[go: up one dir, main page]

WO2001072751A1 - Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases - Google Patents

Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases Download PDF

Info

Publication number
WO2001072751A1
WO2001072751A1 PCT/US2000/008593 US0008593W WO0172751A1 WO 2001072751 A1 WO2001072751 A1 WO 2001072751A1 US 0008593 W US0008593 W US 0008593W WO 0172751 A1 WO0172751 A1 WO 0172751A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
pyrimidin
pynolo
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2000/008593
Other languages
English (en)
Inventor
Gavin C. Hirst
David Calderwood
Rainer Munschauer
Lee D. Arnold
David N. Johnston
Paul Rafferty
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH, BASF SE filed Critical Knoll GmbH
Priority to AU2000240570A priority Critical patent/AU2000240570A1/en
Priority to PCT/US2000/008593 priority patent/WO2001072751A1/fr
Publication of WO2001072751A1 publication Critical patent/WO2001072751A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • protein kinases There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates.
  • the phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate.
  • the specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.
  • the phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes.
  • a cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protem kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.
  • Protein Tyrosine Kinases Protein tyrosine Kinases.
  • Protein tyrosine kinases are enzymes which catalyse the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ullrich, 1992, Neuron 9:383-391).
  • Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease.
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas).
  • inappropriate vascularization e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas.
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • Receptor Tyrosine Kinases (RTKs).
  • the RTKs comprise a large family of transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified.
  • the receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61 :243-254, 1990).
  • RTKs The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212).
  • receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans- phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response. (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) see Schlessinger and Ullrich, 1992, Neuron 9:1-20.
  • Proteins with SH2 (src homology -2) or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals into cell. Both of the domains recognize phosphotyrosine.
  • RTKs receptor tyrosine kinases
  • FLK-1 fetal liver kinase 1
  • KDR kinase insert domain-containing receptor
  • FLK-1/KDR vascular endothelial cell growth factor receptor 2
  • NAGFR-2 vascular endothelial cell growth factor receptor 2
  • DNAs encoding mouse, rat and human FLK-1 have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews et al, Proc. Natl. Acad. Sci. USA, 88:9026-30, 1991; Terman et al, 1991, supra; Terman et al, Biochem. Biophys. Res. Comm. 187:1579-86, 1992; Sarzani et al, supra; and Millauer et al, Cell 72:835-846, 1993). Numerous studies such as those reported in
  • VEGF and FLK-1 /KDR/VEGFR-2 are a ligand- receptor pair that play an important role in the proliferation of vascular endothelial cells, and formation and sprouting of blood vessels, termed vasculogenesis and angiogenesis, respectively.
  • Another type III subclass RTK designated "fins-like tyrosine kinase- 1" (Flt-
  • Flt-1 vascular endothelial cell growth factor receptor 1
  • VEGF vascular endothelial cell growth factor
  • VEGF Vascular endothelial cell growth factor
  • Flt-1 is believed to be essential for endothelial organization during vascular development.
  • Flt-1 expression is associated with early vascular development in mouse embryos, and with neovascularization during wound healing (Mustonen and Alitalo, supra).
  • Expression of Flt-1 in monocytes, osteoclasts, and osteoblasts, as well as in adult tissues such as kidney glomeruli suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra).
  • VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al, Endocrinology 133: 848-859, 1993; Kolch et al, Breast Cancer Research and Treatment 36: 139-155, 1995; Ferrara et al, Endocrine Reviews 18(1); 4-25, 1997; Ferrara et al., Regulation of Angiogenesis (ed. L. D. Goldberg and E.M. Rosen), 209-232, 1997).
  • VEGF has been implicated in the control and enhancement of vascular permeability (Connolly, et al, J. Biol. Chem.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • the members of the VEGF family are often coexpressed with VEGF in a number of tissues and are, in general, capable of forming heterodimers with VEGF. This property likely alters the receptor specificity and biological effects of the heterodimers and further complicates the elucidation of their specific functions as illustrated below (Korpelainen and Alitalo, Curr. Opin. Cell Biol, 159- 164, 1998 and references cited therein).
  • Placenta growth factor has an amino acid sequence that exhibits significant homology to the VEGF sequence (Park et al, J. Biol. Chem. 269:25646- 54, 1994; Maglione et al. Oncogene 8:925-31, 1993).
  • PIGF Placenta growth factor
  • different species of PIGF arise from alternative splicing of mRNA, and the protein exists in dimeric form (Park et al, supra).
  • P1GF-1 and P1GF-2 bind to Flt-1 with high affinity, and P1GF-2 also avidly binds to neuropilin-1 (Migdal et al, J. Biol. Chem.
  • PIGF has been reported to potentiate both the vascular permeability and mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (purportedly due to heterodimer formation) (Park et al, supra).
  • VEGF-B is produced as two isofo ⁇ ns (167 and 185 residues) that also appear to bind Fit- 1/VEGFR- 1. It may play a role in the regulation of extracellular matrix degradation, cell adhesion, and migration through modulation of the expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1 (Pepper et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(20): 11709-11714).
  • VEGF-C was originally cloned as a ligand for VEGFR-3/Flt-4 which is primarily expressed by lymphatic endothelial cells.
  • VEGF-C can also bind KDR/VEGFR-2 and stimulate proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models ( Lymboussaki et al, Am. J. Pathol (1998), 153(2): 395-403; Witzenbichler et al, Am. J. Pathol (1998), 153(2), 381-394).
  • the transgenic overexpression of VEGF-C causes proliferation and enlargement of only lymphatic vessels, while blood vessels are unaffected.
  • the expression of VEGF-C is not induced by hypoxia (Ristimaki et al, J. Biol. Chem. (1998), 273(14),8413-8418).
  • VEGF-D is structurally very similar to VEGF- C.
  • VEGF-D is reported to bind and activate at least two VEGFRs, VEGFR-3/Flt-4 and KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominently expressed in the mesenchymal cells of the lung and skin (Achen et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(2), 548-553 and references therein).
  • VEGF-C and VEGF-D have been claimed to induce increases in vascular permeability in vivo in a Miles assay when injected into cutaneous tissue (PCT/US97/14696; WO98/07832, Witzenbichler et al, supra).
  • PCT/US97/14696; WO98/07832, Witzenbichler et al, supra The physiological role and significance of these ligands in modulating vascular hyperpermeability and endothelial responses in tissues where they are expressed remains uncertain.
  • VEGF-E vascular endothelial growth factor-E
  • NZ-7 VEGF vascular endothelial growth factor
  • VEGF-E sequences possess 25% homology to mammalian VEGF and are encoded by the parapoxvirus Orf virus (OV). This parapoxvirus that affects sheep and goats and occasionally, humans, to generate lesions with angiogenesis.
  • VEGF-E is a dimer of about 20 kDa with no basic domain nor affinity for heparin, but has the characteristic cysteine knot motif present in all mammalian VEGFs, and was surprisingly found to possess potency and bioactivities similar to the heparin-binding VEGF165 isoform of VEGF-A, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo.
  • tissue factor TF
  • VEGF-E Like VEGF 165, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentrations, while in contrast to VEGF 165, VEGF-E did not bind to VEGF receptor-1 (Flt-1). Based upon emerging discoveries of other homologs of VEGF and VEGFRs and the precedents for ligand and receptor heterodimerization, the actions of such VEGF homologs may involve formation of VEGF ligand heterodimers, and/or heterodimerization of receptors, or binding to a yet undiscovered VEGFR (Witzenbichler et al, supra). Also, recent reports suggest neuropilin-1 (Migdal et al, supra) or VEGFR-3/Flt-4 (Witzenbichler et al, supra), or receptors other than
  • KDR/NEGFR-2 may be involved in the induction of vascular permeability (Stacker, S.A., Vitali, A., Domagala, T., Nice, E., and Wilks, A.F., "Angiogenesis and Cancer” Conference, Amer. Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40: S118-120 (1997)).
  • Tie-2 (TEK) is a member of a recently discovered family of endothelial cell specific receptor tyrosine kinases which is involved in critical angiogenic processes, such as vessel branching, sprouting, remodeling, maturation and stability.
  • Tie-2 is the first mammalian receptor tyrosine kinase for which both agonist ligand(s) (e.g., Angiopoietinl ("Angl”), which stimulates receptor autophosphorylation and signal transduction), and antagonist ligand(s) (e.g., Angiopoietin2 (“Ang2”)), have been identified.
  • agonist ligand(s) e.g., Angiopoietinl (“Angl”
  • Ang2 Angiopoietin2
  • Knock-out and transgenic manipulation of the expression of Tie-2 and its ligands indicates tight spatial and temporal control of Tie-2 signaling is essential for the proper development of new vasculature.
  • the current model suggests that stimulation of Tie-2 kinase by the Angl ligand is directly involved in the branching, sprouting and outgrowth of new vessels, and recruitment and interaction of periendothelial support cells important in maintaimng vessel integrity and inducing quiescence.
  • the soluble extracellular domain of Tie-2 (“ExTek”) can act to disrupt the establishment of tumor vasculature in a breast tumor xenograft and lung metastasis models and in tumor-cell mediated ocular neovasculatization.
  • ExTek soluble extracellular domain of Tie-2
  • adenoviral infection By adenoviral infection, the in vivo production of mg/ml levels ExTek in rodents may be achieved for 7-10 days with no adverse side effects. These results suggest that disruption of Tie-2 signaling pathways in normal healthy animals may be well tolerated.
  • These Tie-2 inhibitory responses to ExTek may be a consequence sequestration of ligand(s) and/or generation of a nonproductive heterodimer with full-length Tie-2.
  • Tie-2 plays a role in the progression of rheumatoid arthritis.
  • Point mutations producing constitutively activated forms of Tie-2 have been identified in association with human venous malformation disorders. Tie-2 inhibitors are, thereful, useful in treating such disorders, and in other situations of inappropriate neovascularization.
  • the Non-Receptor Tyrosine Kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified.
  • the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bohlen,
  • tyrosine kinases whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyper-immune responses.
  • PCT WO 94/03427 selenoindoles and selenides
  • PCT WO 92/21660 tricyclic polyhydroxylic compounds
  • PCT WO 91/15495 benzylphosphonic acid compounds
  • Anilinocinnolines PCT WO97/34876
  • quinazoline derivative compounds PCT WO97/22596; PCT WO97/42187
  • Plk-1 is a serine/threonine kinase which is an important regulator of cell cycle progression. It plays critical roles in the assembly and the dynamic function of the mitotic spindle apparatus. Plk-1 and related kinases have also been shown to be closely involved in the activation and inactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of Plk-1 expression are associated with cell proliferation activities. It is often found in malignant tumors of various origins. Inhibitors of Plk-1 are expected to block cancer cell proliferation by disrupting processes involving mitotic spindles and inappropriately activated cyclin-dependent kinases.
  • Cdc2/Cvclin B Kinase Inhibitors (Cdc2) is also known as cdkl)
  • Cdc2/cyclin B is another serine/threonine kinase enzyme which belongs to the cyclin-dependent kinase (cdks) family. These enzymes are involved in the critical transition between various phases of cell cycle progression. It is believed that uncontrolled cell proliferation, which is the hallmark of cancer is dependent upon elevated cdk activities in these cells. The inhibition of elevated cdk activities in cancer cells by cdc2/cyclin B kinase inhibitors could suppress proliferation and may restore the normal control of cell cycle progression.
  • cdks cyclin-dependent kinase
  • CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits (Draetta, Trends in Cell Biology, 3:287-289 (1993)); Murray and Kirschner, Nature, 339:275-280 (1989); Solomon et al, Molecular Biology of the Cell, 3:13-27 (1992)).
  • a further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit (Draetta, Trends in Cell Biology, 3:287-289 (1993)); Murray and Kirschner, Nature, 339:275-280 (1989); Solomon et al, Molecular Biology of the Cell, 3:13-27 (1992); Ducommun et al, EMBO Journal, 10:3311-3319 (1991); Gautier et al, Nature 339:626-629 (1989); Gould and Nurse, Nature, 342:39-45 (1989); Krek and Nigg, EMBO Journal, 10:3331-3341 (1991); Solomon et al, Cell, 63 : 1013 - 1024 (1990)).
  • E/CDK2 are thought to mediate the onset of S-phase (Matsushima et al, Molecular & Cellular Biology, 14:2066-2076 (1994); Ohtsubo and Roberts, Science, 259:1908- 1912 (1993); Jo et al, Genes & Development, 7:1559-1571 (1993); Resnitzky et al, Molecular & Cellular Biology, 14:1669-1679 (1994)).
  • Inhibitors of kinases involved in mediating or maintaining disease states represent novel therapies for these disorders.
  • Examples of such kinases include, but are not limited to: (1) inhibition of c-Src Brickell, Critical Reviews in Oncogenesis, 3:401-406 (1992); Courtneidge, Seminars in Cancer Biology, 5:236-246 (1994), raf (Powis, Pharmacology & Therapeutics, 62:57-95 (1994)) and the cyclin-dependent kinases (CDKs) 1, 2 and 4 in cancer (Pines, Current Opinion in Cell Biology, 4:144- 148 (1992); Lees, Current Opinion in Cell Biology, 7:773-780 (1995); Hunter and Pines, Cell, 79:573-582 (1994)), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger et al, Proceedings of the National Academy of Science USA, 92:2258-2262 (1995)), (3) inhibition of CDK5 and GSK3
  • inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not misregulated, but it nonetheless essential for maintenance of the disease state.
  • inhibition of the kinase activity would act either as a cure or palliative for these diseases.
  • many viruses such as human papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle (Vousden, FASEB Journal, 7:8720879 (1993)).
  • Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2 may disrupt the virus life cycle by preventing virus replication.
  • NF-kB regulates genes involved in inflammatory responses (such as hematopoetic growth factors, chemokines and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology, 12:141-179 (1994)) and may be involved in the suppression of apoptotic signals within the cell (Beg and Baltimore, Science, 274:782-784 (1996); Wang et al, Science, 274:784-787 (1996); Van Antwerp et al, Science, 274:787-789 (1996)).
  • inhibition of CDK2 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-kB.
  • CDK2 activity may also have utility in other cases where regulation of NF-kB plays a role in etiology of disease.
  • a further example may be take from fungal infections: Aspergillosis is a common infection in immune-compromised patients (Armstrong, Clinical Infectious Diseases, 16:1-7 (1993)). Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A (Osmani et al, EMBO Journal, 10:2669-2679 (1991); Osmani et al, Cell, 67:283-291 (1991)) may cause arrest or death in the fungi, improving the therapeutic outcome for patients with these infections.
  • the present invention provides compounds of Formula I,
