.90

MH+: 585.3

RT :2.84

MH+: 585.3

RT :2.90

MH+: 576.3

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302

RT :2.90

MH+: 584.4

Example 286

RT :2.74

MH+: 565.6

RT :3.06

MH+: 576.3

RT :2.53

MH+: 575.3

72.227/BE

303

CH3 Example 289 RT :3.32 MH+: 624.3 ^F \ / c _H3 h Ο N—ci \—/ O NH2 \_/ h 1 7 o ^λ —N CH3 Example 291 RT :2.76 MH+: 592.3 ch ₃ Example 290 RT :2.85 MH+: 594.4 H3C N—CH3 ch ₃ h OON—A \—/ ^x o NH2 \_/ h 1 / o '—N CH3 Example 292 RT : 2.86 MH+: 583.3

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304

RT :2.29

MH+: 508.3

Examples 294-301:

General procedure

a) The procedure

A mixture of 7.60 mmol of the appropriate piperazine derivative, 2.53 mmol of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-ylcyclohexanone, 7.60 mmol of concentrated, anhydrous acetic acid and 50 ml of methylene chloride is stirred for 1.5 hours at room temperature, then 3.28 mmol of sodium [triacetoxyhydridoborate] is added, and stirring is continued for another 16 hours at room temperature. Subsequently, a solution of 1.35 g of sodium bicarbonate in 50 ml of water is added, the aqueous mixture is allowed to stir for another hour, then the organic phase is separated, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The

72.227/BE

305 ................ ..

··· · · ·«· ··· *· ·· ·· ·· The remaining brown oil is purified by flash chromatography on silica gel to give the corresponding cis- and trans-5-(4-phenoxyphenyl)-7-[(4-substituted-piperazin1 yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

b) Procedure B

A mixture of 7.53 mmol of the appropriate pyrrolidine derivative, 2.51 mmol of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-ylcyclohexanone, 7.35 mmol of concentrated, anhydrous acetic acid and 45 ml of methylene chloride is stirred for 30 minutes at room temperature, then 3.26 mmol of sodium [triacetoxyhydridoborate] is added, and stirring is continued for a further 22 hours at room temperature. This is followed by the addition of 1.35 g of sodium bicarbonate in 50 ml of water, the aqueous mixture is allowed to stir for another hour, then the organic phase is separated, dried over magnesium sulfate, filtered and the filtrate is evaporated. The remaining brown oil was purified by flash chromatography on silica gel to give the corresponding cis- and trans-5-(4-phenoxyphenyl)-7-[(4-substituted-pyrrolidin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

c) Salt formation

2.48 mmol of the pyrrolopyrimidine derivative prepared as described in a) or b) above are dissolved in hot ethanol, and 7.28 mmol of a solution of maleic acid in ethanol are added. The mixture is then cooled to room temperature, the white solid precipitate formed is filtered off, and then dried in vacuo to give the desired trimaleate salt. In this manner, the following compounds are prepared, which are

72.227/BE

In addition to the formula of 306, we also provide the retention times (RT) and the mass of the molecular ion (MH + ) measured during the analysis by reversed-phase high-pressure liquid chromatography [Hypersil HyPurity Elite C18 column, 5 μm, 200 A, 250 x 4.6 mm; forming a linear gradient at a flow rate of 1 ml/min in a mixture of acetonitrile and 0.1 M ammonium acetate solution, the ratio of acetonitrile is increased from 25% to 100% in 10 minutes (Gradient a) or 25 minutes (Gradient ^b )].

Example 294

RT :7,967

MH+: 511.1 Gradient a

Example 295

RT :7.383 MH+: 527.2 Gradient a

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307

Example 29β

RT: 13.941 MH+: 497.1

Gradient b

Example 297

RT : 7.733 MH+: 511.2 Gradient a

Example 298

RT : 14.067 MH+: 497.1 Gradient b

Example 299

RT: 13.891 MH+: 497.1

Gradient b

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308

Example 300

RT : 14.067 MH+: 497.1 Gradient b

RT : 7,750

MH+: 527.2 Gradient a

Example 302:

cis- and trans-4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-(1-hydroxycyclohexyl)methylcyanide

0.649 g (0.0050 mol) of diisopropylamine was dissolved in 10 ml of tetrahydrofuran and the solution was cooled to 0 °C. 3.14 ml (0.0050 mol) of a 1.6 M butyllithium solution in hexane was added dropwise, keeping the temperature below 5 °C throughout, the mixture was stirred for another 20 minutes at 0 °C, then cooled to -78 °C and 0.175 g (0.0043 mol) of anhydrous acetonitrile was added at a temperature below -70 °C. This time, the mixture is allowed to stir at -78 °C for 20 minutes, then a solution of 1.000 g (0.0025 mol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone in 10 ml of tetrahydrofuran is added, and 10 ml of

72.227/BE

309 hexamethylphosphoric triamide, taking care to keep the temperature below -70 °C throughout. After the addition, stirring is continued at -78 °C for 30 minutes and then at room temperature for 18 hours, then the reaction mixture is partitioned between methylene chloride and saturated aqueous ammonium chloride solution. The organic phase is washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, finally the solvent is evaporated in vacuo, and the cis- and trans-isomer is separated by flash chromatography on silica gel, eluting the column with a 95:5 mixture of methylene chloride and methanol. In this way, 0.120 g (0.00027 mol) of less polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-(1-hydroxycyclohexyl)-methyl cyanide and 0.170 g (0.00038 mol) of more polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-(1-hydroxycyclohexyl)-methyl cyanide are obtained.

The less polar isomer has a high-performance liquid chromatography retention time of 15.90 minutes (reversed phase, Delta Pák C18, 5 pm, 300 A, 15 cm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 minutes, 1 ml/minute).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (s, 1H); 7.48 (d, 2H); 7.41 (t, 2H); 7.37 (s, 1H); 7.15 (t, 1H); 7.093 (d, 2H); 7.088 (d, 2H); 6.11 (broad, 2H); 5.05 (s, 1H); 4.53-4.61 (m, 1H); 2.66 (s, 2H); 2.18 (q, 3H); 1.80 (t, 4H); 1.66 (t, 2H). Mass spectrum: MH+ = 440.

The more polar isomer (probably trans-isomer, the aryl axial, the hydroxy axial) has a high-pressure liquid chromatography retention time of 15.88 minutes (reversed phase, Delta Pák C18, 5 pm, 300

72.227/BE

310 ..................

• · · · · * ··· * * · ··· • · · *· ·· ··

A, 15 cm; 5%-85% acetonitrile-0.1 M ammonium acetate solution over 20 min, 1 ml/min).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.13 (s, 1H); 7.63 (s,

1H); 7.48 (d, 2H); 7.41 (t, 2H); 7.15 (t, 1H); 7.11 (d, 2H);

7.08 (d, 2H); 6.11 (broad, 2H); 5.22 (s, 1H); 4, 62-4, 67 (m,

1H); 2.98 (s, 2H); 1.82-1.99 (m, 6H); 1.65-1.73 (m, 2H).

Mass spectrum: MH+ = 440.

303, example:

cis- and trans-5-(4-Amino-3-fluorophenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

a) (tert-Butyl)-[N-(4-bromo-2-fluorophenyl)carbamate]

24.78 g (130.4 mmol) of 4-bromo-2-fluoroaniline are dissolved in 250 ml of tetrahydrofuran, and 270 ml (270 mmol; 2.05 equivalents) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran are added dropwise over 15 minutes under a nitrogen atmosphere. After 15 minutes, 34.12 g (156.3 mmol; 1.2 equivalents) of di(tert-butyl)dicarbonate are added in portions, carefully, as the reaction is slightly exothermic, and the reaction mixture, which has become very viscous, is stirred for another 4 hours, at which time thin-layer chromatography analysis (solvent system ethyl acetate and heptane 1:9) shows that the reaction is complete. The mixture was then concentrated in vacuo, the residue was partitioned between 300 ml of ethyl acetate and 150 ml of saturated aqueous sodium bicarbonate solution, and the aqueous portion was extracted twice more with 200 ml of ethyl acetate. The combined organic solvent extracts were dried over sodium sulfate, the

72.227/BE

311 ..................

• · · · · ♦ ·«4 *4 ·* ·· the solvent is evaporated in vacuo, and finally the remaining crude product is purified by chromatography, forming a gradient, eluting with a solvent mixture containing 10 15o ethyl acetate and heptane. The resulting 30.0 g waxy, pale yellow solid is (tert-butyl)-[N-(4-bromo-2-fluorophenyl)carbamate], the yield is 79%.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz, δ): 1.51 (9H, s); 7.22 (1H, m); 7.24 (2H, m).

b) (tert-Butyl)-{N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-carbamate}

A mixture of 54.0 g (0.186 mmol) (tert-butyl) -[ N - (4-bromo-2-fluorophenyl) -carbamate], 56.8 g (223.3 mmol; 1.2 equivalents) bis(pinacolato)-diborane, 54.7 g (558 mmol; 3.0 equivalents) potassium acetate, 4.65 g (5.58 mmol; 0.03 equivalents) [1,1'-bis(diphenylphosphino)-ferrocene] -palladium(II)-chloride and 1000 ml of degassed N,N-dimethylformamide is heated to 80 °C under nitrogen gas, kept at this temperature for 16 hours, then the N,N-dimethylformamide is evaporated in vacuo and the dark, solid residue is dissolved in 500 ml of methylene dichloride. The inorganic residues are filtered off on a filter bed made of silica gel and the filtrate is purified by chromatography, eluting with a gradient of 10-15% ethyl acetate/heptane. In this way, 56.5 g of (tert-butyl)-{N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl]carbamate are obtained as a yellow, viscous oil that crystallizes on standing, yield 92%. High-pressure liquid chromatography retention time of the product: 10.16 min (reversed phase, Hypersil

72.227/BE

312 .................

* · · » ♦ * ··« · · « ··4

HyPurity Elite C18 column, 5 gm, 200 Å, 250 x 4.6 mm; 5%-100% acetonitrile—0.1 M ammonium acetate solution over 15 min, 1 mL/min), (90%).

¹ H-NMR spectrum (CDCl ₃ , 400 MHz, δ): 1.33 (12H, s); 1.53 (9H, s); 6.82 (1H, broad s); 7.46 (1H, d, J = 11 Hz); 7.55 (1H, broad d); 8.12 (1H, broad t).

Mass spectrum: m/z = 337.2.

c) (tert-Butyl) - [N-{4-[7-(1,4-dioxa-spiro[4.5]decan-8-yl)-

-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}carbamate]

31.18 g (74.41 mmol) of 7-(1,4-dioxa-spiro[4.5]decan-8-yl)-5-iodo-4-chloropyrrolo[2,3-d]pyrimidine, 37.6 g (111.6 mmol; 1.5 equivalents) of (tert-butyl)-{N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate, 19.72 g (186 mmol; 2.5 equivalents) of sodium carbonate, 3.44 g (2.98 mmol; 4 mol%) of [tetrakis(triphenylphosphine)palladium(0)], 1200 ml of diethylene glycol dimethyl ether and 320 ml of degassed water are mixed and the resulting suspension is under nitrogen gas at 80 °C for 17 hours. Subsequently, another 0.86 g (0.74 mmol; 1 mol%) of [tetrakis(triphenylphosphine)palladium(0)] was added to the mixture, and the reaction was continued at 80 °C for 24 hours, at which time thin layer chromatography analysis (ethyl acetate:heptane = 3:7; R _f = 0.7) showed that the reaction was complete. At this time, the solvent was evaporated in vacuo, the distillation residue was dissolved in 500 ml of ethyl acetate, and the inorganic salts were filtered off on a filter pad made of Celite. The filtrate was washed with 200 ml of 10% aqueous sodium carbonate solution and 200 ml of saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated in vacuo. bepá72.227/BE

313 ............. ..

• * *·*»»* ··· « » « ·«« • 4 · · · ’ · * ««· «· ♦ ·* 4« rol, and the distillation residue is purified by chromatography on silica gel, eluting the column with a 1:2 mixture of ethyl acetate and heptane. The resulting 21.0 g white solid is (tert-butyl) -[ N-{4-[7-(1,4-dioxa-spiro[4.5] decan-8-yl)-4-chloro-7Hpyrrolo[2, 3-d] pyrimidin-5-yl] -2-fluoro-phenyl) -carbamate], the yield is 56%. The product has a HPLC retention time of 10.48 min (reversed phase, Hypersil HyPurity Elite C18 column, 5 gm, 200 Å, 250 x 4.6 mm; 5%-100% acetonitrile-0.1 M ammonium acetate solution over 15 min, 1 ml/min), (100%).

3-NMR spectrum (CDCl ₃ , 400 MHz, δ): 1.55 (9H, s); 1.89 (4H, m); 2.07 (4H, m); 4.01 (4H, s); 4.89 (1H, m); 6.75 (1H, broad s);

7.23 (1H, broad s); 7.25 (1H, broad s); 7.34 (1H, broad s);

8.14 (1H, br. t); 8.64 (1H, s).

d) 5-(4-Amino-3-fluorophenyl)-7-(1,4-dioxa-spiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

10.5 g (20.92 mmol) of (tert-butyl)-[N-{4-[7-(1,4-dioxa-spiro[4.5]decan-8-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]carbamate], 100 ml of 28-30% ammonium hydroxide and 100 ml of dioxane are weighed, then the cloudy mixture is stirred in a sealed reaction vessel at 120 °C for 24 hours. After thin layer chromatography analysis (ethyl acetate:heptane = 9:1), the reaction mixture is evaporated in vacuo, the evaporation residue is taken up in 300 ml of ethyl acetate, then washed twice with 150 ml of saturated sodium chloride solution, dried over sodium sulfate, the solvent is evaporated in vacuo, and finally the remaining product is carefully dried. The resulting 7.93 g of yellow solid is 5-(4-amino-3-fluorophenyl) -7-(1,4-dioxa-spiro[4.5] decan-8-yl) -7H-pyrrolo[2,3-d] 72.227/BE

314 pyrimidine-4-amine, yield 99%.

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 1.74 (4H, m); 1.90 (2H, m); 2.06 (2H, m); 3.90 (4H, m); 4.64 (1H, m); 5.18 (2H, broad s); 6.02 (2H, broad s); 6.84 (1H, t); 6.97 (1H, d); 7.08 (1H, d); 7.26 (1H, s); 8.10 (1H, s).

