WO2008060248A1 - Pyrimidines substituées par indole, et leur utilisation dans le traitement d'un cancer - Google Patents

Pyrimidines substituées par indole, et leur utilisation dans le traitement d'un cancer Download PDF

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WO2008060248A1
WO2008060248A1 PCT/SG2007/000392 SG2007000392W WO2008060248A1 WO 2008060248 A1 WO2008060248 A1 WO 2008060248A1 SG 2007000392 W SG2007000392 W SG 2007000392W WO 2008060248 A1 WO2008060248 A1 WO 2008060248A1
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group
kinase
leukemia
acute
cancer
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PCT/SG2007/000392
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English (en)
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Dizhong Chen
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S*Bio Pte Ltd.
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    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to pyrimidine compounds that may be useful as anti proliferative agents. More particularly, the present invention relates to indole substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers.
  • Proliferative disorders such as cancer are characterised by the uncontrolled growth of cells within the body. As such proliferative disorders generally involve an abnormality in the control of cell growth and/or division leading to the formation of tumour and ultimately death. Without wishing to be bound by theory it is thought that this is caused by the pathways that regulate cell growth and division being altered in cancer cells. The alteration is such that the effects of these normal regulatory mechanisms in controlling cell growth and division either fails or is bypassed.
  • the cancer cells then typically metastasize to colonize other tissues or parts of the body other than the part of origin of the cancer cell leading to secondary tumours which eventually lead to organ failure and the death of the patient. It is the difficulty in controlling the rapid cell growth and division that is characteristic of cancer cells that make it hard to come up with effective chemotherapeutic strategies.
  • combination therapies typically involve the use of anti-cancer drugs with different properties and cellular targets which in turn tends to increase the overall effectiveness of any chosen chemotherapy regime and limits the possibility of drug resistance developing in the patient.
  • Small-molecule kinase inhibitors that are now approved for oncology indications include imatinib, gefitinib, erlotinib, sorafenib, sunitinib and dasatinib [Baselga J., Science, 2006, 312, 1175-1178].
  • a number of kinases such as JAK2, FLT3 and CDK2 are promising kinase targets for pharmacological intervention in solid tumours, hematological malignancies, myeloproliferative disorders and non-malignant proliferative disorders like keloids.
  • the Janus kinases are a family of cytoplasmic tyrosine kinases consisting of JAK1 , JAK2, JAK3 and Tyk2. They play a pivotal role in the signaling pathways of numerous cytokines, hormones and growth factors [Rawlings JS et al, J. Cell Sci., 2004, 117, 1281-1283]. Their intracellular substrates include the family of proteins called Signal Transducer and Activator of Transcription (STAT). The JAK-STAT pathways, through the proper actions of the ligands, regulate important physiological processes such as immune response to viruses, erythropoiesis, lactation, lipid homeostasis, etc.
  • STAT Signal Transducer and Activator of Transcription
  • JAK2 myeloproliferative disorders
  • myeloproliferative disorders including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis
  • leukemias and lymphomas include polycy MJ et al, Hematol. Oncol., 2005, 23, 91-93.
  • the myeloproliferative disorders belong to an area of unmet medical need where some treatment modalities have not been updated over the past few decades [Schafer Al, Blood, 2006, 107, 4214-4222].
  • the myeloproliferative disorders belong to a group of hematological malignancies arising from clonal expansion of mutated progenitor stem cells in the bone marrow.
  • the association of one MPD, chronic myeloid leukemia, with the Philadelphia chromosome has been well documented.
  • the Philadelphia negative MPDs include Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Chronic Idiopathic Myelofibrosis (MF). No effective treatment is currently available.
  • JAK2 Essential Thrombocythemia
  • PV Polycythemia Vera
  • MF Chronic Idiopathic Myelofibrosis
  • Essential Thrombocythemia is a chronic MPD characterized by an increased number of circulating platelets, profound marrow megakaryocyte hyperplasia, splenomegaly and a clinical course punctuated by hemorrhagic or thrombotic episodes or both.
  • Current treatment options include low dose aspirin, or platelet lowering agents such as anagrelide, interferon or hydroxyurea. These treatments have severe side effects that compromise the quality of life of patients.
  • Polycythemia Vera is a chronic progressive MPD characterized by an elevated hematocrit, an increase in the red cell mass, and usually by an elevated leukocyte count, an elevated platelet count and an enlarged spleen.
  • Treatment options include: phlebotomy with low dose aspirin or myelosuppressive therapy options such as hydroxyurea, interferon or anagrelide. Again, these treatments are not ideal due to severe side effects.
  • Chronic Idiopathic Myelofibrosis is a chronic malignant hematological disorder characterized by an enlarged spleen, varying degrees of anemia and low platelet counts, red cells in the peripheral blood that resemble tear drops, the appearance of small numbers of immature nucleated red cells and white cells in the blood, varying degrees of fibrosis of the marrow cavity (myelofibrosis) and the presence of marrow cells outside the marrow cavity (extramedullary hematopoiesis or myeloid metaplasia).
  • Current treatment is directed at alleviation of constitutional symptoms, anemia and symptomatic splenomegaly. Treatment options include hydroxyurea, interferon, thalidomide with prednisone, and allogeneic stem cell transplant.
  • MF has the worst prognosis among the Philadelphia negative MPD and represents an area of greatest unmet medical need.