  • Ring A is a six membered aromatic ring or a five or six ' membered heteroaromatic ring. Ring A is optionally substituted such as with one or more of the following substituents: a substituted or unsubstituted aliphatic group, a halogen, a substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, cyano, nitro, -NR 4 R 5 , -C(O) 2 H, -OH, a substituted or unsubstituted alkoxycarbonyl, -C(O) 2 -haloalkyl, a substituted or unsubstituted alkylthio ether, a substituted or unsub
  • R and R' are each, independently, -H, an acyl group, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted cycloalkyl group.
  • L is -R b N(R)S(O) 2 -, -R b N(R)P(O)-, or -R b N(R)P(O)O-.
  • R réelle is an alkylene group which when taken together with the sulphonamide, phosphinamide, or phosphonamide group to which it is bound forms a five or six membered ring fused to ring A.
  • L is represented by one of the following structural formulas:
  • R 85 taken together with the phosphinamide, or phosphonamide is a 5-, 6-, or
  • R is a substituted aliphatic group, a substituted cycloalkyl, a substituted bicycloalkyl, a substituted cycloalkenyl, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, an optionally substituted heteroaralkyl, an optionally substituted heterocycloalkyl, an optionally substituted heterobicycloalkyl, an optionally substituted alkylamindo, and optionally substituted arylamido, an optionally substituted -S(O) 2 -alkyl or optionally substituted -S(O) 2 -cycloalkyl, a -C(O)-alkyl or an optionally substituted -C(O)- alkyl.
  • Rj can be substituted with one or more substituents.
  • R j is substituted with a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic ether, a substituted or unsubstituted aliphatic ether, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted
  • B is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aromatic, a substituted or unsubstituted heteroaromatic, an alkylene, an aminoalkyl, an alkylenecarbnonyl, or an aminoalkylcarbonyl.
  • E is a substituted or unsubstituted azacycloalkyl, a substituted or unsubstituted azacycloalkylcarbonyl, a substituted or unsubstituted azacycloalkylsulfonyl, a substituted or unsubstituted azacycloalkylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroarylcarbonyl, a substituted or unsubstituted heteroarylsulfonyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl sulfonamido, a substituted or unsubstituted aryl sulfonamido, a substituted or unsubstituted bicycloalkyl, a substituted or unsubstituted ureido, a substituted or unsubstituted
  • G is a direct bond; -(CH 2 ) j -, wherein j is 1 to 6; a C 2 -C 6 - alkenylene group, a C 3 -C 8 -cycloalkylene group or a C r C 6 -oxaalkylene group;
  • R j is an aliphatic group or cycloalkyl group
  • R ⁇ is not exclusively substituted with one or more substitutent selected from the group consisting of hydroxyl and lower alkyl ethers.
  • a heterocycloalkyl is not 2-phenyl-l,3-dioxan-5-yl, and an aliphatic group is not substituted exclusively with one or more aliphatic groups.
  • R 2 is -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl, a halogen, -OH, cyano, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, -NR 4 R 5 , or -C(O)NR 4 R 5 .
  • R 3 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocycloalkyl.
  • R 4 , R 5 and the nitrogen atom together form a 3, 4, 5, 6 or 7- membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic.
  • R 4 and R 5 are each, independently, -H, azabicycloalkyl, heterocycloalkyl, a substituted or unsubstituted alkyl group or Y-Z.
  • Y is selected from the group consisting of -C(O)-, -(CH 2 ) p -,-S(O) 2 -, -C(O)O-, -SO 2 NH-, -CONH-, (CH 2 ) p O-, -(CH 2 ) p NH-, -(CH 2 ) p S-, -(CH 2 ) p S(O)-, and - (CH 2 ) p S(O) 2 -.
  • p is an integer from 0 to to about 6.
  • Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group.
  • j an integer from 0 to 6.
  • L is -CH 2 NR-, -C(O)NR- or -NRC(O)- and R 3 is azacycloalkyl or azaheteroaryl
  • j is 0.
  • L is -O- and R 3 is phenyl
  • j is O.
  • Rj is B-E, where E is a heterocyclyl group; L is -CH 2 NHC(O)-; -CH 2 NHC(O)NH-; -CH 2 NHC(O)O-; - CH 2 C(O)NH-; -CH 2 NHS(O) 2 -; -NHC(O)-; -NHC(O)NH-; -NHC(O)O-; -C(0)NH- -NS(O) 2 -; A is 1,4-phenylene or 1,4-phenylene substituted with one or more methoxy groups or fluorine atoms; R 3 is phenyl or phenyl substituted with one or more substituents selected from the group consisting of chloro, cyano, bromo, fluoro, trifluoromethoxy, methoxy, methylenedioxy, methyl, amino, dimethylamino and nitro; R 2 is hydrogen; and G is a direct bond
  • ring A is 1,4- phenylene, L is -O-, G is a direct bond and R 3 is phenyl.
  • the compounds of this invention are useful as inhibitors of serine/threonine and tyrosine kinases.
  • compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially in cancer and in the process of angiogenesis.
  • certain of these compounds are inhibitors of such receptor kinases as KDR, Fit- 1 , FGFR, PDGFR, c-Met, TIE-2 or IGF-l-R. Since certain of these compounds are anti- angiogenic, they are important substances for inhibiting the progression of disease states where angiogenesis is an important component.
  • Certain compounds of the invention are effective as inhbitors of such serine/threonine kinases as PKCs, erk, MAP kinases, MAP kinase kinases, MAP kinase kinases, cdks, Plk-1 or Raf- 1. These compounds are useful in the treatment of cancer, and hyperproliferative disorders.
  • certain compounds are effective inhibitors of non-receptor kinases such as those of the Src (for example, Ick, blk and lyn), Tec, Csk, Jak, Map, Nik and Syk families. These compunds are useful in the treatment of cancer, hyperproliferative disorders and immunologic diseases.
  • Certain compounds of this invention are selective TIE-2 kinase inhibitors which may be anti-angiogenic (especially in combination with one or more VEGFR inhibitors), or pro-angiogenic, when employed in the presence of, or in conjunction with, a VEGF-related stimulus.
  • Such inhibitors can be used in the promotion of therapeutic angiogenesis to treat, for example, ischemia, infarct or occlusion, or to promote wound healing.
  • the present invention provides a method of inhibiting the kinase activity of tyrosine kinases and serine/threonine kinases comprising the administration of a compound represented by formula I to said kinase in sufficient concentration to inhibit the enzyme activity of said kinase.
  • the present invention further includes the use of these compounds in pharmaceutical compositions with a pharmaceutically effective amount of the above- described compounds and a pharmaceutically acceptable carrier or excipient.
  • These pharmaceutical compositions can be administered to individuals to slow or halt the process of angiogenesis in angiogenesis-aided diseases, or to treat edema, effusions, exudates or ascites and other conditions associated with vascular hyperpermeability.
  • Certain pharmaceutical compositions can be administered to individuals to treat cancer and hyperproliferative disorders by inhibiting serine/threonine kinases such as cdk, Plk-1, erk, etc.
  • L is -N(R)C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, - C(O)N(R)-, or-O-.
  • G is a direct bond; -(CH 2 ) r , wherein j is from 1 or 2; trans -
  • CH CH-; -cydoC 3 H 4 -; or-CH 2 O-.
  • R 3 is a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted benzotriazole, a substituted or unsubstituted tetrahydropyranyl, a substituted or unsubstituted tefrahydrofuranyl, a substituted or unsubstituted dioxane, a substituted or unsubstituted dioxolane, a substituted or unsubstituted quinoline, a substituted or unsubstituted thiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted cyclopentanyl, a substituted or unsubstituted benzofuran, substituted or unsubstit
  • R 3 can be a substituted or unsubstituted aliphatic group or a substituted or unsubstituted alkenyl, provided that L is -SN(R)-, -S(O)N(R)-, -S(O) 2 N(R , -N(R)S-, -N(R)S(O)-, -N(R)S(O) 2 -, -N(R)C(O)N(R)-, -N(R)SN(R')-, -N(R)S(O)N(R')-, or -N(R)S(O) 2 N(R')-;
  • R 3 is a substituted or unsubstituted phenyl or phenyl fused to a five- or six-membered heterocyclic group.
  • suitable examples of R 3 include, but are not limited to, the groups shown below.
  • R is hydrogen or alkyl.
  • R 3 can be substituted by one or more substituents. Preferable substituents for
  • R 3 are F, Cl, Br, I, CH 3 , NO 2 , OCF 3 , OCH 3 , CN, CO 2 CH 3 , CF 3 , t-butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, -S-(substituted or unsubstituted aryl), -S-(substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl, -C(O
  • R f , R g and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterobicycloalkyl or a substituted or unsubstituted heteroaromatic.
  • R_ and R g are each, independently, a substituted or unsubstituted aliphatic group or a substituted or unsubstuituted aromatic group.
  • R c is hydrogen, or substituted or unsubstituted alkyl or substituted or unsubstituted aryl; -W-(CH 2 ) t -NR d R e , -W-(CH 2 ) t -O-alkyl, , -W-(CH 2 ) t -S-alkyl, or - W-(CH 2 ) r OH.
  • t is an integer from 0 to about 6.
  • W is a bond or -O-, -S-, -S(O)-, -S(O) 2 -, or -NR k -.
  • R k is -H or alkyl.
  • R d , R e and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterobicyclic group.
  • R d and R e are each, independently, -H, alkyl, alkanoyl or -K- D.
  • K is -S(O) 2 -, -C(O)-, -C(O)NH-, -C(O) 2 -, or a direct bond.
  • D is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminocycloalkyl, COOR j , or substituted or unsubstituted alkyl.
  • R is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
  • R 3 More preferred substituents for R 3 are F, Cl, Br, I, cyano, nitro, OCF 3 , CH 3 , and CF 3 .
  • ring A is a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted pyridyl, or a substituted or unsubstituted indole.
  • ring A is a substituted or unsubstituted phenyl.
  • ring A is a substituted or unsubstituted 1,4-phenylene group which is optionally substituted with one or more methoxy or fluoro groups. Ring A can be substituted by one or more substituents.
  • substituents for ring A are F, Cl, Br, I, CH 3 , NO 2 , OCF 3 , OCH 3 , CN, CO 2 CH 3 , CF 3 , t- butyl, pyridyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenyl, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted tetrazolyl, styryl, -S-(substituted or unsubstituted aryl), -S-(substituted or unsubstituted heteroaryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, alkynyl,
  • Ring A is more preferably substituted with F, Cl, and nitro.
  • R 2 is preferably hydrogen.
  • R j is of the formula
  • n is an integer from 0 to about 3.
  • R t is of the formula
  • R 8 , g and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heteroaromatic or substituted or unsubstituted heterobicyclicalkyl group.
  • R 8 and Rg are each, independently, -H, azabicycloalkyl, heterocycloalkyl, alkyl; hydroxyalkyl; dihydroxyalkyl or Y 2 -Z 2 .
  • Y 2 is -C(O)-, - (CH 2 ) q -,-S(O) 2 -, -C(O)O-, -SO 2 NH-, -CONH-, (CH 2 ) q O-, -(CH 2 ) q NH-, -(CH 2 ) q S-, ⁇ (CH 2 ) q S(O)-, or -(CH 2 ) q S(O) 2 -.
  • q is an integer from 0 to 6.
  • Z 2 is a substituted or unsubstituted alkyl, a substituted or unsubstituted amino, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl group.
  • R x is of the formula
  • R 77 is -OR 78 , or -NR 79 R 80 .
  • R 78 is -H or a substituted or unsubstituted aliphatic group.
  • R 79 , R 80 and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group.
  • R 79 and R 80 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or — Y 3 -Z 3 .
  • Y 3 is selected from the group consisting of -C(O)-, -(CH 2 ) q -,-S(O) 2 -, -C(0)O-, -SO 2 NH-, - CONH-, (CH 2 ) q O-, -(CH 2 ) q NH-, -(CH 2 ) q S-, -(CH 2 ) q S(O)- and-(CH 2 ) q S(O) 2 -.
  • Z 3 is - H, 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.
  • m is 2; s is 0; and R 77 is -OH.
  • Rj is selected from the groups shown below.
  • R is of the formula
  • v is an integer from 1 to about 3.
  • R 10 is -H, azabicycloalkyl, heterocycloalkyl or Y 2 Z 2 .
  • Y 2 and Z 2 are as defined previously.
  • R j is of the formula
  • R n represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, oxo, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroarylcarbonyl, a substituted or unsubstituted aminoalkyl and a substituted or unsubstituted aralkyl groups, provided that the carbon atoms adjacent to the nitrogen atom are not substituted by a hydroxy group.
  • R t is of the formula
  • R i0 is as previously defined.
  • R 10 is methyl, isopropyl or methoxyethyl
  • Ri is of the formula
  • R 8 and Rg are as previously defined. Ih another embodiment, R 1 is of the formula
  • R 8 , Rg and t are as previously defined, w is an integer from 0 to about 4. u is 0 or 1.
  • R !2 is hydrogen or a substituted or unsubstituted alkyl group.
  • Ri is of the formula
  • Rj is of the formula
  • R 8X and R 82 are each, independently, selected from the group consisting of hydrogen, hydroxyl, cyanomethyl, carboxymethyl, aminocarbonylmethyl, aminocarbonyl; aminomethyl, hydroxymethyl and amino,
  • R 8j and R S2 can also together form oxo; -O-(CH 2 ) r O, wherein i is 2 or 3; -NH-C(O)-NH-C(O)-; or-NH-
  • R t can be, but is not limited to, one of the groups shown below.
  • R ! is of the formula B-E, wherein B is cyclohexyl and E is substituted or unsubstituted heterocyclyl, heterocyclylalkylor heterocyclylazaalkyl.
  • E can be a substituted or unsubstituted pyrazolyl, diazepinyl, piperazyl, piperidyl or morpholyl group.
  • Suitable examples of R 2 include, but are not limited to, the groups shown below.
  • R t is 1(g) or 1(H)
  • R 8 , Rg and the nitrogen atom together form a heterocycloalkyl group of the formula
  • R 13 , R 14 , R 15 , R ⁇ 6 , R 17 , R i8 , R 19 and R 20 are each, independently, lower alkyl or hydrogen.
  • at least one pair of substituents R 13 and R M ; R 15 and R l6 ; R 17 and R 18 ; or R j9 and R 20 together are an oxygen atom.
  • at least one of R and R l5 is cyano, CONHR 21 , COOR 2 ⁇ , CH 2 OR 2 ⁇ or CH 2 NR 2 ⁇ (R 22 ).
  • R 21 , R 22 and the nitrogen atom together form a 3-, 4-, 5-, 6- or 7-membered, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted heteroaryl group, or a substituted heterobicyclicalkyl group.
  • R 2l and R 22 are each, independently, -H, azabicycloalkyl, heterocycloalkyl or Y 3 -Z 3 ; Y 3 and Z 3 are as previously defined.
  • X is -O-, -S-, -SO-, -SO 2 ⁇ , -CH 2 -, -CH(OR 23 )- or NR 23 .
  • R 23 is -H, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, -C(NH)NH 2 , -C(O)R 24 , or -C(O)OR 24 .
  • R 24 is hydrogen, substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl.
  • R 8 , Rg and the nitrogen atom together form a heterocycloalkyl of the formula
  • R 25 and R 26 are each, independently, hydrogen or lower alkyl.
  • R 25 and R 26 together are an oxygen atom, i is an integer from 1 to about 6.
  • R 8 , Rg and the nitrogen atom together form a heterocycloalkyl group; of the formula
  • R 27 is CH 2 OH, C(O)NR 24 R 28 or COOR 24 .
  • R 24 and R 28 are as previously defined.
  • R 8 , Rg and the nitrogen atom together form a heteroaromatic group of the formula
  • R 29 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl group, carboxylic acid, cyano, C(O)OR 30 ,
  • R 30 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heterocycloalkyl or heterocycloaryl group.
  • R 2 ⁇ and R 22 are as previously defined.
  • at least one of R 8 and Rg is of the formula Y 3 -D, wherein D is of the formula
  • Y 3 is as previously defined, x is 0, 1 or 2.
  • T is -O-, -C(O)-, -S-, -SO-, -SO 2 -, -CH 2 -, -CH(OR 24 )- or -N(R 24 )-.
  • R 24 is as previously defined.
  • at least one of R 8 and Rg is of the formula Y 3 -
  • R 3i and R 32 are each, independently, substituted or unsubstituted carboxyalkyl, a substituted or unsubstituted alkoxycarbonylalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted cyanoalkyl.
  • R 3X and R 32 together with the nitrogen atom, form a five- or six-membered heterocycloalkyl group, a substituted or unsubstituted heteroaromatic or a substitutituted or unsubstituted heterobicycloalkyl.
  • Z 2 is of the formula N(R 35 )R 36 .
  • R 35 and R 36 are each, independently, hydrogen, alkyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl, aminocarbonyl, cyano, alkylcarbonyl or aralkyl.
  • Each X j is, independently, CH or N.
  • R 37 is hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group.
  • R 37 is hydrogen, cyano or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted aminocarbonyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl group.