Mass spectrum: m/z = 384.2 (MH ⁺ ).

e) 4-[4-Amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-cyclohexanone

18.49 g (48.28 mmol) of 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in 800 ml of acetone and 300 ml of 5 M hydrochloric acid were slowly added at 0 °C. The resulting dark orange/brown mixture was heated to 60 °C and kept at this temperature for 4 hours (analysis by thin layer chromatography, 10% methanol in methylene chloride), then the acetone was evaporated in vacuo and the acidic residue was basified to approximately pH 8 with saturated aqueous sodium carbonate solution. The precipitate was collected on a filter and dried carefully to give 12.67 g of 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone as a light brown solid, yield 77%. The second generation product recovered from the mother liquor was 2.01 g (12%).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 2.27 (2H, m); 2.30(4H, broad d); 2.73 (2H, m); 5.14 (1H, m); 5.20 (2H, wide s) ; 6.05 (2H, wide s) ; 6.85 (1H, t); 6.97 (1H, dd); 7.06 (1H, dd) ; 7.35 (1H, s) ; 8, 12 (1H, s).

Mass spectrum: m/z = 340.1 (MH ⁺ ).

72.227/BE

315 ··># ***** ♦·-· ·*·$ ·· ·*·

Example 304:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate

1.0 g (2.95 mmol) of 4-[4-amino-5-(4-amino-3-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanone, 0.885 g (0.98 ml; 0.885 mmol; 3 equivalents) of N-methyl-piperazine and 0.51 ml (8.85 mmol; 3 equivalents) of concentrated, anhydrous acetic acid are dissolved in 50 ml of methylene chloride, then 0.81 g (3.84 mmol; 1.3 equivalents) of sodium [triacetoxyhydridoborate] is added to the solution under nitrogen gas. The reaction mixture was stirred for 18 hours, then an additional 0.40 g (1.9 mmol) of sodium [triacetoxyhydridoborate] was added and stirring was continued for another 48 hours. The mixture was then concentrated in vacuo, the residue was partitioned between 100 ml of methylene chloride and 100 ml of saturated aqueous sodium bicarbonate solution, and the aqueous portion was extracted four more times with 100 ml of methylene chloride. The combined organic solvent extracts were dried over magnesium sulfate, evaporated to dryness, and the remaining 0.95 g of yellow foam was purified by chromatography on silica gel, starting with a 9:1 mixture of methylene chloride and methanol, followed by a gradient elution with a 5:1 mixture. In this way, the faster-moving component, cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7Hpyrrolo[2,3-d]pyrimidin-4-amine, is obtained as a cream-colored solid, weighing 400 mg, yield 32%. The product has a high-pressure liquid chromatography retention time of 8.619 minutes (Waters Symmetry 72.227/BE

316 »<••0 ·*·· ··*· -»W *»· * * V *··

a. «* V-· *r- ^v '*' *·*

C18 reverse phase column, 250 x 4.6 mm; 10%-90% acetonitrile—0.1 M ammonium acetate solution over 12 min, 2 ml/min), (96%). ¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 1.56 (3H, broad t) ; 1.68 (2H, broad d) ; 1.99 (5H, m) ; 2.20 (3H, s) ; 2.43 (7H, broad m) ; 4.65 (1H, m) ; 5.20 (2H, s) ; 6.01 (2H, broad s) ; 6.85 (1H, t, J 9.6 Hz); 6.98 (1H, dd, J = 8.0 and 1.6 Hz); 7.10 (1H, dd, J = 12.4 and 1.6 Hz); 7.12 (1H, s); 8.10 (1H, s).

The weight of the mixed fraction coming off the column is 440 mg, containing both the cis- and trans-isomers in a 50:50 ratio, while the most advanced isomer, i.e. trans-N-[4-{4-amino-7-[4-(4methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4amine, is 110 mg, yield 9%. This product is a yellow solid, high-pressure liquid chromatography retention time 7.595 minutes (Waters Symmetry C18 reverse phase column, 250 x 4.6 mm; 10%-40% acetonitrile-0.1 M ammonium acetate solution over 12 minutes, 2 ml/min), (97%).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 1.94 (6H, m); 2.17 (3H, ^{s); 2} ' ³³ < ^7H ' wide m) ; 2.51 (3H, m); 3.28 (1H, m); 4.51 (1H, m); 5.18 (2H, s); 6.01 (2H, broad s); 6.84 (1H, t); 6.96 (1H, dd); 7.04 (1, dd); 7.30 (1H, s); 8.08 (1H, s).

Example 305:

trans-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate

100 mg (0.236 mmol) trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

72.227/BE

317 is dissolved in 2 ml of pyridine, and 49.5 mg (0.236 mmol) of 4-fluorobenzenesulfonyl chloride is added to the solution at 40 °C. The reaction mixture is stirred for 27 hours at 40 C, then evaporated in vacuo, and the evaporation residue is purified by chromatography on silica gel, in which a gradient is formed, starting with a solvent mixture containing 10% methanol and methylene dichloride, and then ending with a solvent mixture containing 50% methanol and methylene dichloride. The resulting colorless oil (0.78 g) was dissolved in ethanol with maleic acid (27 mg, 0.233 mmol, 3 equivalents) and heated until a homogeneous solution was obtained. The solution was then cooled, at which point trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate precipitated from the solution in the form of yellowish-brown crystals. The product weight was 37 mg, HPLC retention time: 14.528 min ((Waters Symmetry C18 reverse phase column, 250 x 4.6 mm; 10%-40% acetonitrile—0.1 M ammonium acetate solution over 12 min, 2 ml/min), (97%), yield 17%.

Mass spectrum: m/z = 582.0 (MH ⁺ ).

Example 306:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-Pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide

Cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide is prepared in the same way as trans-N72.227/BE

318

[4 {4 amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide free base was given, but here the scale is 3.36 mmol, thus 400 mg of product is obtained, the high-pressure liquid chromatography retention time of which is: 15.232 min ((Waters Symmetry C18 reverse phase column, 250 x 4.6 mm; 10%-40% acetonitrile-0.1 M ammonium acetate solution over 12 min, 2 ml/min), (94%), the yield is 32%.

Mass spectrum: m/z = 582.1 (MH ⁺ ).

307, example:

(4-Amino-3-fluorophenyl)-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

a) 7-(1-Benzyl-piperidin-4-yl)-5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

14.55 g (52.4 mmol) of 3-iodo-4-chloropyrrolo[2,3-d]pyrimidine, 30.06 g (157.16 mmol; 3.0 equivalents) of l-benzyl-4-hydroxypiperidine and 27.51 g (104.8 mmol; 2 equivalents) of triphenylphosphine are dissolved in 730 ml of tetrahydrofuran, and then 18.19 g (41.2 ml; 104.8 mmol; 2.0 equivalents) of diethyl (azodicarboxylate) are added dropwise at room temperature over approximately 1 hour under a nitrogen atmosphere. Based on thin-layer chromatography analysis (ethyl acetate: heptane = 1:1, R _f = 0.2) after 72 hours, the reaction is considered complete, at which time the mixture is evaporated in vacuo, and a 1:4 mixture of ethyl acetate and heptane is added to the evaporation residue until a precipitate is observed to separate from the clear solution. The precipitate is collected on a filter (Ph3PO), 72.227/BE

319 Solvent is evaporated and the residue is dissolved in 500 ml ethyl acetate. The ethyl acetate solution is extracted three times with 200 ml of 1 M hydrochloric acid, the acidic solutions are combined, basified with 4 M sodium hydroxide solution to pH 12, and the product is back-extracted three times with 300 ml of ethyl acetate. The combined organic solvent extracts are dried over magnesium sulfate, evaporated in vacuo, and the remaining crude product is purified by chromatography on silica gel, eluting the column with a 5:4 mixture of petroleum ether and ethyl acetate with a boiling point of 30-60 °C. The first of the two main fractions contains the corresponding compound, which is a pale yellow crystalline substance. This was recrystallized from ethyl acetate to give 5.7 g of 7-(1-benzylpiperidin-4-yl)-5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as cream crystals, yield 24%.

3-NMR spectrum (CDCl ₃ , 400 MHz, δ): 2.02 (4H, m); 2.24 (2H, m); 3.06 (2H, broad d) ; 3.58 (2H, s); 4.76 (1H, m); 7.27 (2H, m); 7.32 (3H, m); 7.49 (1H, s); 8.60 (1H, s).

Mass spectrum: m/z = 452.8 (MH ⁺ ).

b) (tert-Butyl)-[N-{4-[7-(1-benzyl-piperidin-4-yl)-4-chloro-

- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate]

5.1 g (12.6 mmol) of 7-(1-benzyl-piperidin-4-yl)-5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 18.9 g (6.38 mmol; 1.5 equivalents) of (tert-butyl)-{N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-carbamate, 3.34 g (31.5 mmol; 2.5 equivalents) of sodium carbonate, 0.58 g (0.5 mmol; 4 mol%) of [tetrakis(triphenylphosphine)palladium(0)], 1200 ml of diethylene glycol dimethyl ether and 320 ml of degassed water are mixed, and the resulting

72.227/BE

320 suspensions were reacted under nitrogen at 80 °C for 17 hours (thin layer chromatography analysis: ethyl acetate: heptane

1:1). The solvent is then evaporated in vacuo, the distillation residue is dissolved in 400 ml of ethyl acetate, then washed three times with 200 ml of 10% aqueous sodium carbonate solution, dried over magnesium sulfate, evaporated in vacuo, and the distillation residue is purified by chromatography on silica gel, eluting the column with a 1:1 mixture of ethyl acetate and heptane. The resulting 5.2 g (9.7 mmol) of white, solid, crystalline material is (tert-butyl)-[N-{4-[7-(1-benzyl-piperidin-4-yl)-4-chloro-7Hpyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-carbamate, the yield is 77%.

3-NMR spectrum (CDCl ₃ , 400 MHz, δ): 1.55 (9H, s); 2.05 (4H, m); 2.24 (2H, m); 3.06 (2H, broad d) ; 3.60 (2H, s); 4.83 (1H, m); 7.25 (2H, m); 7.29 (1H, m); 7.33 (6H, m); 8.12 (1H, broad t); 8.64 (1H, s).

c) 5-(4-Amino-3-fluorophenyl)-7-(1-benzylpiperidin-4-yl)-

- 7H-pyrrolo[2,3-d]pyrimidin-4-amine

A mixture of 5.2 g (9.7 mmol) of (tert-butyl)-[N-{4-[7-(1-benzylpiperidin-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl)carbamate], 100 ml of 28-30% ammonium hydroxide and 100 ml of 1,4-dioxane is charged into a sealable reaction vessel at room temperature and the vessel is sealed. The reaction mixture is stirred at 120 °C for 16 hours (analysis by thin layer chromatography, ethyl acetate) and then evaporated in vacuo. The evaporation residue is taken up in 300 ml of ethyl acetate, washed twice with 200 ml of saturated sodium chloride solution, then the solvent is evaporated in vacuo and the .227/BE

321 ..................

• · · Λ · · • · · · · · · »« *· the remaining brown solid is triturated with about 50 ml of diethyl ether. 3.0 g of a cream-colored solid is thus obtained, which is 5-(4-amino-3-fluorophenyl)-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, yield 74%. The melting point of the product is 141-142 °C.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz, δ): 2.06 (4H, m); 2.27 (2H, m); 3.06 (2H, m); 3.59 (2H, broad s); 3.70 (2H, broad s); 4.73 (1H, m); 5.12 (2H, s); 6.85 (1H, t); 7.01 (1H, s); 7.06 (1H, dd); 7.10 (1H, dd); 7.28 (2H, m); 7.34 (3H, m); 8.31 (1H, s)

Example 308:

N-{4-[4-Amino-7-(1-benzyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]~2-fluoro-phenyl]-4-fluoro-benzenesulfonamide kz N-{4-[4-amino-7-(1-benzyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide (470981) was prepared following the procedure described in detail for trans N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide trimaleate, but here the reaction was carried out on a 6.96 mmol scale. synthesis. The thus obtained N-{4-[4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide is a cream-colored solid, melting point: 265-266 °C, weight: 3.2 g, yield: 80%.

Mass spectrum: m/z = 575 (MH ⁺ ).

Example 309:

N-{4-[4-Amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide

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322

N {4 [4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-2,3-dichlorobenzenesulfonamide was prepared as described above, but here the synthesis was carried out on a 5.04 mmol scale. The thus obtained N-{4-[4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-2,3-dichlorobenzenesulfonamide is a brown solid, weighing 1.0 g, with a high-pressure liquid chromatography retention time of 14.963 min (Waters Delta pack 5m C18 reverse phase column, 300 A, 150 x 3.9 mm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 min, 1 ml/min), (95%), yield 32%.

Mass spectrum: m/z = 625 (MH ⁺ )

Example 310:

N-{4-[4-Amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidine-5~41]-2-fluorophenyl]-4-fluorobenzenesulfonamide

A mixture of 2.40 g (4.18 mmol) of N-{4-[4-amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide, 2.62 g (41.8 mmol; 10 equivalents) of ammonium formate, 1.2 g of 10% palladium-on-carbon catalyst and 100 ml of ethanol was heated under reflux with vigorous stirring for 6 hours, then filtered and the filtrate was evaporated in vacuo. The solid residue was partitioned between 50 ml of methylene chloride and 50 ml of water, and the brown solid at the interface was filtered off. According to the analysis, this product is N-{4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide, weight 0.33 g, melting point: 238-239 °C (decomposition).

Mass spectrum.· m/z = 485 (MH ⁺ )

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323

Example 311:

N-{4-[4-Amino-7-(1-formyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide

The procedure described for the preparation of N-{4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide was followed, but the reaction was carried out on a smaller scale of 0.35 mmol. The combined organic solvent extracts obtained by working up the reaction mixture were dried over sodium sulfate, the solvent was evaporated, and the residual white oil was purified by preparative high-pressure liquid chromatography on a 100 x 21.2 mm Hypersil 5 m BDS C18 column. The elution was started with 100% 50 M ammonium acetate solution (pH 4.5) at a flow rate of 25 ml/min, the eluent was changed to 100% acetonitrile over 8.5 min, and the elution was continued isocratically for 1.5 min. The resulting white solid was 50 mg of N-{4-[4-amino-7-(1-formyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-2-fluoro-phenyl}-4-fluoro-benzenesulfonamide, yield 27%. The product has a HPLC retention time of 13.091 minutes (Waters Delta pack 5m C18 reversed phase column, 300 Å, 150 x 3.9 mm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 minutes, 1 ml/min), (95%).