  • JAK2 is also implicated in the etiology of cardiovascular diseases like congestive heart failure and pulmonary hypertension [Berk BC et a/, Circ. Res, 1997, 80, 607-616]. Furthermore, a putative role for JAK2 has been demonstrated in keloid pathogenesis and may constitute a new approach for keloid management [Lim CP ef a/, Oncogene, 2006, 25, 5416-5425].
  • JAK2 inhibitors lie in the treatment of retinal diseases as JAK2 inhibition was found to offer protective effects on photoreceptors in a mouse model of retinal degeneration [Samardzija M ef a/, FASEB J., 2006, 10, 1096].
  • a family of Class III receptor tyrosine kinases including c-Fms, c-KIt, fms-like receptor tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptors (PDGFR ⁇ and ⁇ ), play an important roie in the maintenance, growth and development of hematopoietic and non-hematopoietic cells.
  • FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, point mutations, deletions, and insertions surrounding the D835 coding sequence have been
  • FLT3 mutations are the most frequent genetic alterations reported in acute myeloid leukemia (AML) and are involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells [Tickenbrock L et al, Expert Opin. Emerging Drugs, 2006, 11 , 1-13].
  • AML acute myeloid leukemia
  • Cyclin-dependent kinases are serine-threonine kinases that play
  • CDK1 cell cycle control
  • CDK7 and 9 transcription initiation
  • CDK5 neuronal function
  • 2S pharmacological inhibition of CDK1 , 2, 4, 6 and/or 9 may provide a new therapeutic option for diverse cancer patients.
  • the simultaneous inhibition of CDK1 , 2 and 9 has recently been shown to result in enhanced apoptotic killing of lung cancer
  • the present invention provides a compound of formula (I):
  • R 1 is H
  • R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzy
  • each R 3 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
  • each R 6 is independently selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
  • Ar 1 is selected from the group consisting of aryl and heteroaryl, which may be optionally substituted;
  • L is a linking moiety
  • R 9 and R 10 are each independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phen
  • j is an integer selected from the group consisting of 0, 1 , 2 and 3;
  • k is an integer selected from the group consisting of 0, 1 and 2;
  • the compounds is a compound of formula (Ia):
  • R 1 , R 2 , R 9 , R 10 , j, k Ar 1 , and L are as defined above, or a pharmaceutically acceptable salt or prodrug thereof.
  • Ar 1 may be a monocyclic, bicyclic or polycyclic moiety.
  • Ar 1 is a moiety of the formula
  • V 5 , V 6 , V 7 and V 8 are each independently selected from the group consisting of N, and C(R 11 ); wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroaikyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy
  • D is selected from the group consisting of N and CR 16 ;
  • p is an integer selected from the group consisting of O, 1 , 2, 3, 4, 5, and 6;
  • R 12 and R 13 are each independently selected from the group consisting of H, optionally substituted C 1 -Ci 2 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted CrC 10 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -Ci 2 heterocycloalkyl, optionally substituted C 1 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted CrC 18 heteroaryl, or R 12 and R 13 when taken together with the atom to which they are attached form an optionally substituted cyclic moiety;
  • R 14 , R 15 and R 16 are each independently selected from the group consisting of H and Ci-C 6 -alkyl;
  • R 11 substituents on adjacent carbon atoms may, when taken together with the carbon atoms to which they are attached, form an optionally substituted fused cyclic group which may be fully unsaturated, partially unsaturated or fully saturated;
  • Ar 1 is selected from the group consisting of:
  • the compounds of the invention o is 0. In one embodiment of the compounds of the invention o is 1. In one embodiment of the compounds of the invention o is 2. In one embodiment of the compounds of the invention o is 3. In one embodiment of the compounds of the invention o is 4.
  • Ar 1 is selected from the group consisting of:
  • R 11 is independently as defined above.
  • Ar 1 is selected from the group consisting of:
  • the compound is of the formula (II):
  • the group L may contain a plurality of heteroatoms in the normal chain. In one embodiment the group L has more than 1 heteroatom in the normal chain. In one embodiment L has only one heteroatom in the normal chain.
  • the total number of atoms in the normal chain may also vary. In one embodiment the total number of atoms in the normal chain of L is selected from the group consisting of 3, 4, 5, 6, 7, 8 and 9. In one specific embodiment the total number of atoms in the normal chain of L is 6. In another specific embodiment the total number of atoms in the normal chain of L is 7.
  • X 1 is a group of formula -(CH 2 ) m - wherein m is an integer selected from the group consisting of 1 , 2, 3, 4, and 5;
  • X 2 is an optionally substituted heteroalkyl group
  • R a and R b are each independently selected from the group consisting of
  • R a and R b may be joined such that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group.
  • R 1 , R 2 , R 9 , R 10 , R 11 , X 1 , X 2 , Y, j, k and o are as defined above,
  • X 1 is selected from the group consisting of:
  • X 1 is selected from the group consisting of:
  • X 1 is -CH 2 -.
  • X 1 is -(CH 2 J 2 -.
  • X 2 is selected from the group consisting of:
  • R 17 is H or alkyl
  • X 2 is selected from the group consisting of:
  • R 17 is H or alkyl
  • R 17 is H.
  • R 17 is C 1 -C 4 alkyl. In a specific embodiment R 17 is CH 3 .
  • X 2 is -CH 2 OCH 2 -.
  • X 2 is -CH 2 N(CH 3 )CH 2 -.