  • Z 2 is of the formula
  • g and R 37 are as previously defined unsubstituted aralkyl group.
  • T, g and R 37 are as previously defined.
  • R 37 is as previously defined.
  • R 38 is hydrogen, substituted or unsubstituted alkyl, a ' substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted alkoxyalkyl, a substituted or unsubstituted aminocarbonyl, perhaloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkylcarbonyl or a substituted or unsubstituted aralkyl.
  • Ri is of the formula
  • R 39 , R 40 , R 4i , R 42 , R 43 , , R 45 and R 46 are each, independently ,methyl or hydrogen. Alternatively, at least one pair of substituents R 39 and R 40 ; R 36 and R 37 ; R 38 and R 39 . Alternatively, R 40 and R 4 ⁇ together are an oxygen atom.
  • R 47 is H, azabicycloalkyl, heterocycloalkyl or Y 2 -Z 2 . Y 2 and Z 2 are as previously defined. Alternatively, R 47 is of the formula
  • R 48 , R 49 , R 50 , R 5 ⁇ , R 52 , R 53 , R 5 and R 55 are each, independently, methyl or hydrogen. Alternatively, at least one pair of substituents R 48 and R 49 ; R 50 and R 5 ⁇ ; R 52 and R 53 ; or R 54 and R 55 together are an oxygen atom.
  • R_ 6 is -H, azabicycloalkyl, heterocycloalkyl or Y 3 -Z 3 . Y 3 and Z 3 are defined as above.
  • R t is of the formula
  • R 6 5 and R 66 are each, independently, methyl or hydrogen. Alternatively, at least one pair of substituents R 57 and R ⁇ ; R 59 and R ⁇ ; R 6i and Rg 2 ; or R 63 and R_ 4 together are an oxygen atom.
  • R 67 is H, azabicycloalkyl, heterocycloalkyl or Y 2 -Z 2 . Y 2 and Z 2 are defined as above. Alternatively, R 67 is of the formula
  • aromatic groups include carbocyclic ring systems (e.g. benzyl and cinnamyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1,2,3,4-tetrahydronaphthyl).
  • Aromatic groups are also referred to as aryl groups herein.
  • Heteroaromatic groups include heteroaryl ring systems (e.g., thienyl, pyridyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furanyls, pyrroles, ' imidazoles, pyrazoles, triazoles, pyrimidines, pyrazyls, thiazolyls, isoxazolyls, isothiazolyls, tetrazolyls, oxadiazolyls,) and heteroaryl ring systems in which a carbocyclic aromatic ring, carbocyclic non-aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings (e.g., benzo(b)thienyl, benzimidazole, indole, tetrahydroindole, azaindole, indazole, quinoline, imidazo
  • heteroaralkyl group is a heteroaromatic substituent that is linked to a compound by an aliphatic group having from one to about six carbon atoms.
  • a heterocycloalkyl group is a non-aromatic ring system that has 3 to 8 atoms and includes at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • An acyl group as used herein, is an -C(O)NR x R z , -C(O)OR x , -C(O)R-., in which R_ and R_ are each, independently, -H, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group.
  • aliphatic groups include straight chained, branched or cyclic -Cg hydrocarbons which are completely saturated or which contain one or more units of unsaturation (e.g. one or more double or triple bonds).
  • alkyl refers to a saturated hydrocarbyl group; “alkoxy” refers to an alkyl-O- group.
  • a “lower alkyl group” is a saturated aliphatic group having form 1-6 carbon atoms; a “lower alkoxy group” is a lower-alkyl-O- group.
  • oxaalkylene refers to an alkylene chain which is interrupted at one or more points by an oxygen atom.
  • examples of oxaalkylene groups include, but are not limited to, -OCH 2 -, -CH 2 O- and -CH 2 OCH 2 -.
  • substituents can include, but are not to be construed as being limited to, one or more substituents independently selected from halo, hydroxy, oxo, nitro, amino, mono- or di-alkylamino, alkoxy, cyano, perfluoroalkyl (preferably CF 3 ), perfluoroalkoxy (preferably OCF 3 ), COOR (where R is H or alkyl), carboxamide, acetyl, cycloalkyl, aryloxy, heteroaryl, heteroaryloxy, heterocycloalkyl, amido, aminocarbonyl, alkylthio ether, alkylsulfonyl, alkylsulfonamido, aliphatic group (optionally substituted with one or more of the following: halo, hydroxy, oxo, nitro, amino, mono- or di-alkylamino, alkoxy, cyano, perfluoroalkyl, perfluoroalk
  • Compounds of formula I may exist as salts with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of formula I which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present invention includes such salts.
  • Example of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of formula I may contain one or more chiral centres, and exist in different optically active forms.
  • compounds of formula I may contain one chiral centre, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula I contains more than one chiral center it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.
  • Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of formula I and mixtures thereof.
  • a preferred group of compounds of the present invention are:
  • the compounds of this invention have antiangiogenic properties. These antiangiogenic properties are due at least in part to the inhibition of protein tyrosine kinases essential for angiogenic processes. For this reason, these compounds can be used as active agents against such disease states as arthritis, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia reperfusion injury, wound healing, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, or age-related macular degeneration.
  • POEMS Crow-Fukase syndrome
  • some of these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • thyroid hyperplasia especially Grave's disease
  • cysts such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, brain tumor- associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, glomerulonephritis and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease.
  • the compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g.
  • VEGF production potentiates inflammatory processes such as monocyte recruitment and activation.
  • the compounds of this invention will also be useful in treating inflammatory disorders such as inflammatory bowel disease (IBD) and Crohn's disease.
  • VEGF's are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF mediated responses.
  • VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. Because blastocyst implantation, placental development and embryogenesis are angiogenesis dependent, certain compounds of the invention areuseful as contraceptive agents and antifertility agents.
  • the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity involving the KDR VEGFR-2 and/or the Flt-l/VEGFR-1 and/or TIE-2 tyrosine kinases.
  • protein tyrosine kinase activity involving the KDR VEGFR-2 and/or the Flt-l/VEGFR-1 and/or TIE-2 tyrosine kinases.
  • Certain compounds of the invention are also effective inhibitors of FGFR, PDGFR, c-Met and IGF-l-R. These receptor kinases can directly or indirectly potentiate angiogenic and hyperproliferative responses in various disorders, hence their inhibition can impede disease progression.
  • the compounds of this invention have inhibitory activity against protein kinases. That is, these compounds modulate signal transduction by protein kinases.
  • Compounds of this invention inhibit protein kinases from serine/threoriine and tyrosine kinase classes. In particular, these compounds selectively inhibit the activity of the KDR/FLK-1 /VEGFR-2 tyrosine kinases.
  • Certain compounds of this invention also inhibit the activity of additional tyrosine kinases such as Flt- 1/VEGFR-l, Tie-2, FGFR, PDGFR, IGF-IR, c-Met, Src-subfamily kinases such as Lck, Src, fyn, yes, etc. Additionally, some compounds of this invention significantly inhibit serine/threonine kinases such as PKC, MAP kinases, erk, CDKs, Plk-1, or Raf-1 which play an essential role in cell proliferation and cell-cycle progression.
  • additional tyrosine kinases such as Flt- 1/VEGFR-l, Tie-2, FGFR, PDGFR, IGF-IR, c-Met, Src-subfamily kinases such as Lck, Src, fyn, yes, etc. Additionally, some compounds of this invention significantly inhibit serine/threonine kinases such as PKC, MAP kinases, er
  • the potency and specificity of the generic compounds of this invention towards a particular protein kinase can often be altered and optimized by variations in the nature, number and arrangement of the substituents (i.e., R t , R 2 , R 3 , A and ring 1) and conformational restrictions.
  • the metabolites of certain compounds may also possess significant protein kinase inhibitory activity.
  • the compounds of this invention when admimstered to individuals in need of such compounds, inhibit vascular hyperpermeability and the formation of edema in these individuals. These compounds act, it is believed, by inhibiting the activity of KDR tyrosine kinase which is involved in the process of vascular hyperpermeability and edema formation.
  • the KDR tyrosine kinase may also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase or VEGFR-2 tyrosine kinase.
  • KDR tyrosine kinase is activated when vascular endothelial cell growth factor (VEGF) or another activating ligand (such as VEGF-C, VEGF-D, VEGF-E or HIV Tat protein) binds to a KDR tyrosine kinase receptor which lies on the surface of vascular endothelial cells.
  • VEGF vascular endothelial cell growth factor
  • another activating ligand such as VEGF-C, VEGF-D, VEGF-E or HIV Tat protein
  • KDR tyrosine kinase stimulation results in the proliferation and chemotaxis of vascular endothelial cells and formation of new vessels.
  • KDR tyrosine kinase activity By inhibiting KDR tyrosine kinase activity, either by blocking the production of the activating ligand, by blocking the activating ligand binding to the KDR tyrosine kinase receptor, by preventing receptor dimerization and transphosphorylation, by inhibiting the enzyme activity of the KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme) or by some other mechanism that interrupts its downstream signaling (D. Mukhopedhyay et al, Cancer Res. 55.T278-1284 (1998) and references therein), hyperpermeability, as well as associated extravasation, subsequent edema formation and matrix deposition, and angiogenic responses, may be inhibited and minimized.
  • One group of prefened compounds of this invention have the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt-1 tyrosine kinase activity (Flt-1 tyrosine kinase is also referred to as VEGFR-1 tyrosine kinase). Both KDR tyrosine kinase and Flt-1 tyrosine kinase are activated by VEGF binding to KDR tyrosine kinase receptors and to Flt-1 tyrosine kinase receptors, respectively.
  • Certain prefened compounds of this invention are unique because they inhibit the activity of one VEGF-receptor tyrosine kinase (KDR) that is activated by activating ligands but do not inhibit other receptor tyrosine kinases, such as Flt-1, that are also activated by certain activating ligands. In this manner, certain prefened compounds of this invention are, therefore, selective in their tyrosine kinase inhibitory activity.
  • KDR VEGF-receptor tyrosine kinase
  • the present invention provides a method of treating a protein kinase-mediated condition in a patient, comprising adiminstering to the patient a therapeutically or prophylactically effective amount of one or more compounds of Formula I.
  • a "protein kinase-mediated condition” is a medical condition, such as a disease or other undesirable physical condition, the genesis or progression of which depends, at least in part, on the activity of at least one protein kinase.
  • the protein kinase can be, for example, a protein tyrosine kinase or a protein serine/threonine kinase.
  • the patient to be treated can be any animal, and is preferably a mammal, such as a domesticated animal or a livestock animal. More preferably, the patient is a human.
  • a “therapeutically effective amount” is an amount of a compound of Formula I or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • the method of the present invention is useful in the treatment of protein kinase-mediated conditions, such as any of the conditions described above.
  • the protein kinase-mediated condition is characterized by undesired angiogenesis, edema, or stromal deposition.
  • the condition can be one or more more ulcers, such as ulcers caused by bacterial or fungal infections, Mooren ulcers and ulcerative colitis.
  • the condition can also be due to a microbial infection, such as Lyme disease, sepsis, septic shock or infections by Herpes simplex, Herpes Zoster, human immunodeficincy virus, protozoa, toxoplasmosis or parapoxvirus; an angiogenic disorders, such as von Hippel Lindau disease, polycystic kidney disease, pemphigoid, Paget's disease and psoriasis; a reproductive condition, such as endometriosis, ovarian hyperstimulation syndrome, preeclampsia or menometrorrhagia; a fibrotic and edemic condition, such as sarcoidosis, fibrosis, cirrhosis, thyroiditis, hyperviscosity syndrome systemic, Osier- Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, and edema following burns, trauma, radiation, stroke, hypoxia or ischemia; or an iriflammatory/i
  • Suitable protein kinase- mediated conditions also include sickle cell anaemia, osteoporosis, osteopetrosis, tumor-induced hypercalcemia and bone metastases.
  • Additional protein kinase- mediated conditions which can be treated by the method of the present invention include ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt's disease and Eales disease, in addition to retinopathy and macular degeneration.
  • ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, conjun
  • the compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease.
  • the compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukaemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukaemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • the compounds of the present invention are also useful in the treatment of Crow-Fukase (POEMS) syndrome and diabetic conditions such as glaucoma, diabetic retinopathy and microangiopathy.
  • POEMS Crow-Fukase
  • the Src, Tec, Jak, Map, Csk, NFKB and Syk families of kinases play pivotal roles in the regulation of immune function.
  • the Src family currently includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yrk, Fyk, Yes, Hck, and Blk.
  • the Syk family is currently understood to include only Zap and Syk.
  • the TEC family includes Tec, Btk, Rlk and Itk.
  • the Janus family of kinases is involved in the transduction of growth factor and proinflammatory cytokine signals through a numlrer of receptors.
  • BTK and ITK members of the Tec family of kinases
  • the Csk family is currently understood to include Csk and Chk.
  • the kinases RIP, IRAK-1, IRAK-2, NIK, p38 MAP kinases, Jnk, IKK-1 and IKK-2 are involved in the signal transduction pathways for key pro-inflammatory cytokines, such as TNF and IL-1.
  • compounds of formula I may function as immunomodulatory agents useful for the maintenance of allografts, the treatment of autoimmune disorders and treatment of sepsis and septic shock.
  • T cells T cells, B-cells, mast cells, monocytes and neutrophils
  • these compounds could be used to treat such autoimmune diseases and sepsis.
  • Prevention of transplant rejection either host versus graft for solid organs or graft versus host for bone marrow, are limited by the toxicity of currently available immunosuppressive agents and would benefit from an efficacious drug with improved therapeutic index.
  • Gene targeting experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for bone resorption.
  • Compounds of formula I may also be useful in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor- induced hypercalcemia and in the treatment of bone metastases.
  • Chromosome breakage at the Itk kinase break point on chromosome 5
  • translocation as in the case of the Abl gene with BCR (Philadelphia chromosome)
  • truncation in instances such as c-Kit or EGFR
  • mutation e.g., Met
  • oncogenesis is driven by an autocrine or paracrine ligand/growth factor receptor interactions.
  • src-family kinases are typically involved in downstream signal transduction thereby potentiating the oncogenesis and themselves may become oncogenic by over-expression or mutation. By inhibiting the protein kinase activity of these proteins the disease process may be disrupted.
  • Vascular restenosis may involve FGF and/or PDGF - promoted smooth muscle and endothelial cell proliferation.