Mass spectrum: m/z = 512.9 (MH ⁺ ).

Example 312:

^N ~ {4-[4-Amino-7-{1-[(1-methyl-1H-imidazol-4-yl)-sulfonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide dimaleate

72.227/BE

324

30 mg (0.062 mmol) of 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 26 μΐ (0.186 mmol; 3 equivalents) of triethylamine and 1 ml of methylene dichloride are weighed, 12.3 mg (0.068 mmol; 1.1 equivalents) of (1-methylimidazol-4-yl)sulfonyl chloride are added to the resulting suspension, and the reaction mixture is stirred at room temperature for 24 hours, then the solvent is evaporated in vacuo. The distillation residue was partitioned between 100 ml of methylene chloride and 50 ml of water, the aqueous phase was extracted three times with 100 ml of methylene chloride, the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The remaining crude product was purified by chromatography on silica gel, eluting with a 10% methanol/methylene chloride mixture, to give 10 mg of a waxy solid, to which 4 mg (2 equivalents) of maleic acid were added, dissolved in hot ethanol. Upon cooling the solution, N-{4-[4-amino-7-(1-[(1-methyl-1H-imidazol-4-yl)-sulfonyl]-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl}-4-fluoro-benzenesulfonamide dimaleate crystallizes out, weight 10 mg. The product has a high-pressure liquid chromatography retention time of 14.186 min (Waters Delta pack 5m C18 reverse phase column, 300 Å, 150 x 3.9 mm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 min, 1 ml/min), (100%) Mass spectrum: m/z = 629 (MH ⁺ ).

Example 313:

N-{4-[4-Amino-7-{1-[(1,2-dimethyl-1H-imidazol-4-yl)-sulfonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide

72.227/BE

325

The procedure described for the synthesis of the free base form of N {4 [ 4 amino 7 { 1 [ (1-methyl-1H-imidazol-4-yl) -sulfonyl] -piperidin-4-yl} -7H-pyrrolo[ 2,3-d] pyrimidin-5-yl] -2-fluoro-phenyl} -4-fluoro-benzenesulfonamide dimaleate was followed to give N-{ 4-[ 4-amino-7-{ l-[ (1,2-dimethyl1H-imidazol-4-yl) -sulfonyl] -piperidin-4-yl} -7H-pyrrolo} 2,3-d] -pyrimidin-5-yl] -2-fluoro-phenyl} -4-fluoro-benzenesulfonamide as a cream solid. The product weighed 9 mg and had a melting point of 217-218 °C.

Mass spectrum: m/z = 643.2 (MH ⁺ ).

Example 314:

N-{4-[4-Amino-7-{1-[(1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide

30 mg (0.062 mmol) of 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 17.1 mg (0.124 mmol; 2 equivalents) of potassium carbonate and 2 ml of N-methylpyrrolidone are weighed, 14.8 mg (0.093 mmol; 1.5 equivalents) of 1,3-dimethyl-5-pyrazolecarbonyl chloride are added to the resulting suspension, and the reaction mixture is stirred for 16 hours under nitrogen at room temperature, then the solvent is evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 5% methanol/methylene chloride solvent mixture, to give 10 mg of a colorless glassy substance. This product was identified as N-{4-[4-amino-7-{1-[(1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide, which had a high

72.227/BE

326 . ..·..........

• ·* · · a «»a pressure liquid chromatography retention time: 2.98 minutes (96%) A 33 x 4.6 mm Perkin Elmer Pecosphere 3m C18 reversed-phase column is used for the analysis, elution is started with 100% 50 M ammonium acetate solution ( ^H2O2 ) at a flow rate of 3.5 ml/min, the eluent is changed to 100% acetonitrile over 4.5 minutes, and the elution is continued isocratically for 0.5 minutes.

Mass spectrum: m/z = 629 (MH ⁺ ).

Example 315:

N-{4-[4-Amino-7-{1-[(2-pyridyl)carbonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide

N-{4-[4-amino-7-{l-[(2-pyridyl)carbonyl]-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide was prepared following the procedure described for the synthesis of N-{4-[4-amino-7-{l-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide. The product weighed 12 mg and the HPLC retention time was 2.73 min (98 s). A 33 x 4.6 mm Perkin Elmer Pecosphere 3m C18 reversed-phase column was used for the analysis. is used, the elution is started with 100% 50 M ammonium acetate solution (pH = 4.5) at a flow rate of 3.5 ml/min, the eluent is changed to 100% acetonitrile over 4.5 min, and the elution is continued isocratically for 0.5 min.

Mass spectrum: m/z = 590.2 (MH ⁺ )

72.227/BE

327

Example 316:

N-[4-{4-Amino-7-[1-(1-methyl-piperidin-4-yl)-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate mg (0.103 mmol) N-{4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide, 0.92 ml (0.155 mmol) 1-methyl-4-piperidinone and 0.025 ml concentrated, anhydrous acetic acid were dissolved in 3 ml N-methylpyrrolidinone, and 28.1 mg (0.134 mmol) sodium triacetoxyhydridoborate were added to the solution. The reaction mixture is stirred for 20 hours, then a further 1.3 equivalents of sodium triacetoxy-hydridoborate are added and stirring is continued for another 24 hours to complete the reaction. The solvent is then evaporated in vacuo and the residue is partitioned between 100 ml of methylene chloride and 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted four more times with 100 ml of methylene chloride, then the combined organic solvent extracts are dried over magnesium sulphate and evaporated to dryness. The remaining crude product is purified by chromatography on silica gel, eluting the column with a 78:19:3 mixture of methylene chloride, methanol and ammonium hydroxide, and the separated brown solid is converted into the trimaleate salt in the usual manner. The resulting 45 mg brown solid is N-[4-{4-amino-7-[1-(1-methyl-piperidin-4-yl)-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide trimaleate, yield 75%. The product has a high-pressure liquid chromatography retention time of 10.658 minutes (Waters 72.227/BE

328 • ·- * '·'* *-r * W*

Delta pack 5m C18 reversed phase column, 300 Å, 150 χ 3.9 mm; 5%-85% acetonitrile—0.1 M ammonium acetate solution over 20 min, 1 ml/min), (95%).

Mass spectrum: m/z = 582 (MH ⁺ ).

Example 317:

N-{4-[4-Amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}benzamide

a) 7-(1,4-Dioxa-spiro[4.5]decan-8-yl)-5-iodo-4-chloro-7H-

-pyrrolo[2,3-d]pyrimidine

25.0 g (0.09 mol) of 5-iodo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 35.8 g (0.0267 mol) of 1,4-dioxaspiro[4.4]decan-8-ol and 46.7 g (0.178 mol) of triphenylphosphine are dissolved in 1200 ml of tetrahydrofuran, then 30.9 g (0.178 mol) of diethyl azodicarboxylate are added to the solution under nitrogen. The reaction mixture is stirred for 20 hours, then most of the solvent is evaporated, and 450 ml of ethyl acetate is added to the remaining, approximately 250 ml solution. The solid precipitate formed was filtered off, washed twice with 50 ml of ethyl acetate and finally dried in vacuo to give 22.5 g of the title compound, yield 60%. The product was a cream-coloured solid, TLC R _f value: 0.12 (ethyl acetate:heptane = 1:4). ¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.64 (1H, s) ; 8.10 (1H, s); 4.74 (1H, m) ; 3.90 (4H, m) ; 2.12 (2H, m) ; 1.91 (2H, m) ; 1.71-183 (4H, m).

b) (tert-Butyl)-[N-{4-[7-(1,4-dioxa-spiro[4.5]decan-8-yl)-

-4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate]

72.227/BE

329

A mixture of 8.2 g (23.5 mmol) (tert-butyl)-{N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-phenyl]-carbamate}, 6.57 g (15.7 mmol) 7-(1,4-dioxaspiro[4.5]decan-8-yl)-5-iodo-4-chloropyrrolo[2,3-d]pyrimidine, 1.1 g (0.93 mmol) [tetrakis(triphenylphosphine)palladium(0)], 4.16 g (39.2 mmol) sodium carbonate, 200 ml diethylene glycol dimethyl ether and 100 ml water was allowed to react at 80 °C for 20 hours, then cooled to room temperature, then 300 ml ethyl acetate and The mixture was partitioned between 100 ml of water. The aqueous phase was extracted three more times with 150 ml of ethyl acetate and the combined organic extracts were washed with 150 ml of water. The organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated to leave a solid. This was dissolved in a 1:4 mixture of ethyl acetate and heptane, but 2.5 g of a cream-colored crystalline material separated from the solution. The filtrate was absorbed onto silica gel and purified by chromatography, initially eluting with a 10:1 mixture of heptane and ethyl acetate, then 4:1, then 1:1 and finally 1:4 mixture. The appropriate fractions were combined to give a white solid which was triturated with a 5:1 mixture of heptane and ethyl acetate to give the title compound, HPLC retention time: 21.24 min (5%-95% acetonitrile-0.1 M ammonium acetate solution over 20 min), (100%). Total product weight: 3.2 g, yield: 71%.

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.66 (1H, s); 7.93 (2H, m); 7.74 (1H, m); 7.19 (1H, m); 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).

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330

c) 4-[4-Amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo-

[2,3-d]pyrimidin-7-yl]cyclohexanone

A mixture of 5.7 g (0.011 mol) of (tert-butyl)-[N-{4-[7-(1,4-dioxaspiro[4.5] decan-8-yl)-4-chloro-7H-pyrrolo[2,3-d] pyrimidin-5-yl]-2-methoxyphenyl]carbamate], 100 ml of concentrated ammonia solution and 100 ml of dioxane is heated to 120 °C in a pressure vessel, kept at this temperature for 20 hours, then the solvent is evaporated. The evaporation residue is partitioned between 250 ml of ethyl acetate and 100 ml of water, then the organic phase is separated, dried over sodium sulfate, filtered and evaporated. The residual solid was identified by HPLC analysis (5%-95% acetonitrile-0.1 M aqueous ammonium acetate solution) as a 2:1 mixture of (tert-butyl)-[N-{4-[7-(1,4-dioxa-spiro-[4.5]decan-8-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl)carbamate] and 5-(4-amino-3-methoxyphenyl)-7-(1,4-dioxa-spiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture is dissolved in 200 ml of acetone, 100 ml of 5 M hydrochloric acid is added dropwise over 0.5 h, then the mixture is left to stir overnight, and the solvent is evaporated off the next day. The acidic solution is made alkaline with 2 M sodium hydroxide solution under ice-cooling, the alkaline mixture is extracted three times with 150 ml of ethyl acetate, then the combined organic solvent extracts are washed twice with 100 ml of water. In the meantime, the solid material precipitated during the extraction operations is collected on a filter, triturated with a hot mixture of ethyl acetate and methanol, the insoluble material is filtered off, the filtrate is evaporated, then the residue is triturated with a mixture of diethyl ether and ethyl acetate, thus obtaining a yellow solid. The original extraction operation so72.227/BE

The organic phase obtained in 331 was dried over sodium sulfate, filtered, the solvent was evaporated, and the distillation residue was triturated with a 5:1 mixture of diethyl ether and ethyl acetate, and finally filtered off. In this way, a total of 2.3 g of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone was obtained as a yellow solid, the overall yield being 78%. The product had a high-pressure liquid chromatography retention time of 11.24 min (5%-95% acetonitrile-0.1 M ammonium acetate solution over 20 min), (95%).

^] H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 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, broad s); 5.14 (1H, m); 3.81 (3H, s); 2.72 (2H, m); 2.35 (4H, m); 2.18 (2H, m).

d) N-{4-[4-Amino-5-(4-oxo-cyclohexyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-2-methoxyphenyl}-benzamide

0.105 g (0.3 mmol) of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo] 2,3-d] pyrimidin-7-yl] cyclohexanone is dissolved in a mixture of 2 ml of pyridine and 5 ml of methylene dichloride, then a solution of 63 mg (0.45 mmol) of benzoyl chloride in 1 ml of methylene dichloride is added under nitrogen at 0 C. The reaction mixture is stirred for 2 hours at 0 C, then quenched with 5 ml of water, further 40 ml of 1 M hydrochloric acid are added, and the aqueous mixture is extracted three times with 25 ml of methylene dichloride. The combined organic solvent extracts were washed with 30 ml of water, dried over sodium sulfate, filtered, the filtrate was evaporated, and the residual oil was purified by flash chromatography on silica gel, eluting the column with a solvent mixture containing 2-10% methanol and ethyl acetate. The resulting 0.130 g of white solid was

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N-{4-[4-amino-5-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidine-2-methoxyphenyl}-benzamide, yield 96%. Melting point of the product: 234-237 °C, thin layer chromatography R _f value: 0.30 (ethyl acetate:methanol = 9:1), high pressure liquid chromatography retention time: 14.82 min (5%-95% acetonitrile-0.1 M ammonium acetate solution over 20 min), (96%) 1 H NMR spectrum (DMSO-d ₆ , 400 MHz, H): 9.43 (1H, s); 8.19 (1H, s); 7.94 (3H, m); 7.59 (4H, m); 7.18 (1H, s); 7.06 (1H, d, J = 8 Hz); 6.18 (2H, broad s); 5.20 (1H, m); 3.92 (3H, s); 2.76 (2H, m); 2.35 (4H, m); 2.22 (2H, m).