  • X 2 is -CH 2 O-.
  • R 2 is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylaikyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalky, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, arylamino, sulfonylamino, sulfinylamino, COOH, COR 3 , COOR 3 , CONHR 3 , NHCOR, NHCOOR
  • R 2 is selected from the group consisting of H, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, phenyl, hydroxy, methoxy, ethoxy, phenoxy, benzyloxy, amino, methylamino, ethylamino, propylamino, butylamino, pentylamino and hexylamino, each of which may be optionally substituted.
  • R 2 is selected from the group consisting of H, chloro, bromo, iodo, amino, methylamino, ethylamino, propylamino, butylamino, pentylamino and hexylamino, each of which may be optionally substituted.
  • R 2 is selected from the group consisting of H and alkyl.
  • R 2 is H or methyl
  • R 3 is selected from the group consisting of H, CrC 6 alkyl and acyl. In another embodiment R 3 is selected from the group consisting of H and C 1 -C 4 alkyl. In a specific embodiment R 3 is C 1 -C 4 alkyl.
  • R 5 is selected from the group consisting of C 1 -C 4 alkyl, heteroalkyl and acyl. In a specific embodiment R 5 is C 1 -C 4 alkyl.
  • R 6 is selected from the group consisting of a bond, C 1 - C 4 alkyl, heteroalkyl and acyl. In specific embodiment R 6 is C 1 -C 4 alkyl or a bond.
  • each R 9 is independently selected from the group consisting of H, halogen, amino, alkyl, haloalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted.
  • each R 9 is independently selected from the group consisting of H, hydroxyl, fluoro, amino, methoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may be optionally substituted.
  • each R 9 is H.
  • the compounds of the invention j is 0. In one embodiment of the compounds of the invention j is 1. In one embodiment of the compounds of the invention j is 2. In one embodiment of the compounds of the invention j is 3.
  • each R 10 is independently selected from the group consisting of H, halogen, amino, alkyl, haloalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted.
  • each R 10 is H.
  • k is 0. In one embodiment of the compounds of the invention o is 1. In one embodiment of the compounds of the invention k is 2.
  • each R 11 is independently selected from the group consisting of H, halogen, alkyl, amino, NR 3 R 4 , alkylsulfonyl, haloalkyl, heteroalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylsulfonyloxy, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted.
  • each R 11 is independently selected from the group 5 consisting of H, hydroxyl, methoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may be optionally substituted.
  • each R 11 is independently selected from the group consisting of H, NH 2 , alkoxy, heteroalkyl, heterocycloalkyl, 10 heterocycloalkylheteroalkyl, heteroarylheteroalkyl, and arylsulfonyloxy, each of which may be optionally substituted.
  • Y is a cyclopropyl group.
  • the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • the invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides a method of reducing the activity of one or more protein kinase(s) including exposing the one or more protein kinase(s) and/or co-factor(s) thereof to an effective amount of a compound of the invention.
  • the compounds disclosed herein may act directly and solely on the kinase molecule to reduce the biological activity. However, it is understood that the compounds may also act at least partially on co-factors that are involved in the phosphorylation process. For example, where the kinase is cyclin-dependent, a co- factor such as cyclinA is involved in the transfer of phosphate from ATP (also considered a co-factor in itself) to the substrate molecule.
  • co-factors include ionic species (such as zinc and calcium), lipids (such as phosphatidylserine), and diacylglycerols.
  • the one or more protein kinase(s) is a cyclin-dependent protein kinase.
  • the cyclin-dependent kinase is a Group I CMCG kinase.
  • the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.
  • the Group I CMCG kinase is CDK2 or a functional equivalent thereof.
  • the one or more protein kinase(s) is a protein tyrosine kinase.
  • the protein tyrosine kinase is a Group VII protein tyrosine kinase.
  • the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1 , JAK2 and HOP or a functional equivalent thereof.
  • the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.
  • the JAK2 includes a recurrent unique acquired clonal mutation.
  • This mutation is observed in a majority of polycythemia vera (PV) patients and a significant proportion of patients with other myeloproliferative disorders, including, essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF).
  • the mutation is a valine to phenylalanine substitution at position 617 (V617F).
  • V617F valine to phenylalanine substitution at position 617
  • the JAK2 mutation is somatic and occurs at the level of a hematopoietic stem cell.
  • myeloid cells i.e., bone marrow cells, granulocytes, platelets and erythroblasts derived from CD34+ cells, but not in T cells.
  • mutant JAK2 was found in hematopoietic colonies derived from hematopoietic progenitor cells. Applicant has demonstrated that kinase inhibitors described herein are capable of inhibiting the activity of wild type and mutant JAK2.
  • the protein tyrosine kinase is a Group XIV protein tyrosine kinase.
  • the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1 R, c-kit, Flk2, FLT1 , FLT2, FLT3 and FLT4 or a functional equivalent thereof.
  • the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.
  • the FLT3 kinase includes a mutation.
  • FLT3 mutations are important in the initiation or maintenance of AML in some patients.
  • Activating mutations of FLT3 result in constitutive activation of FLT3 tyrosine kinase activity and can transform factor-dependent hematopoietic cells as evidenced by conversion to factor-independent growth and formation of tumours in immunodeficient mice.
  • retroviral transduction of primary murine bone marrow with an AML patient-derived FLT3 ITD (internal tandem duplication) cDNA results in a lethal myeloproliferative syndrome.