  • the ligand stimulation of FGFR, PDGFR, IGF1-R and c-Met in vivo is proangiogenic, and potentiates angiogenesis dependent disorders. Inhibition of FGFr, PDGFr , c-Met, or IGF1-R kinase activities individually or in combination may be an efficacious strategy for inhibiting these phenomena.
  • compounds of formula I which inhibit the kinase activity of normal or aberrant c-kit, c-met, c-fins, src-family members, EGFr, erbB2, erbB4, BCR- Abl, PDGFr, FGFr, IGF1-R and other receptor or cytosolic tyrosine kinases may be of value in the treatment of benign and neoplastic proliferative diseases.
  • pathological conditions for example, solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inappropriate ocular neovascularization, psoriasis and atherosclerosis
  • disease progression is contingent upon persistent angiogenesis.
  • Polypeptide growth factors often produced by the disease tissue or associated inflammatory cells, and their corresponding endothelial cell specific receptor tyrosine kinases are essential for the stimulation of endothelial cell growth, migration, organization, differentiation and the establishment of the requisite new functional vasculature.
  • VEGF-stimulation of a VEGFR kinase is also believed to play an important role in the formation of tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusions, delayed- type hypersensitivity reactions, tissue edema and organ dysfunction following trauma, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), post-cardiopuhnonary bypass-related hypotension and hyperpermeability, and ocular edema leading to glaucoma or blindness due to inappropriate neovascularization.
  • ARDS adult respiratory distress syndrome
  • VEGF-C and VEGF-D can also cause a vascular hyperpermeability response through the stimulation of a VEGFR kinase.
  • KDR/VEGFR-2 and/or Tie-2 are expressed also in a select population of hematopoietic stem cells. Certain members of this population are pluripotent in nature and can be stimulated with growth factors to differentiate into endothelial cells and participate in vasculogenetic angiogenic processes. For this reason these have been called Endothelial Progenitor Cells (EPCs) (J Clin. Investig. 103 : 1231 - 1236 (1999)).
  • EPCs Endothelial Progenitor Cells
  • Tie-2 may play a role in their recruitment, adhesion, regulation and differentiation (Blood , 4317-4326 (1997)). Certain agents according to formula I capable of blocking the kinase activity of endothelial cell specific kinases could therefore inhibit disease progression involving these situations.
  • vascular destabilization of the antagonist ligand of Tie-2 is believed to induce an unstable "plastic" state in the endothelium.
  • Ang2 Tie-2
  • a robust angiogenic response may result; however, in the absence of VEGF or a VEGF-related stimulus, frank vessel regression and endothelial apoptosis can occur (Genes and Devel. 13: 1055-1066 (1999)).
  • a Tie- 2 kinase inhibitor can be proangiogenic or antiangiogenic in the presence or absence of a VEGF-related stimulus, respectively.
  • Tie-2 inhibitors can be employed with appropriate proangiogenic stimuli, such as VEGF, to promote therapeutic angiogenesis in situations such as wound healing, infarct and ischemia.
  • the compounds of formula I or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system, as described above.
  • diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (eg.
  • kidney rejection graft versus host disease
  • benign and neoplastic proliferative diseases human cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings.
  • inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • the compounds of the present invention may also be useful in the prophylaxis of the above diseases.
  • the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity involving the VEGF receptors (e.g. KDR, Flt-1 and/or Tie-2).
  • VEGF receptors e.g. KDR, Flt-1 and/or Tie-2.
  • the present invention provides compounds of formula I as defined initially above for use as medicaments, particularly as inhibitors of protein kinase activity for example tyrosine kinase activity, serine kinase activity and threonine kinase activity.
  • the present invention provides the use of compounds of formula I as defined initially above in the manufacture of a medicament for use in the inhibition of protein kinase activity.
  • Physiologically acceptable salts can refer to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like.
  • Alkyl refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups having 1 to 6 carbons or cyclic hydrocarbons having 3 to 6 carbons.
  • Alkoxy refers to an "O-alkyl” group, where “alkyl” is defined as described ' above.
  • the compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate vascular hyperpermeability, edema and associated disorders. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • a therapeutically effective dose further refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of inappropriate neovascularization, progression of hyperproliferative disorders, edema, VEGF-associated hyperpermeability and/or VEGF-related hypotension.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional ' mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpynolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl py ⁇ olidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl py ⁇ olidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, xrichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, xrichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g.in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pynolidone; and other sugars or polysaccharides may substitute for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions of the invention may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other pro tonic solvents than are the conesponding free base forms.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated imtially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity).
  • the IC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity).
  • it is appropriate to determine the IC 50 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound.
  • Such information can be used to more accurately determine useful doses in humans.
  • the most prefened compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
  • Compounds which exhibit high therapeutic indices are prefened.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi).
  • the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein.
  • Dosage intervals can also be determined using the MEC value.
  • Compounds should be admimstered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the preceding
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • Tablets can be prepared from the following ingredients. Parts by weight Active compound 10
  • the active compound, the lactose and some of the starch can be de- aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinyl- py ⁇ olidone in ethanol.
  • the dry granulate can be blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanohdichloromethane (1:1).
  • suppositories 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be admimstered in combination with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the invention can be admimstered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include but are not limited to anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-IR inhibitors, PKC inhibitors and PI3 kinase inhibitors.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • angiogenesis vascular hyperpermeability
  • edema vascular hyperpermeability or edema than the administration of either substance alone.
  • the present invention also comprises the use of a compound of formula I as a medicament.
  • a further aspect of the present invention provides the use of a compound of formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.
  • the present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of formula I to a mammal, particularly a human being, in need thereof.
  • the potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al, Nature. 373:536-539)) by a test compound relative to control.
  • an exogenous substrate e.g., synthetic peptide (Z. Songyang et al, Nature. 373:536-539)
  • the coding sequence for the human KDR intra-cellular domain was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
  • MOI plaque forming units per cell
  • SF-9 cells expressing (His) 6 KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, ImM PMSF, lO ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin) to the cell pellet from IL of cell culture.
  • the lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4°C.
  • the cell lysate was applied to a 5 ml NiCl 2 chelating sepharose column, equilibrated with 50 mM HEPES, ⁇ H7.5, 0.3 M NaCl.
  • KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity.
  • the purified KDR was exchanged into 25mM HEPES, ⁇ H7.5, 25mM NaCl, 5 mM DTT buffer and stored at -80 °C.
  • the coding sequence for the human Tie-2 intra-cellular domain was generated through PCR using cDNAs isolated from human placenta as a template. A poly-His 6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
  • the baculoviral expression vector pVL 1393 (PharMingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
  • EGFR was purchased from Sigma (Cat # E-3641 ; 500 units/50 ⁇ l) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
  • the baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.)
  • the nucleotide sequence encoding amino acids M(H)6 LVPRgS was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619).
  • the nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cD A libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra).
  • the LVPRgS bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling removal of the affinity tag from the enzyme.
  • SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection.
  • Extraction and purification of ZAP70 SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 ⁇ g/ml leupeptin, 10 ⁇ g/ml aprotinin and 1 mM sodium orthovanadate.
  • the soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole.
  • the enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.
  • Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained (e.g. from Upstate Biotechnology Inc. (Saranac Lake, N,Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.
  • Enzyme linked immunosorbent assays were used to detect and measure the presence of tyrosine kinase activity.
  • the ELISA were conducted according to known protocols which are described in, for example, Voller, et al, 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.
  • the disclosed protocol was adapted for determining activity with respect to a specific PTK.
  • prefened protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determimng a compound's activity for other members of the receptor PTK family, as well as non- receptor tyrosine kinases, are well within the abilities of those in the art.
  • a universal PTK substrate e.g., random copolymer of poly(Glu 4 Tyr), 20,000-50,000 MW
  • ATP typically 5 ⁇ M
  • PBS phosphate buffered saline
  • Reaction Buffer lOOmM Hepes, 20mM MgCl 2 , 4mM MnCl 2 , 5mM DTT,
  • ATP Store aliquots of lOOmM at -20°C. Dilute to 20 ⁇ M in water
  • Washing Buffer PBS with 0.1% Tween 20 Antibody Diluting Buffer: 0.1 % bovine serum albumin (BSA) in PBS
  • TMB Substrate mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue Substrate from Neogen
  • -Prepare inhibitor solutions at a 4x concentration in 20% DMSO in water.
  • -Prepare reaction buffer -Prepare enzyme solution so that desired units are in 50 ⁇ l, e.g. for KDR make to 1 ng/ ⁇ l for a total of 50ng per well in the reactions.
  • Store on ice -Make 4x ATP solution to 20 ⁇ M from lOOmM stock in water.
  • the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl 2 ,
  • Compounds of formula I may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formula I.
  • All compounds exemplified herein significantly inhibit either FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, Blk, Lyn or Src at concentrations of 50 micromolar or below.
  • Some compounds of this invention also significantly inhibit other tyrosine or serine/threonine kinases such as cdc2 (cdkl) at concentrations of 50 micromolar or below.
  • the human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • the protocol used was that provided with the purchased reagents with minor modifications.
  • the reaction was carried out in a buffer consisting of 50mM Tris pH 7.5, lOOmM NaCl, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and lOmM MgCl 2 (commercial buffer) supplemented with fresh 300 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ g/ml histone type IIIss final concentrations.
  • a reaction volume of 80 ⁇ L, containing units of enzyme was run for 20 minutes at 25 degrees C in the presence or absence of inhibitor.
  • the reaction was terminated by the addition of 120 L of 10%) acetic acid.
  • the substrate was separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts were measured by a betacounter in the presence of liquid scintillant.
  • Certain compounds of this invention significantly inhibit cdc2 at concentrations below 50 uM.
  • PKC kinase source The catalytic subunit of PKC may be obtained commercially (Calbiochem). PKC kinase assay
  • a radioactive kinase assay was employed following a published procedure (Yasuda, I., IQrshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 5: 166, 1220-1227 (1 90)). Briefly, all reactions were performed in a kinase buffer consisting of 50 mM Tris- HCl pH7.5, lOmM MgCl 2 , 2mM DTT, ImM EGTA, 100 ⁇ M ATP, 8 ⁇ M peptide, 5% DMSO and 33 P ATP (8Ci/mM).
  • the recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 2 (commercial buffer) supplemented with fresh 100 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ M myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity were as described for the PKC assay (vide supra).
  • T-cells Upon activation by mitogen or antigen, T-cells are induced to secrete IL-2, a growth factor that supports their subsequent proliferative phase. Therefore, one may measure either production of IL-2 from or cell proliferation of, primary T-cells or appropriate T-cell lines as a su ⁇ ogate for T-cell activation. Both of these assays are well described in the literature and their parameters well documented (in Cunent Protocols in Immunology, Vol 2, 7.10.1-7.11.2).
  • T-cells may be activated by co-culture with allogenic stimulator cells, a process termed the one-way mixed lymphophocyte reaction.
  • Responder and stimulator peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) per directions of the manufacturer.
  • Stimulator cells are mitotically inactivated by treatment with mitomycin C (Sigma) or gamma i ⁇ adiation.
  • Responder and stimulator cells are co-cultured at a ratio of two to one in the presence or absence of the test compound.
  • 10 5 responders are mixed with 5 x 10 4 stimulators and plated (200 ⁇ l volume) in a U bottom microtiter plate (Costar Scientific).
  • the cells are cultured in RPMI 1640 supplemented with either heat inactivated fetal bovine serum (Hyclone Laboratories) or pooled human AB serum from male donors, 5 x 10 "5 M 2mercaptoethanol and 0.5% DMSO,
  • the cultures are pulsed with 0.5 ⁇ Ci of 3 H thymidine (Amersham) one day prior to harvest (typically day three).
  • the cultures are harvested (Betaplate harvester, Wallac) and isotope uptake assessed by liquid scintillation (Betaplate, Wallac).
  • the same culture system may be used for assessing T-cell activation by measurement of IL-2 production. Eighteen to twenty-four hours after culture initiation, the supernatants are removed and the IL-2 concentration is measured by ELISA (R and D Systems) following the directions of the manufacturer.
  • T-cells can be activated in vivo by ligation of the constant portion of the T-cell receptor with a monoclonal anti-CD3 antibody (Ab).
  • Ab monoclonal anti-CD3 antibody
  • BALB/c mice are given lO ⁇ g of anti-CD3 Ab intraperitoneally two hours prior to exsanguination. Animals to receive a test drug are pre-treated with a single dose of the compound one hour prior to anti-CD3 Ab administration.
  • Serum levels of the proinflammatory cytokines interferon- ⁇ (IFN- ⁇ ) and tumor necrosis factor- ⁇ (TNF- ⁇ ), indicators of T-cell activation are measured by ELISA.
  • a similar model employs in vivo T-cell priming with a specific antigen such as keyhole limpet hemocyanin (KLH) followed by a secondary in vitro challenge of draining lymph node cells with the same antigen.