Example 318:

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

0.40 g (1.15 mmol) of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone is dissolved in a mixture of 5 ml of pyridine and 10 ml of methylene chloride, then 0.29 g (1.73 mmol) of benzyl-(chloroformate) is added to the solution at -5 °C under nitrogen. The reaction mixture is allowed to warm to 0 °C, stirred for 1 hour, then quenched with 5 ml of water and the solvent is evaporated. The evaporation residue is partitioned between 100 ml of ethyl acetate and 100 ml of water, the aqueous portion is extracted three more times with 50 ml of ethyl acetate, then the combined organic solvent extracts are dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with a mixture of ethyl acetate and diethyl ether to give 0.28 g of benzyl-[N-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl} 72.227/BE

333

-carbamate] is obtained. The product is a yellow solid, melting point: 175-176 °C, thin layer chromatography R _f value: 0.24 ( ^{ethyl acetate :} methanol = 9:1), high pressure liquid chromatography retention time: 16.69 minutes (5%-95% acetonitrile-0.1 M ammonium acetate solution over 20 minutes), (98%).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.64 (1H, s); 8.17 (1H, s); 7.75 (1H, d, J = 8.4 Hz); 7.50 (1H, s); 7.36 (5H, m); 7.10 (1H, s); 7.02 (1H, d, J = 8 Hz); 6.15 (2H, broad s); 5.19 (3H, m); 3.81 (3H, s); 2.72 (2H, m); 2.35 (4H, m); 2.22 (2H, m).

Example 319:

cis-Benzyl-{N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate trimaleate and trans-Benzyl- (N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate trimaleate

0.83 g (1.74 mmol) of benzyl-[N-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}carbamate], 0.52 g (5.22 mmol) of N-methylpiperazine and 0.31 g (5.22 mmol) of concentrated, anhydrous acetic acid were dissolved in 100 ml of methylene chloride, and 0.55 g (2.61 mmol) of sodium [triacetoxyhydridoborate] was added in small portions under nitrogen. The reaction mixture was stirred for 6 hours and then quenched with 20 ml of 2 M sodium hydroxide solution. The organic phase is separated, the aqueous phase is extracted twice more with 50 ml of methylene dichloride, and then the combined organic solvent extracts are washed with 50 ml of saturated sodium hydroxide solution.

334 µm chloride solution, dried over sodium sulfate, filtered and evaporated. The residual oil was purified by flash chromatography on silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol and a 9:1 mixture of methylene chloride and methanol to give 480 mg of compound F20-25 as an oil. The oil was dissolved in ethyl acetate, 280 mg of maleic acid dissolved in ethyl acetate was added to the solution, and the solid precipitate formed was filtered off under nitrogen gas and then dried in vacuo for 4 hours to give 580 mg of cis-benzyl-{N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate trimaleate. The product was a cream-colored solid, melting point: 158 °C (decomposition), HPLC retention time: 13.30 min (5%-95% acetonitrile—0.1 M ammonium acetate solution over 20 min), (94%).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 8.74 (1H, s); 8.27 (1H, s); 7.78 (1H, d); 7.35-7.77 (5H, m); 7.10 (1H, s); 7.04 (1H, s); 6.16 (6H, s); 5.17 (2H, s); 4.74 (1H, m); 3.82 (3H, s); 3.23 (5H, m); 2.78 (3H, s); 2.51 (3H, m); 2.41 (1H, s); 2.09 (4H, m).

F28-45 is a glassy foam, weighing 186 mg. This is dissolved in 10 ml of ethyl acetate and a solution of 114 mg of maleic acid in 3 ml of ethyl acetate is added. The separated solid is filtered under nitrogen and dried in vacuo for 4 hours to give 250 mg of trans-benzyl {N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-2-methoxy-phenyl]-carbamate trimaleate. The product is a cream-colored solid, melting point: 146-148 °C (decomposition), the high-pressure liquid chromatography 72.227/BE

335 matographic retention time: 13.54 min (5%-95% acetonitrile—0.1 M ammonium acetate solution over 20 min), (94.6%).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 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 (UH, m); 2.50 (3H, s); 1.97 (6H, m); 1.56 (2H, m).

Example 320:

trans-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-benzamide

1.2 g (2.66 mmol) of N-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d] yrimidin-5-yl] -2-methoxyphenyl} -benzamide, 0.48 g (7.98 mmol) of concentrated, anhydrous acetic acid and 0.80 g (7.98 mmol) of N-methylpiperazine are dissolved in 150 ml of methylene dichloride, then 0.85 g (3.99 mmol) of sodium [triacetoxyhydridoborate] is added in small portions under nitrogen. The reaction mixture is left to stir at room temperature overnight, then the next day it is decomposed with 20 ml of 2 M sodium hydroxide solution and the aqueous part is extracted three more times with 50 ml of methylene dichloride. The combined organic solvent extracts were dried over sodium sulfate, filtered, evaporated, and the solid residue was purified by flash chromatography on silica gel, starting with methylene dichloride, followed by successively 5%, 10%, 15%, and 20% methanol and methylene chloride.

The solutions containing compound F23-36 are combined, the solvent is evaporated, and the remaining 0.11 g of a cream-colored, clear

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336 g of the substance was dissolved in 10 ml of ethyl acetate. To this solution was added a solution of maleic acid in 5 ml of ethyl acetate, and the finely divided precipitate was collected on a filter under nitrogen. The resulting 0.108 g of a cream-colored solid was trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-2-methoxy-phenyl]-benzamide, which had a high-pressure liquid chromatography (HPLC-MS) retention time of 1.83 min (Pecosphere 3 C ₁₈ 3 gm column, 100% 100 mM ammonium acetate solution—100% acetonitrile over 5 min).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 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, broad s); 6.16 (6H, s); 4.61 (1H, m); 3.92 (3H, s); 2.70-3.11 (UH, m); 2.01 (7H, m); 1.58 (2H, m).

Mass spectrum: MH ⁺ = 540.8.

Example 321:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-3-phenyl-propionic acid amide and trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-3-phenyl-propionic acid amide ^a ) 0.8 g (2.3 mmol) of 4-[4-amino-3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanone is dissolved in a mixture of 13 ml of pyridine and 32 ml of methylene chloride, then at 0 °C, under nitrogen gas, 0.57 g of A solution of 3-phenylpropionyl chloride in 5 ml of methylene chloride was added. The reaction mixture was stirred at 0 °C for 2 hours.

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337 stirred, then allowed to warm to room temperature and decomposed by adding 50 ml of saturated, aqueous citric acid solution. The organic phase was washed twice with 50 ml of saturated, aqueous citric acid solution, dried over sodium sulfate, filtered and evaporated, resulting in 1.0 g of crude N-{4-[4-amino-7-(4-oxo-cyclohexyl) 7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl}-3-phenyl-propionic acid amide, yield 92%. High-pressure liquid chromatography retention time of the product: 14.48 min (5%-95% acetonitrile-0.1 M aqueous ammonium acetate solution over 20 min) (92.2%).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 9.17 (1H, s); 8.18 (1H, s); 8.06 (1H, d); 7.51 (1H, s); 7.18-7.29 (6H, m); 7.09 (1H, m); 6.99 (1H, d); 6.21 (2H, broad s); 5.18 (1H, m); 3.88 (3H, s); 1.99-2.93 (12H, m).

b) 1.0 g (2.1 mmol) of 92% purity N-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl} 3-phenylpropionic acid amide, 0.63 g (6.3 mmol) N-methylpiperazine and 0.38 g (6.3 mmol) acetic acid are dissolved in 100 ml of methylene dichloride, then 0.67 g (3.15 mmol) of sodium [triacetoxyhydridoborate] is added in small portions under nitrogen. The reaction mixture is allowed to stir for 20 hours, then it is decomposed with 50 ml of saturated aqueous sodium bicarbonate solution, and the aqueous portion is extracted three more times with 50 ml of methylene dichloride. The combined organic solvent extracts are dried over sodium sulfate, filtered, evaporated, and the distillation residue is purified by flash chromatography on silica gel, starting with methylene dichloride and then eluting with a solvent mixture containing methanol and methylene dichloride in 10% increments up to 50%.

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338 elution. The fractions containing compound F84-96 were combined and the solvent was evaporated to give 0.26 g of cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-3-phenyl-propionic acid amide as a cream-colored, foamy, glassy residue, with a HPLC retention time of 12.65 min (5%-95% acetonitrile-0.1 M aqueous ammonium acetate solution over 20 min) (95.2%).

¹ H-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 9.17 (1H, s); 8.14 (1H,

s); 8.05 (1H, d); 7.28 (5H, m); 7.18 (1H, m); 7.10 (1H, s); 6.99 (1H, d); 6.11 (2H, broad s); 4.67 (1H, m); 3.88 (3H, s); 2.90 (2H, m); 2.73 (2H, m); 2.50 (7H, m); 2.28 (3H, s); 2.06 (3H, m); 1.55 (2H, m).

The fractions containing F121-138 were combined and evaporated to give 0.11 g of white solid trans-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3-phenylpropionic acid amide, which had a HPLC retention time of 12.61 min (5%-95% acetonitrile-0.1 M aqueous ammonium acetate solution over 20 min) (96.2%).

3-NMR spectrum (DMSO-d ₆ , 400 MHz, δ): 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, broad s); 4.53 (1H, m); 3.88 (3H, s); 2.93 (2H, m); 2.71 (2H, m); 2.50 (4H, m); 2.30 (5H, m);

2.14 (3H, s); 1.89 (6H, m); 1.46 (2H, m).

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Examples 322-363:

General procedure for the preparation of arenesulfonamides of pyrrolopyrimidines

To a 0.19 M solution of 5-(4-Amino-3-fluorophenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in pyridine, one equivalent of substituted arenesulfonyl chloride was added. The reaction mixture was shaken for 24 h at 45 °C on an Incubator Shaker, and the product was purified by preparative reversed-phase high-pressure liquid chromatography coupled to a mass spectrometer [Micromass/Gilson, Hypersil BDS C18, 5 μιη, 100 x 21.2 mm; gradient elution, 0%-100% 0.05 M aqueous (pH = 4.5) ammonium acetate/acetonitrile over 12.5 min, 25 ml/min]. This is how we prepare the following compounds:

Example 322:

trans-N~[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-4-(trifluoromethoxy)-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.18 min. Mass spectrum: m/z = 648.39.

Example 323:

trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-5-chloro-2-thiophenesulfonamide trimaleate

HPLC retention time of the product: 3.14 min. Mass spectrum: m/z = 604.03.

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Example 324:

trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-2-chloro-benzene sulfonamide trimaleate

HPLC retention time of the product: 3.07 min. Mass spectrum: m/z = 616.1.

Example 325:

trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.39 min. Mass spectrum: m/z = 632.12.

Example 326:

cis-N-[4-{4-Amino-7-(4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-2-chloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.82 min. Mass spectrum: m/z = 616.2.

Example 327:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2, 6-difluoro-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.66 min. Mass spectrum: m/z = 600.3.

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Example 328:

trans-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-difluorobenzenesulfonamide trimaleate

HPLC retention time of the product: 2.53 min. Mass spectrum: m/z = 600.3.

Example 329:

trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,1,3-benzothidiazole-

-4-sulfonamide trimaleate

Product HPLC retention time: 2.63 min. Mass spectrum: m/z = 622.1.

Example 330:

trans-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,3,4-trifluorobenzenesulfonamide trimaleate

HPLC retention time of the product: 2.87 min. Mass spectrum: m/z = 618.1.

Example 331:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-nitrobenzenesulfonamide trimaleate

HPLC retention time of the product: 3.13 min. Mass spectrum: m/z = 609.1.

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Example 332:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.89 min. Mass spectrum: m/z = 582.1.

Example 333:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2,4,6-trichloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.4 min. Mass spectrum: m/z = 688.

334, example:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2,6-dichloro-benzenesulfonamide trimeate

HPLC retention time of the product: 3.04 min. Mass spectrum: m/z = 632.1.

Example 335:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2-chloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.94 min. Mass spectrum: m/z = 598.1.

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Example 336:

cis—N—[4—{4—Amino—7—[4— (4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide dimaleate

HPLC retention time of the product: 2.76 min. Mass spectrum: m/z = 582.1.

Example 337:

cis-N-[4-(4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] ~7H~Py ^rrolo [2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl] -5-chloro-2-thiophenesulfonamide dimaleate

HPLC retention time of the product: 3.01 min. Mass spectrum: m/z = 604.3.

Example 338:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2,5-difluorobenzenesulfonamide trimaleate

HPLC retention time of the product: 3.38 min. Mass spectrum: m/z = 718.3.

Example 339:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluoro-3-chlorobenzenesulfonamide trimaleate

HPLC retention time of the product: 2.98 min. Mass spectrum: m/z = 616.3.

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Example 340:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2-iodo-benzene sulfonamide trimaleate

HPLC retention time of the product: 3.02 min. Mass spectrum: m/z = 690.3.

341, example:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-(trifluoromethoxy)benzenesulfonamide trimaleate

HPLC retention time of the product: 3.22 min. Mass spectrum: m/z = 648.3.

Example 342:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,3-dichloro-benzenesulfonamide trimalate

HPLC retention time of the product: 2.97 min. Mass spectrum: m/z = 600.3.

Example 343:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2-chloro-6-methyl-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.12 min. Mass spectrum: m/z = 612.3.

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345 ........

• 4* «· ·

344, example:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-cyano-2-chlorobenzenesulfonamide trimaleate

HPLC retention time of the product: 3.02 min. Mass spectrum: m/z = 623.2.

345, example:

cis-N-[4-{4-Amino~7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] ~7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,3,4-trifluorobenzene sulfonamide trimaleate

HPLC retention time of the product: 3.08 min. Mass spectrum: m/z = 618.3.

Example 346:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3, 4-difluoro-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.98 min. Mass spectrum: m/z = 600.3.

Example 347:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2-fluorobenzenesulfonamide trimaleate

HPLC retention time of the product: 3.13 min. Mass spectrum: m/z = 660.2.

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348, example:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]~7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-5-bromo-2-thiophenesulfonamide trimaleate

HPLC retention time of the product: 3.16 min. Mass spectrum: m/z = 648.1.

Example 349:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl] ~7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,4-dichloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.09 min. Mass spectrum: m/z = 632.1.

Example 350:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2,3,4-trichloro-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.41 min. Mass spectrum: m/z = 668.1.

Example 351:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-bromo-5-chloro-2-thiophenesulfonamide trimaleate

HPLC retention time of the product: 3.29 min. Mass spectrum: m/z = 683.9.