  • the FLT3 includes an internal tandem duplication.
  • the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.
  • exposing the one or more protein kinase(s) to the compound includes administering the compound to a mammal containing the one or more protein kinase(s).
  • the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, .FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.
  • the invention provides the use of a compound of the invention to reducing the activity of one or more protein kinase(s).
  • the one or more protein kinase(s) is a cyclin-dependent protein kinase.
  • the cyclin-dependent kinase is a Group I
  • the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R and functional equivalents thereof.
  • the Group I is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc
  • 3S CMCG kinase is CDK2 or a functional equivalent thereof.
  • the one or more protein kinase(s) is a protein tyrosine kinase.
  • the protein tyrosine kinase is a Group VII protein tyrosine kinase.
  • the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1 , JAK2 and HOP or a functional equivalent thereof.
  • the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.
  • the JAK2 includes a V to F mutation at position 617.
  • the protein tyrosine kinase is a Group XIV protein tyrosine kinase.
  • the Group XlV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1 R, c-kit, Flk2,
  • FLT1 , FLT2, FLT3 and FLT4 or a functional equivalent thereof.
  • the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.
  • FLT3 includes an internal tandem duplication.
  • the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.
  • the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.
  • the invention provides a method of treating or preventing a condition in a mammal in which reducing the activity of one or more protein kinase(s) and/or co-factor(s) thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of a therapeutically effective amount of a compound of the invention.
  • the one or more protein kinase(s) is a cyclin-dependent protein kinase.
  • the cyclin-dependent kinase is a Group I CMCG kinase.
  • the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9,
  • PCTAIRE1 PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK,
  • Group I CMCG kinase is CDK2 or a functional equivalent thereof.
  • the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.
  • the one or more protein kinase(s) is a protein tyrosine kinase.
  • the protein tyrosine kinase is a
  • Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1 , JAK2 and HOP or a functional equivalent thereof.
  • the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.
  • the JAK2 includes a V to F mutation at position 617.
  • the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T- cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.
  • Myeloproliferative disorders chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelo
  • the protein tyrosine kinase is a Group XIV protein tyrosine kinase.
  • the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1 R, c-kit, FIk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof.
  • the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.
  • FLT3 includes an internal tandem duplication.
  • the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.
  • the condition is selected from the group consisting of acute myeloid leukemia, acute promyelocyte leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, myeloproliferative disorders, and chronic myelomonocytic leukemia.
  • the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for treating a condition in an animal in which reducing the activity of one or more protein kinase(s) can prevent, inhibit or ameliorate the pathology or symptomology of the condition.
  • the one or more protein kinase(s) is a cyclin-dependent protein kinase.
  • the cyclin-dependent kinase is a Group I CMCG kinase.
  • the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.
  • the Group I CMCG kinase is CDK2 or a functional equivalent thereof.
  • the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.
  • the one or more protein kinase(s) is a protein tyrosine kinase.
  • the protein tyrosine kinase is a Group VII protein tyrosine kinase.
  • the Group VIl protein tyrosine kinase is selected from the group consisting of TYK2, JAK1 , JAK2 and HOP or a functional equivalent thereof.
  • the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.
  • the JAK2 includes a V to F mutation at position 617.
  • the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T- cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.
  • Myeloproliferative disorders chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelo
  • the protein tyrosine kinase is a Group XIV protein tyrosine kinase.
  • the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof.
  • the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.
  • FLT3 includes an internal tandem duplication.
  • the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.
  • the condition is selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia
  • I 5 promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, myeloproliferative disorders, and chronic myelomonocytic leukemia.
  • the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.
  • the invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.
  • the kinase-related disorder is a proliferative disorder.
  • the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic
  • leukemia acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplasia syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.
  • the proliferative disorder is a myeloproliferative disorder.
  • the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis.
  • the proliferative disorder is cancer.
  • the cancer is a solid tumour.
  • the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.
  • the cancer is a hematological cancer.
  • the hematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B- cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.
  • the kinase-related disorder is a cardiovascular disorder.
  • the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis.
  • the kinase-related disorder is a neurodegenerative disorder.
  • the neurodegenerative disorder is Alzheimer's disease.
  • the invention provides a method of treating or preventing a kinase-related disorder including administration of a therapeutically effective amount of a compound of the invention to a patient in need thereof.
  • the kinase-related disorder is a proliferative disorder.
  • the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast,
  • the proliferative disorder is a myeloproliferative disorder.
  • the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis.
  • the proliferative disorder is cancer.
  • the cancer is a solid tumour.
  • the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.
  • the cancer is a hematological cancer.
  • the hematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B- cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.
  • the kinase-related disorder is a cardiovascular disorder.
  • the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis.
  • the kinase-related disorder is a neurodegenerative disorder.
  • the neurodegenerative disorder is Alzheimer's disease.
  • the term "optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 14 alkyl, more preferably C 1 -C 10 alkyl, most preferably C 1 -C 6 unless otherwise noted. Examples of suitable straight and branched
  • C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t- butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • “Mono-alkylamino” means a -NH-Alkyl group, in which alkyl is as defined above.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group.
  • acyl means an alkyl-CO- group in which the alkyl group is as described herein.
  • examples of acyl include acetyl and benzoyl.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • the group may be a terminal group or a bridging group.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • Alkoxy refers to an -O-alkyl group in which alkyl is defined herein.