  • KLH keyhole limpet hemocyanin
  • measurement of cytokine production is used to assess the activation state of the cultured cells. Briefly, C57BL/6 mice are immunized subcutaneously with 100 ⁇ g KLH emulsified in complete Freund's adjuvant (CFA) on day zero.
  • CFA complete Freund's adjuvant
  • EAE auto-immune encephalomyelitis
  • CIA collagen-induced arthritis
  • EAE models which mimic aspects of human multiple sclerosis have been described in both rats and mice (reviewed FASEB J. 5:2560-2566, 1991; murine model: Lab. Invest. 4(3):278, 1981; rodent model: J. Immunol 146(4):1163-8, 1991 ).
  • mice or rats are immunized with an emulsion of myelin basic protein (MBP), or neurogenic peptide derivatives thereof, and CFA.
  • MBP myelin basic protein
  • Acute disease can be induced with the addition of bacterial toxins such as bordetella pertussis. Relapsing/remitting disease is induced by adoptive transfer of T-cells from MBP/ peptide immunized animals.
  • CIA may be induced in DBA/1 mice by immunization with type II collagen (J. Immunol: 142(7):2237-2243). Mice will develop signs of arthritis as early as ten days following antigen challenge and may be scored for as long as ninety days after immunization. In both the EAE and CIA models, a compound may be admimstered either prophylactically or at the time of disease onset. Efficacious drugs should reduce severity and/or incidence.
  • Certain compounds of this invention which inhibit one or more angiogenic receptor PTK, and/or a protein kinase such as lck involved in mediating inflammatory responses can reduce the severity and incidence of arthritis in these models.
  • mice can also be tested in mouse allograft models, either skin (reviewed in Ann. Rev. Immunol., 10:333-58, 1992; Transplantation: 57(12): 1701-17D6, 1994) or heart (Am.J.Anat: 113:273, 1963).
  • full thickness skin grafts are transplanted from C57BL/6 mice to BALB/c mice.
  • the grafts can be examined daily, beginning at day six, for evidence of rejection.
  • neonatal heart transplant model neonatal hearts are ectopically transplanted from C57BL/6 mice into the ear pinnae of adult CBA/J mice. Hearts start to beat four to seven days post transplantation and rejection may be assessed visually using a dissecting microscope to look for cessation of beating.
  • HUVEC cells (from pooled donors) were purchased from Clonetics
  • EBM media (Clonetics). 2. For evaluating a compound's inhibitory activity, cells were trypsinized and seeded at 0.5-1.0 x 10 s cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA).
  • Equal amounts of proteins were then precipitated by addition of cold (-20 C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. Pellets were reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins were resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transfened onto a nitrocellulose membrane using the Novex system.
  • This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation.
  • This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature.
  • Cullinan-Bove and Koss demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus.
  • Vehicle components (DMSO, Cremaphor EL) were purchased from Sigma (St.
  • mice (Balb/c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional
  • mice were randomized and divided into groups of 5-10. Test compounds were administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group received vehicle only and two groups were left untreated.
  • Results demonstrate that certain compounds of the present invention inhibit the formation of edema when administered systemically by various routes.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization.
  • the Matrigel neovascularization model involves the formation of new blood vessels within a clear "marble" of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519- 528; Anal Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vase. Biol. (1995), 15(11), 1857-6).
  • the model preferably runs over 3-4days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors.
  • the model may alternatively employ bFGF or HGF as the stimulus.
  • Certain compounds of this invention which inhibit one or more oncogenic, protooncogenic, or proliferation-dependent protein kinases, or angiogenic receptor PTK also inhibit the growth of primary murine, rat or human xenograft tumors in mice, or inhibit metastasis in murine models.
  • Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention.
  • the processes are preferably carried out at atmospheric pressure.
  • R,, R 2 , R 3 , L and ring A are as previously defined with formamide at a temperature in the range of 50 to 250°C optionally in the presence of a catalyst for example 4-dimethylaminopyridine.
  • a catalyst for example 4-dimethylaminopyridine for example 4-dimethylaminopyridine.
  • R is bromo or iodo bromo or iodo with one of the following compounds: R 3 B(OH) 2 , R 3 Sn(CH 3 ) 3 or a compound represented by formula IV
  • R 3 is as defined above, in the presence of a catalyst for example palladium (0) compounds eg. Pd(PPh 3 ) 4 .
  • a catalyst for example palladium (0) compounds eg. Pd(PPh 3 ) 4 .
  • R 2 and R 3 are as previously defined with a compound of formula Ri ' in which R j represents an alkyl group or an aralkyl group and X' represents a leaving group, for example halo, mesyloxy or tosyloxy.
  • R2 and R3 are as previously defined with a compound of formula R ⁇ X 5 in which X' is as previously defined and R j is an optionally substituted cyclic ether.
  • Compounds of formula I in which Ri represents cyclic ether, such as tefrahydrofuryl or tetrahydropyranyl, optionally substituted by formyl may be prepared by alkylating a compound of formula VI with a compound R]X in which Rl represents a cyclic ether substituted by a formyl group which has been protected, by a method known to those skilled in the art, for example by means of an acetal, (See for example Test. Letts.
  • Rj represents a cyclic ether, such as tetrahydrofuryl or tetrahydropyranyl, substituted by an (optionally substituted amino)methyl group
  • Rj represents a cyclic ether substituted by formyl
  • Compounds of formula I in which Ri represents optionally substituted furyl, thienyl or pynolyl may be prepared by reacting 4-chloro-5-iodo-7H-pynolo[2,3- d]pyrm ⁇ idine with the appropriate heteroarylboronic acid in the presence of a copper salt catalyst, for example copper (II) acetate in the presence of a solvent for the reactants, e.g. a halogenated solvent for example, dichloromethane, in the presence of a drying agent, for example 4A molecular sieves, in the presence of an organic base, e.g. triethylamine or pyridine, at a temperature in the range of 0-50°C, preferably at ambient temperature.
  • a copper salt catalyst for example copper (II) acetate
  • a solvent for the reactants e.g. a halogenated solvent for example, dichloromethane
  • a drying agent for example 4A molecular sieves
  • R l9 R 2 , R 3 , L and ring A are as previously defined and R y represents a leaving group, for example halo or phenoxy, with ammonia or an ammonium salt, for example ammonium acetate, at a temperature in the range of 15-250°C, preferably in a pressure vessel.
  • R l5 R 3 L and ring A are as previously defined with a halogenating agent for example an iodinating agent, e.g. N-iodosuccinimide, or a brominating agent, e.g. N- bromosuccinimide, or a chlorinating agent, e.g. N-chlorosuccinimide.
  • a halogenating agent for example an iodinating agent, e.g. N-iodosuccinimide, or a brominating agent, e.g. N- bromosuccinimide, or a chlorinating agent, e.g. N-chlorosuccinimide.
  • a halogenating agent for example an iodinating agent, e.g. N-iodosuccinimide, or a brominating agent, e.g. N- bromosuccinimide, or a chlorinating agent, e.g. N-chloro
  • Rj, R 2 and ring A are as previously defined and Y represents a protected amine, with a compound of formula R 3 COR_.
  • R_ represents a leaving group, for example chloro.
  • compounds of formula IX in which Y represents halo, for example chloro may be reacted with a compound of formula R 3 COR-. and the product reacted with ammonia to give a compound of formula I.
  • Analogous methods may be used to prepare compounds of formula I in which -L-R 3 is - NRSO 2 R 3 .
  • Analogous methods may be used to prepare compound of formula I in which -L-R 3 is -NRCO 2 -R 3 or -NRCONR' .
  • R and R' are as previously defined.
  • compounds of fprmula I may be converted into other compounds of formula I by known chemical reactions.
  • an alkoxy group may be cleaved to give hydroxy
  • nitro groups may be reduced to amines
  • amines may be acylated or sulfonylated
  • N-acyl compounds may be hydrolyzed to amines.
  • Compounds of formula I in which -L- is S may be oxidized to give compounds of formula I in which -L- represents SO and SO 2 , respectively, by methods known to those skilled in the art.
  • Compounds of formula m are commercially available or may be prepared by methods known to those skilled in the art.
  • Compounds of formula V in which R 2 represents hydrogen may be prepared as shown in Scheme 2. The amino group may be protected prior to the final step and then deprotected after the final step of scheme 2 by methods known to those skilled in the art.
  • Compounds of formula V in which R 2 is other than hydrogen may be prepared by analogous methods. (see J. Med. Chem. (1990), 33, 1984.)
  • (ring A)-L-R 3 may be coupled first, prior to amination.
  • a substituent R j as defined previously may be present prior to carrying out either process.
  • R may be modified by the method depicted in Schemes 5 and 6.
  • Schemes 5 and 6 P represents a protecting group.
  • Tetrahydro-2H-4-pyranyl trifluoromethanesulfonate was added dropwise and the reaction mixture was stined at ambient temperature for 24 hours. The mixture was poured to ice water (lOOml) and the solid was collected by filtration and purified by re-crystallization to give 4-chloro-5-iodo-7-tetrahydro-2H-4-pyranyl- 7H-pynolo[2,3-d]pyrimidine.
  • ⁇ NMR (CDC1 3 ) ⁇ 2.06 (m, 2H), 3.63 (m, 2H), 4.16 ( , 2H), 5.00 (m, IH), 7.45 (s, IH), 8.61 (s, IH).
  • Benzylchloroformate(16 uL, 0.110 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7- tefrahydro-2H-4-pyranyl-7H-pynolo[2,3-d]pyrimidm-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 ml) and dichloromethane (0.7 ml) under nitrogen at 0°C. After 10 minutes, the ice water bath was removed and the resulting mixture was stined for 4 hours.
  • Example 2 Neopentyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H- pynolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate.
  • Neopentylchloroformate(13 uL, 0.110 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H- pynolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 ml) and dichloromethane (0.7 ml) under nitrogen at 0°C. After 10 minutes, the ice water bath was removed and the resulting mixture was stined for 4 hours.
  • Tetrahydro-2H-4-pyranol (1.0 ml, 10.5 mmol) was mixed with 4- methylmorpholine (2.0 ml) in dichloromethane (20 mL). 4- Nifrochloroformate (1.98 g, 9.82 mmol) was added slowly to the reaction mixture. After stirring for 5 hours, the reaction mixture was diluted with dichloromethane. The organic layer was washed with water, 1.0 N HCI, saturated sodium bicarbonate, brine, dried over MgSO 4 , filtered and evaporated.
  • Phenyl N-[4-(4- amino-7-tetrahydro-2H-4-pyranyl-7H-pynolo[2,3-d]pyrimidin-5-yl)-2- methoxyphenyl]carbamate 28 mg, 0.061 mmol was mixed with (4-bromo-l,3- thiazol-5-yl)methanol (50 mg, 0.434 mmol) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H- ⁇ ynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with tefrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Example 11 2-Pyridyhnethyl N-[4-(4-a ⁇ nino-7-tetrahydro-2H-4-pyranyl-7H- pynolo[2,3-d]pyrirnidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride Phenyl N-[4-(4-amino-7-tefrahydro-2H-4-pyranyl-7H-pynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 2- pyridylmethanol (0.05 mL) in pyridine (0.5 mL).
  • Example 12 4-Pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H- pynolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate Hydrochloride Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 4- pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl)methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pynolo[2,3- d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5S)-5-(hydroxymethyl)tetrahydro-lH-2-pynolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100°C overnight.
  • Example 15 4-Ammobe ⁇ __ ⁇ l N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H- pynolo [2,3 -d]pyrimidin-5 -yl)-2-methoxyphenyl)carbamate a) tert-Butyl N-(4-(hydroxymethyl)phenyl)carbamate. (4-Aminophenyl)methanol (1.23 g, 10 mmol) and diisopropylethylamine ( 2.6 mL, 15 mmol) was mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL).
  • Example 22 5-(4-phenoxyphenyl)-7-(3-tefrahydrofuryl)-7H-pynolo[2,3- d]pyrimidin-4-ylamine.
  • Example 23 5 -(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pynolo [2,3 - d]pyrimidin-4-ylamine.
  • 4-amino-5-(4-phenoxyphenyl)-7H- pynolo[2,3-d]pyrimidine was reacted with 4-tosyloxytefrahydropyran to give after flash column chromatography 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H- py ⁇ olo[2,3-d]pyrimidin-4-ylamine, m.p. 193-193.5°C.
  • Example 24 4-amino-5-(4-phenoxyphenyl)-7-[4-(N-tert-butoxycarbonyl) tetrahydroisoxazolyl]-7H-pynolo[2,3-d]pyrimidin-4-ylamine.
  • Example 25 5-(4-phenoxyphenyl)-7-(4-tetrahydroisoxazolyl)-7H-pynolo[2,3-d]- pyrimidin-4-ylamine dihydrochloride.
  • the product from Example 3 (0.29 g) was dissolved in dichloromethane (8 ml) and then stined at 0°C whilst trifluoroacetic acid (2.0 ml) was added. The mixture was allowed to warm to ambient temperature and stined at ambient temperature for 2 hours.
  • Example 34 4-[(4-(4-amino-7-(3-tefrahy ⁇ o_u ⁇ l)-7H-pynolo[2,3-d]-pyrimidin-5- yl)phenoxy]benzyl alcohol
  • Example 35 5-[4-(4-fluorophenoxy)phenyl]-7-(3-tefrahydrofuryl)-7H-pynolo[2,3- d]pyrimidin-4-ylamine
  • the reaction mixture was filtered through a small pre-flushed silica pad and eluted with dichloromethane (200 ml) then ethyl acetate (250 ml) and finally ethyl acetate/methanol 9:1 (250 ml).
  • the dichlormethane and ethyl acetate fractions were combined and purified by flash column chromatography on silica using ethyl acetate/methanol as the mobile phase to give 5-[4-(4-fluorophenoxy)phenyl]-7-(3- tetrahydrofuryl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine, m.p. 198-199°C.
  • Example 38 2-[4-(4-amino-7-(3-tefrahydroft ⁇ ryl)-7H-pynolo[2,3-d]pyrimidin-5- yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)-benzonitrile
  • Example 39 2-[4-(4-amino-7-(3-tefrahydroft ⁇ ryl)-7H-pynolo[2,3-d]pyrimidin-5- yl)phenoxy]-6-(3-imidazol-l-yl)propylaminobenzonixrile
  • Example 40 4-amino-6-bromo-5-(4-phenoxyphenyl)-7-(3-tefrahy ⁇ _rofuryl)-7H- pynolo[2,3-d]pyrimidine
  • Example 41 2-[4-(4-a ⁇ nino-7-(3-tefrahydro_n ⁇ yl)-7H-pynolo[2,3-d]pyrimidin-5- yl)phenoxy]-6-(3-methoxypropylamino) benzonitrile
  • 4-amino-5-(4-phenoxyphenyl)-7H- py ⁇ olo[2,3-d]pyrimidine (0.65 g)
  • 2-fluoro-6-(3-methoxypropylamino)benzonitrile (0.46 g)
  • potassium carbonate (0.61 g) and dimethylformamide (40 ml) was heated under nitrogen at 120°C for 8 hours to give, after workup, 2-[4-(4-amino-7-(3- tefrahydroftuyl)-7H-pynolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(3- memoxy
  • Examples 43-48 were prepared in a similar manner to the previous example by reacting 4-[4-amino-7-(4-tefrahydropyranyl)-7H-pynolo[2,3-d]pyrimidin-5- yl]phenol with the appropriate nitrile except that the mixtures were shaken together for periods up to 48 hours. The reactions were monitored for the disappearance of starting material and heated for the appropriate time.
  • Example 49 2-[4-(4-Amino-7-(4-tetrahydropyranyl)-7H-pynolo[2,3-d]pyrimidin- 5-yl)phenoxy]-6-(3-imidazol-l-yl)propylaminobenzonitrile from 2-fluoro-6-(3- (imidazol- 1 -yl)propyl_ ⁇ mino)-benzonitrile.
  • Example 50 2-(4-(4-Amino-7-(4-tefrahydropyranyl)-7H-pynolo [2,3 -d]pyrimidin- 5-yl)phenoxy]- 6-(2-morpholinoethoxy)benzonitrile, m.p. 110°C (glass), from 2- fluorobenzonitrile.
  • Example 51 2-[4-(4-Amino-7-(4-tetrahydropyranyl)-7H-pynolo[2,3-d]pyrimidin- 5-yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)benzonitrile, m.p. 120-123°C (glass), from 2-fluoro-6-(2-(4-pyridyl)ethylamino)benzonitrile.