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347

352, example:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,1,3-benzothiadiazole-4-sulfonamide trimaleate

HPLC retention time of the product: 2.73 min. Mass spectrum: m/z = 622.1.

Example 353:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,1,3benzoxadiazole-

- 4-Phonamid trimaleate

High-performance liquid chromatography retention time of the product:

2.8 min. Mass spectrum: m/z = 606.1.

Example 354:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dichloro-1-thiophenesulfonamide trimaleate

HPLC retention time of the product: 3.18 min. Mass spectrum: m/z = 638.

Example 355:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-7-chloro-2,1,3-benzoxadiazole-4-sulfonamide trimaleate

HPLC retention time of the product: 2.84 min. Mass spectrum: m/z = 640.2.

72.227/BE

356, example:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-7-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimalate

HPLC retention time of the product: 2.89 min. Mass spectrum: m/z = 636.2.

Example 357:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-5-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate

HPLC retention time of the product: 2.82 min. Mass spectrum: m/z = 636.2.

Example 358:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-5-chloro-2,1,3-benzothiadiazole-4-sulfonamide trimaleate

HPLC retention time of the product: 2.82 min. Mass spectrum: m/z = 656.2.

359, example:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-chloro-2-methyl-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.01 min. Mass spectrum: m/z = 612.

72.227/BE

349

Example 360:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2-bromo-benzenesulfonamide trimaleate

HPLC retention time of the product: 2.81 min. Mass spectrum: m/z = 644.2.

Example 361:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2,5-dibromo~ ~3 , 6-difluoro-benzenesulfonamide trimaleate

HPLC retention time of the product: 3.29 min. Mass spectrum: m/z = 758.1.

362, example:

cis-N-[4-{4-Amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]~7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate

HPLC retention time of the product: 2.77 min. Mass spectrum: m/z = 632.

Example 363:

cis-N-[4-{4-Amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-(2-nitro-phenyl)-methanesulfonamide trimaleate

HPLC retention time of the product: 2.73 min. Mass spectrum: m/z = 623.2.

72.227/BE

350

P02-403

Examples 364-369:

General procedure

a) The procedure

A mixture of 1.0 g (2.51 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone, 7.54 mmol of the corresponding amine, 0.45 g (7.54 mmol) of acetic acid and 50 ml of methylene dichloride was stirred under nitrogen at room temperature for 30 minutes, then 0.69 g (3.26 mmol) of sodium [triacetoxyhydridoborate] was added and stirring was continued at room temperature for 18 hours. Then, a solution of 1.26 g (15.1 mmol) of sodium hydrogen carbonate in 20 ml of water is added, the mixture is allowed to stir for another 1 hour, then filtered through a filter bed made of Celite, and the filter is washed with 75 ml of methylene dichloride. The organic phase is separated from the filtrate, dried over magnesium sulfate, filtered again, and finally evaporated to dryness in vacuo. The cis- and trans-isomers are separated and purified by flash chromatography on silica gel, eluting with a mixture of methanol and methylene dichloride, using a gradient elution.

b) Procedure B

Where necessary, salts are prepared as follows. 0.909 mmol of the above amine is dissolved in 100 ml of warm ethyl acetate, then a solution of 0.32 g (2.73 mmol) of maleic acid in 30 ml of ethyl acetate is added. The salt precipitates as an oil on the bottom and walls of the flask, this liquid is decanted, dissolved in water, and the aqueous solution is lyophilized.

c) Procedure C

Guanidine derivative is prepared as follows. 0.536

72.227/BE

351 mmol of amine is dissolved in 5 ml of N,N-dimethylformamide, the solution is cooled to -5 C, then 95 mg (0.644 mmol) of 1H-pyrazole-1-carboxamide and 208 mg (1.6 mmol) of N,N-diisopropylethylamine are added. The reaction mixture is allowed to warm to room temperature over 16 hours, evaporated in vacuo, then the evaporation residue is partitioned between 10 ml of water and 10 ml of ethyl acetate, finally the aqueous phase is lyophilized and the crude product is purified by reverse phase high pressure liquid chromatography.

Conditions used for high-performance liquid chromatography purification:

(1) Hypersil HyPurity Elite C18, 5 mm, 200 A 250 x 4.6 mm; 25%-100% acetonitrile—0.1 M ammonium acetate solution over 15 min, 1 ml/min.

(2) Hypersil HyPurity Elite C18, 5 mm, 200 A 250 x 4.6 mm; 5%-100% acetonitrile—0.1 M ammonium acetate solution over 15 min, 1 ml/min.

It is obvious that protecting groups should be used during the synthesis where necessary.

The compounds prepared in the above manner are as follows:

Example 364:

cis-4-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate

The compound was prepared by method C, HPLC retention time (2): 14.56 min. Mass spectrum: m/z = 511.7 (MH ⁺ ).

72.227/BE

V 352

Example 365:

trans-4-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]-1-piperazinecarboximidamide

The compound was prepared by method C, HPLC retention time (2): 14.25 min. Mass spectrum: m/z = 511.7 (MH ⁺ ).

Example 366:

trans-5-(4-Phenoxyphenyl)-7-[4-{N-methyl-N-[2-(2-pyridyl)ethyl]amino]cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate

Compound Ά was prepared by methods A and B, HPLC retention time (2): 8.55 min. Mass spectrum: m/z = 519.6 (MH ⁺ ).

Example 367:

cis-3-[{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}amino]propionic acid

The compound is prepared by method A followed by hydrolysis of the resulting ester, HPLC retention time (2): 10.21 min.

Mass spectrum: m/z = 472.6 (MH ⁺ ).

Example 368:

3-[{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-amino]-propionic acid

The compound was hydrolyzed by method A, and the resulting ester was hydrolyzed by 72.227/BE * 353 ..................

·· · · · · · · • · · · · ·* ·· ·* zein, high-performance liquid chromatography retention time (1): 6.33 min.

Mass spectrum: m/z = 472.6 (MH ⁺ ).

Example 367:

cis-Ethyl-{3-[{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3d]pyrimidin-7-yl]cyclohexyl}-amino]-propionate}-dimaleate

Compound Ά was prepared by methods A and B, HPLC retention time (1): 10.42 min. Mass spectrum: m/z = 500.6 (MH ⁺ ).

Examples 370-375:

General procedure

a) Method D To a mixture of 0.533 mmol of sodium hydride (0.553 mmol) and 2 ml of tetrahydrofuran at 0 °C, 0.533 mmol of the corresponding phosphonate is added, then the reaction mixture is stirred for 20 minutes at constant temperature and for a further 10 minutes at room temperature. The mixture is then cooled to 0 °C again, a solution of 200 mg (0.503 mmol) of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone in 10 ml of tetrahydrofuran is added, and stirring is continued at room temperature for 16 hours. After the reaction, the solvent was evaporated in vacuo, the residue was partitioned between 10 ml of ethyl acetate and 10 ml of water, and the aqueous phase was extracted three times with 5 ml of ethyl acetate. The combined organic solvent extracts were washed three times with 5 ml of water, dried over magnesium sulfate.

72.227/BE

354 is dried, evaporated in vacuo, and the residue is purified by flash chromatography on silica gel in the case of an intermediate product, and by reversed-phase high-pressure liquid chromatography in the case of a final product, thus obtaining the desired compound.

b) This procedure

The hydrogenation is carried out by stirring a mixture of 0.068 mmol of alkene, 12 mg of 10% palladium-on-carbon catalyst and 18 ml of ethanol under a hydrogen atmosphere of 4 bar for 14 hours. The solids are then filtered off, the filtrate is evaporated in vacuo and the distillation residue is purified by reverse phase high pressure liquid chromatography to give the final product.

c) Procedure F

Lithium [tetrahydridoaluminate] — the reduction is carried out by stirring a mixture of 0.19 mmol of starting compound, 40 mg (1.07 mmol) of lithium [tetrahydridoaluminate] and 5 ml of tetrahydrofuran for 16 hours at room temperature, then the reaction mixture is worked up according to Fieser and the product is purified by reverse phase high pressure liquid chromatography.

The conditions used for high-performance liquid chromatography purification were: 33 x 4.6 mm Pecosphere 3 C18, 3 m column, 0%-100% acetonitrile—0.1 M ammonium acetate solution over 5 min, 4 ml/min.

It is obvious that protecting groups should be used during the synthesis where necessary.

The compounds prepared in the above manner are as follows:

72.227/BE

355

370, example:

{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexylidene}methylcyanide

The compound was prepared by method D, HPLC retention time: 3.1 min. Mass spectrum: m/z = 422.5 (MH ⁺ ).

Example 371:

(tert-Butyl)-[2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexylidene}acetate]

The compound was prepared by method D, HPLC retention time: 3.97 min.

Mass spectrum: m/z = 497.1 (MH ⁺ ).

Example 372:

Ethyl -[2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexylidene}acetate]

The compound was prepared by method D, HPLC retention time: 3.56 min.

Mass spectrum: m/z = 469.0 (MH ⁺ ).

Example 373:

2-(4-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexylidene}acetic acid

The compound is prepared by method D followed by hydrolysis of the ethyl ester, HPLC retention time: 2.69 min.

Mass spectrum: m/z = 441.5 (MH ⁺ ).

72.227/BE

356

Example 374:

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

The compound is prepared by method F, reducing the unsaturated cyanide with lithium [tetrahydridoaluminate], high-pressure liquid chromatography retention time: 2.11 minutes.

Mass spectrum: m/z = 428.5 (MH ⁺ ).

Example 375:

2-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetic acid

The compound is prepared by method E, reducing the unsaturated acid, high-performance liquid chromatography retention time: 2.64 minutes.

Mass spectrum: m/z - 443.5 (MH ⁺ ).

Claims (4)

Compounds of general formula (I) — in which formula A represents a 6-membered aromatic ring or a 5- or 6-membered heteroaromatic ring, optionally carrying one or more substituents, and the substituents may be selected from the following: substituted or unsubstituted aliphatic group, halogen atom, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroarylalkyl group, cyano or nitro group, group of the general formula -NR ⁴ R ⁵ , carboxy or hydroxy group, substituted or unsubstituted alkoxycarbonyl group, (haloalkoxy)carbonyl group, substituted or unsubstituted alkylthio-, substituted or unsubstituted alkylsulfinyl-, substituted or unsubstituted alkylsulfonyl-, substituted or unsubstituted arylthio-, substituted or unsubstituted arylsulfinyl-, substituted- 72.227/BE 358 substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkylcarbonyl or (haloalkyl)carbonyl groups, substituted or unsubstituted aliphatic ether groups, substituted or unsubstituted aromatic ether groups, substituted or unsubstituted carboxamido groups, tetrazolyl, [ (trifluoromethyl)sulfonyl]amino, (trifluoroacetyl)amino, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamido or substituted or unsubstituted arylamido groups, -NR ⁹⁵ C(O)R ⁹⁵ group, in which R ⁹⁵ represents an aliphatic or aromatic group, substituted or unsubstituted styryl and substituted or unsubstituted aralkylamido group; L is an oxygen or sulfur atom, a sulfinyl or sulfonyl group, a group of the general formula -N (R)-, -N[C(O)OR]-, -N[C(O)R]- or -N(SO ₂ R)-, a group of the general formula -CH ₂ O- or -CH ₂ S-, -CH ₂ N(R)-, -CH(NR)-, -CH ₂ N[ C (0) R] -, -CH ₂ N[ C (0) OR] -, -CH ₂ N (SO ₂ R)-, -CH(NHR)-, -CH[ NHC (0) R] -, -CH(NHS0 ₂ R) -, CH[ NHC (0) OR] -, -CH[ OC(O)R]- or -CH[ OC (0) NHR] -, a group of the general formula -vinylene group, a group of the general formula -C(=N0R)-, a carbonyl group, -CH(OR)-, -C(0)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(0)0-, -S(O)N(R)-, -S(O) ₂ N(R)-, -N[ C (0) R] S (0)-, -N[ C (0) R] S (0) ₂ -, N (R) S (0) N (R) -, -N(R)S(0) ₂ N(R)-, -C (0)N (R) C (0)-, -S (0)N(R)C(0)-, -S (0) ₂ N (R) C (0)-, -OS(O)N(R)-, -OS (0) ₂ N (R)-, -N(R)S(O)O-, -N (R) S (0) ₂ 0-, - a group of the general formula N (R) S (0) C (0)-, -N(R) S (0) ₂ C (0)-, -SON[ C (0) R] -, -SO ₂ N[ C (0) R] -, -N(R)S0N(R)- or -N(R)SO ₂ N (R) -, 72.227/BE 359 - C(0)0- group, -N (R) P (OR') 0-, -N (R) P (OR* ) - a group of the general formula N (R) P (0) (OR') 0-, -N (R) P (0) (OR')-N[ C (0 ) R] P (OR ' ) 0 - , -N[ C(O)R] P (OR' ) -, -N[ C (O) R] P(0) (OR') O- or -N[ C (0) R] P (O ' R), where in the general formulae R and R' independently represent a hydrogen atom, 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; or L is a group of the general formula -R ^b N (R) S (0) ₂ -, -R ^b N (R) P (0) - or -R ^b N (R) P (0) 0-, in which R ^b represents an alkylene group, and together with the sulfonamide, phosphinamide or phosphonamide group to which it is attached, forms a 5- or 6-membered ring fused to ring A; or L stands for one of the groups of the general formula, in which R ⁸⁵ is a group that leaves the given ring in a 5-, 6- or 72.227/BE 360 It completes into a 7-membered aromatic, heteroaromatic, or heterocycloalkane ring; means a substituted aliphatic group, a substituted cycloalkyl, a substituted bicycloalkyl or a substituted cycloalkenyl group, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, an optionally substituted heteroarylalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterobicycloalkyl, an optionally substituted alkylamido, an optionally substituted arylamido, an optionally substituted alkylsulfonyl, an optionally substituted cycloalkylsulfonyl, an alkylcarbonyl or an optionally substituted alkylcarbonyl group; where one or more substituents of the groups corresponding to the meaning of R ¹ may be selected from the following groups: substituted or unsubstituted aliphatic group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ether group, substituted or unsubstituted aliphatic ether group, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aryl72.227/BE 361 -carbonyl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted (aryloxy)carbonyl group, hydroxy group, substituted or unsubstituted carbamoyl group, hydroxyimino group, substituted or unsubstituted azabicycloalkyl, heterocycloalkyl, oxo or formyl group, substituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, substituted or unsubstituted bicycloalkyl or substituted or unsubstituted heterobicycloalkyl group, cyano, amino, alkylamino, ureido or thioureido group or a group of the general formula -B-E; provided, however, that in a set where R represents an aliphatic group or a cycloalkyl group, and these either carry one or more substituents, among the substituents, there must also be a group other than a hydroxy or lower alkoxy group; furthermore, the heterocycloalkyl group can only be a group other than a 2-phenyl-1,3-dioxan-5-yl group; and the aliphatic group, whether it carries one or more substituents, must also include a group other than an aliphatic group among the substituents; B represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, an alkylene, aminoalkyl, alkylenecarbonyl or (aminoalkyl)carbonyl group; E means substituted or unsubstituted aza-cyclo72.227/BE 362 alkyl, 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 heteroarylsubstituted or unsubstituted alkylsulfonamido, substituted or unsubstituted arylsulfonamido, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted ureido, substituted or unsubstituted thioureido or substituted or unsubstituted aryl group; R represents a hydrogen atom, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl group, a halogen atom, a hydroxy or cyano group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroarylalkyl group, and a group of the general formula -NR ⁴ R ⁵ or -C(O)NR ⁴ R ⁵ ; R represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterocycloalkyl group; furthermore, in the case where L is -SN (R)-, 72.227/BE 363 -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 (0) N (R') - or -N (R) S (0) ₂ N (R') - represents a group of the general formula, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted alkenyl group; R and R are independently hydrogen, azabicycloalkyl, heterocycloalkyl, substituted or unsubstituted alkyl, or a group of the general formula -YZ; or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl, or substituted or unsubstituted heteroaryl group; ^Y is a carbonyl group, a group of the general formula -(CH ₂ ) _p -, a sulfonyl group, a group of the general formula -C(0)0-, -SO ₂ NH- or -CONH-, a group of the general formula -( _{CH 2} ) _p O-, -(CH ₂ ) _p NH~, -(CH 2 ) _p S-, -(CH ₂ ) _p S(O)- or (ÙH ₂ ) _p S(O) ₂ —; P is an integer from 0 to 6; Z is hydrogen, ^substituted or unsubstituted amino, ^substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; and j is an integer from 0 to 6, with the proviso that when L is _-CH2NR- , -C(O)NR-, or -NRC(O)- and ^R3 is azacycloalkyl or azaheteroaryl, j is 0; further 72.227/BE 364 in the case where L is an oxygen atom and R ³ is a phenyl group, j is 0 — and pharmaceutically acceptable salts thereof. ² ' Compounds according to claim 1, in which R is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted dioxolanyl, substituted or unsubstituted quinolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted indolyl or substituted or unsubstituted pyrazolyl. 3. Compounds according to claim 2, having the formula 72.227/BE 365 the group corresponding to the symbol R carries one or more substituents, and these are selected from the following: fluorine, chlorine, bromine and iodine atoms, methyl, nitro, trifluoromethoxy, methoxy or cyano groups, methoxycarbonyl, trifluoromethyl, tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted tetrazolyl or styryl groups, substituted or unsubstituted aryl — thio, substituted or unsubstituted heteroarylthio- substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl or alkynyl group, and a group of the general formula -NR ^f R ^g -C(O)NR ^f R% —R ^c or -CH ₂ OR ^c ; where R ^f and R ⁹ independently represent a hydrogen atom, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group; or R ^f and R ⁹ together with the nitrogen atom represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or substituted or unsubstituted heteroaryl group; < represents a hydrogen atom, a substituted or unsubstituted alkyl or substituted or unsubstituted aryl group, a group of the general ^formula -W-( _CH2 ) _t - ^NRdRe , -W-( _CH2 ) _t -O-alkyl-, -W-( _CH2 ) _t -S-alkyl, W-( _CH2 ) _t -OH or -W-( _CH2 ) _t - ^ORf ; 72.227/BE 366 t has a value of an integer from 0 to 6; W represents a valence line expressing a chemical bond, an oxygen or sulfur atom, a sulfinyl or sulfonyl group, and a group of the general formula -NR -; R ^k represents a hydrogen atom or an alkyl group; R and R independently represent a hydrogen atom, an alkyl or alkanoyl group, and a group of the general formula -KD; or R ^d and R ^e together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heterobicyclic group; K represents a sulfonyl or carbonyl group, a group of the formula -C(O)NH- or -C(O) ₂ - or a valence line expressing a direct chemical bond; D is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aminoalkyl or a substituted or unsubstituted aminocycloalkyl group, a group of the general formula -COOR ¹ or a substituted or unsubstituted alkyl group; and R represents a substituted or unsubstituted aliphatic cso72.227/BE 367 powder or substituted or unsubstituted aromatic group. 4. Compounds according to claim 3, having the formula R represents a substituted or unsubstituted phenyl group. 5- Compounds according to claim 1, in which A represents a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted pyridine ring or a substituted or unsubstituted indole ring. 6. Compounds according to claim 5, in which the ring A carries one or more substituents selected from the following: fluorine, chlorine, bromine and iodine, methyl, nitro, trifluoromethoxy, methoxycyano, methoxycarbonyl, trifluoromethyl, tert-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted tetrazolyl or styryl, substituted or unsubstituted arylthio, substituted or an unsubstituted heteroarylthio, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl or alkynyl group, and a group of the general formula -NR ^f N ⁹ , -C(O)NR ^f R ⁹ , -R ^c or -CH ₂ OR ^c ; where R ¹ and R ⁹ independently represent a hydrogen atom, a substituted or unsubstituted aliphatic group or a substituted 72.227/BE 368 is a substituted or unsubstituted aromatic group; or R ^f and R ^g together with the nitrogen atom represent a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or substituted or unsubstituted heteroaryl group; R ^c represents a hydrogen atom, a substituted or unsubstituted alkyl or a substituted or unsubstituted carbonyl group, a group of the general formula -W-(CH2) _t -NR ^d R ^e , -W-( _CH2 ) t —Ο-alkyl-, -W-(CH2) _t -S-alkyl, W-( _CH2 ) _t -OH or -W-( _CH2 ) _t -OR ^f ; The value of t is an integer from 0 to 6; W represents a valence line expressing a chemical bond, an oxygen or sulfur atom, a sulfinyl or sulfonyl group, and a group of the general formula -NR -; R ^k represents a hydrogen atom or an alkyl group; R and R are independently hydrogen, alkyl or alkanoyl, or a group of the general formula -KD; or R ^d and R ^e together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heterobicycloalkyl group, or a substituted or unsubstituted heteroaromatic group; K represents a sulfonyl or carbonyl group, a group of the formula -C(O)NH- or ~C(O) ₂ - or a valence line expressing a direct chemical bond; D represents substituted or unsubstituted aryl-, substituted72.227/BE 369 substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or substituted ^amino , substituted or unsubstituted aminoalkyl or substituted or unsubstituted aminocycloalkyl group, -COOR ¹ group or substituted or unsubstituted alkyl group; and R represents a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group. 7- Compounds according to claim 6, in which A represents a substituted or unsubstituted benzene ring. 8. Compounds according to claim 1, wherein R ¹ is a group of the general formula wherein m is an integer from 0 to 3. 9- Compounds according to claim 1, in which R ¹ is (CH ₂ )t A group of general formula NRÖR9, in which 72.227/BE 370 m means an integer from 0 to 3; t is an integer from 1 to 6; R and R together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterobicycloalkyl group; or R® and R ⁹ independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula ~Z; Y is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the general formula -C(O)O-, -SO ₂ NH- or -CONH-, _a group of the general formula -(CH _{2 ) q} O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _q S(O) or - (CH 2 ) q S (O) ₂ -, where q is an integer from 0 to 6; Z represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 10. Compounds according to claim 1, in which R ¹ is a group of the general formula (CH ₂ ) _s ( ^CH 2 ) t R 77 NR 8r 9 , in which 72.227/BE 371 m means an integer from 1 to 3; s and t are independently an integer from 0 to 6; R ⁸ and R ⁹ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterobicycloalkyl group; or R ⁸ and R independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ² -Z ² ; Y is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, _a group of the formula -(CH ₂ ) _q O-, ~(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH _{2 ) q S(O) or - (CH 2 ) q} S (O) ₂ -, where q is from 0 to 6 ~* and z is a hydrogen atom, a substituted or unsubstituted substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; R is a group of the general formula -OR ⁷⁸ or -NR ⁷⁹ R ⁸⁰ ; R represents a hydrogen atom or a substituted or unsubstituted aliphatic group; R and R together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted 72.227/BE 372 or an unsubstituted heterobicycloalkyl group; or R ⁷⁹ and R ⁸⁰ independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; Y ³ is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) q S(O)- or - (CH ₂ ) _q s (O) ₂ -, where q is an integer from 0 to 6; and Z represents a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group. 11. Compounds according to claim 1, wherein R ¹ is a group of the general formula R^V, wherein v is an integer from 1 to 3; R ¹⁰ is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -Z ² ; Y ² is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, a group of the formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _q S(O)or -(CH ₂ ) _q S (0) ₂ -, where q is 72.227/BE 373 integer from 0 to 6; and Z represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 12. Compounds according to claim 1, wherein R ¹ is ^{R 11} TT a group of general formula R10, wherein m is an integer from 0 to 3; R ¹⁰ is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -z ² ; Y ² represents a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _{q S(O) or - (CH 2 ) q S} (O) ₂ -, where q is an integer from 0 to 6; u represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; and u represents one or more substituents which are 72.227/BE 374 may be independently selected from the following: hydrogen atom, hydroxy and oxo group, substituted or unsubstituted aliphatic group, substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted aminoalkyl and substituted or unsubstituted aralkyl group, with the proviso that the carbon atoms adjacent to the nitrogen atom may only bear a group other than a hydroxy group. can carry as substituents. 13. Compounds according to claim 1, having the formula R ¹ meaning a group of general formula in which R is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -z ² ; Y ² represents a carbonyl group, -(CH ₂ ) _q - general formula cso72.227/BE 375 powder, sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, a group of the general formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _q S(O)or - (CH ₂ ) _q S (0) ₂ -, where q is an integer from 0 to 6; and Z ² represents a hydrogen atom, a substituted or unsubstituted substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 14. Compounds according to claim 1, wherein R ¹ is a group of general formula wherein r is an integer from 1 to 6; R ⁸ and R ⁹ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterobicycloalkyl group; or R ⁸ and R independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ² -Z ² ; í ² represents a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a -C(0)0-, -SO ₂ NH- or -CONH- of the formula72.227/BE 376 a group of the general formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _q S(O)or - (CH ₂ ) _q S (0) ₂ -, where q is an integer from 0 to 6; and Z ² represents a hydrogen atom, a substituted or unsubstituted substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 15. Compounds according to claim 1, wherein R ¹ is R^c/^C^t (A/ ⁹ Ro is a group of general formula, in which w is an integer from 0 to 4; t is an integer from 0 to 6; u has the value 0 or 1; R represents a hydrogen atom or a substituted or unsubstituted alkyl group; R and R ⁹ together with the nitrogen atom to which they are attached represent a 3-, 4-, 5- or 6-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterobicycloalkyl group; or R ⁸ and R ⁹ independently represent a hydrogen atom, aza-bicyclo72.227/BE 377 alkyl or heterocycloalkyl groups, and a group of the general formula -Y ² -Z ² ; Y ² is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _q O-, ~(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH 2 ) _q S(O)~ or - (CH ₂ ) _q S (0) ₂ -, where q is an integer from 0 to 6; and Z represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group. 16. Compounds according to claim 1, wherein R ¹ is a group of the general formula wherein w is an integer from 0 to 4; t is an integer from 0 to 6; R represents a hydrogen atom or a substituted or unsubstituted alkyl group; R is hydrogen, azabicycloalkyl or heterocycloalkyl, and a group of the general formula -Y ² -Z ² ; í ² means carbonyl group, -(CH ₂ ) _q - general formula cso 72.227/BE 378 powder, sulfonyl group, -C(O)O-, -SO ₂ NH- or -CONH- group, ~(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH ₂ ) _q S(O)or - (CH ₂ ) _q S (0) ₂ - group, where q is an integer from 0 to 6; and represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl·-, a substituted or unsubstituted heteroaryl- or a substituted or unsubstituted heterocycloalkyl group. 17. compounds according to claim 14, in which R ⁸ and R ⁹ together with the nitrogen atom represent a a heterocycloalkyl group of the general formula, in which R ' R ' R ' R ' R , R ¹⁸ , R ¹⁹ and R ²⁰ independently represent a lower alkyl group or a hydrogen atom; or at least one of the pairs R and R , R and R , R ¹⁷ and R ¹⁸ or R ¹⁹ and R ²⁰ together represents an oxygen atom; or at least one of R ¹³ and R ¹⁵ represents a cyano group or a group of the general formula -CONHR , -COOR , -CH2OR ²¹ or -CH2NR ²¹ (R ²² ); R and R together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterobicycloalkyl group; or R ²¹ and R ²² 72.227/BE 379 ··*« ·»«· »»»· ·<·· .·“ independently represents a hydrogen atom, an aza-bicyclo- alkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; Y ³ represents a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the formula -C(0)0~, -SO ₂ NH- or -CONH-, a _group of the formula -( _{CH 2 ) q} O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, -(CH _{2 ) q S(O) or - (CH 2} ) _q S (O) ₂ -, where q is an integer from 0 to 6; Z ³ represents a hydrogen atom, a substituted or unsubstituted ^alkyl , a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; X represents an oxygen or sulfur atom, a sulfinyl, sulfonyl or methylene group or a group of the general formula -CH( _OR23 )- or ^-NR23- ; R ²³ represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, an amidino group or a group of the general formula -C(O)R ²⁴ or -C(O)OR ²⁴ ; R ²⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and u is 0 or 1. 18. Compounds according to claim 14, in which R and R together with the nitrogen atom represent a 72.227/BE 380 a heterocycloalkyl group of the general formula, in which R and R are independently hydrogen or lower alkyl; or R ²⁵ and R ²⁶ together represent an oxygen atom; R and R together with the nitrogen atom to which they are attached represent a 3-, 4-, 5- or 6-membered substituted or unsubstituted heterocycloalkyl group; or R ²¹ and R ²² independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; í represents a hydrogen atom, a carbonyl group, a group of the general formula -(CH ₂ ) _S -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, -(CH ₂ ) _S O-, -(CH ₂ ) _S NH-, -(CH ₂ ) _s S-, - (CH ₂ ) _s S (O) - or - (CH ₂ ) _s S (O) ₂ - a group of general formula, where s is an integer from 0 to 6; ^J is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; means an integer from 1 to 6; and means an integer from 0 to 6. 72.227/BE 381 .................. ··· · · · · · · · · · · · · · * · ·· 19. Compounds according to claim 14, wherein R and R together with the nitrogen atom form a I N R27 is a heterocycloalkyl group of the general formula, wherein i is an integer from 1 to 6; R is a hydroxymethyl group, a group of the general formula -C(O)NR ²⁴ R ²⁸ or -COOR ²⁴ ; and R and R independently represent a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl group. 20. Compounds according to claim 14, wherein R and R together with the nitrogen atom are a group. a heterocycloalkyl group of the general formula, in which R represents a chlorine atom, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, a carboxy or cyano group, a group of the general formula -C(O)OR ³⁰ , -CH ^{2 OR 30} , -CH 2 NR ²¹ R ²² or -C(O)NR R 23 ; R represents a hydrogen atom, substituted or unsubstituted ^{alkyl- ,} substituted or unsubstituted aryl 382 :...... ··· · · · · ··· • · · 4 · ·· ·· ·* substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl or heterocycloaryl group; R ²¹ and R ²² together with the nitrogen atom to which they are attached represent a 3-, 4-, 5- or 6-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterobicycloalkyl group; or R ²¹ and R ²² independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; Y ³ is a carbonyl group, a group of the general formula - (CH ₂ ) _t -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _t O-, -(CH _z ) _t NH-, -(CH ₂ ) _t S-, -(CH 2 ₎ t S(O) or - (CH ₂ ) _t S (0) ₂ -, where t is an integer from 0 to 6; Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group. 21. Compounds according to claim 14, in which at least one of R ⁸ and R ⁹ represents a group of the general formula -y ³ -d, in which Y ³ represents a carbonyl group, a group of the general formula -(CH ₂ ) _t -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, -(CH ₂ ) _t O-, -(CH ₂ ) _t NH-, -(CH ₂ ) _t S-, - (CH ₂ ) _t S (O) 72.227/BE or - (CH ₂ ) _t S (O) ₂ - a group of general formula, where t is an integer from 0 to β; and D meaning a group of general formula in which T represents an oxygen atom, a carbonyl group, a sulfur atom, a sulfinyl, sulfonyl or methylene group, and a group of the general formula -CH(OR ²⁴ )- or -N (R ²⁴ )-; R is hydrogen, substituted or unsubstituted alkyl, aryl or aralkyl; and x is 0, 1 or 2. 22. Compounds according to claim 14, wherein at least one of R and R represents a group of the general formula -Y ³ -N (R ³¹ ) R ³² , in which Y is a carbonyl group, a group of the general formula - (CH ₂ ) _t -, a sulfonyl group, a group of the formula -C(0)0-, -SO ₂ NH- or -CONH-, _a group of the formula -(CH ₂ ) _t O-, -(CH ₂ ) _t NH-, -(CH ₂ ) _t S- _, -(CH 2 ) _{t S} (O)or - (CH ₂ ) t S (0) ₂ -, where t is an integer from 0 to 6; and R and R are independently a substituted or unsubstituted carboxyalkyl, substituted or unsubstituted (alkoxycarbonyl)alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted cyanoalkyl group; or R ³¹ and R ³² are a nitrogen atom72.227/BE 384 mai to which they are attached forms a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl group. 23. Compounds according to claim 15, in which R ⁸ and R ⁹ together with the nitrogen atom represent a heterocycloalkyl group of the general formula, in which R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , r ¹⁹ and R ²⁰ independently represent a lower alkyl group or a hydrogen atom; or at least one of the pairs R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ or R ¹⁹ and R ²⁰ together represents an oxygen atom; or at least one of R ¹³ and R ¹⁵ represents a cyano group or a group of the general formula -CONHR ²¹ , -COOR ²¹ , -CH2OR ²¹ or -CH2NR ²¹ (R ²² ); _z 22 « , and R 22 together with the nitrogen atom to which they are attached represent a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterobicycloalkyl group; or R ²¹ and R ²² independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; means a carbonyl group, a group with the general formula -(CH ₂ ) _S -, a sulfonyl group, a group with the formula -C(0)0-, -SO ₂ NH- or -CONH-, -(CH ₂ ) _s O-, -(CH ₂ ) _s NH-, -(CH ₂ ) _s S-, -(CH _z ) _s S(O) 72.227/BE 385 or (CH ₂ ) _s S(O) ₂ - a group of general formula, where s is an integer from 0 to 6; Z ³ represents a hydrogen atom, a substituted or unsubstituted ^alkyl , a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group; X represents an oxygen or sulfur atom, a sulfinyl, sulfonyl or methylene group or a group of the general formula -CH(OR ²³ )- or -NR ²³ -; R represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, an amidino group or a group of the general formula -C(O)R ² ' or -C(O)OR ²⁴ ; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and y is 0 or 1. 24. Compounds according to claim 15, wherein R and R together with the nitrogen atom form a N R ²⁵ . /,\ R26>q-( ^CH 2) ^r (H2Q _Z \ R22 R21 is a heterocycloalkyl group of the general formula, wherein 72.227/BE 386 ··· · · « ··· ··· · · · · · · · · R and R ²⁶ independently represent a hydrogen atom or a lower alkyl group; or R and R together represent an oxygen atom; R and R ² together with the nitrogen atom to which they are attached represent a 3-, 4-, 5- or 6-membered substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterobicycloalkyl group; or R ²¹ and R 22 independently represent a hydrogen atom, an azabicycloalkyl or heterocycloalkyl group, and a group of the general formula -Y ³ -Z ³ ; Y ³ represents a hydrogen atom, a carbonyl group, a group of the general formula -(CH ₂ ) _S -, a sulfonyl group, -C(O)O-, -SO ₂ NH- or a group of the formula -CONH-, -(CH ₂ ) _S O-, -(CH ₂ ) _S NH-, -(CH ₂ ) _s S-, ~(CH ₂ ) _s S(O)- or - (CH ₂ ) _s S (0) ₂ -, where s is an integer from 0 to 6; Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; r is an integer from 1 to 6; and z is an integer from 0 to 6. 25. Compounds according to claim 15, wherein R and R together with the nitrogen atom form a I N --(CH2)i R27 72.227/BE a heterocycloalkyl group of the general formula 387, wherein i is an integer from 1 to 6; R ² is a hydroxymethyl group or a group of the general formula -C(O)NR ²⁴ R ²⁵ or -COOR ²⁴ ; and R and R independently represent a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl group. 26. Compounds according to claim 15, wherein R and R together with the nitrogen atom form a A heterocycloalkyl group of the general formula A·, in which R is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl group, a carboxy or cyano group, a group of the general formula -C(O)OR ³⁰ , -CH ^{2 OR 30} , -CH ² NR 21 R ²² or -C(O)NR ²¹ R ²² ; R represents a hydrogen atom, a substituted or unsubstituted substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycloalkyl or heterocycloaryl group; R ²¹ and R ²² together with the nitrogen atom to which they are attached represent a 3-, 4-, 5- or 6-membered substituted or unsubstituted heterocycloalkyl group, substituted or 72.227/BE 388 is an unsubstituted heteroaromatic group or a substituted or unsubstituted heterobicycloalkyl group; or R ²¹ and R 22 are independently hydrogen, azabicycloalkyl or heterocycloalkyl, and a group of the general formula -Y ³ -Z ³ ; Y ³ is a carbonyl group, a group of the general formula -(CH ₂ ) _S -, a sulfonyl group, a group of the general formula -C(O)O-, -SO ₂ NH- or -CONH-, a _group of the general formula -(CH ₂ ) _s O-, — (CH ₂ ) _s NH—, -(CH ₂ ) _s S-, -(CH ₂ ) s S(O)or - (CH ₂ ) _s S (0) ₂ -, where s is an integer from 0 to 6; and Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group. 27. Compounds according to claim 15, wherein at least one of R ⁸ and R ⁹ represents a group of the general formula -Y ³ -d, in which Y ³ is a carbonyl group, a group of the general formula -(CH ₂ ) _S -, a sulfonyl group, a group of the general formula -C(0)0-, -S0 ₂ NH- or -CONH-, a _{group of the general formula -(CH 2 ) s O- ,} -(CH ₂ ) _s NH-, -(CH ₂ ) _s S-, -(CH ₂ ) _s S(O) or - (CH ₂ ) s S (0) ₂ -, where s is an integer from 0 to 6; and D meaning 72.227/BE 389 group with general formula, in which T represents an oxygen atom, a carbonyl group, a sulfur atom, a sulfinyl, sulfonyl or methylene group, and a group of the general formula -CH( ^OR33 )- or -N(R33)-; R represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, an amidino group or a group of the general formula -C(O)R ³⁴ or -C(O)OR ³⁴ ; R is hydrogen, substituted or unsubstituted alkyl, aryl or aralkyl; and x is 0, 1 or 2. 28. Compounds according to claim 15, wherein at least one of R ⁸ and R ⁹ represents a group of the general formula -Y ³ -N (R ³¹ ) R ³² , in which Y ³ is a carbonyl group, a group of the general formula -(CH ₂ ) _S -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _s O-, — (CH ₂ ) _s NH —, -(CH ₂ ) _s S- _, -(CH 2 ) s S(O) or - (CH ₂ ) _s S (0) ₂ -, where s is an integer from 0 to 6; and R and R are independently a substituted or unsubstituted carboxyalkyl, substituted or unsubstituted (alkoxycarbonyl)alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted cyanoalkyl group; or R ³¹ and R ³² are a nitrogen atom72.227/BE 390 The group to which they are attached forms a 5- or 6-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterobicycloalkyl group. 29. Compounds according to claim 12, wherein Z is a group of the general formula -N(R )R, in which R ³⁵ and R ³⁶ are independently hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, carbamoyl, cyano, alkylcarbonyl or aralkyl. 30. Compounds according to claim 12, wherein Z ² is ^N^Xi K37 represents a group with a general formula in which the Any of the symbols X! independently represents a methine group or a nitrogen atom; and R represents a hydrogen atom, a cyano group, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. 31. Compounds according to claim 12, wherein Z ² is 72.227/BE 391 means a group of general formula wherein g is an integer from 0 to 3; T represents an oxygen atom, a carbonyl group, a sulfur atom, a sulfinyl, sulfonyl or methylene group, and a group of the general formula -CH(OR ³⁴ )- or -N(R ³⁴ )-; _ 3 4 , _z represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group; and R represents a hydrogen atom, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl. 32. Compounds according to claim 12, wherein Z ² is means a group of general formula wherein g is an integer from 0 to 3; and R represents hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxy72.227/BE 392 -alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl. 33. Compounds according to claim 12, having the formula Z ² represents a group of general formula in which T is an oxygen atom, a carbonyl group, a sulfur atom, a sulfinyl or methylene group, and -CH (OR ³⁴ ) - or a group of general formula N(R ); R represents a hydrogen atom, a substituted or unsubstituted ^alkyl , a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group; g is an integer from 0 to 3; and R represents a hydrogen atom, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl. 34. Compounds according to claim 12, having the formula Z ² is a /~V-R37 R38 72.227/BE 393 means a group of general formula, in which R is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted aralkyl; and R represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted carbamoyl, a perhaloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group. 35. Compounds according to claim 1, wherein R ¹ is a group of general formula wherein u is 0 or 1; ^R ' R» Rf R, R, ^R44 , ^R45 and ^R46 independently represent a methyl group or a hydrogen atom; or at least one of the pairs ^R39 and ^R40 , ^R41 and R, R and R or R and ^R46 together represents an oxygen atom; 72.227/BE 394 R is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -Z ² ; Y ² is a carbonyl group, a group of the general formula -(CH _z ) _q -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, a _group of the formula -(CH ₂ ) _q O-, -(CH ₂ ) _q NH-, -(CH ₂ ) _q S-, ~(CH _{2 ) q S(O)or - (CH 2 ) q} S (0) ₂ -, where q is an integer from 0 to 6; and Z is hydrogen, substituted or unsubstituted substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; or R ⁴⁷ is a means a group of general formula wherein y is 0 or 1; R, R, R, R, R, ^R52 , ^R53 , ^R54 and ^R55 are independently methyl or hydrogen; or at least one of the pairs ^R48 and ^R49 , ^R50 and R, R51 and R52 or ^R53 and ^R55 together is oxygen; R is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ³ -Z ³ ; f ³ represents a carbonyl group, a group of the general formula -(CH ₂ ) _t -, a sulfonyl group, a -C(0)0-, -SO ₂ NH- or -CONH- of the formula72.227/BE 395 tu group, -(CH _z ) _t O-, -(CH ₂ ) _t NH-, -(CH ₂ ) _t S-, -(CH ₂ ) _t S(O)or - (CH ₂ ) _t S (0) ₂ - a group of general formula, where t is an integer from 0 to 6; and means a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group. 36. Compounds according to claim 1, wherein R ¹ is a group of the general formula wherein e, f, h, u and y are independently 0 or 1; R ⁵⁷ , R ⁵³ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ R ⁶² r63 _r 64 r65 , _o _ 66 . η , '>> r·· r R r esR independently represent a methyl group or a hydrogen atom; or at least one of the pairs R ⁵⁷ and R , R ⁵⁹ and R ⁶⁰ , R ⁶¹ and R ⁶² or R ⁶³ and R ⁶⁴ together represents an oxygen atom; R is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ² -Z ² ; Y ² is a carbonyl group, a group of the general formula -(CH ₂ ) _q -, a sulfonyl group, a group of the general formula -C(0)0-, -SO ₂ NH- or -CONH-, a group of the general formula -(CH ₂ ) _q O-, - (CHJ _q NH-, -(CH ₂ ) _q S~, -(CH ₂ ) _qS (0)- or (CH ₂ ) _q S(O) ₂ -, where q is 72.227/BE 396 integers from O to 6; and Z is hydrogen, substituted or unsubstituted substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; or R ⁶⁷ represents a group of the general formula / R 71 _z R 72 r 76 in which d is 0 or 1; ^R ' ^R ' R ' R , ^r72 ' ^r ”' ^r?4 and R ⁷⁵ independently represent a lower alkyl group or a hydrogen atom; or at least one of the pairs R and R ⁶⁹ , R ⁷⁰ and R ⁷¹ , R ⁷² and R ³³ or R ⁷⁴ and R ⁷⁵ together represents an oxygen atom; R is hydrogen, azabicycloalkyl or heterocycloalkyl or a group of the general formula -Y ³ -Z ³ ; í ³ represents a carbonyl group, a group of the general formula -(CH ₂ ) _t -, a sulfonyl group, a group of the formula -C(O)O-, -SO ₂ NH- or -CONH-, a group of the formula -(CH ₂ ) _t O-, -(CH ₂ ) _t NH~, -(CH ₂ ) _t S-, -(CH ₂ ) _{t S} (O)or - (CH 2 ) _t S (0) ₂ -, where t is an integer from 0 to 6; and ' means a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group ^. 37. Compounds according to claim 1, wherein ^R2 is hydrogen. 