  • the alkoxy is a C r C 6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • Alkenyloxy refers to an -O- alkenyl group in which alkenyl is as defined herein.
  • Preferred alkenyloxy groups are C 1 -C 6 alkenyloxy groups.
  • the group may be a terminal group or a bridging group.
  • Alkynyloxy refers to an -O-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups. The group may be a terminal group or a bridging group.
  • Alkoxycarbonyl refers to an -C(O)-O-alkyl group in which alkyl is as defined herein.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group.
  • Alkyisulfinyl means a -S(O)-alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group.
  • Alkylsulfonyl refers to a -S(O) 2 -alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkylaminocarbonyl refers to an alkylamino-carbonyl group in which alkylamino is as defined above. The group may be a terminal group or a bridging group.
  • Cycloalkyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
  • the group may be a 10 terminal group or a bridging group.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include I 5 cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • the group may be a terminal group or a bridging group.
  • alkyl and cycloalkyl substituents also applies to the 20 alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and 2S alkyl moieties are as previously described.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Heterocycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • Examples of 35 suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkenyl refers to a heterocycloalkyl as described above but 5 containing at least one double bond.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • ExemplaryQ heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl,
  • the group may be a terminal group or a bridging group.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferablys having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • the group may be a terminal group or a bridging group.
  • reference to the normal chain when used in the context of a bridging groupQ refers to the direct chain of atoms linking the two terminal positions of the bridging group.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms 5 that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5 . 7 cycloalkyl or C 5 . 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a0 bridging group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described.
  • Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group.
  • 5 "Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci. 5 alkyl moiety.
  • Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. The group may be a terminal group or a bridging group.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1 H-indazoie, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the group may be a terminal group or a bridging group.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydratedC forms.
  • the compounds of the various embodiments include pharmaceutically acceptable salts, prodrugs, N-oxides and active metabolites of such compounds, and pharmaceutically acceptable salts of such5 metabolites.
  • SuitableQ pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic,5 glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • organic salts are: ammonium0 salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts5 may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • "Prodrug” means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I).
  • an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, isethionates, di-p- toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p- toluenesulphonates, cyclohexylsulphamates and quinates.
  • ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987).
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • normal chain refers to the direct chain joining the two end of a linking moiety.
  • an alkoxyalkyl group is a heteroalkyl group containing a heteroatom in the normal chain (in this case an oxygen atom).
  • An amide group is also a heteroalkyl group but it does not contain an oxygen atom in the normal chain (it has a nitrogen atom in the normal chain).
  • kinases may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given kinase isoform is different to the protoypical kinase, the molecule maintains biological activity as a protein kinase. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription. Many kinases (including JAK2 and CDK2) have isoforms that arise from transcript variation. It is also known that FLT3 has an isoform that is the result of exon-skipping. Other functional equivalents include kinases having altered post-translational modification such as glycosylation. Specific compounds of the invention include the following:
  • the compounds of the invention have the ability to reduce the activity of certain compounds
  • the ability to reduce kinase activity may be a result of the compounds of the invention acting directly and solely on the kinase molecule to reduce biological activity. However, it is understood that the compounds may also act at least partially on co-factors of the kinase in question that are involved in the phosphorylation process.
  • a co-factor such as cyclinA is
  • kinase co-factors include ionic species (such as zinc and calcium), lipids (such as phosphatidylserine), and diacylglycerols.
  • the compounds may have activity against a wide range of protein kinases.
  • CMCG kinases One suitable family of protein kinases are the cyclin-dependent protein kinases.
  • An example of the cyclin-dependent kinases is the Group I CMCG kinases.
  • Group I CMCG kinases include CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAI RE 1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2,
  • CMCG kinase of particular interest is CDK2.
  • protein tyrosine kinases Another family of protein kinases are protein tyrosine kinases.
  • An example of protein tyrosine kinases is a Group VII protein tyrosine kinase.
  • Examples of Group VII protein tyrosine kinase include TYK2, JAK1, JAK2 and HOP.
  • JAK2 protein kinase may include a recurrent unique acquired clonal mutation. As stated previously this mutation is observed in a majority of polycythemia vera (PV) patients and a significant proportion of patients with other myeloproliferative disorders, including, essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF).
  • PV polycythemia vera
  • IMF chronic idiopathic myelofibrosis
  • the 30 mutation is a valine to phenylalanine substitution at position 617 (V617F).
  • the incidence of this mutation in PV patients is very high (around 78% of patients).
  • Another example of protein tyrosine kinases is the Group XIV protein tyrosine kinases.
  • Examples of the Group XIV protein tyrosine kinase include PDGFR-b, PDGFR-a, CSF1 R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4.
  • a Group XIV protein tyrosine kinase of particular interest is FLT3.
  • the FLT3 kinase may include a mutation.
  • FLT3 mutations are important in the initiation or maintenance of AML in some patients.
  • Activating mutations of FLT3 result in constitutive activation of FLT3 tyrosine kinase activity and can transform factor-dependent hematopoietic cells as evidenced by conversion to factor-independent growth and formation of tumours in immunodeficient
  • kinase inhibitors described herein are capable of inhibiting FLT3 including an ITD where there is a duplication of amino acids VDFREYEYDH at amino acid position 592-601.
  • the FLT3 includes an internal tandem
  • the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.
  • the reduction of activity of the protein kinase may be carried out in any of a number of well known ways in the art. For example if reducing the activity of the 2S protein kinase in vitro is desired an appropriate amount of the compound of the invention may be added to a solution containing the kinase. In circumstances where it is desired to reduce the activity of the kinase in a mammal the reducting the activity of the kinase typically involves administering the compound to a mammal containing the kinase.
  • the compounds of the invention may find a multiple number of applications in which their ability to reduce the activity protein kinases of the type mentioned above can be utilised.
  • the compounds may be used to reduce the activity of protein kinases.
  • the compounds may also be used in treating or
  • Examples of conditions that may be treated by reducing the activity of protein kinases include prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.
  • Other conditions that may be treated by reducing the activity of protein kinases include conditions such as Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T- cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.
  • Myeloproliferative disorders chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), mye
  • ⁇ myeloid leukemia acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, myeloproliferative disorders, and chronic myelomonocytic leukemia.
  • the compounds of the invention may also be used the preparation of a medicament for treating a condition in an animal in which reducing the activity of a protein kinase can prevent, inhibit or ameliorate the pathology or symptomology of the condition.
  • the compounds of the invention may also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.
  • a kinase-related disorder is a proliferative disorder.
  • the proliferative disorder is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast
  • the cancer may be a solid tumour.
  • the solid tumour may be a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.
  • hematological cancer is a hematological cancer.
  • hematological cancers include acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T- cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.
  • cardiovascular disorder Another kinase-related disorder is a cardiovascular disorder.
  • cardiovascular disorder include congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis.
  • Another kinase-related disorder is a neurodegenerative disorder.
  • the neurodegenerative disorder may be Alzheimer's disease.
  • the compounds disclosed have the ability to be used in the treatment of proliferative disorders.
  • An example of such a disorder is cancer.
  • Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating ceils, e.g. cancerous tumours, than to normal cells.
  • 'cancer' is a general term intended to encompass the vast number of conditions that are characterised by uncontrolled abnormal growth of cells.
  • the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasma, gastrointestinal cancers including stomach cancer, oesophageal cancer, small intestine cancer, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostrate cancer, gynaecological cancers including cervical cancer,
  • Exemplary cancers that may be treated by compounds of this invention include Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic my ⁇ lomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as
  • Exemplary cancers that may be treated by compounds of this invention include but are not limited to bladder cancer, breast cancer, cervical cancer, colorectal cancer, colon cancer, gastric cancer, neuroblastoma, retinoblastoma, ovarian cancer, pancreatic cancer, leukemia, lymphoma, prostate cancer and lung cancer.
  • Exemplary cancers that may be treated by compounds of this invention are colon cancer, colorectal cancer, pancreatic cancer and cervical cancer.
  • B-cell lymphoma e.g. Burkitt's lymphoma
  • leukemia e.g. acute promyelocytic leukemia, erythroleukemia
  • CCL cutaneous T-cell lymphoma
  • peripheral T-cell lymphoma e.g., hematologic malignancies.
  • the compounds of the invention will also be useful in treating various myeloproliferative disorders which may include polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis.
  • the compounds of the invention can be administered in any form or mode which makes the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the compounds of the invention while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pack or kit can be found a container having a unit dosage of the agent (s).
  • the kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
  • single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s).
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of the invention may be used or administered in combination with one or more additional drug (s) that are anti-cancer drugs and/or procedures (e.g. surgery, radiotherapy) for the treatment of the disorder/diseases mentioned.
  • additional drug s
  • the components can be administered in the same formulation or in separate formulations.
  • the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
  • the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, 5 or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the compounds can be I 0 incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • the amount of compound administered will preferably treat and reduce or alleviate the condition.
  • a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • R 1 , R z , R a , R", R 8 , R 10 , Ar 1 , X 1 and X z are as defined above;
  • the methods of the invention involve cyciisation of a diene compound of the formula described above which can be produced using procedures well known in the art or by the ones detailed below.
  • the exact choice of method used to produce the diene for cyciisation will depend upon the diene selected and methods of synthesis of the dienes are within the skill of the skilled addressee.
  • the compound may be reacted in its free form although it is typical that it is first converted to a suitable acid salt. Acid salts are well known as is discussed above with the hydrochloride salt and the trifluoroacetic acid salt being found to be particularly suitable.
  • Suitable ruthenium based catalysts include well-known ruthenium based catalysts used in olefin metathesis reactions, such as Grubb's catalyst (first and second generation), Hoveyda's catalyst (first and second generation) and Nolan's catalyst. In each instance it may be necessary to make appropriate adjustments to the reaction conditions to allow ring-closing to occur.
  • the catalyst is Grubb's second generation catalyst.
  • Ruthenium-based catalysts useful for the metathesis cyclisation step are all known catalysts that may be obtained by known synthetic techniques. For example, see the following references for examples of suitable ruthenium-based catalysts:
  • the ratio of diene to catalyst may vary widely as would be clear to a skilled addressee in the art. Nevertheless a suitable ratio is such that the ratio is from 100:1 to 1 :1. A particularly suitable ratio is from 20:1 to 2:1. A more specific ratio is from 20:1 to 10:1.
  • the ring closing metathesis step may be carried out over a broad temperature range with the range of temperatures typically being chosen based upon the diene being cyclised, the time of reaction, and the catalyst chosen. In one embodiment the reaction is carried out at a temperature of from 20 to 200 0 C. In another embodiment the temperature is from 30 to 12O 0 C. In another embodiment the temperature is in the range of from 30 to 5O 0 C. In a specific embodiment the temperature is 4O 0 C.
  • the ring-closing step may be carried out in the presence of any suitable non-interfering solvent that does not inhibit with the reaction.
  • suitable solvents include alkanes, such as n-pentane, n-hexane or n-heptane, aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane or dichloroethane, ether solvents, such as tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether or dioxane and methyl alcohol.
  • An example of a specific solvent is dich
  • the ring closing metathesis step may be carried out over a wide range of diene dilutions in the solvent with the ratio of diene to diluent typically being in the range of from 1:4000 by weight to 1:25 by weight. In another embodiment the ratio is from 1 :200 by weight to 1 :50 by weight.
  • the cycloalkylation step may be carried out using any cycloalkylation agent well known in the art.
  • An example of a suitable cycloalkylation agent is a cyclopropanation agent.
  • Examples of cyclopropanation agents are well known in the art and include diazomethane and carbenes. The use of these agents are well known and it is within the scope of a skilled addressee to be able to carry out reactions of this type.
  • the cycloalkylation reactions are typically carried out in a non-interfering solvent such as acetonitrile, ethyl acetate/hexane admixtures, ethyl acetate, tetrahydrofuran, ether, toluene, acetone, carbon tetrachloride, and dichloromethane or mixtures thereof.
  • a non-interfering solvent such as acetonitrile, ethyl acetate/hexane admixtures, ethyl acetate, tetrahydrofuran, ether, toluene, acetone, carbon tetrachloride, and dichloromethane or mixtures thereof.
  • a range of solvents would in fact be suitable for use in conducting the reaction of the invention. In any specific case an optimum solvent can be identified by trial and experiment using the above solvents and others.
  • the agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
  • THF Tetrahydrofuran
  • DMF N,N-dimethylformamide
  • the reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks are fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and/or heat-dried. Analytical thin-layer chromatography was performed on glass-backed silica gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v/v). The reactions were assayed by TLC and terminated as judged by the consumption of starting material.
  • the TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodine chamber. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography [Still et al, J.
  • NMR spectra were recorded on a Bruker instrument operating at 400 MHz, and 13 C-NMR spectra were recorded operating at 100 MHz. NMR spectra are obtained as CDCI 3 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
  • Mass spectra were obtained using LC/MS either in ESI or APCl. All melting points are uncorrected.
  • Scheme 1 is a general synthetic scheme outlining the procedure for the preparation of Examples 1 to 8. This general procedure can be modified to produce other compounds of the invention with different substitutions by appropriate modification of the reagents and starting materials used. A skilled addressee would readily be able to make these changes. Scheme 1 :
  • Scheme 2 is a general synthetic scheme outlining the procedure for the preparation of Examples 9 and 10. This general procedure can be modified to produce other compounds of the invention with different substitutions by appropriate modification of the reagents and starting materials used. A skilled addressee would readily be able to make these changes.
  • Scheme 3 outlines a general procedure for the preparation of aniline V.
  • the nitro- aldehyde (Xl) is reduced with sodium borohydride to give alcohol (XII), which is further alkylated the alcohol with allyl bromide.
  • the nitro group of the nitro-alkene is then reduced by a reducing agent (e.g., SnCI 2 or Fe) to afford aniline (V).
  • a reducing agent e.g., SnCI 2 or Fe
  • Scheme 4 is a general synthetic scheme for the preparation of aniline (XV), a subtype of (V).
  • the nitro-phenol (XIII) is alkylated to give nitro-alkene (XIV) 1 which is further reacted with a reducing agent to afford aniline (XV).
  • aniline (XV) is finally converted to examples12 and 22 via intermediates (IV) and (Vl).
  • Scheme 5 is a general synthetic scheme for the preparation of aniline (XIX), a subtype of aniline (V).
  • the nitro-aniline (XVI) couples with an acid to form amide (XVII).
  • the phenol group of (XVII) is alkylated with bromide to give nitro-alkene (XVIII), which is further reduced to aniline (XIX) by reacting with a reducing agent.
  • examples 23 and 24 are produced from aniline (XIX).
  • Scheme 6 is a general synthetic scheme outlining the procedure for the preparation of examples 13,14,15,18,19, 20, and 21. It provides an alternative synthetic route to Scheme 1 for forming a cyclic ring or cyclic alkene.
  • the alcohol (XX) is alkylated with a dibromide to provide ally bromide (XXI), which is further reacted with an inole- pyrimidine to form the indole-alkene (XXII).
  • the nitro group is reduced and the resultant aniline reacts with chloropyrimidine moiety via intra-molecular displacement to afford the cyclic alkene (XXIII).
  • the chloro at side chain is further functionalized with a variety of amines to produce the final cyclic alkene amines (XXIV).
  • This general procedure can be modified to produce other compounds of the invention with different substitutions by appropriate modification of the reagents and starting materials used. A skilled addressee would readily be able to make these changes.
  • Scheme 7 is a general synthetic scheme outlining the procedure for the preparation of aniline (XXVIII), a subtype of aniline (V).
  • the dinitrobenzyl alcohol (XXV) is alkylated to give (XXVI), the nitro groups are reduced to aniline (XXVII), which is protected by Fmoc-CI to afford (XXVIII).
  • aniline (XXVIII) is converted to cyclic alkene (XXX) via intermediate (XXIX). Removal of Fomc protecting group of (XXIX) furnishes example 11.
  • Scheme 8 is a general synthetic scheme for the preparation of aniline (XXXIV), a subtype of aniline (V). Displacement of chloro of (XXXI) affords nitro-aniline (XXXII), which is further reduced to alcohol (XXXIII). The alcohol is then alkylated and reduced to form aniline (XXXIV), which is used to produce examples'! 6 and 17.
  • Example 1 was obtained by re-crystallisation with EA. HPLC purity at 254nm: 99%; LC-MS (ESI positive mode) m/z 482 ([M+H] + ).
  • 1 H NMR (DMSO-d 6 ) ⁇ 9.66 (s, 1 H), 8.53 (m, 1 H), 8.47 (m, 1H), 8.42 (m, 1 H), 7.72 (m, 1 H), 7.66 (m, 1 H), 7.60 (m, 1 H), 7.41 (m, 1 H), 7.12 (m, 1 H), 7.04 (m, 1 H), 6.53 (m, 1 H), 5.68 (m, 1 H), 5.55 (m, 1H), 5.20 (m, 2H), 4.73 (m, 2H), 4.27-4.31 (m, 4H), 3.62-3.68 (m, 4H), 3.18 (m, 2H), 2.06 (m, 2H),
  • Aniline (VIII) is obtained from nitro-aldehyde (Xl) by reductive amination with allyl amine followed by SnCI 2 reduction of the nitro function.
  • the recombinant enzymes (CDK2/CyclinA; FLT3, JAK2 and JAK2 V617F) were purchased from Invitrogen (Cat # PV3267, 3182, 4210 and 4347 respectively). All assays were carried out in 384-well white microtiter plates using the PKLight assay system from Cambrex (East rutherford, New Jersey). This assay platform is essentially a luminometric assay for the detection of ATP in the reaction using a luciferase-coupled reaction.
  • the reaction mixture consisted of the following components in 25 ⁇ L assay buffer (50 mM Hepes pH 7.5, 10 mM MgCI 2 , 5 mM MnCI 2 , 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 ⁇ g/mL of CDK2/Cyclin A complex, 0.5 ⁇ M of RbING substrate (Invitrogen, Cat # PV2939) and 0.5 ⁇ M of ATP. The compounds were tested at 8 concentrations prepared from 4-fold serial dilution starting at 10 ⁇ M. The reaction was incubated at room temperature for 2 hr.
  • PKLight ATP detection reagent 13 ⁇ L of PKLight ATP detection reagent was added and the reaction was incubated for 10 min. Luminescence signals were detected on a multi-label plate reader (Victor 2 V 1420, Perkin-Elmer). The other kinase assays were identical except for the following differences in reagents.
  • the reaction contained 2.0 ⁇ g/mL FLT3 enzyme, 5 ⁇ M of poly(GIu,Tyr) substrate (Sigma, Cat # P0275) and 4 ⁇ M of ATP.
  • the reaction contained 0.6 ⁇ g/mL of JAK2 enzyme, 2 ⁇ M of poly(Glu ,Ala,Tyr) substrate (Sigma, Cat # P3899) and 0.2 ⁇ M of ATP.
  • the reaction contained 8.0 ⁇ g/mL of JAK2 mutant enzyme, 2 ⁇ M of poly(Glu,Ala,Tyr) substrate (Sigma, Cat # P3899) and 0.2 ⁇ M of ATP.
  • the analytical software, Prism 4.0 GraphPad Software Pte Ltd was used to generate IC 50 values from the data.
  • IC 50 is defined as the concentration of compound required for 50% inhibition of kinase enzyme activity. IC 50 values are shown below in Table 2.
  • NT not tested IC 50 ⁇ 1 ⁇ M +++ 1 ⁇ M ⁇ IC 50 ⁇ 5 ⁇ M ++ IC 50 >5 ⁇ M +
  • Human cancer cell lines HL60 acute myeloid leukemia cell line
  • HEL92.1.7 erythroleukemia cell line
  • MV4-11 acute myeloid leukemia cell line
  • HEL92.1.7 and MV4-11 cells were seeded at 6000 cells per well while HL60 cells were seeded at 8000 cells per well in 96 well plate.
  • the plates were incubated at 37 0 C, 5% CO 2 , for 24 h. Cells were treated with compounds at various concentrations for 96 h.
  • Gl 50 is defined as the concentration of compound required for 50% inhibition of cell growth.
  • the compounds of this invention inhibited cell proliferation as shown in Table 2 below. Unit is in micromolar. The data indicated that the compounds of this invention are active in the inhibition of tumour cell growth.

Abstract

La présente invention concerne des composés de pyrimidine de formule (I) utiles en tant qu'agents antiprolifératifs. Plus particulièrement, la présente invention concerne des composés de pyrimidine substitués par indole, leur procédé de préparation, des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés dans le traitement de troubles prolifératifs. Ces composés peuvent être utiles en tant que médicaments pour le traitement de plusieurs troubles prolifératifs, y compris des tumeurs et des cancers.
PCT/SG2007/000392 2006-11-15 2007-11-14 Pyrimidines substituées par indole, et leur utilisation dans le traitement d'un cancer WO2008060248A1 (fr)

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