  • Example 52 2- [4-(4- Amino-7-(4-tetrahydropyranyl)-7H-pynolo [2,3 -d]pyrimidin- 5-yl)phenoxy)-6-(3-methoxypropylamino)benzonitrile, m.p. 205-207°C, from 2- fluoro-6-(3-methoxy-propylamino)benzonitrile.
  • Example 53 2-[4-(4-Amino-7-(4-tetrahydropyranyl)-7H-pynolo[2,3-d]pyrimidin- 5-yl)phenoxy]-5-fluorobenzonitrile, m.p. 216-217°C, from 2,5-difluorobenzonitrile.
  • the desired products were either found in the original dichloromethane extract, in which case they are indicated as being present in the liquid, or were found in the insoluble solid on reworking and are refened to as being found in the solid. Certain products were found in both phases. These phases are indicated in Table 1.
  • Example 56 4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- (2-hydroxypropyl)acetamide
  • Example 57 4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyri ⁇ mdin-7-yl-N- (2-methoxyethyl)acetamide
  • Example 62 4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- (1 -hydroxybut-2-yl)acetamide
  • Example 64 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- (2 ,3 -dihy droxypropyl)acetamide
  • Example 66 (R)-4-An ⁇ no-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrintidin-7-yl- N-(2,3-dihydroxypropyl)acetamide
  • Example 67 4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d] ⁇ yrimidin-7-yl- N,N-(3-azapentamethylene)acetamide
  • Example 68 4-An___no-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [3 -(N,N-dimethylamino)propyl] acetamide
  • Example 70 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [2-(N,N-dimethylamino)propyl]acetamide
  • Example 72 7- ⁇ 2-[4-(2-Morpholino-2-oxoethyl)piperazin-l-yl]-2-oxo-ethyl ⁇ -5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine
  • Example 76 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [2-(pynolidin- 1 -yl)ethyl]acetamide
  • Example 77 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl- N,N-(3-azahexamethylene)acetamide
  • Example 78 4-An_dno-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyriniidin-7-yl-N- [ 1 -(hydroxymethyl)cyclopentyl] acetamide
  • Example 80 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [2-(N,N-diethylamino)ethyl] acetamide
  • Example 85 4-_ mino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [3 -(imidazol- 1 -yl)propyl] acetamide
  • Example 86 7- ⁇ 2-[4-(2-Morpholinoethyl)piperazin-l-yl]-2-oxo-ethyl ⁇ -5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrh din-4-ylamine
  • Example 87 4-A ⁇ r__no-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- (N-ethylpynolidin-2-yl)methylacetamide
  • Example 96 4-Annno-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [3 -(2-pynolidinon- 1 -yl)propyl] acetamide
  • Example 97 4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- (3-piperidino ⁇ ropyl)acetamide
  • Example 100 4-An_ino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [3-(N-3-aminopropyl,N-methyl)aminopropyl]acetamide
  • Example 101 4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl-N- [N-bis(2-aminoethyl)aminoethyl]acetamide
  • Example 102 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-hydroxyethyl)propanamide
  • Example 103 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-( 1 -hydroxy ⁇ rop-2-yl)propanamide
  • Example 104 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-hydroxypropyl)propanamide
  • Example 105 l-[4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-methoxyethyl)propanamide
  • Example 106 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(3 -hydroxypropyl)pro ⁇ anatnide
  • Example 107 (S)-l-[4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl]-N-(l-hydroxyprop-2-yl)propanamide
  • Example 108 (R)-l-[4-Ammo-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl]-N-(2-hydroxypropyl)propanamide
  • Example 109 l-[4-An__ino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrirnidin-7-yl]- N-[2-(N,N-dimethylamino)ethyl]propanamide
  • Example 110 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(l -hydroxybut-2-yl)propanamide
  • Example 111 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-hydroxybutyl)propanamide
  • Example 112 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2,3-dihydroxypropyl)propanamide
  • Example 115 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[3-(N,N-dimethylamino)propyl]propanamide
  • Example 116 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(N,N-dimethylamino)propyl]propanarnide
  • Example 117 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N- [ 1 -(N,N-dimethylamino)prop-2-yl]propanamide
  • Example 118 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-( 1 -hydroxy-3 -methylbut-2-yl)propanamide
  • Example 120 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-( 1 -hydroxy-2-methylprop-2-yl)propanamide
  • Example 121 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(l,3-dihydroxy-2-methylprop-2-yl)propanamide
  • Example 122 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N ⁇ [2-(2-hydroxyethoxy)ethyl]propanamide
  • Example 123 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]py ⁇ imidin-7-yl]- N-[2-(pynolidin-l-yl)ethyl]propanamide
  • Example 125 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-hydroxycyclohexyl)propanamide
  • Example 126 l-[4-An_ano-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimi(_in-7-yl]- N-[2-(N,N-diethylamino)ethyl]propanamide
  • Example 127 l-[4-Anfrno-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(3-hydroxypropyla ⁇ nino)ethyl]propanamide
  • Example 128 1 -[4-Anaino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(2-hydroxyethylthio)ethyl]propanamide
  • Example 129 l-[4-An_ no-5-(4-phenox ⁇ henyl)-7H- ⁇ ynolo[2,3-d]pyrirnidin-7-yl]- N-[2-(pyrid-2-yl)ethyl]propanamide
  • Example 130 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(pyrid-3-yl)ethyl]propanamide
  • Example 132 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(N-methylpynolidin-2-yl)ethyl]propanamide
  • Example 133 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[(N-ethylpynolidin-2-yl)methyl]propanamide
  • Example 135 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[3-(pynolidin-l-yl)propyl]propanamide
  • Example 137 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(2-morpholinoethyl)propanamide
  • Example 138 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[3-(N,N-diethylamino)propyl]propanamide
  • Example 139 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[3-(N,N-dimethylamino)-2,2-dimethylpropyl]propanamide
  • Example 140 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2,2-bis(hydroxymethyl)butyl]propanamide
  • Example 141 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[3-(2-pynolidinon-l-yl)propyl]propanamide
  • Example 142 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(3 -piperidinopropyl)propanamide
  • Example 143 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-(3 -morpholinopropyl)propanamide
  • Example 144 1 -[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-[2-(N,N-di-isopropylamino)ethyl]propanamide
  • Example 145 1 - [ Amino-5 -(4-phenoxyphenyl)-7H-pynolo [2,3 -d]pyrimidin-7-yl] -N- [3-(N-3-aminopropyl,N-methyl)aminopropyl]propanamide
  • Example 146 l-[4-Amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]- N-P r-bis(2-aminoethyl)aminoethyl]propanamide
  • Example 147 2- [4-amino-5 -(4-phenoxyphenyl)-7H-pynolo [2,3 -d]pyrirnidin-7-yl]-- buxyrolactone a) 4-Ammo-5-(4- ⁇ henoxyphenyl)-7H-pynolo[2,3-d]pyrimidine (1.0 g) was added to a mixture of sodium hydride (0.158 g of a 60% dispersion in mineral oil) in dimethyl formamide (70 ml) with stirring under nitrogen at 0°C.
  • N,N-Dimethylethylenediamine (5.0 ml) was added to a mixture ofthe product from a) (1.2 g) and pyridin-2-one (50 mg) in toluene (100 ml). The mixture was heated to 100°C for 2 hours and then evaporated to dryness under reduced pressure. The residue was suspended in ethyl acetate and washed with water. The organic extracts were then extracted with 5M hydrochloric acid (3 x 50 ml) and the acidic extracts were washed with ethyl acetate then basified with 6M sodium hydroxide solution at 0°C and then back extracted with ethyl acetate and then dichloromethane.
  • Example 148 Ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin- 7-yl]propionate
  • Sodium hydride 120 mg, of a 60% dispersion in mineral oil
  • 4-__mino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidine 906 mg
  • dry dimethyformamide (30 ml) and the mixture was stined under nitrogen for 30 minutes at ambient temperature.
  • a solution of ethyl 2-bromopropionate (543 mg) in dry DMF (10 ml) was added dropwise via a syringe over 10 minutes.
  • Example 150 Ethyl 2-[4-amino-5-(4- ⁇ henoxyphenyl)-7H-pynolo[2,3-d]pyrimidin- 7-yl]acetate
  • Example 158 Ethyl 4-[4-amido-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin- 7-yl]butyrate A mixture of 5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine
  • Example 159 ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin- 7-yl]carbox-amide
  • Example 161 4-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimin-7-yl] N- (2-dimethylaminoethyl)buxyramide
  • Examples 162, 163 and 164 were prepared in a similar manner to Example 108 by reacting the same ester with the appropriate amine listed.
  • the hydrobromide salt was converted into the free base by warming with dilute sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filfration and washed well with water to give 5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine, m.p. 272°C.
  • Example 168 7-cyclopentanesulphonyl-5-(4-phenoxyphenyl)-7H-pynolo[2,3- d]pyrirnidin-4-ylamine
  • the ethyl acetate layer was separated and purified by flash column chromatography using ethyl acetate as the mobile phase to give 5-(4- phenoxyphenyl)-7-(8-phthalinndooctyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine, m.p. 85-86°C.
  • Example 171 N- ⁇ 2-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl] ethyl ⁇ phthalimide
  • 5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine was reacted with 2-bromoethylphthalimide to give N- ⁇ 2-[4-amino-5-(4-phenoxyphenyl)-7H- pynolo[2,3-d]pyrimidin-7-yl]ethyl ⁇ phthalimide, m.p. 111-112°C.
  • Example 469 In a similar manner to Example 469, the product from the previous example was treated with hydrazine hydrate to give 7-(2-aminoethyl)-5-(4-phenoxyphenyl)- 7H-pynolo[2,3-d]pyrimidin-4-ylamine hydrochloride, m.p. 284-285°C.
  • Isobutyryl chloride (1.8 g) was added dropwise to a mixture of 5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine (4.32 g), dry dimethyl- formamide (200 ml) and dry pyridine (2 ml) with stirring under nitrogen at 20°C. The mixture was stined at ambient temperature for 1 hour and evaporated under vacuum. The residue was partitioned between water and ethyl acetate.
  • Example 175 4-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl]cyclohexanone
  • acetone (20 ml)
  • 3M hydrochloric acid (10 ml) was stined under nitrogen at ambient temperature for 20 minutes. The mixture was then heated at 60°C for 1 hour and then the acetone was removed under reduced pressure.
  • Example 176 and 177 cis-5-(4-phenoxyphenyl)-7-(4-morpholinocyclohex-l-yl)- 7H-pynolo[2,3-d]pyrimidin-4-ylamine,-andfrans-5-(4-phenoxyphenyl)-7-(4- morpholinocyclohex-l-yl)-7H-pynolo[2,3-d] pyrimidin-4-ylamine
  • the acidic extracts were basified with 5M sodium hydroxide solution and extracted with dichloromethane to give a residue which was purified by chromatography on silica to give cis-5-(4-phenoxyphenyl)-7-(4-morpholinocyclohex-l-yl)-7H-pynolo[2,3- d]pyrimidin-4-ylamine, and trans-5-(4-phenoxyphenyl)-7-(4-morpholinocyclohex-l - yl)-7H-pynolo[2,3 -d] pyrimidin-4-ylamine.
  • Examples 178 and 179 cis-7-(4-N-ethoxycarbonyl)piperazin-l-ylcyclohexyl)-5-(4- phenoxy-phenyI)-7H-pynolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N- ethoxycarbonyl)-piperazin-l-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pynolo[2,3- d]pyrimidin-4-ylamine
  • Example 180 2-[4-amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl]pyridine-3 -carbonitrile 5-(4-Phenoxyphenyl)-7H-pynolo[2,3-d]-pyrimidin-4-ylamine (906 mg) was reacted with 2-chloronicotinonitrile (510 mg) in the presence of sodium hydride (150 mg) in dimethylformamide (30 ml) at 100°C for 5 hours to give 2-[4-amino-5- (4-phenoxyphenyl)-7H-pynolo[2,3-d]pyri ⁇ mdin-7-yl]pyridine-3-carbo ⁇ _itrile, m.p. 242-242.5°C, after workup.
  • Example 181 7-[3-(aminomethyl)pyrid-2-yl]-5-(4-phenoxyphenyl)-7H-pynolo[2,3- d]-pyrimidin-4-ylamine dimaleate
  • Examples 183 and 184 cis-7-(N-methylhomopiperazin-l-ylcyclohexyl)-5-(4- phenoxyphenyl)-7H- ⁇ ynolo[2,3-d]p ⁇ yrnidin-4-ylamine and trans 7-(N-methylhomo- piperazin-l-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]prymidin-4- ylamine
  • 4-[4-amino-5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]cyclohexanone 0.4 g from 1.0 g of a 40% pure material
  • N-methylhomopiperazine 114 mg
  • sodium triacetoxyborohydride (296 mg)
  • glacial acetic acid 60 mg
  • Examples 185 and 186 cis 7-(N-methylpiperazin-l-ylcyclohexyl)-5-(4- phenoxyphenyl)-7-pynolo[2,3-d] ⁇ rymidin-4-ylamine and trans 7-(N- methylpiperazin-l-ylcyclohexyl)-5-(4-phenoxy-phenyl)-7-pynolo[2,3-d]prymidin-4- ylamine
  • N-methylpiperazine 100 mg was reacted with the same amounts of cyclohexanone derivative and other reagents to give cis 7-(N-methylpiperazin-l-ylcyclohexyl)-5-(4-phenoxyphenyl)-7- ' pynolo[2,3-d]prymidin-4-ylamine and trans 7-(N-methylpiperazin-l-ylcyclohexyl)
  • Example 188 cis-7-(3 -morpholinocyclopent- 1 -yl)-5 -(4-phenoxyphenyl)-7H- pynolo[2,3-d]pyrimidin-4-ylamine and trans-7-(3-morpholinocyclopent-l-yl)-5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]-pyrimidin-4-ylamine
  • Morpholine (45 mg) was added to the solution obtained in the previous Example followed by sodium triacetoxyborohydride (151 mg) and glacial acetic acid (47 mg). The mixture was stined at ambient temperature under nitrogen for 18 hours during which time the dichloromethane evaporated. Tetrahydrofuran (100 ml) was added and the mixture was stined for a further 8 hours.
  • Example 192 3-(4-an ⁇ ino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7- yl)cyclopentyl N-(2-mo ⁇ holinoethyl)carbamate hydrochloride
  • N-Methylmo ⁇ holine (0.007 ml, 0.062 mmol) was added dropwise to solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) with stirring under nitrogen at 0°C. After 20 minutes, the ice- water bath was removed and the mixture was allowed to warm up to ambient temperature. 3-[4- amino-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-7-yl]cyclopentanol (20 mg, 0.052 mmol) was added to the mixture and the resulting solution was stined for 24 hours.
  • the solid was purified by preparative HPLC on a silica column using dichloromethane/propan-2-ol/ ethanol, 98:1:1 as the mobile phase to give 7-tert-butyl-5-(4-phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4- yla ⁇ nine (4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pynolo[2,3-d]pyrimidine), m.p. 157-158°C.
  • the hydrobromide salt was converted into the free base by warming with dilute sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filtration and washed well with water to give 5-(4- phenoxyphenyl)-7H-pynolo[2,3-d]pyrimidin-4-ylamine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés chimiques ayant la formule structurale (I) ainsi que leurs sels et métabolites physiologiquement acceptables, lesquels sont des inhibiteurs de l'activité sérine/thréonine et tyrosine kinase. Plusieurs des kinases, dont l'activité est inhibée par ces composés chimiques, sont impliquées dans des processus immunologiques, hyperprolifératifs ou angiogéniques. Ainsi, ces composés chimiques peuvent améliorer des états pathologiques dans lesquels l'angiogénèse ou l'hyperprolifération de cellules endothéliales constituent un facteur. Ces composés peuvent être utilisés pour traiter le cancer ainsi que des troubles hyperprolifératifs, la polyarthrite rhumatoïde, des troubles du système immun, des rejets de greffe et des maladies inflammatoires.
PCT/US2000/008593 2000-03-29 2000-03-29 Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases Ceased WO2001072751A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2000240570A AU2000240570A1 (en) 2000-03-29 2000-03-29 Pyrrolopyrimidines as tyrosine kinase inhibitors
PCT/US2000/008593 WO2001072751A1 (fr) 2000-03-29 2000-03-29 Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/008593 WO2001072751A1 (fr) 2000-03-29 2000-03-29 Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases

Publications (1)

Publication Number Publication Date
WO2001072751A1 true WO2001072751A1 (fr) 2001-10-04

Family

ID=21741221

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/008593 Ceased WO2001072751A1 (fr) 2000-03-29 2000-03-29 Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases

Country Status (2)

Country Link
AU (1) AU2000240570A1 (fr)
WO (1) WO2001072751A1 (fr)

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054581A3 (fr) * 2002-12-13 2005-02-03 Smithkline Beecham Corp Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
WO2005037836A3 (fr) * 2003-10-15 2005-06-09 Osi Pharm Inc Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase
WO2005070906A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Composes organiques
WO2005097800A1 (fr) * 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
WO2005116035A1 (fr) * 2004-05-27 2005-12-08 Pfizer Products Inc. Derives pyrrolopyrimidiniques convenant au traitement du cancer
WO2006012422A1 (fr) 2004-07-20 2006-02-02 Osi Pharmaceuticals, Inc. Imidazotriazines comme inhibiteurs de la tyrosine kinase
EP1496910A4 (fr) * 2002-03-21 2006-03-29 Abbott Lab Inhibiteurs de kinases
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
WO2007035744A1 (fr) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Marqueurs biologiques predictifs d'une reaction anticancereuse aux inhibiteurs kinase du recepteur du facteur de croissance 1 analogue a l'insuline
WO2007064993A2 (fr) 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
JP2007520559A (ja) * 2004-02-03 2007-07-26 アボット・ラボラトリーズ 治療薬としてのアミノベンゾオキサゾール類
US7271262B2 (en) 2002-12-19 2007-09-18 Pfizer Inc Pyrrolopyrimidine derivatives
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
US7326699B2 (en) 2001-05-14 2008-02-05 Novartis Ag 4-Amino-5-phenyl-7-cyclobutyl-pyrrolo(2,3-d)pyrimidine derivatives
US7427616B2 (en) 2002-08-06 2008-09-23 Astrazeneca Ab Condensed pyridines and pyrimidines with tie2 (TEK) activity
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7566721B2 (en) 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
WO2009098715A2 (fr) 2008-01-11 2009-08-13 Natco Pharma Limited Nouveaux dérivés de pyrazolo [3, 4 -d] pyrimidine en tant qu’agents anticancéreux
CN100538364C (zh) * 2003-06-06 2009-09-09 健泰科生物技术公司 调节HGFβ链和C-MET的相互作用
US7645778B2 (en) 2005-01-19 2010-01-12 Bristol-Myers Squibb Company Heteroaryl compounds as P2Y1 receptor inhibitors
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
WO2010099137A2 (fr) 2009-02-26 2010-09-02 Osi Pharmaceuticals, Inc. Procédés in situ pour surveiller l'état emt de cellules tumorales in vivo
WO2010099363A1 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
WO2010099139A2 (fr) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Thérapie anti-cancer combinée
WO2010099364A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
EP2251340A1 (fr) 2003-07-10 2010-11-17 Aventis Pharma S.A. Tetrahydro-1h-pyrazolo[3,4-c] pyridines substituees, compositions les contenant et utilisation
US7838541B2 (en) * 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
WO2011029915A1 (fr) * 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2011109572A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011109584A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011112666A1 (fr) 2010-03-09 2011-09-15 OSI Pharmaceuticals, LLC Thérapie anticancéreuse combinatoire
WO2012116040A1 (fr) 2011-02-22 2012-08-30 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de la kinase du récepteur du facteur de croissance 1 analogue à l'insuline dans le carcinome hépatocellulaire
WO2012149014A1 (fr) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
US8481733B2 (en) 2008-05-19 2013-07-09 OSI Pharmaceuticals, LLC Substituted imidazopyr- and imidazotri-azines
US8513415B2 (en) 2009-04-20 2013-08-20 OSI Pharmaceuticals, LLC Preparation of C-pyrazine-methylamines
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
US8575164B2 (en) 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
CN103534257A (zh) * 2011-04-05 2014-01-22 辉瑞有限公司 作为原肌球蛋白相关激酶抑制剂的吡咯并[2,3-d]嘧啶衍生物
US8673925B1 (en) 2013-04-09 2014-03-18 Principia Biopharma Inc. Tyrosine kinase inhibitors
JP2014193925A (ja) * 2008-10-16 2014-10-09 Regents Of The Univ Of California 融合環ヘテロアリールキナーゼ阻害剤
US8940744B2 (en) 2012-09-10 2015-01-27 Principia Biopharma Inc. Pyrazolopyrimidine compounds as kinase inhibitors
US8962831B2 (en) 2011-05-17 2015-02-24 Principia Biopharma Inc. Tyrosine kinase inhibitors
WO2015027067A3 (fr) * 2013-08-23 2015-05-07 Virginia Commonwealth University Dérivés de type nitrates d'ester d'aldéhydes aromatiques doués de multiples propriétés pharmacologiques pour traiter la drépanocytose
WO2015068767A1 (fr) 2013-11-08 2015-05-14 小野薬品工業株式会社 Dérivé de pyrrolopyrimidine
WO2015077866A1 (fr) * 2013-11-26 2015-06-04 Pharmascience Inc. Inhibiteurs de protéines kinases
WO2015132799A3 (fr) * 2014-02-03 2015-11-12 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9376438B2 (en) 2011-05-17 2016-06-28 Principia Biopharma, Inc. Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
US9624224B2 (en) 2013-09-30 2017-04-18 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
WO2017215485A1 (fr) * 2016-06-16 2017-12-21 中国科学院上海药物研究所 Nouveau composé présentant une activité inhibitrice du fgfr, préparation et application correspondantes
US9862722B2 (en) 2011-07-13 2018-01-09 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
CN108431007A (zh) * 2015-09-16 2018-08-21 洛克索肿瘤学股份有限公司 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物
US10092569B2 (en) 2014-02-21 2018-10-09 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
JP2018536716A (ja) * 2015-12-02 2018-12-13 アストライア セラピューティクス， エルエルシーＡｓｔｒａｅａ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｌｌｃ ピペリジニルノシセプチン受容体化合物
NO344399B1 (no) * 2006-11-22 2019-11-25 Incyte Holdings Corp Imidazotriaziner og imidazopyrimidiner som kinaseinhibitorer
US10485797B2 (en) 2014-12-18 2019-11-26 Principia Biopharma Inc. Treatment of pemphigus
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
WO2021038540A1 (fr) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Acides cycloalkylidènecarboxyliques et dérivés en tant qu'inhibiteurs de la btk
JP2021143175A (ja) * 2020-03-12 2021-09-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物
US11155544B2 (en) 2015-06-24 2021-10-26 Principia Biopharma Inc. Heterocycle comprising tyrosine kinase inhibitors
US11827617B2 (en) 2015-12-02 2023-11-28 Astraea Therapeutics, Llc Piperidinyl nociceptin receptor compounds
US11872229B2 (en) 2016-06-29 2024-01-16 Principia Biopharma Inc. Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
US11912668B2 (en) 2020-11-18 2024-02-27 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof
US12091413B2 (en) 2020-05-08 2024-09-17 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase
US12178818B2 (en) 2019-10-14 2024-12-31 Principia Biopharma Inc. Methods for treating immune thrombocytopenia by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
JP2025511287A (ja) * 2022-03-31 2025-04-15 エースランド セラピューティクス（ホンコン）リミテッド スピロビシクリック化合物
US12410176B2 (en) 2020-01-22 2025-09-09 Principia Biopharma Inc. Crystalline forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
US12577249B2 (en) 2021-12-03 2026-03-17 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3036390A1 (de) * 1980-09-26 1982-05-13 Troponwerke GmbH & Co KG, 5000 Köln Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen
EP0496617A1 (fr) * 1991-01-23 1992-07-29 Gensia, Inc. Inhibiteurs de kinase d'adénosine
WO1994017803A1 (fr) * 1993-02-03 1994-08-18 Gensia, Inc. Inhibiteurs de l'adenosine kinase
WO1996010028A1 (fr) * 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
WO1996040686A1 (fr) * 1995-06-07 1996-12-19 Abbott Laboratories Composes de cyclopentane substitue heterocycliques
US5639757A (en) * 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
WO1997028161A1 (fr) * 1996-02-01 1997-08-07 Novartis Ag Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase
US5665721A (en) * 1995-06-07 1997-09-09 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
WO1997032879A1 (fr) * 1996-03-06 1997-09-12 Novartis Ag 7-ALKYLE-PYRROLO[2,3-d]PYRIMIDINES
WO1997034895A1 (fr) * 1996-03-15 1997-09-25 Novartis Ag NOUVELLES N-7-HETEROCYCLYL-PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
WO1997049706A1 (fr) * 1996-06-25 1997-12-31 Novartis Ag 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES
WO1998041525A1 (fr) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo [2,3] pyrimidines et leur utilisation comme inhibiteurs de la tyrosine kinase
WO2000017203A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft Pyrrolopyrimidines utilisees comme inhibiteurs de proteines kinases
WO2000017202A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft 4-aminopyrrolopyrimidines utilisees comme inhibiteurs de kinases

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3036390A1 (de) * 1980-09-26 1982-05-13 Troponwerke GmbH & Co KG, 5000 Köln Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen
EP0496617A1 (fr) * 1991-01-23 1992-07-29 Gensia, Inc. Inhibiteurs de kinase d'adénosine
WO1994017803A1 (fr) * 1993-02-03 1994-08-18 Gensia, Inc. Inhibiteurs de l'adenosine kinase
WO1996010028A1 (fr) * 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
US5639757A (en) * 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
US5665721A (en) * 1995-06-07 1997-09-09 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
WO1996040686A1 (fr) * 1995-06-07 1996-12-19 Abbott Laboratories Composes de cyclopentane substitue heterocycliques
WO1997028161A1 (fr) * 1996-02-01 1997-08-07 Novartis Ag Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase
WO1997032879A1 (fr) * 1996-03-06 1997-09-12 Novartis Ag 7-ALKYLE-PYRROLO[2,3-d]PYRIMIDINES
WO1997034895A1 (fr) * 1996-03-15 1997-09-25 Novartis Ag NOUVELLES N-7-HETEROCYCLYL-PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
WO1997049706A1 (fr) * 1996-06-25 1997-12-31 Novartis Ag 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES
WO1998041525A1 (fr) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo [2,3] pyrimidines et leur utilisation comme inhibiteurs de la tyrosine kinase
WO2000017203A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft Pyrrolopyrimidines utilisees comme inhibiteurs de proteines kinases
WO2000017202A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft 4-aminopyrrolopyrimidines utilisees comme inhibiteurs de kinases