38. Compounds according to claim 1, wherein L is oxygen, -NHSO ₂ R-, or -NHC(O)O- or -NHC(O)-. 39. A method for inhibiting the function of protein kinases, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt, prodrug derivative or biologically active metabolite thereof. 40. The method of claim 39, wherein said protein kinase is one of the following: KDR, FGFR-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, Flt-1, TIE-2, Lek, Src, fyn, Lyn, Blk, and yes. 41. The method of claim 39, wherein said protein kinase activity is associated with hyperproliferative diseases. 42. The method of claim 39, wherein said protein kinase activity is associated with angiogenesis, vascular permeability, immune response, or inflammation. 43. A method for treating a pathological condition in a patient associated with the activity of a protein kinase, characterized in that the patient is administered a compound of general formula (I) according to claim 1 or a physiologically acceptable salt, prodrug derivative or biologically active metabolite thereof as a therapeutic agent.227/BE An effective amount of 398 san is administered. 44. The method of claim 43, wherein said protein kinase is one of the following: KDR, Flt-1, PDGFRβ, PDGFRα, IGF-1R, c-Met, TIE-2, Lek, Src, fyn, Lyn, Blk, and yes. 45. The method of claim 43, wherein the pathological condition associated with protein kinase activity is a hyperproliferative disease. 46. The method of claim 43, wherein said protein kinase activity is associated with angiogenesis, vascular permeability, an immune response, or an inflammatory reaction. 47. The method of claim 43, wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase. 48. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one or more ulcers. 49. The method of claim 48, wherein the one or more ulcers are caused by a bacterial or fungal infection; or the one or more ulcers are Mooren ulcers; or the one or more ulcers are a symptom of ulcerative colitis. 50. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one of the following: Lyme disease, sepsis, or infection caused by herpes simplex, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasma. 72.227/BE 399 51. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one of the following: von Hippel-Lindau syndrome, pemphigus, psoriasis, Paget's disease, or polycystic kidney disease. 52. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one of the following: fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic obstructive pulmonary disease, asthma, exudates, ascites, pleural effusions, pulmonary edema, cerebral edema, and edema induced by burns, trauma, radiation, stroke, hypoxia or ischemia. 53. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one of the following: ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, or endometriosis. 54. The method of claim 43, wherein the pathological condition associated with protein kinase activity is one of the following: chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, glomerulonephritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, and graft rejection. 55. The method of claim 43, wherein the pathological condition associated with protein kinase activity is sickle cell anemia. 56. The method of claim 43, wherein the pathological condition associated with protein kinase activity is an eye disease. 72.227/BE .. 400 57. The method of claim 56, wherein the pathological condition associated with proteinase activity is one of the following: ocular or macular edema, neovascularization eye disease, scleritis, radial keratotomy, uveitis, vitreous, myopia, orbital diseases, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt syndrome, Eales syndrome, retinopathy or macular degeneration. 58. The method of claim 43, wherein the pathological condition associated with proteinase activity is a cardiovascular disease. 59. The method of claim 58, wherein the disease associated with protein kinase activity is one of the following: atherosclerosis, restenosis, ischemic/reperfusion injury, vascular occlusion, venous malformation, or carotid artery stenosis. 60. The method of claim 43, wherein the pathological condition associated with protein kinase activity is cancer. _________ 61. The method of claim 60, wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignancy, or malignant ascites. 62. The method of claim 61, wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia. 72.227/BE 401 63. The method of claim 43, wherein the pathological condition associated with protein kinase activity is Crow-Fucase syndrome (POEMS) or a diabetes-related disease. 64. The method of claim 63, wherein the diabetes-related disease is insulin-dependent diabetes mellitus, glaucoma, diabetic retinopathy or microangiopathy. 5. A method for reducing the fertility of a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) according to claim 1, or a physiologically acceptable salt, prodrug derivative or biologically active metabolite thereof. 66. The method of claim 43, comprising administering to the patient an amount of a compound of formula (i) or a salt, prodrug derivative or biologically active metabolite thereof effective to promote angiogenesis or vasculogenesis. 67. The method of claim 66, wherein the protein kinase is Tie-2. 68. The method of claim 66, wherein a compound of general formula (I) or a salt, prodrug derivative or biologically active metabolite thereof is used in combination with a proangiogenic growth factor. 69. The method of claim 68, wherein the proangiogenic growth factor is selected from the group consisting of VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF-2, derivatives thereof, and anti-idiotypic antibodies. 72.227/BE 402 70. The method of claim 66, wherein the pathological condition associated with proteomase activity is one of the following: anemia, ischemia, infarction, transplant rejection, wound, gangrene or necrosis. 71- The method of claim 43, wherein the activity of the pro-T cell kinase is associated with T cell activation, B cell activation, mast cell degranulation, monocyte activation, potentiation of an inflammatory response, or combinations thereof. 72 Cis 5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1; trans-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; cis 5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride; trans 5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo}2,3-d]pyrimidin-4-amine; trans-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride; 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride; 72.227/BE 403 cis 5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; trans 5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; cis-5-(4-phenoxyphenyl)-7- _{ 4-[4-(2-methoxyethyl)-piperazine-1-11]-cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; trans-5-(4-phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)-piperazine- -1-yl]-cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; cis-7-[4-(4-ethyl-piperazin-1-yl)-cyclohexyl]-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; trans-7-[4-(4-ethylpiperazin-1-H)-cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; cis 5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; trans-5-(4-phenoxyphenyl)-7-[4-(4-isopropylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; cis-5-(4-phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)piperazin-1-H]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; trans-5-(4-phenoxyphenyl)-7-{4-[4-(2-methoxyethyl)-piperazine- - 1-yl]-cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-aminotrimaleate; cis-5-(4-phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)propyl- -amino}-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-aminotrimaleate; trans-5-(4-phenoxyphenyl)-7-[4-{[3-(1H-imidazol-1-yl)-propylamino]-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-aminodimaleate; cis-7-[4-(dimethylamino)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate; 72.227/BE 404 trans 5-(4-phenoxyphenyl)-7-(4-piperidinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate; trans-5-(4-phenoxyphenyl)-7-[4-(1-pyrrolidinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dimaleate; cis-5-(4-phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; trans-5-(4-phenoxyphenyl)-7-[4-(1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; 5-(4-phenoxyphenyl)-7-[3-(4-methyl-piperazin-1-yl)-cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-aminotrimaleate; trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; trans-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride; cis 5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; cis-5-(4-phenoxyphenyl)-7-[3-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trihydrochloride; trans-5-(4-phenoxy-2-methylphenyl)-7-(4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; cis-benzyl {N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-carbamate}-trimaleate; 72.227/BE 405 trans benzyl {N [4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxy-phenyl]-carbamate}-trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]benzamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxy-phenyl]-3-phenyl-propionic acid amide; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3-phenylpropionic acid; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3-phenylpropionic acid amide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl]-3- ^{phenyl _} Propionic acid amide trimaleate; cis-2-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-pyrrolo[2,3-d]pyrimidin-5-yl}-phenoxy]-6-[(3-methoxy-propyl)-amino]-benzonitrile trimaleate; trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]7H-pyrrolo}2,3-d]pyrimidin-5-yl}phenoxy]-6-[(3-methoxypropyl)amino]benzonitrile trimaleate; 72.227/BE 406 cis 2-amino-6-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzonitrile trimaleate; trans-2-amino-6-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy]benzonitrile trimaleate; cis-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-[(4-tolyl)thio]benzonitrile trimaleate; trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy]-6-[(4-tolyl)thio]benzonitrile trimaleate; cis-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-[(2-pyridyl)thio]benzonitrile trimaleate; trans-2-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy]-6-[(2-pyridyl)thio]benzonitrile trimaleate; cis-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; trans-5-(4-phenoxy-2-methylphenyl)-7-[4-(4-methylpiperazin-1)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate; 72.227/BE 407 trans-N [4 {4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-fluorobenzenesulfonamide trimaleate; N-{4-[4-Ammo-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4-fluorobenzenesulfonamide; N-{4-[ N -amino-7-(1-benzylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide; N-{4-[4-Amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide; N-{4-[4-amino-7-(1-formyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4-fluorobenzenesulfonamide; N {4-[4-amino-7-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-4fluorobenzenesulfonamide dimaleate; N {4[4-amino-7-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-piperidin-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl}-4fluorobenzenesulfonamide; N-(4-(4-amino-7-{ H (1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-piperidin-4-yl)-7H-pyrrolo[2,3-d)pyrimidin-S-yl]-2-fluorophenyl)-4-fluorobenzenesulfonamide; N-(4-[4-amino-7-{1-[(2-pyridyl)carbonyl)-piperidin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl]-2-fluorophenyl)-4-fluorobenzenesulfonamide; N [4-{4-amino-7-[1-(1-methyl-piperidin-4-yl)-piperidin-4-yl]-7H-pyrrolo[2,3-d)pyrimidin-5-yl)-2-fluorophenyl)-4-fluorobenzenesulfonamide trimaleate; 72.227/BE 408 trans N [4 {4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-(trifluoromethoxy)benzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-5-chloro-2-thiophenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-2-chlorobenzenesulfonamide trimaleate; trans N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-2-chloro-benzenesulfonamide trimaleate; cis-Nd 4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-difluorobenzenesulfonamide trimaleate; trans N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,3,4-trifluorobenzenesulfonamide trimaleate; 72.227/BE 409 cis N [4 {4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2-nitro-benzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2-fluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,4,6-trichlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,6-dichlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-chlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-fluorobenzenesulfonamide dimaleate; cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-5-chloro-2-thiophene sulfonamide dimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-bromo-2,6-difluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-3-chloro-benzenesulfonamide trimaleate; 72.227/BE 410 cis N [4 {4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2-iodo-benzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2-(trifluoromethoxy)-benzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate; cis-N-}4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-chloro-6-methylbenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-cyano-2-chlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3,4-trifluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-3,4-difluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-bromo-2-fluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-5-bromo-2-thiophenesulfonamide trimaleate; 72.227/BE * 411 .................. • · · · 4 « »··* * ·* * »* * *·· * * cis N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2,4-dichloro-benzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3,4-trichlorobenzenesulfonamide trimaleate; cis N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-3-bromo-5-chloro-2-thiophenesulfonamide trimaleate; cis N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; cis N [4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluoro-phenyl]-2,1,3-benzoxadiazole-4-sulfonamide trimaleate; cis N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,5-dichlorothiophenesulfonamide trimaleate; cis N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-7-chloro-2,1,3-benzoxadiazole-4-sulfonamide trimaleate; cis-N-[4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-7-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; cis N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; 72.227/BE 412 ....... ··** *·** **-* ‘e·’ w* cis-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-5-chloro-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-3-chloro-2-methylbenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2-bromobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo(2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,5-dibromo-3,6-difluorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate; cis-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-(2-nitrophenyl)methanesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2-nitrobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-fluorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,4,6-trichlorobenzenesulfonamide trimaleate; 72.227/BE 413 “ 4- ··«*»»*««·» 9 «ν ··« · « « ·*· <>4* *«·* % * ⁴ «r* 9·' trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-l-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-2, 6-dichloro-benzenesulfonamide-trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-chlorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-fluorobenzenesulfonamide dimaleate; trans-N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-4-bromo-2,5-difluoro-benzenesulfonamide trimaleate; trans-N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-4-fluoro-3-chloro-benzenesulfonamide trimaleate; trans-N-[4-(4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2-iodobenzenesulfonamide trimaleate; trans-N-[4-(4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-2,3-dichlorobenzenesulfonamide trimaleate; trans-N-[4-(4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoro-phenyl]-2-chloro-6-methyl-benzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-4-cyano-2-chlorobenzenesulfonamide trimaleate; 72.227/BE trans N [4 {4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3,4-difluorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-bromo-2-fluorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-5-bromo-2-thiophenesulfonamide trimaleate, trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-2,4-dichloro-benzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,3,4-trichlorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-{4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-3-bromo-5-chloro ^- 2-thiophenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2,1,3-benzoxadiazole-4-sulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,5-dichloro-1-thiophene sulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluorophenyl]-7-chloro-2,1,3-benzoxadiazole-4-sulfonamide trimaleate; 72.227/BE 415 .... .... ..., ♦ * t - * 4 Μ V *·<? *.· · W M trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2, 3-d]pyrimidin-5-yl}-2-fluorophenyl]-7-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-5-methyl-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-5-chloro-2,1,3-benzothiadiazole-4-sulfonamide trimaleate; trans-N-[4-{4-amino-7-(4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-3-chloro-2-methylbenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl]-2-bromobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-2,5-dibromo-3,6-difluorobenzenesulfonamide trimaleate; trans-N-[4-{4-amino-7-{4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluoro-phenyl]-(2-nitro-phenyl)-methanesulfonamide trimaleate.