Cited By (153)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US7223757B2 (en) 2001-03-28 2007-05-29 Bristol-Myers Squibb Company Tyrosine kinase inhibitors
US7326699B2 (en) 2001-05-14 2008-02-05 Novartis Ag 4-Amino-5-phenyl-7-cyclobutyl-pyrrolo(2,3-d)pyrimidine derivatives
US7838541B2 (en) * 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
EP1496910A4 (fr) * 2002-03-21 2006-03-29 Abbott Lab Inhibiteurs de kinases
US7427616B2 (en) 2002-08-06 2008-09-23 Astrazeneca Ab Condensed pyridines and pyrimidines with tie2 (TEK) activity
US7589207B2 (en) 2002-12-13 2009-09-15 Smithkline Beecham Corporation Cyclohexyl compounds as CCR5 antagonists
WO2004054581A3 (fr) * 2002-12-13 2005-02-03 Smithkline Beecham Corp Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
US7271262B2 (en) 2002-12-19 2007-09-18 Pfizer Inc Pyrrolopyrimidine derivatives
CN100538364C (zh) * 2003-06-06 2009-09-09 健泰科生物技术公司 调节HGFβ链和C-MET的相互作用
EP2251340A1 (fr) 2003-07-10 2010-11-17 Aventis Pharma S.A. Tetrahydro-1h-pyrazolo[3,4-c] pyridines substituees, compositions les contenant et utilisation
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
JP4916883B2 (ja) * 2003-10-15 2012-04-18 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド イミダゾピラジンチロシンキナーゼ阻害剤
AU2004282219B2 (en) * 2003-10-15 2009-07-30 Osi Pharmaceuticals, Inc. Imidazo [1, 5 - a] pyrazine tyrosine kinase inhibitors
AU2004282219C1 (en) * 2003-10-15 2009-12-17 Osi Pharmaceuticals, Inc. Imidazo [1, 5 - a] pyrazine tyrosine kinase inhibitors
WO2005037836A3 (fr) * 2003-10-15 2005-06-09 Osi Pharm Inc Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase
US7459554B2 (en) 2003-10-15 2008-12-02 Osi Pharmaceuticals, Inc. Imidazopyrazine tyrosine kinase inhibitors
KR100872204B1 (ko) * 2003-10-15 2008-12-09 오에스아이 파마슈티컬스, 인코포레이티드 이미다조피라진 티로신 키나제 억제제
JP2007509060A (ja) * 2003-10-15 2007-04-12 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド イミダゾピラジンチロシンキナーゼ阻害剤
RU2405784C2 (ru) * 2003-10-15 2010-12-10 Оси Фармасьютикалз, Инк. Имидазопиразины в качестве ингибиторов тирозинкиназ
CN100567273C (zh) * 2004-01-21 2009-12-09 诺瓦提斯公司 有机化合物
WO2005070906A1 (fr) * 2004-01-21 2005-08-04 Novartis Ag Composes organiques
EP2281819A1 (fr) * 2004-01-21 2011-02-09 Novartis AG Dérivés du benzimidazole ou du benzoxazole
JP2007520559A (ja) * 2004-02-03 2007-07-26 アボット・ラボラトリーズ 治療薬としてのアミノベンゾオキサゾール類
EP1730148A4 (fr) * 2004-02-03 2009-08-19 Abbott Lab Utilisation d'aminobenzoxazoles comme agents therapeutiques
US8735405B2 (en) 2004-04-02 2014-05-27 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8367826B2 (en) 2004-04-02 2013-02-05 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8101613B2 (en) 2004-04-02 2012-01-24 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
JP4832426B2 (ja) * 2004-04-02 2011-12-07 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド ６，６−二環置換されたヘテロ二環式タンパク質キナーゼ阻害剤
WO2005097800A1 (fr) * 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
EA012873B1 (ru) * 2004-04-02 2009-12-30 Оси Фармасьютикалз, Инк. 6,6-бициклические кольцевые замещенные гетеробициклические ингибиторы протеинкиназ
EP2308879A1 (fr) 2004-04-02 2011-04-13 OSI Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de la protéine kinase à anneau bicyclique substitué en 6,6
EP2305682A1 (fr) 2004-04-02 2011-04-06 OSI Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de la protéine kinase à anneau bicyclique substitué en 6,6
RU2379308C2 (ru) * 2004-04-02 2010-01-20 Оси Фармасьютикалз, Инк. 6, 6-бициклические кольцевые замещенные гетеробициклические ингибиторы протеинкиназ
EP2168968A1 (fr) * 2004-04-02 2010-03-31 OSI Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de la protéine kinase à anneau bicyclique substitué en 6,6
CN102924458B (zh) * 2004-04-02 2014-11-05 Osi制药有限责任公司 6,6-双环取代的杂双环蛋白激酶抑制剂
US7820662B2 (en) 2004-04-02 2010-10-26 Osi Pharmaceuticals, Inc. 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
CN102924458A (zh) * 2004-04-02 2013-02-13 Osi制药有限责任公司 6,6-双环取代的杂双环蛋白激酶抑制剂
US7534797B2 (en) 2004-04-02 2009-05-19 Osi Pharmaceuticals, Inc. 6,6-Bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8653268B2 (en) 2004-04-02 2014-02-18 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2005116035A1 (fr) * 2004-05-27 2005-12-08 Pfizer Products Inc. Derives pyrrolopyrimidiniques convenant au traitement du cancer
US7595325B2 (en) 2004-05-27 2009-09-29 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidine derivatives useful in cancer treatment
US7741324B2 (en) 2004-07-20 2010-06-22 Osi Pharmaceuticals, Inc. Imidazotriazines as protein kinase inhibitors
JP2008507546A (ja) * 2004-07-20 2008-03-13 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド チロシンキナーゼ阻害剤としてのイミダゾピラジン
AU2005267120B2 (en) * 2004-07-20 2011-06-02 Osi Pharmaceuticals, Inc. Imidazopyrazine as tyrosine kinase inhibitors
WO2006012422A1 (fr) 2004-07-20 2006-02-02 Osi Pharmaceuticals, Inc. Imidazotriazines comme inhibiteurs de la tyrosine kinase
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
US7645778B2 (en) 2005-01-19 2010-01-12 Bristol-Myers Squibb Company Heteroaryl compounds as P2Y1 receptor inhibitors
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US8329718B2 (en) 2005-06-27 2012-12-11 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7566721B2 (en) 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
WO2007035744A1 (fr) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Marqueurs biologiques predictifs d'une reaction anticancereuse aux inhibiteurs kinase du recepteur du facteur de croissance 1 analogue a l'insuline
EP2372363A1 (fr) 2005-09-20 2011-10-05 OSI Pharmaceuticals, Inc. Marqueurs biologiques prédictifs d'une réaction anticancéreuse aux inhibiteurs kinase du récepteur du facteur de croissance 1 analogue à l'insuline
US7648987B2 (en) 2005-12-02 2010-01-19 Osi Pharmaceuticals, Inc. Bicyclic protein kinase inhibitors
WO2007064993A2 (fr) 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
US8575164B2 (en) 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
NO344399B1 (no) * 2006-11-22 2019-11-25 Incyte Holdings Corp Imidazotriaziner og imidazopyrimidiner som kinaseinhibitorer
US12084449B2 (en) 2006-11-22 2024-09-10 Incyte Holdings Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US11261191B2 (en) 2006-11-22 2022-03-01 Incyte Holdings Corporation Imidazotriaines and imidazopyrimidines as kinase inhibitors
US10738052B2 (en) 2006-11-22 2020-08-11 Incyte Holdings Corporation Imidazotriaines and imidazopyrimidines as kinase inhibitors
WO2009098715A2 (fr) 2008-01-11 2009-08-13 Natco Pharma Limited Nouveaux dérivés de pyrazolo [3, 4 -d] pyrimidine en tant qu’agents anticancéreux
US8481733B2 (en) 2008-05-19 2013-07-09 OSI Pharmaceuticals, LLC Substituted imidazopyr- and imidazotri-azines
JP2014193925A (ja) * 2008-10-16 2014-10-09 Regents Of The Univ Of California 融合環ヘテロアリールキナーゼ阻害剤
WO2010099139A2 (fr) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Thérapie anti-cancer combinée
WO2010099137A2 (fr) 2009-02-26 2010-09-02 Osi Pharmaceuticals, Inc. Procédés in situ pour surveiller l'état emt de cellules tumorales in vivo
WO2010099363A1 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
WO2010099364A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
US8513415B2 (en) 2009-04-20 2013-08-20 OSI Pharmaceuticals, LLC Preparation of C-pyrazine-methylamines
CN102596963A (zh) * 2009-09-10 2012-07-18 诺瓦提斯公司 二环杂芳基的醚衍生物
JP2013504543A (ja) * 2009-09-10 2013-02-07 ノバルティス アーゲー 二環ヘテロアリール類のエーテル誘導体
WO2011029915A1 (fr) * 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
WO2011109584A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011109572A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011112666A1 (fr) 2010-03-09 2011-09-15 OSI Pharmaceuticals, LLC Thérapie anticancéreuse combinatoire
WO2012116040A1 (fr) 2011-02-22 2012-08-30 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de la kinase du récepteur du facteur de croissance 1 analogue à l'insuline dans le carcinome hépatocellulaire
CN103534257A (zh) * 2011-04-05 2014-01-22 辉瑞有限公司 作为原肌球蛋白相关激酶抑制剂的吡咯并[2,3-d]嘧啶衍生物
WO2012149014A1 (fr) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
US9376438B2 (en) 2011-05-17 2016-06-28 Principia Biopharma, Inc. Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
US8962831B2 (en) 2011-05-17 2015-02-24 Principia Biopharma Inc. Tyrosine kinase inhibitors
US9862722B2 (en) 2011-07-13 2018-01-09 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9895373B2 (en) 2011-09-02 2018-02-20 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9546172B2 (en) 2011-12-30 2017-01-17 Pharmacyclics Llc Pyrazolo[3,4-d]pyrimidine and pyrazolo[2,3-d]pyrimidine compounds as kinase inhibitors
US9273051B2 (en) 2011-12-30 2016-03-01 Pharmacyclics Llc Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
US9994576B2 (en) 2012-09-10 2018-06-12 Principia Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as kinase inhibitors
US11040980B2 (en) 2012-09-10 2021-06-22 Principia Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as kinase inhibitors
US8940744B2 (en) 2012-09-10 2015-01-27 Principia Biopharma Inc. Pyrazolopyrimidine compounds as kinase inhibitors
US10533013B2 (en) 2012-09-10 2020-01-14 Principia Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as kinase inhibitors
US9266895B2 (en) 2012-09-10 2016-02-23 Principia Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as kinase inhibitors
US11613544B2 (en) 2012-09-26 2023-03-28 The Regents Of The University Of California Substituted imidazo[1,5-a]pyrazines for modulation of IRE1
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
US10822340B2 (en) 2012-09-26 2020-11-03 The Regents Of The University Of California Substituted imidazolopyrazine compounds and methods of using same
US8962635B2 (en) 2013-04-09 2015-02-24 Principia Biopharma Inc. Tyrosine kinase inhibitors
US9090621B2 (en) 2013-04-09 2015-07-28 Principia Biopharma Inc. Tyrosine kinase inhibitors
US8673925B1 (en) 2013-04-09 2014-03-18 Principia Biopharma Inc. Tyrosine kinase inhibitors
US8759358B1 (en) 2013-04-09 2014-06-24 Principia Biopharma Inc. Tyrosine kinase inhibitors
US8946241B2 (en) 2013-04-09 2015-02-03 Principia Biopharma Inc. Tyrosine kinase inhibitors
US8957080B2 (en) 2013-04-09 2015-02-17 Principia Biopharma Inc. Tyrosine kinase inhibitors
WO2015027067A3 (fr) * 2013-08-23 2015-05-07 Virginia Commonwealth University Dérivés de type nitrates d'ester d'aldéhydes aromatiques doués de multiples propriétés pharmacologiques pour traiter la drépanocytose
US9624224B2 (en) 2013-09-30 2017-04-18 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
WO2015068767A1 (fr) 2013-11-08 2015-05-14 小野薬品工業株式会社 Dérivé de pyrrolopyrimidine
EP3067356A4 (fr) * 2013-11-08 2017-03-22 ONO Pharmaceutical Co., Ltd. Dérivé de pyrrolopyrimidine
JPWO2015068767A1 (ja) * 2013-11-08 2017-03-09 小野薬品工業株式会社 ピロロピリミジン誘導体
US9586967B2 (en) 2013-11-08 2017-03-07 Ono Pharmaceutical Co., Ltd. Pyrrolo pyrimidine derivative
CN105764906A (zh) * 2013-11-26 2016-07-13 制药科学公司 蛋白激酶抑制剂
WO2015077866A1 (fr) * 2013-11-26 2015-06-04 Pharmascience Inc. Inhibiteurs de protéines kinases
US9840509B2 (en) 2014-02-03 2017-12-12 Cadila Healthcare Limited Heterocyclic compounds
JP2017504627A (ja) * 2014-02-03 2017-02-09 カディラ ヘルスケア リミティド 新規複素環式化合物
WO2015132799A3 (fr) * 2014-02-03 2015-11-12 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US11369613B2 (en) 2014-02-21 2022-06-28 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10456403B2 (en) 2014-02-21 2019-10-29 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10092569B2 (en) 2014-02-21 2018-10-09 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10828307B2 (en) 2014-02-21 2020-11-10 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10485797B2 (en) 2014-12-18 2019-11-26 Principia Biopharma Inc. Treatment of pemphigus
US10946008B2 (en) 2014-12-18 2021-03-16 Principia Biopharma Inc. Treatment of pemphigus
US11155544B2 (en) 2015-06-24 2021-10-26 Principia Biopharma Inc. Heterocycle comprising tyrosine kinase inhibitors
CN108431007B (zh) * 2015-09-16 2022-06-07 洛克索肿瘤学股份有限公司 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物
JP2018527384A (ja) * 2015-09-16 2018-09-20 ロクソ オンコロジー， インコーポレイテッドＬｏｘｏ Ｏｎｃｏｌｏｇｙ， Ｉｎｃ． がんの治療のためのｂｔｋ阻害剤としてのピラゾロピリミジン誘導体
JP7337502B2 (ja) 2015-09-16 2023-09-04 ロクソ オンコロジー， インコーポレイテッド がんの治療のためのｂｔｋ阻害剤としてのピラゾロピリミジン誘導体
CN108431007A (zh) * 2015-09-16 2018-08-21 洛克索肿瘤学股份有限公司 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物
JP2023134428A (ja) * 2015-09-16 2023-09-27 ロクソ オンコロジー， インコーポレイテッド がんの治療のためのｂｔｋ阻害剤としてのピラゾロピリミジン誘導体
USRE49825E1 (en) 2015-12-02 2024-02-06 Astraea Therapeutics, Llc Piperidinyl nociceptin receptor compounds
US11827617B2 (en) 2015-12-02 2023-11-28 Astraea Therapeutics, Llc Piperidinyl nociceptin receptor compounds
JP7011596B2 (ja) 2015-12-02 2022-02-10 アストライア セラピューティクス， エルエルシー ピペリジニルノシセプチン受容体化合物
JP2018536716A (ja) * 2015-12-02 2018-12-13 アストライア セラピューティクス， エルエルシーＡｓｔｒａｅａ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｌｌｃ ピペリジニルノシセプチン受容体化合物
JP2019521992A (ja) * 2016-06-16 2019-08-08 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｍａｔｅｒｉａ Ｍｅｄｉｃａ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ Ｆｇｆｒ阻害活性を有する新規な化合物およびその製造と使用
CN109328187A (zh) * 2016-06-16 2019-02-12 中国科学院上海药物研究所 一种具有fgfr抑制活性的新型化合物及其制备和应用
WO2017215485A1 (fr) * 2016-06-16 2017-12-21 中国科学院上海药物研究所 Nouveau composé présentant une activité inhibitrice du fgfr, préparation et application correspondantes
US11872229B2 (en) 2016-06-29 2024-01-16 Principia Biopharma Inc. Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
US12336999B2 (en) 2016-06-29 2025-06-24 Principia Biopharma Inc. Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo[3,4-d] pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl) piperazin-1-yl]pent-2-enenitrile
US12077531B2 (en) 2018-09-13 2024-09-03 Kissei Pharmaceutical Co., Ltd. Imidazopyridinone compound
JPWO2020054788A1 (ja) * 2018-09-13 2021-08-30 キッセイ薬品工業株式会社 イミダゾピリジノン化合物
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
JP7458987B2 (ja) 2018-09-13 2024-04-01 キッセイ薬品工業株式会社 イミダゾピリジノン化合物
WO2021038540A1 (fr) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Acides cycloalkylidènecarboxyliques et dérivés en tant qu'inhibiteurs de la btk
US12178818B2 (en) 2019-10-14 2024-12-31 Principia Biopharma Inc. Methods for treating immune thrombocytopenia by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
US12410176B2 (en) 2020-01-22 2025-09-09 Principia Biopharma Inc. Crystalline forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
JP7504822B2 (ja) 2020-03-12 2024-06-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物
JP2021143175A (ja) * 2020-03-12 2021-09-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物
US12091413B2 (en) 2020-05-08 2024-09-17 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase
US11912668B2 (en) 2020-11-18 2024-02-27 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof
US12577249B2 (en) 2021-12-03 2026-03-17 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof
JP2025511287A (ja) * 2022-03-31 2025-04-15 エースランド セラピューティクス（ホンコン）リミテッド スピロビシクリック化合物

Also Published As

Publication number Publication date
AU2000240570A1 (en) 2001-10-08

Similar Documents

Publication Publication Date Title
US6713474B2 (en) Pyrrolopyrimidines as therapeutic agents
AU753555C (en) Pyrrolopyrimidines as protein kinase inhibitors
WO2001072751A1 (fr) Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases
EP1114052B1 (fr) 4-aminopyrrolopyrimidines utilisees comme inhibiteurs de kinases
EP1212327B1 (fr) Pyrazolopyrimidines en tant qu'agents therapeutiques
CA2440714C (fr) Pyrazolopyrimidines utiles comme agents therapeutiques
US6921763B2 (en) Pyrazolopyrimidines as therapeutic agents
US20030187001A1 (en) 4-aminopyrrolopyrimidines as kinase inhibitors
WO2001019828A2 (fr) Inhibiteurs de kinase utilises comme agents therapeutiques
US20030225098A1 (en) Kinase inhibitors
EP1496910A1 (fr) Inhibiteurs de kinases
MXPA01002785A (en) Pyrrolopyrimidines as protein kinase inhibitors
AU2002316030A1 (en) Pyrazolopyrimidines as therapeutic agents

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP