MX2008006432A

MX2008006432A - Oxygen linked pyrimidine derivatives

Info

Publication number: MX2008006432A
Application number: MXMX/A/2008/006432A
Authority: MX
Inventors: T Sun Eric; Poulsen Anders; Blanchard Stephanie; Hsia Angeline Lee Cheng; Kumar Mysore Nagaraj Harish; Ling Evelyn Tan Yee; Deodaunia William Anthony
Original assignee: Blanchard Stephanie; Hsia Angeline Lee Cheng; Kumar Mysore Nagaraj Harish; Poulsen Anders; S*Bio Pte Ltd; T Sun Eric; Ling Evelyn Tan Yee; Deodaunia William Anthony
Priority date: 2005-11-16
Filing date: 2008-05-16
Publication date: 2008-09-26

Abstract

The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and 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 as well as other disorders or conditions related to or associated with kinases.

Description

DERIVATIVES OF PYRIMIDINE LINKED WITH OXYGEN FIELD OF THE INVENTION The present invention relates to pyrimidine compounds which may be useful as antiproliferative agents. More particularly, the present invention relates to pyrimidine compounds bound to oxygen and substituted, to methods for their preparation, to pharmaceutical compositions containing said compounds and to 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 tumors and cancers as well as other conditions or disorders associated with kinases.

BACKGROUND OF THE INVENTION Proliferative disorders such as cancer are characterized by the uncontrolled growth of cells within the body. As such, proliferative disorders generally involve an abnormality in the control of growth and / or cell division that leads to tumor formation and ultimately death. Without wishing to be Limited to the theory, it is believed that this is caused by the alteration of the routes that regulate cell growth and division in cancer cells. The alteration is such that the effects of these normal regulatory mechanisms to control cell growth and division fail or are avoided. Uncontrolled cell growth and / or division eventually becomes fatal to the patient because successive rounds of cell mutations typically lead to cancer cells having a selective advantage over healthy normal cells in the patient's body. which leads cancer cells to predominate in the patient's cell mass. Cancer cells then typically undergo metastases to colonize other tissues or parts of the body other than the originating part of the cancer cell which leads to secondary tumors that eventually lead to organ failure and death of the patient. It is the difficulty in controlling the rapid growth and cell division that are characteristic of cancer cells, which makes it difficult to obtain effective chemotherapeutic strategies. A number of traditional treatments for proliferative disorders such as cancer seek to take advantage of their higher proliferative capacity and so both of its higher sensitivity towards DNA damage. The treatments that have been used include ionizing radiation (rays and X-rays and the like) as well as cytotoxic agents such as bleomycin, cis-platinum, vinblastine, cyclophosphamide, 5'-fluorouracil and methotrexate. All these treatments are based on causing DNA damage and destabilization of the chromosomal structure which eventually leads to the death of cancer cells. The problem with many of these strategies is that they are non-selective for cancer cells and healthy cells can, and are often adversely affected by the treatment. This is hardly surprising given that the cellular mechanisms targeted by these strategies occur in healthy cells as well as cancer cells (although typically at slower speeds) and only serve to highlight the difficulty in achieving successful cancer treatment in the patient. without causing irreparable damage to healthy cells. As such with many of these treatments there can be devastating side effects which can not only significantly reduce the patient's short-term quality of life but may also have long-term harm to the patient's health if they survive the patient's health. attack of cancer.

Although some of the above problems have been substantially overcome by the development of selective anti-cancer agents (such as tamoxifen) the effectiveness of all chemotherapeutic agents is subject to the development of drug resistance. from the cancer cells in the patient. The development of drug resistance in a patient's cancer cells tends to be class-specific and therefore if a patient's cancer cells develop resistance to drugs for a class of anticancer drugs then all compounds within that class they typically become ineffective in the subsequent treatment of said patient. Therefore in the improvement of clinical outcomes for patients the identification of alternative chemotherapeutic agents is essential to provide the oncologist with an arsenal of drugs that can be used in any given situation. The development of different classes of therapeutic agents is therefore important because it can help prevent the development of drug resistance and can also be used in combination therapies. Such combination therapies typically involve the use of anti-cancer drugs with different cellular properties and targets which in turn tend to increase the overall effectiveness of any chosen chemotherapy regimen and limit the possibility of drug resistance developing in the patient. One of the greatest advances in cancer research has been the clinical validation of molecularly targeted drugs that inhibit the activity of protein kinases. The small molecule kinase inhibitors currently approved for indications in oncology 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 tumors, malignant hematological diseases, myeloproliferative disorders and non-malignant proliferative disorders such as keloids. Janus kinases (JAK) are a family of cytoplasmic tyrosine kinases consisting of JAK1, JAK2, JAK3 and Tyk2. These 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 Transducer of Signal and Activator of Transcription (STAT by its abbreviations in English). The routes of JAK-STAT, through the appropriate actions of the ligands, regulate physiological processes important such as the immune response to viruses, erythropoiesis, lactation, lipid homeostasis, etc. However, dysfunctional signaling caused by a multitude of factors results in pathophysiological conditions such as allergies, asthma, rheumatoid arthritis, severe combined immune deficiency, malignant hematological diseases, etc. In particular, mutations in JAK2 have been associated with myeloproliferative disorders (including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis) and a wide range of leukemias and lymphomas [Percy MJ et al, Hema tol. Oncol. , 2005, 23, 91-93). As an important aspect, myeloproliferative disorders belong to an area of unmet medical need in which some treatment modalities have not been updated over the past decades [Schafer AI, Blood, 2006, 107, 4214-4222] . Myeloproliferative disorders (MPDs) belong to a group of malignant hematological diseases that arise from the clonal expansion of mutated progenitor stem cells in the bone marrow. The association of an MPD, chronic myeloid leukemia, with the Philadelphia chromosome has been well documented. Philadelphia-negative MPDs include Essential Thrombocytopenia (ET), Polycythemia Vera (PV) and Chronic Idiopathic myelofibrosis (MF). Currently there is no effective treatment available. The recent discovery that a single somatic mutation acquired in JAK2 appears to be responsible for many of the characteristics of these MPDs promises to impact the diagnosis and treatment of patients with these disorders and drive further research into the origins of deregulated cell growth and function. Until recently, it has been considered that most of the MPDs are rare or orphan diseases but the studies that are being carried out suggest a much higher predominance. Essential Thrombocytopenia is a chronic MPD characterized by an increased number of platelets in circulation, megakaryocytic hyperplasia of deep marrow, splenomegaly and a clinical course accentuated by hemorrhagic or thrombotic episodes or both. Current treatment options include aspirin at low doses, or agents that reduce the number of platelets such as anagrelide, interferon or hydroxyurea. These treatments have serious side effects that compromise the quality of life of patients. Polycythemia Vera is a chronic progressive MPD characterized by a high hematocrit, an increase in the mass of red blood cells, and usually by an elevated white blood cell count, a high platelet count and a enlarged spleen The most common cause of morbidity and mortality is the predisposition of patients with PV to develop arterial and venous thromboses that endanger life. Treatment options include: phlebotomy with low-dose aspirin or myelosuppressive therapy options such as hydroxyurea, interferon, or anagrelide. Again, these treatments are not ideal because of the serious side effects. Chronic idiopathic myelofibrosis (MF) is a chronic malignant hematologic disorder characterized by an enlarged spleen, variable degrees of anemia and low platelet counts, red blood cells in the peripheral blood that look like tears, the appearance of small numbers of red blood cells and immature nucleated leukocytes in the blood, variable degrees of fibrosis of the marrow cavity (myelofibrosis) and the presence of marrow cells outside the marrow cavity (extramedullary hematopoiesis or myeloid metaplasia). The current treatment is aimed at the relief of the constitutive symptoms, anemia and symptomatic splenomegaly. Treatment options include hydroxyurea, interferon, thalidomide with prednisone, and allogeneic stem cell transplantation. MF has the worst prognosis among Philadelphia-negative MPDs and represents an area of greatest unmet medical need.

In addition, due to its participation in the angiotensin II signaling pathway, JAK2 is also implicated in the etiology of cardiovascular diseases such as congestive heart failure and pulmonary hypertension [Berk BC et al, Circ. Res, 1997, 80, 607-616]. Likewise, a putative role for JAK2 has been demonstrated in the pathogenesis of keloid and may constitute a new strategy for keloid management [Lim CP et al, Oncogene, 2006, 25, 5416-5425]. Even another potential application for JAK2 inhibitors lies in the treatment of retinal diseases because JAK2 inhibition was found to offer protective effects in photoreceptors in a mouse retinal degeneration model [Samardzija M et al, FASEB J ., 2006, 10, 1096]. A family of Class III receptor tyrosine kinases (RTK), including c-Fms, c-Kit, tyrosine kinase receptor type fms 3 (FLT3), and platelet-derived growth factor receptors (PDGFRa and β), plays an important role in the maintenance, growth and development of hematopoietic and non-hematopoietic cells. It is known that the over-expression and activating mutations of these RTKs are involved in the pathophysiology of various human cancers of both solid and hematological origins [Hannah AL, Curr. Mol. Med., 2005, 5, 625- 642]. 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 coding sequence of D835 have been discovered [Parcells BW et al, Stem Cells, 2006, 24, 1174-1184]. FLT3 mutations are the most frequent genetic alterations reported in acute myeloid leukemia (AML) and are implicated in the autonomic proliferation signaling pathway and blocking differentiation in leukemia cells [Tickenbrock L et al, Expert Opin. Emerging Drugs, 2006, 11, 1-13]. Several clinical studies have confirmed that FLT3 / ITD is strongly associated with a poor prognosis. Because high-dose chemotherapy and stem cell transplantation can not overcome the adverse effects of FLT3 mutations, the development of FLT3 kinase inhibitors could produce a more effective therapeutic strategy for leukemia therapy. The cyclin-dependent kinases (CDKs) are serine-threonine kinases that play important roles in cell cycle control (CDK1, 2, 4 and 6), initiation of transcription (CDK7 and 9), and neuronal function (CDK5) [ Knockaert M et al, Trends Pharmacol. Sci. , 2002, 23, 417-425]. Aberrations have been observed in the cycle CDKs cell and its cyclin partners in various types of tumors, including those of breast, colon, liver and brain tissue [Shapiro Gl, J. Clin. Oncol. , 2006, 24, 1770-1783]. It is believed that the pharmacological inhibition of CDK1, 2, 4, 6 and / or 9 can provide a new therapeutic option for various cancer patients. In particular, it has recently been shown that simultaneous inhibition of CDK1, 2 and 9 results in increased apoptotic annihilation of lung cancer (H1299) and osteosarcoma (U20S) cells, as compared to single CDK inhibition alone [ Cai D et al, Cancer Res, 2006, 66, 9270-9280]. Accordingly, compounds that are kinase inhibitors have the potential to satisfy the need to provide additional biologically active compounds that could be expected to have useful pharmaceutical properties, improved in the treatment of kinase-related conditions or disorders such as cancer and other proliferative disorders.

SUMMARY OF THE INVENTION In one aspect the present invention provides a compound of the formula (I): Formula (I) wherein: R1 and R2 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, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aicoxiarilo, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, -COOH, -COR3, -COOR3, -CONHR3, -NHCOR3, -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, aryisulfonyl, arylsulfinyl, aminosulfonyl, -SR3, R4S (0) R6-, R4S (0) 2R6-, R4C (O) N (R5) R6-, RS02N (R5) R6-, RN (R5) C (0) R6-, R4N (R5) S02R6-, R 4 N (R 5) C (0) N (R 5) R 6 - and acyl, each of which may be optionally substituted; each R3, R4, and R5 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each one of which may be optionally substituted; each R6 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 it may be optionally substituted; Z2 is selected from the group consisting of a bond, O, S, -N (R7) -, -N (R7) -alkyl (C? _2) -, and -alkyl (C? _2) -NCR7) -; each R7 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; Ar1 and Ar2 are each independently selected from the group consisting of aryl and heteroaryl, each of which may be optionally substituted; L is a group of the formula: -X ^ Y-X2- in which X1 is linked to Ar1 and X2 is linked to Ar2, and in which X1, X2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain , X1 and X2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain, Y is a group of the formula -CRa = CR- or an optionally substituted cycloalkyl group, in which Ra and Rb are each 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, or Ra and R may be attached in such a way that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. As with any group of structurally related compounds possessing a particular utility, some variable modalities of the compounds of formula (I) are particularly useful in their end-use application. In some embodiments Z2 is selected from the group consisting of a bond, -N (R7) - and -S-. In a specific modality Z2 is -N (R7) -. In an even more specific modality Z2 is -N (H) -. Ar1 and Ar2 are each independently selected from the group consisting of aryl and heteroaryl and may be monocyclic, bicyclic or polycyclic portions. In some embodiments each of Ar1 and Ar2 is a monocyclic or bicyclic portion. In some embodiments each of Ar1 and Ar2 are a monocyclic portion. In some modalities Ar1 is selected from the group consisting of: wherein V1, V2, V3 and V4 are each independently selected from the group consisting of N, and C (R10); W is selected from the group consisting of O, S and NR10; W1 and W2 are each independently selected from the group consisting of N and CR10; wherein each R10 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, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, -COOH, -COR3, -COOR3, -CONHR3, -NHCOR3, -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, aryisulfonyl, arylsulfinyl, aminosulfonyl, -SR3, R4S ( 0) R6-, R4S (0) 2R6-, R4C (O) N (R5) R6-, R4S02N; R5) R6-, R4N (R5) C (0) R6-, R4N (R5) S02R6-, R 4 N (R 5) C (0) N (R, 5 ° v) R ° - and acyl, each of which may be optionally substituted, in which R 3, R 4, R 5 and R 6 are as defined above. In some modalities Ar1 is selected from the group consisting of: in which V1, V2, V3, V4, W, W1, W2, R3, R4, R5 and R6 are as defined above. In some modalities Ar1 is selected from the group consisting of: in which each R10 is independently as defined above, k is an integer that is selected from the group consisting of 0, 1, 2, 3, and 4; and n is an integer that is selected from the group consisting of 0, 1, 2 and 3. In an even further mode Ar1 is selected from the group consisting of: in which R10 is as defined above. In some modalities Ar1 is selected from the group consisting of: in which each R10 is independently as defined above, and q is an integer that is selected from the group consisting of 0, 1, and 2. In some embodiments Ar1 is selected from the group consisting of: In some modalities Ar1 is selected from the group consisting of: In some modalities Ar is selected from the group consisting of: in which V5, V6, V7 and V8 are selected from independently from the group consisting of N, and C (RU); in which each R11 is independently selected from the group consisting of: Hhalogen, 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, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, -COOH, -COR3, -COOR3, -CONHR3, - NHCOR, -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, -SR3, R4S (0) R6-, R4S (0) 2R6-, RC (O) N (R5) R6 -, R4S02N (R5) R6-, R4N (R5) C (0) R6-, RN (R5) S02R6-, R 4 N (R 5) C (0) N (R 5) R 6 - and acyl, each of which may be optionally substituted. In some modalities Ar2 is selected from of the group consisting of: in which each R > 11 is independently as defined above, "o" is an integer that is selected from the group consisting of 0, 1, 2, 3, and 4; and p is an integer that is selected from the group consisting of 0, 1, 2, and 3. In some embodiments Ar2 is selected from the group consisting of: in which each R11 is as defined above. Even in an additional embodiment Ar2 is selected from the group consisting of: In one embodiment of the invention the compound is of the formula (II): H Formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1, R 2, R 10, R 11, X 1, X 2, Y, k and "o" are as defined above.

In one embodiment of the invention, the compound is of the formula (III): )or Formula (III) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R10, R11, X1, X2, Y, q and "o" are as defined above. In one embodiment of the invention, the compound is of the formula (IV): )or Formula (IV) or a pharmaceutically acceptable salt or prodrug thereof in which R1, R2, R10, R11, X1, X2, Y, q and "o" are as defined above. In one embodiment of the invention, the compound is of the formula (V): Formula (V) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R10, R11, X1, X2, Y, q and "o" are as defined above. In one embodiment of the invention the compound is of the formula (VI): )or Formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, • wherein R1, R2, R10, R11, X1, X2, Y, q and "o" are as defined above. In one embodiment of the invention the compound is of the formula (VII): )or Formula (VII) or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1, R 2, R 10, R 11, X 1, X 2, Y, q and "o" are as defined above. In the compounds of the invention X1, X2 and Y are chosen such that there are between 5 and 15 atoms in the normal chain, In one embodiment of the compounds of the invention X1, X2 and Y are chosen such that they exist between 6 and 15 atoms in the normal chain. In a specific embodiment of the compounds of the invention X1, X2 and Y are chosen in such a way that there are 7 atoms in the normal chain. In another specific embodiment of the compounds of the invention X1, X2 and Y are chosen in such a way that there are 8 atoms in the normal chain.

In the compounds of the invention X1 and X2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain. In some embodiments X1 is selected from the group consisting of: (a) -0-alkyl (C? -5) -, (b) -alkyl (C? -) -0-, and (c) -alkyl ( C1-5) -O-C1-5 alkyl. In some embodiments X1 is selected from the group consisting of: (a) -OCH2- (b) -CH20-, (c) -OCH2CH2-, (d) -CH2CH20-, (e) -CH2OCH2-, and ( f) -CH2CH2OCH2-. In a specific embodiment X1 is -OCH2-. In another specific embodiment X1 is -CH20-. In another specific embodiment X1 is -OCH2CH2-. In another specific embodiment X1 is -CH2CH20-. In another specific embodiment X1 is -CH2OCH2-.

In another specific embodiment X1 is -CH2CH2OCH2-. In some embodiments X2 is selected from the group consisting of: (a) -O-alquiMC? -5) -, (b) -alkyl (C? -5) -O-, and (c) -alkyl (C? -5) -O-C1-5 alkyl. In some embodiments X2 is selected from the group consisting of: (a) -OCH2- (b) -CH20-, (c) -OCH2CH2-, (d) -CH2CH20-, (e) -CH2OCH2-, and ( f) -CH2CH2OCH2-. In a specific embodiment X2 is -OCH2-. In another specific embodiment X1 is -CH20-. In another specific embodiment X2 is -OCH2CH2-. In another specific embodiment X2 is -CH2CH20-. In another specific embodiment X2 is -CH2OCH2-. In another specific embodiment X2 is -CH2CH2OCH2-. A particularly useful subset of compounds of the invention is selected from the group consisting of: or a pharmaceutically acceptable salt or prodrug thereof; wherein R1, R2, R10, R11, k, Y, q and "o" are as defined above. In some embodiments, R 1 is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy. , alkoxyalkyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, arylamino, sulfonylamino, sulfinylamino, COOH, COR3, COOR3, CONHR3, NHCOR3, NHCOOR3, NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl , aryisulfonyl, arylsulfinyl, aminosulfonyl, and acyl, each of the which may be optionally substituted. In some embodiments of the invention R1 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. In some embodiments R1 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. In a specific embodiment R1 is H. In some embodiments R2 is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl. , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, arylamino, sulfonylamino, sulfinylamino, COOH, COR3, COOR3, CONHR3, NHCOR3, NHCOOR3, NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, and acyl, each of which may be optionally substituted. In some embodiments R2 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. In some embodiments R2 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. In a specific embodiment R2 is selected from the group consisting of H and alkyl. In another specific embodiment R2 is H or methyl. In some embodiments R3 is selected from the group consisting of H, Ci-Ce alkyl and acyl, In another embodiment R3 is selected from the group consisting of H and C?-C4 alkyl. In a specific embodiment R3 is C?-C4 alkyl. In some modalities R4 is selected from of the group consisting of H and C? -C4 alkyl. In a specific embodiment R 4 is C 1 -C 4 alkyl. In some embodiments R 5 is selected from the group consisting of C 1 -C 4 alkyl, heteroalkyl and acyl. In a specific embodiment R5 is C? -C alkyl. In some embodiments R6 is selected from the group consisting of a bond, C? -C alkyl, heteroalkyl and acyl. In a specific embodiment R6 is C? -C4 alkyl or a bond. In some embodiments R7 is selected from the group consisting of H and C? -C4 alkyl. In a specific embodiment R7 is H. In some embodiments of the compounds of the invention each R10 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. In some embodiments each R10 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. In some embodiments, 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. , heteroaryl heteroalkyl, arylsulfonyloxy, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted. In some embodiments each R 11 is independently selected from the group consisting of H, hydroxyl, methoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may be optionally substituted. In some embodiments of the invention each R 11 is independently selected from the group consisting of H, alkoxy, heteroalkyl, heterocycloalkyl, heterocycloalkylheteroalkyl, and arylsulfonyloxy, each of which may be optionally substituted. In some embodiments of the invention, k is 0 or 1. In a modality k is 0. In another modality k is 1. In some embodiments of the invention q is 0 or 1. In a modality q is 0. In another modality q is 1. In some embodiments of the invention "or" is 0, 1, or 2. In one mode "o" is one. In another embodiment "or" is 1. In another embodiment "or" is 2. In some embodiments of the invention each R11 is independently selected from the group consisting of: In a Y mode it is selected from the group consisting of: \ iD In a specific mode Y is In another specific modality Y is In another specific embodiment Y is a cyclopropyl group. Many, if not all, of the variables discussed above may be optionally substituted. If the variable is optionally substituted then, in some embodiments, the optional substituent is selected from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino , sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) 0R5, -SH, -SR5, -OR6, and acyl, In some embodiments the substituents are selected from the group consists of: halogen, = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl or, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, aryisulfonyl, aminosulfonyl, -C (0) 0R5, COOH, SH, and acyl. In addition to the compounds of the formula I, the embodiments described are also directed to pharmaceutically acceptable salts, pharmaceutically-N-oxides acceptable, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds, and pharmaceutically acceptable salts of said metabolites. The invention also relates to pharmaceutical compositions that include a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient. In a further aspect, the invention provides a method for inhibiting one or more protein kinase (s) which includes exposing said one or more protein kinase (s) and / or cofactor (s) thereof (s) to a effective amount of a compound of the invention. In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). The compounds described in the present invention can act directly and exclusively on the kinase molecule to inhibit biological activity. However, it is understood that the compounds can also act at least partially on cofactors that are involved in the phosphorylation process. For example, in cases where the kinase is cyclin-dependent, a cofactor such as cyclin A is involved in the transfer of phosphate from ATP (also considered as a factor in itself) to the substrate molecule. Other kinase cofactors include species ionic (such as zinc and calcium), lipids (such as phosphatidylserine), and diacylglycerols. In one embodiment of the method said one or more protein kinase (s) is a cyclin-dependent protein kinase. In a specific embodiment the cyclin-dependent kinase is a Group I CMCG kinase I. In a modality the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKl, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. In a specific embodiment, the CMCG Group I kinase is CDK2 or a functional equivalent thereof. In another embodiment of the method said one or more protein kinase (s) is a protein tyrosine kinase. In one form of this embodiment, the protein tyrosine kinase is a protein tyrosine kinase of group VII. In one embodiment the protein tyrosine kinase of group VII is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. In one form of the method, JAK2 includes a single, recurrent, acquired clonal mutation. This mutation is observed in a majority of patients with polycythemia vera (PV) and in a proportion of patients with other myeloproliferative disorders, including essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (MFI). In one form of the method, the mutation is a substitution of valine to phenylalanine at position 617 (V617F). The incidence of this mutation in patients with PV is very high (about 78% of patients). The JAK2 mutation is somatic and occurs at the level of a hematopoietic stem cell. Studies have shown that mutated JAK2 was found in myeloid cells, ie bone marrow cells, granulocytes, platelets and erythroblasts obtained from CD34 + cells, but not in T cells. In addition, JAK2 mutant was found in hematopoietic colonies obtained from hematopoietic progenitor cells. The Applicant has demonstrated that the kinase inhibitors described in the present invention can inhibit the activity of wild type and mutant JAK2. In another embodiment of the method, the protein tyrosine kinase is a protein tyrosine kinase of Group XIV. In one form of this embodiment the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFlR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent of the same. In a specific embodiment, the protein tyrosine kinase of Group XIV is FLT3 or a functional equivalent thereof. In another form of the method, the FLT3 kinase includes a mutation. There is substantial experimental and clinical evidence to support the hypothesis that FLT3 mutations are important in the initiation or maintenance of AML in some patients. Activating mutations of FLT3 result in constitutive activation of the tyrosine kinase activity of FLT3 and can transform the factor-dependent hematopoietic cells as demonstrated by the conversion to factor-independent growth and tumor formation in immunodeficient mice. In addition, retroviral transduction of murine primary bone marrow with an ITD cDNA (internal tandem duplication) of FLT3 obtained from patient with AML results in a lethal myeloproliferative syndrome. Likewise, retroviral bone marrow transduction obtained from transgenic promyelocytic leukemia / retinoic acid receptor (PML-RAR) mice with ITT of FLT3 results in a marked increase in the incidence of acute progranulocytic-type leukemia (APL) in said mice when compared to mice receiving a bone marrow transplant of simulated transduction. Applicants have demonstrated that the kinase inhibitors described in the present invention can inhibit FLT3 including a ITD in cases where there is a duplication of the amino acids VDFREYEYDH at amino acid position 592-601. In an even more specific mode of the method, the FLT3 includes an internal tandem duplication. In an even more specific modality, internal tandem duplication is a duplication of the amino acids VDFREYEYDH at position 592-601. In one embodiment of the method, exposing said one or more protein kinase (s) to the compound includes administering the compound to a mammal containing said one or more protein kinase (s). In one embodiment said one or more protein kinase (s) includes (n) at least two kinases that are selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment said one or more protein kinase (s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof. In a still further aspect, the invention provides the use of a compound of the invention to inhibit one or more protein kinase (s). In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). In one embodiment said one or more protein kinase (s) is a cyclin-dependent protein kinase. In In a specific embodiment, the cyclin-dependent kinase is a Group I CMCG kinase. In a modality, the Group I CMCG kinase is selected from the group consisting of CDC2HS, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKl, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and 0sC2R and functional equivalents thereof. In a specific embodiment, the CMCG Group I kinase is CDK2 or a functional equivalent thereof. In another embodiment said one or more protein kinase (s) is a protein tyrosine kinase. In one form of this embodiment, the protein tyrosine kinase is a protein tyrosine kinase of group VII. In one embodiment the protein tyrosine kinase of group VII is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. In a more specific embodiment, JAK2 includes a mutation from V to F at position 617. In another embodiment, the protein tyrosine kinase is a protein tyrosine kinase of Group XIV. In one form of this embodiment the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. In a specific embodiment, the protein tyrosine kinase of Group XIV is FLT3 or a functional equivalent thereof. In an even more specific mode FLT3 includes internal tandem duplication. In an even more specific modality, internal tandem duplication is a duplication of the amino acids VDFREYEYDH at position 592-601. In one embodiment said one or more protein kinase (s) includes (n) at least two kinases that are selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment said one or more protein kinase (s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof. In a still further aspect, the invention provides a method for treating or preventing a condition in a mammal in which the inhibition of one or more protein kinase (s) and / or co-factor (s) of the same ( s) prevents, inhibits or ameliorates a pathology or symptomatology of the condition, the method includes the administration of a therapeutically effective amount of a compound of the invention. In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). In one method modality said one or more Protein kinase (s) is a cyclin-dependent protein kinase. In a specific embodiment the cyclin-dependent kinase is a CMCG kinase of Group I. In a modality the CMCG kinase of Group I is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRKj. LmmCRK1, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and 0sC2R or a functional equivalent thereof. In a specific embodiment, the CMCG Group I kinase is CDK2 or a functional equivalent thereof. In one embodiment, the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma. , hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, colon adenocarcinoma, T cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's disease. In another embodiment of the method said one or more protein kinase (s) is a protein tyrosine kinase. In one form of this embodiment, the protein tyrosine kinase is a protein tyrosine kinase of group VII. In a modality the Group VII tyrosine kinase protein is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. In a more specific embodiment, JAK2 includes a mutation from V to F at position 617. In one embodiment the condition is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and degeneration of the retina. In another embodiment of the method, the protein tyrosine kinase is a protein tyrosine kinase of Group XIV. In one form of this embodiment the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent of the same.

In a specific embodiment, the protein tyrosine kinase of Grμpo XIV is FLT3 or a functional equivalent thereof. In an even more specific mode FLT3 includes internal tandem duplication. In an even more specific modality, internal tandem duplication is a duplication of the amino acids VDFREYEYDH at position 592-601. In one embodiment the condition is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, T-cell leukemia acute, myeloproliferative disorders, and chronic myelomonocytic leukemia. In one embodiment said one or more protein kinase (s) includes (n) at least two kinases that are selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment said one or more protein kinase (s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof. In a still further aspect, 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 the inhibition of one or more protein Kinase (s) can prevent, inhibit or improve the pathology or symptomatology of the condition. In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). In one embodiment said one or more protein kinase (s) is a cyclin-dependent protein kinase. In a specific embodiment the cyclin-dependent kinase is a Group I CMCG kinase I. In a modality the Group I CMCG kinase is selected from the group consisting of CDC2HS, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1 , PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK-1, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. In a specific embodiment, the CMCG kinase of Group I is CDK2 or a functional equivalent thereof. In one embodiment, the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma. , hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, musculoskeletal neoplasms and Alzheimer's disease. In another embodiment said one or more protein kinase (s) is a protein tyrosine kinase. In one form of this embodiment, the protein tyrosine kinase is a protein tyrosine kinase of group VII. In one embodiment the protein tyrosine kinase of group VII is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. In a more specific embodiment, JAK2 includes a mutation from V to F at position 617. In one embodiment the condition is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and degeneration of the retina.

In another embodiment, the protein tyrosine kinase is a protein tyrosine kinase of Group XIV. In one form of this embodiment the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent of the same. In a specific embodiment, the protein tyrosine kinase of Group XIV is FLT3 or a functional equivalent thereof. In an even more specific mode FLT3 includes internal tandem duplication. In an even more specific modality, internal tandem duplication is a duplication of the amino acids VDFREYEYDH at position 592-601. In one embodiment the condition is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, T-cell leukemia acute, myeloproliferative disorders, and chronic myelomonocytic leukemia. In one embodiment said one or more protein kinase (s) includes (n) at least two kinases that are selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment said one or more protein kinase (s) they include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof. In a still further aspect, 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. In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). In one embodiment, the kinase-related disorder is a proliferative disorder. In a specific embodiment, the proliferative disorder is chosen from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-cell lung cancer small, melanoma, hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, and neoplasms musculoskeletal In one embodiment, the proliferative disorder is a myeloproliferative disorder. In a specific modality, the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. In another embodiment, the proliferative disorder is cancer. In one modality, cancer is a solid tumor. In one embodiment the solid tumor is a tumor present in or metastasized from an organ or tissue that is 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. In one modality, cancer is a hematological cancer. In a specific modality the hematologic cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, leukemia of acute B cell, chronic myeloid leukemia, acute T cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblast leukemia, Hodgkin's disease, and B-cell lymphoma. In another embodiment, the kinase-related disorder is a cardiovascular disorder. In one embodiment, the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis. In one embodiment, the kinase-related disorder is a neurodegenerative disorder. In a specific modality, the neurodegenerative disorder is Alzheimer's disease. In a still further aspect, the invention provides a method for treating or preventing a kinase-related disorder that includes administering a therapeutically effective amount of a compound of the invention to a patient in need thereof. In one embodiment the compound is a compound of the formula (I), (II), (III), (IV), (V), (VI) or (VII). In one embodiment, the kinase-related disorder is a proliferative disorder. In a specific embodiment, the proliferative disorder is chosen from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast tissue, tumor malignant colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, adenocarcinoma of the colon, glioma, glioblastoma , oligodendroglioma, lymphoma, ovarian cancer, subtract nosis, astrocytoma, neoplasms of the bladder, and musculoskeletal neoplasms. In one embodiment, the proliferative disorder is a myeloproliferative disorder. In a specific modality, the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. In another modality the proliferative disorder is Cancer. In one modality, cancer is a solid tumor. In one embodiment, the solid tumor is a tumor present in or metastasized from an organ or tissue that is 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. In one modality, cancer is a hematological cancer. In a specific modality the hematologic 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, cell leukemia Acute T, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblast leukemia, Hodgkin's disease, and B-cell lymphoma. In another embodiment, the kinase-related disorder is a cardiovascular disorder. In one embodiment, the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis. In one embodiment, the kinase-related disorder is a neurodegenerative disorder. In a modality Specific neurodegenerative disorder is Alzheimer's disease. The invention also provides a method for inhibiting cell proliferation that includes the administration of an effective amount of a compound according to formula (I). In one embodiment the compound is a compound of the formula (II), (III), (IV), (V), (VI) or (VII). In a still further aspect, the invention provides a method of synthesis of a compound of the formula (I), the method includes the steps of: (a) providing a compound of the formula wherein R1, R2, Ra, Rb, Z2, Ar1, Ar2, X1 and X2 are as defined above; (b) subjecting the compound to ring closure metathesis; (c) optionally reacting the double bond formed in this manner to form a cycloalkyl group.

DETAILED DESCRIPTION OF THE INVENTION In this description a number of terms are used which are well known to the person skilled in the art. However, for clarity purposes a number of terms will be defined. As used in the present invention, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen. The term "optionally substituted" as used throughout the description indicates that the group may or may not be further substituted or merged (to form a condensed polycyclic system), with one or more substituent groups other than hydrogen. In some embodiments the substituent groups are one or more groups that are independently selected from the group consisting of halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, halogenoalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocicloalquilheteroalquilo, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alcoxiheterocicloalquilo, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, aryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR5, -C (0) OR5 , CONHR5, NHCOR5, NHCOOR5, NHCONHR5, C (= NOH) R5, -SH, -SR5, -OR5 and acyl. "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C? -C? 4 alkyl, more preferred Ci-Cio alkyl, even more preferred C? -C6 a unless indicated otherwise. Examples of straight and branched Ci-Cß alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group can be a terminal group or a structure forming group in bridge. "Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Monoalkylamino" means a group -NH-alkyl, in which alkyl is as defined above. "Dialkylamino" means a group -N (alkyl) 2, in which each alkyl may be the same or different and each is as defined in the present invention for alkyl. The alkyl group is preferably a C? -C6 alkyl group. The group can be a terminal group or a bridge structure forming group. "Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of the formula aryl-NH-, in which aryl is as defined in the present invention, di-arylamino means a group of the formula (aryl) 2N- in which each aryl may be the same or different and each is as defined in the present invention for aril. The group can be a terminal group or a bridge structure forming group. "Acyl" means an alkyl-CO- group in which the alkyl group is as described in the present invention. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably an alkyl group of Ci-Cß. The group can be a terminal group or a Bridge structure forming group. "Alkenyl" as a group or part of a group indicates an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched having preferably 2-14 carbon atoms, more preferred 2- 12 carbon atoms, even more 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 around each is independently E or Z. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl , heptenyl, octenyl and nonenyl. The group can be a terminal group or a bridge structure forming group. "Alkoxy" refers to an -O-alkyl group in which alkyl was defined in the present invention. Preferably, the alkoxy is a C6-C6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group can be a terminal group or a bridge building group. "Alkenyloxy" refers to an -O-alkenyl group in which alkenyl is as defined in the present invention. Preferred alkenyloxy groups are alkenyloxy groups of Ci-Cß- The group may be a terminal group or a bridging group.

"Alkynyloxy" refers to an -O-alkynyl group in which alkynyl is as defined in the present invention. Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups. The group can be a terminal group or a bridge structure forming group. "Alkoxycarbonyl" refers to a -C (0) -0-alkyl group in which alkyl is as defined in the present invention. The alkyl group is preferably a C? -C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group can be a terminal group or a bridge structure forming group. "Alkylsulfinyl" means a group -S (O) -alkyl in which alkyl is as defined above. The alkyl group is preferably an alkyl group of Ci-Ce. Examples of alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. The group can be a terminal group or a bridge structure forming group. "Alkylsulfonyl" refers to a -S (0) 2 -alkyl group in which alkyl is as defined above. The alkyl group is preferably a C? -C6 alkyl group. Examples include, but are not limited to, methylsulfonyl and ethylsulfonyl. The group can be a terminal group or a bridge structure forming 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 having preferably 2-14 carbon atoms, more preferred 2-12 atoms of carbon, even more preferred 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group can be a terminal group or a bridge structure forming group. "Alkylaminocarbonyl" refers to an alkylaminocarbonyl group in which alkylamino is as defined above. The group can be a terminal group or a bridge structure forming group. "Cycloalkyl" refers to a carbocyclic, monocyclic or fused or polycyclic, saturated or partially saturated spiro preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. another way. This includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group can be a terminal group or a bridge structure forming group. "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least less one carbon-carbon double bond and preferably having from 5 to 10 carbon atoms per ring. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted with one or more substituent groups. The group can be a terminal group or a bridge structure forming group. The above discussion of alkyl and cycloalkyl substituents is also applied to the alkyl portions of other substituents, such as without limitation, alkoxy substituents, alkylamines, alkylketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester and the like. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl portions are as previously described. Examples of monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group can be a terminal group or a bridge structure forming 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, preference of 1 to 3 heteroatoms in at least one ring. Each ring of preference is from 3 to 10 members, more preferred from 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapan, 1, 4-diazapan, 1 -oxazepan, and 1, 4-oxatiapan. The group can be a terminal group or a bridge structure forming group. "Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond. The group can be a terminal group or a bridge structure forming group. "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl portions are as previously described. Examples of heterocycloalkylalkyl groups include (2-tetrahydrofuryl) methyl, (2-tetrahydrothiofuranyl) methyl. The group can be a terminal group or a bridge structure forming group. "Heteroalkyl" refers to a straight or branched chain alkyl group preferably having 2 to 14 carbons, more preferred 2 to 10 carbons in the chain, which one or more has been replaced by a heteroatom which is selected from S, 0, P and N. Examples of heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, and the like. The group can be a terminal group or a bridge structure forming group. As used in the present invention, the reference to the normal chain when used in the context of a bridging structure forming group refers to the direct chain of atoms that links the two terminal positions of the bridging structure forming group . "Aryl" as a group or part of a group represents (i) a carbocycle (ring structure having ring atoms that are all carbon) optionally substituted monocyclic or polycyclic fused aromatic group having preferably from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (Ii) a partially saturated aromatic carbocyclic moiety, bicyclic, optionally substituted on which fuse together a phenyl group and a cycloalkyl group having C5_7 cycloalkyl or C5_7 to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group can be a terminal group or a bridge structure forming group. "Arylalkenyl" means an aryl-alkenyl group wherein the aryl and the alkenyl are as previously described. Examples of arylalkenyl groups include phenylalyl. The group can be a terminal group or a bridge structure forming group. "Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl portions are as previously described. Preferred arylalkyl groups contain an alkyl portion of C 1-5. Examples of arylalkyl groups include benzyl, phenethyl and naphthelenylmethyl. The group can be a terminal group or a bridging structure forming group. "Heteroaryl" either alone or as 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 being ring atoms carbon the rest of the ring atoms. Suitable heteroatoms include nitrogen, oxygen and sulfur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizina, xantholene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine , indole, isoindol, lH-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, iso-oxazole, furazano, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl, 1-, 2-, or 3-indolyl, and 2-, or 3-thienyl. The group can be a terminal group or a bridge structure forming group. "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl portions are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Examples of heteroarylalkyl groups include pyridylmethyl. The group can be a terminal group or a bridge structure forming 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 preferred 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tert-butyl). The group can be a terminal group or a bridge structure forming group. It is understood that in the family of compounds of the formula (I) are included isomeric forms including diastereoisomers, enantiomers, tautomers, and geometric isomers in the "E" or "Z" configuration or a mixture of E and Z isomers. understands that some Isomeric forms such as diastereomers, enantiomers, and geometric isomers can be separated by those skilled in the art by physical and / or chemical methods. Some of the compounds of the described embodiments may exist as individual stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. It is intended that all of said individual stereoisomers, racemates and mixtures thereof be within the scope of the subject matter described and claimed. Additionally, formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Therefore, each formula includes compounds having the indicated structure, including hydrated as well as non-hydrated forms. In addition to the compounds of the formula (I), the compounds of the various embodiments include pharmaceutically acceptable salts, prodrugs, N-oxides and pharmaceutically acceptable metabolites of said compounds, and pharmaceutically acceptable salts of said metabolites. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compounds identified above, and include acid addition salts and basic addition salts pharmaceutically acceptable Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula (I) can be prepared from an inorganic acid or from an organic acid. Examples of said inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, carboxylic and sulfonic organic acid classes of acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acids , citric, fumaric, maleic, alkylsulfonic, arylsulfonic. Suitable pharmaceutically acceptable basic addition salts of the compounds of the formula (I) include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as Hill, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as the 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 solid, the experts in the art they will understand that the compounds, agents and salts of the invention may exist in different crystalline or polymorphic forms, of which all are intended to be within the scope of the present invention and of the specified formulas. "Prodrug" means a compound that can be converted in vivo by metabolic means (for example by hydrolysis, reduction or oxidation) into a compound of the formula (I). For example, an ester prodrug of a compound of formula I containing a hydroxyl group can be converted by hydrolysis in vivo into the precursor molecule. Suitable esters of compounds of formula (I) which contain a hydroxyl group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthates, gestisinates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. As another example, an ester prodrug of a compound of formula I containing a carboxy group can be converted by hydrolysis in vivo into the parent molecule. (Examples of ester prodrugs are those described by F.J. Lein eber, Drug Metab. Res., 18: 379, 1987).

The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect the beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to alleviate, improve, stabilize, reverse, slow or delay the progression of the disease state. The term "normal chain" refers to the direct chain joining the two ends of a linker portion. With reference to the compounds of the present invention, an alkoxyalkyl group is a heteroalkyl group that contains 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 (this has a nitrogen atom in the normal chain). The term "functional equivalent" is intended to include the variants of the specific protein kinase species described in the present invention. It will be understood that kinases can have isoforms, so that although the primary, secondary, tertiary or quaternary structure of a given kinase isoform is different from the prototypical kinase, the molecule maintains biological activity as a protein kinase. Isoforms can arise from the normal allelic variation within a population and include mutations such as substitution, deletion, addition, truncation, or amino acid duplication. The variants generated at the transcription level are also included within the term "functional equivalent". Many kinases (including JAK2 and CDK2) have isoforms that arise from variation in transcription. It is also known that FLT3 has an isoform that is the result of exon skipping. Other functional equivalents include kinases that have altered post-translational modification such as glycosylation. Specific compounds of the invention include the following: H H H H H H H H H H The compounds of the invention have the ability to inhibit the activity of some protein kinases. The ability to inhibit kinase activity may be the result of the compounds of the invention acting directly and exclusively on the kinase molecule to inhibit biological activity. However, it is understood that the compounds can also act so less partially on cofactors of the kinase in question that are involved in the phosphorylation process. For example, in cases where the kinase is cyclin-dependent, a cofactor such as cyclin A is involved in the transfer of phosphate from ATP (also considered as a factor in itself) to the substrate molecule. Other kinase cofactors 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. An appropriate family of protein kinases are cyclin-dependent protein kinases. An example of the cyclin dependent kinases are the CMCG kinases of Group I. Examples of CMCG kinases of Group I include CDC2Hs, CDK2, CDK3, CDK4, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTA1RE3, CAK / M015, Dm2 , Dm2c, Ddcdc2, DdPRK, LmmCRKl, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and OsC2R. One CMCG kinase of Group I of particular interest is CDK2. Another family of protein kinases are protein tyrosine kinases. An example of protein tyrosine kinases is a protein tyrosine kinase of group VII. Examples of protein tyrosine kinase from Group VII include TYK2, JAK1, JAK2 and HOP. A protein kinase of particular interest is the protein tyrosine kinase of group VII JAK2. The JAK2 protein kinase can include an acquired clonal mutation, unique, recurrent. As previously indicated, this mutation is observed in a majority of patients with polycythemia vera (PV) and in a significant proportion of patients with other myeloproliferative disorders, including essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (MFI). A typical mutation is a substitution of valine to phenylalanine at position 617 (V617F). The incidence of this mutation in patients with PV is very high (about 78% of patients). Another example of protein tyrosine kinases are the protein tyrosine kinases of group XIV. Examples of protein tyrosine kinase from Group XIV include PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4. A protein tyrosine kinase of Group XIV of particular interest is FLT3. The FLT3 kinase can include a mutation. There is substantial experimental and clinical evidence to support the hypothesis that FLT3 mutations are important in the initiation or maintenance of AML in some patients. Activating mutations of FLT3 result in the constitutive activation of the tyrosine kinase activity of FLT3 and can transform factor-dependent hematopoietic cells as demonstrated by the conversion to factor-independent growth and tumor formation in immunodeficient mice. In addition, retroviral transduction of murine primary bone marrow with an ITD cDNA (internal tandem duplication) of FLT3 obtained from patient with AML results in a lethal myeloproliferative syndrome. Likewise, retroviral bone marrow transduction obtained from transgenic promyelocytic leukemia / retinoic acid receptor (PML-RAR) mice with ITT of FLT3 results in a marked increase in the incidence of acute progranulocytic-type leukemia (APL) in said mice when compared to mice receiving a bone marrow transplant of simulated transduction. Applicants have demonstrated that the kinase inhibitors described in the present invention can inhibit FLT3 including an ITD in cases where there is a duplication of the amino acids VDFREYEYDH at amino acid position 592-601. In an even more specific mode of the method, the FLT3 includes an internal tandem duplication. In an even more specific modality, internal tandem duplication is a duplication of the amino acids VDFREYEYDH at position 592-601. Inhibition of the protein kinase can be carried out in any of a number of ways well known in the art. For example, if inhibition of protein kinase in vi tro is desired, an amount can be added of the compound of the invention to a solution containing the kinase. In circumstances where it is desired to inhibit the activity of the kinase in a mammal, inhibition of the kinase typically involves administering the compound to a mammal containing the kinase. Accordingly, the compounds of the invention can find a multiple number of applications in which their ability to inhibit protein kinases of the aforementioned type can be used. For example, the compounds can be used to inhibit protein kinases. The compounds can also be used to treat or prevent a condition in a mammal in which the inhibition of a protein kinase and / or cofactor thereof prevents, inhibits or ameliorates a pathology or symptomatology of the condition. Examples of conditions that can be treated by inhibiting protein kinases include prostate cancer, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma. , hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, musculoskeletal neoplasms and Alzheimer's disease. Other conditions that can be treated by inhibiting protein kinases include conditions such as myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythaemia vera, essential thrombocytopenia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute leukemia of erythroblast, disease of Hodgkin, B cell lymphoma, acute T cell leukemia, breast tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, hypertension pulmonary, and degeneration of the retina. Other conditions that can be treated by inhibiting protein kinases include acute 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, Myelo-proliferative disorders, and chronic myelomonocytic leukemia. The compounds of the invention can also be used in the preparation of a medicament for treating a condition in an animal in which the inhibition of a protein kinase can prevent, inhibit or improve the pathology or symptomatology of the condition. The compounds of the invention can also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder. An example of a kinase-related disorder is a proliferative disorder. In a specific embodiment, the proliferative disorder is chosen from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatic cell carcinoma, neoplasm malignant pancreas, myeloid leukemia, carc cervical inoma, tumor fibroid, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, and musculoskeletal neoplasms. An example of a proliferative disorder is cancer. Cancer can be a solid tumor. The solid tumor may be a tumor present in or metastasized from an organ or tissue that is 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. Another example of a cancer is a blood cancer. Examples of hematologic 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 erythroblast leukemia, Hodgkin's disease, and B-cell lymphoma. Another kinase-related disorder is a cardiovascular disorder. Examples of cardiovascular disorder include congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis. Another kinase related disorder is a neurodegenerative disorder. The neurodegenerative disorder can be Alzheimer's disease. The disclosed compounds 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 of administration. The injection can be bolus or through constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, eg, cancerous tumors, than to normal cells. As used in the present invention, the term "cancer" is a general term intended to encompass the vast number of conditions that are characterized by the abnormal, uncontrolled growth of cells.

It is anticipated that the compounds of the invention may be useful for treating various cancers including, but not limited to, bone tissue cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumors including acoustic neuroma, neuroblastomas, glioma and other brain tumors, spinal cord tumors, breast tissue cancers, colorectal cancers, advanced colorectal adenocarcinomas, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, cancer of the thymus, multiple endocrine neoplasm, gastrointestinal cancers including stomach cancer, esophageal cancer, small bowel cancer, liver cancer, additional hepatic bile duct cancer, gastrointestinal carcinoid tumor, gallbladder cancer, genitourinary cancers including testicular cancer, cancer of the penis, cancer prostate, gynecological cancers including cervical cancer, ovarian cancer, vaginal cancer, uterine / endometrial cancer, vulvar cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers including cancer of the cavity oral, cancer of the lips, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, cancer paranasal, nasopharyngeal cancer, leukemias including childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia, myelomas, hematological disorders including myelodysplastic syndromes, myelin disorders -proliferative, aplastic anemia, Fanconi anemia, aldenstrom's macroglobulinemia, lung cancers including small cell lung cancer, non-small cell lung cancer, lymphomas including Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T cell lymphoma, B cell lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, ocular cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma, non-melanoma skin cancer, Merkel cell cancer, soft tissue sarcomas such as sa infant soft tissue rcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumor, bladder cancer, urethral cancer, and transition cell cancer. Examples of cancers that can be treated using the compounds of this invention include hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute eritroblastic leukemia, Hodgkin's and non-Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, cell disorder Plasma, hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer such as mammary tissue carcinoma, ovarian cancer, cervical cancer, cancer of the vagina and vulva, endometrial hyperplasia; cancer of the gastrointestinal tract such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer such as prostate cancer, kidney and kidney cancer; urinary bladder cancer, urethral cancer, cancer of the penis; skin cancer such as melanoma; brain tumor such as glioblastoma, neuroblastoma, astrocytoma, ependinoma, brainstem gliomas, medulloblastoma, menigyomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; cancer of the respiratory tract such as lung carcinoma (non-small cell and small cell lung cancer), mesothelioma; ocular disease such as retinoblastoma; musculoskeletal diseases such as osteosarcoma, musculoskeletal neoplasm; squamous cell carcinoma and fibroid tumor. Examples of cancers that can be treated using the 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. Examples of cancers that can be treated using the compounds of this invention are colon cancer, colorectal cancer, pancreatic cancer and cervical cancer. Even additional examples of cancers that can be treated using the compounds of the present inventions include but are not limited to, B cell lymphoma (e.g., Burkitt's lymphoma), leukemia (e.g., acute promyelocytic leukemia, erythroleukemia), T cell lymphoma. Cutaneous (CTCL) and peripheral T cell lymphoma. Even additional examples of cancers that can be treated using the compounds of the present invention include solid tumors and haematological malignancies. It is anticipated that, due to their inhibition of JAK2, the compounds of the invention may also be useful to treat several myeloproliferative disorders which may include polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. When the compounds of the invention are used, they can be administered in any form or mode that makes the compound bioavailable. The person skilled in the art of preparing formulations can easily select the appropriate form and mode of administration depending on the particular characteristics of the selected compound, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. For more information, the reader is asked to consult the reference Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co, (1995). 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. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts because these forms are typically more stable, crystallize more easily and have increased solubility. However, the compounds are typically used in the form of pharmaceutical compositions which they are formulated according to the desired mode of administration. Therefore, in a further embodiment the present invention provides a pharmaceutical composition that includes a compound of the formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in ways well known in the art. The invention, in other embodiments, provides a package or pharmaceutical case comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In said package or case a container having a unit dose of the agent or agents can be found. The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be further diluted before use or these can be provided at the use concentration, where the bottles can include one or more dose. Conveniently, in the kits, individual doses can be provided in sterile bottles so that the doctor can use the bottles directly, wherein the bottles can have the desired amount and concentration of the agent (s). With said container (s) several printed materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, whose notice reflects approval by the manufacturing agency, use or sale for human administration. The compounds of the invention can be used or administered in combination with one or more additional drugs that are anti-cancer drugs and / or procedures (eg, surgery, radiotherapy) for the treatment of the aforementioned disorder / diseases. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations, the compounds of the invention can be administered sequentially or simultaneously with the other or the other drugs. In addition to being administered in combination with one or more additional drugs including anti-cancer drugs, the compounds of the invention can be used in combination therapy. When this happens, the compounds are typically administered in combination with one another. Therefore, one or more of the compounds of the invention can be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable in cases where the therapeutic profile of each compound is different, so such that the combined effect of the two drugs provides an improved therapeutic result. The pharmaceutical compositions of this invention for parenteral injection comprise sterile or non-aqueous sterile solutions, dispersions, suspensions or pharmaceutically acceptable emulsions, as well as sterile powders that can be reconstituted as sterile injectable solutions or dispersions just before being used. Examples of suitable vehicles, diluents, solvents or aqueous and non-aqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and appropriate mixtures thereof, vegetable oils (such as olive oil). , and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol-sorbic acid, and the like. It may also be desirable to include agents for isotonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be produced by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow-release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporation of 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 be used. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose , mannitol, and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and gum acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch potato or cassava, alginic acid, some silicates, and sodium carbonate, e) dissolving retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be used as filling materials in hard and soft gelatin capsules using excipients such 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 well-known coatings in the pharmaceutical formulation technique. These may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. If desired, and for more effective distribution, the compounds can be incorporated into slow-release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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 such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavors and essences. The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and gum tragacanth, and mixtures thereof. thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound 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 necessary preservatives, buffers, or propellants that may be required. The amount of the compound administered preferably can treat and reduce or alleviate the condition. The attending physician can easily determine a therapeutically effective amount by the use of conventional techniques and by observing the results obtained under analogous circumstances. To determine the therapeutically effective amount a number of factors should be considered including, but not limited to, the species of the animal, its size, age and general health, the specific condition involved, the severity of the condition, the patient's response to treatment , the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the selected dosage regimen, the use of other medicaments and other relevant circumstances. A preferred dose is in the range of 0.01 up to approximately 300 mg per kilogram of body weight per day. A more preferred dose is in the range of 0.1 to 100 mg per kilogram of body weight per day, more preferred 0.2 to 80 mg per kilogram of body weight per day, even more preferred 0.2 to 50 mg per kilogram of body weight per day. An appropriate dose can be administered in multiple sub-doses per day. As discussed above, the compounds of the modalities may be useful for treating proliferative diseases. Examples of such diseases or cell proliferative conditions include cancer (including any metastases), psoriasis, and smooth muscle cell proliferative disorders such as restenosis. The compounds of the invention may be particularly useful for treating tumors such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal, gastric, and pancreatic cancer. brain cancer as well as malignant hematological diseases such as lymphoma and leukemia. In addition, the compounds of the invention may be useful for treating a proliferative disease that is refractory to treatment with other anticancer drugs.; and to treat hyperproliferative conditions such as leukemia, psoriasis and restenosis. In other embodiments, the compounds of this invention can be used to treat pre-cancerous conditions or hyperplasia including familial adenomatous polyposis, adenomatous colon polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intra-epithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx , actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

SYNTHESIS OF MACROCICLES OF PYRIMIDINE As discussed above the invention provides a method of synthesis of a compound of the formula (I), the method includes the steps of: (a) providing a compound of the formula wherein R1, R2, Ra, Rb, Z2, Ar1, Ar2, X1 and X2 are as defined above; (b) subjecting the compound to ring closure metathesis; [c) optionally reacting twice bond formed in this manner to form a cycloalkyl group. The methods of the invention involve cyclization of a diene compound of the formula described above which can be produced using procedures well known in the art or using those described below. The exact choice of the method used to produce the diene for cyclization will depend on the selected diene and the methods of synthesis of the dienes are within the skill of the person skilled in the art. The compound can be reacted in its free form, although it is typical that it first becomes an appropriate acid salt. The acid salts are well known as discussed above with the hydrochloride salt and the trifluoroacetic acid salt which have been found to be particularly suitable. Once the diene is provided with an appropriate formula as discussed above, it is then subjected to ring closure metathesis using standard conditions. It is known that a number of catalysts are suitable for ring closure metathesis including a number of ruthenium-based catalysts. Suitable ruthenium-based catalysts include well-known ruthenium-based catalysts used in olefin metathesis reactions, such as the Grubb catalyst (first and second generation), Hoveyda catalyst (first and second generation) and the Nolan catalyst. In each case, it may be necessary to make appropriate adjustments to the reaction conditions to allow ring closure to occur. In a specific embodiment, the catalyst is a second generation Grubb catalyst. The ruthenium-based catalysts useful for the metallhesis cyclization step, as discussed above, are all known catalysts which can be obtained using known synthesis techniques. For example, see the following references for examples of suitable ruthenium-based catalysts: Organometallics 2002, 21, 671; 1999, 18, 5416; and 1998, 17, 2758; J. Am. Chem. Soc. 2001, 123, 6543; 1999, 121, 791; 1999, 121, 2674; 2002, 124, 4954; 1998, 120, 2484; 1997, 119, 3887; 1996, 118, 100; and 1996, 118, 9606; J. Org. Chem. 1998, 63, 9904; and 1999, 64, 7202; Angew. Chem. Int. Ed. Engl. 1998, 37, 2685; nineteen ninety five, 34, 2038; 2000, 39, 3012 and 2002, 41, 4038; U.S. Patent Nos. 5,811,515; 6,306,987 Bl; and 6,608,027 Bl. The ratio of diene to catalyst can vary widely as will be apparent to the skilled artisan. technique. However, an appropriate ratio is such that the ratio is from 100: 1 to 1: 1. A particularly appropriate ratio is from 20: 1 to 2: 1. A more specific ratio is from 20: 1 to 10: 1. The ring closure metathesis step can be carried out over a wide temperature range in which the temperature range is typically chosen based on the diene being cyclized, the reaction time, and the chosen catalyst. In one embodiment, the reaction is carried out at a temperature of 20 to 200 ° C. In another mode the temperature is from 30 to 120 ° C.

In another embodiment, the temperature is in the range of 30 to 50 ° C. In a specific modality the temperature is 40 ° C. The ring closure step can be carried out in the presence of any suitable non-interfering solvent that does not interfere with the reaction. The person skilled in the art can easily select suitable solvents that do not interfere with the reaction, however, examples of 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, solvents ether type, such as tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, cyclopentyl methyl ether, methyl ether tert-butyl, dimethyl, diethyl or dioxane and methyl alcohol. An example of a specific solvent is dichloromethane. The ring closure metathesis step can be effected through a wide range of diene dilutions in the solvent typically being the ratio of diene to diluent in the range of 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 can be carried out using any agent for cycloalkylation well known in the art. An example of an appropriate cycloalkylating agent is an agent for cyclopropane (cyclopropanation) formation. Examples of agents for cyclopropane formation are well known in the art and include diazomethane and carbenes. The use of such agents is well known and it is within the scope of the person skilled in the art to be able to effect reactions of this type. Cycloalkylation reactions are typically carried out in a non-interfering solvent such as acetonitrile, intimate mixtures of ethyl acetate / hexane, ethyl acetate, tetrahydrofuran, ether, toluene, acetone, carbon tetrachloride, and dichloromethane or mixtures thereof. Those skilled in the art will appreciate that a Wide range of solvents may in fact be appropriate to be used in the execution of the reaction of the invention. In any specific case, an optimum solvent can be identified through tests and experimentation using the above solvents and others. Agents of the various embodiments can be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the field using readily available starting materials. The preparation of particular compounds of the embodiments is described in greater detail in the following examples, but the skilled artisan will recognize that the described chemical reactions can easily be adapted to prepare a number of other agents of the various modalities. For example, the synthesis of non-exemplified compounds can be effected satisfactorily by modifications apparent to those skilled in the art, for example, by appropriately protecting the interfering groups, switching to other suitable reagents known in the art, or making routine modifications. of the reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1991. Alternatively, it will be recognized that other reactions described in the present invention or known in the art have applicability to prepare other compounds of the various embodiments. Reagents useful for synthesizing the compounds can be obtained or prepared in accordance with techniques known in the art. In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius and all parts and percentages are by weight, unless otherwise indicated. Various starting materials and other reagents are purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and are used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) are purchased from Aldrich in bottles "SureSeal" and are used as received. All solvents are purified using standard methods in the art, unless otherwise indicated. The reactions indicated below are carried out under positive pressure of nitrogen, argon or with a desiccant tube, at room temperature (unless otherwise indicated), in anhydrous solvents, and the flasks of reaction are equipped with rubber stoppers divided (rubber septa) for the introduction of substrates and reagents by syringe. The glass material is dried in the oven and / or dried with heat. Analytical thin-layer chromatography is carried out on glass plates coated with silica gel 60 F 254 (E Merck (0.25 mm)) and eluted with the appropriate proportions of solvents (v / v). The reactions are analyzed by TLC and stopped as judged by the consumption of the starting material. The CCF plates are visualized by UV absorption or by spraying the p-anisaldehyde reagent or a phosphomolybdic acid reagent (Aldrich Chemical, at 20% by weight in ethanol) which is activated by heat, or by staining in an iodine chamber. The treatments are typically performed by doubling the reaction volume with the reaction solvent or solvent for extraction and then washed with the indicated aqueous solutions using 25 volume% of the extraction volume (unless otherwise indicated). The product solutions are dried with anhydrous sodium sulfate before filtering, and the evaporation of the solvents is carried out under reduced pressure in a rotary evaporator and indicated as solvents removed in vacuo. Flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] is carried out using Merck grade E flash silica gel (47-61 mm) and a silica gel: raw material ratio of approximately 20: 1 to 50: 1, unless otherwise indicated. Hydrogenolysis is carried out at the indicated pressure or at ambient pressure. The 1 H NMR spectra are recorded on a Bruker instrument operating at 400 MHz, and the 13 C-NMR spectra are recorded operating at 100 MHz. The NMR spectra are obtained as solutions in CDC 13 (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal reference standard of tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents are used as needed. When multiplying the peaks, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = widened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when provided, are reported in Hertz. Mass spectra are obtained using LC / MS either in ESI or APCI. All melting points are uncorrected. All final products are more than 90% pure (by HPLC at wavelengths of 220 nm and 254 nm).

The following examples are intended to illustrate the modalities described and should not be considered as limitations to them. Additional compounds can be prepared, in addition to those described below, using the following reaction scheme described or appropriate variations or modifications thereof.

GENERAL SYNTHESIS SCHEME The reaction scheme 1 is a general synthesis scheme that outlines the processes for the manufacture of the compounds of the invention of the general formula (Villa) and (IXa) which are compounds of the invention in which X1 and X2 are heteroalkyl groups which contain at least one oxygen atom in the normal chain, and Ar1 and Ar2 are phenylene. This general procedure can be modified to produce other compounds of the invention with different values for X1, X2, Ar1 and Ar2 by appropriate modification of the reagents and starting materials used. One skilled in the art can easily make such changes. The compounds of the formula (Villa) can be reacted with appropriate reagents to produce the associated cyclopropyl analogs of the formula (IXa). )or Villa IXa As can be observed in the reaction scheme 1, 2,4-dichloropyrimidine (la) is suitably substituted under Suzuki coupling conditions with a boronic acid of the (Ha) type functionalized in an appropriate manner to obtain the biaryl compounds of kind (Illa), which when treated with allyl bromides (IV) in the presence of a base such as Cs2C03 allow to obtain the allyl compounds of type (Va). Both the compound of the formula (Illa) and the compound of the formula (IVa) are functionalized with groups L and L1 respectively appropriate to produce the desired group X1 after the reaction. The variation of the identity of the groups L and L1 easily allows entry into the wide range of different groups X1 contemplated by the present invention. Substitution with an aniline (Via) functionalized appropriately under standard conditions allows obtaining the terminal alkenes (VHa), a key intermediate ready for metathesis to close Ring (RCM for its acronym in English). Again, the selection of the aniline (Via) functionalized appropriately allows entry into a wide range of possible X2 groups contemplated by the present invention. The use of RCM with 2nd generation Grubbs catalyst produces (Villa) as a mixture of trans and cis isomers which can be separated by chromatography. Compounds of type (IXa) can be obtained by cyclopropane formation under standard conditions.

REACTION SCHEME 1 By varying the identities of the starting materials, a number of different combinations of X1 and X2 can be contemplated and produced as much as possible with a number of differently substituted forms of Ar1 and Ar2. In the reaction scheme shown both Ar1 and Ar2 are represented as phenyl portions, however other arils can be accessed using analogous chemistry as represented in the reaction scheme 1. The synthesis procedures for the synthesis of a number of analogs of the compounds of the formula Villa are presented in detailed form below.

SYNTHESIS OF XVIIIb AND XVIIIc The reaction scheme 2 illustrates the process used to prepare the compounds of the formula (XVIIIb and XVIIIc) which can be prepared by analogous methods, for example, by the choice of appropriate starting materials.

Again, the coupling of 2,4-dichloropyrimidine (la) commercially available under Suzuki coupling conditions with boronic acids of the (XHa) type produces biaryl compounds of the type (XHIa), which when treated with alkenyl bromides ( XIV) in the presence of a base such as Cs2C03 allows obtaining unsaturated ethers of type (XVa). Substitution with aniline (XVIb or XVIc) under standard conditions produces the terminal alkenes (XVIIb or XVIIc), a key intermediate ready for ring closure metathesis (RCM). The use of RCM with Grubbs 2nd generation catalyst produces (XVIIIb or XVIIIc). Compounds of type (XlXb) are obtained by cyclopropane (cyclopropanation) formation under standard conditions.

REACTION SCHEME 2 Synthesis of intermediary XVIb The aniline (XVIb) is obtained from the nitro-aldehyde (XX) by alkylation of the corresponding alcohol (prepared by reduction of the aldehyde (XX) with sodium borohydride) with allyl bromide (IVal) followed by reduction with SnCl 2 of the functional group nitro.

Synthesis of intermediary XVIc The aniline (XVIc) is obtained from a 3-nitrophenol by alkylation with allyl bromide (Ival) followed by reduction with SnCl 2.

SYNTHESIS OF XVIIId The reaction scheme 3 illustrates the process used to prepare the compounds of the formula (XVIIId) which can be prepared using analogous procedures, for example, by the choice of appropriate starting materials.

REACTION SCHEME 3 Xlll The coupling of 2,4-dichloropyrimidine (la) commercially available under Suzuki coupling conditions with boronic acids of the (XHd) type makes it possible to obtain the biaryl compounds of type (XIIIc), which when treated with allyl bromides (XIVc) ) in the presence of a base such as Cs2C03 produce the allyl ethers of type (XVd). Substitution with aniline (XVIb) under standard conditions produces the terminal alkenes (XVIId), a key intermediate ready for ring closure metathesis (RCM). The use of RCM with catalyst 2nd generation of Grubbs produces (XVIIId). Compounds of type (XlXd) are obtained by cyclopropane formation under standard conditions.

Synthesis of xyille-i Macrocycles containing a five-membered heterocyclic ring linked to the pyrimidine system can be prepared using a procedure analogous to that described for compound XVIIId starting from alternative boronic acids. The following structures XVIIIe-i are representative of compounds of this class.

XVIIIß XVIIIf XVIIIg XVIIIh XVIIII REACTION SCHEME 4 XVIIß-l XVIIIe-l Reaction scheme 4 illustrates the preparation of compounds of type XVIIIe, XVIIIf, XVIIIg and XVIHh. Coupling of 2, -dichloropyrimidine (la) commercially available under Suzuki coupling conditions with boronic acids of the type (XHe-i) makes it possible to obtain the biaryl compounds of type (XIHe-i), which when treated with bromides of allyl (XIVc) in the presence of a base such as Cs2C03 produce the allyl ethers of type (XVe-h). The reaction of aniline (XVIb) under standard conditions followed by ring closure metathesis (RCM) using second generation Grubbs catalyst allows the desired products to be obtained (XVIIIe-i).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF TYPE COMPOUNDS (XVIIIB) 3- (2-chloro-pyrimidin-4-yl) -phenol (XlIIal) (la) (XlIIal) To a degassed solution of (la) (1.0 g, 6.71 mmoles) and (Xllal) (1.1 g, 8.05 mmoles) in 1,2-dimethoxyethane (10 ml) is added sequentially, aqueous Na2C03 ((1.06 g, 10.06 mmoles) and Pd (PPh3) 4 (0.387 g, 0.335 mmoles). The The resulting mixture is stirred at 80-85 0 ° C for 4 hours, cool to 0 ° C and quench with saturated NH4C1. He product is extracted with CH2C12 three times and the extracts The combined organics are washed with brine, dried with Na 2 SO 4 and concentrated under reduced pressure. The raw mixture purify on a column (EtOAc / Hexane) to obtain 0.450 g of (XHIal). LC-MS (ESI positive mode) m / z 207 ([M + H] +). X H NMR (400 MHz, CDC13): d 9.74 (s, 1H), 9.23 (d, 1H), 8.83 (d, 1H), 8.01 (dd, 1H), 7.60-7.65 (m, 1H), 7.35 (t , 1H), 6.94-6.99 (m, 1H). 4- (3-but-3-enyloxy-phenyl) -2-chloro-pyrimidine (XVal) To a mixture of (XlIIal) (2.0 g, 9.68 mmol) and (XIV) (7.8 g, 5.80 mmol) in dry DMF (10 ml) at room temperature is added cesium carbonate (14.19 g, 43. 55 mmoles) and the resulting mixture is stirred at 40 ° C for 6 hours. The reaction mixture is cooled to 0 ° C and quenched with H20. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried with Na2SO4 and concentrated under reduced pressure to obtain an oil, which is purified by column (EtOAc / Hexane) to obtain 1.61. g of (XVal). LC-MS (ESI positive mode) m / z 261 ([M + H] +); X H NMR (400 MHz, DMSO d 6): d 8.82 (d, 1 H), 8.12 (d, 1 H), 7.77 (d, 1 H), 7.70 (br s, 1 H), 7.48 (t, 1 H), 7.18 (dd) , 1H), 5.86-5.98 (m, 1H), 5.16-5.24 (m, 1H), 5.09-5.13 (m, 1H), 4.13 (t, 2H), 2.49-2.56 (m, 2H). (3-nitrophenyl) -methanol (XXIb) (XXb) (XXI b) To a solution of (XXb) (5 g, 33.1 mmol) in MeOH (25 mL) at room temperature is added NaBH 4 (1.25 g, 33.1 mmol) and the resulting mixture is stirred for 30 minutes. The reaction mixture is quenched with water. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried over Na2SO and concentrated under reduced pressure to obtain without purification 5 g of the compound (XXIb) . LC-MS (ESI positive mode) m / z 154 ([M + H] +). XH NMR (CDC13) d 8.27 (s, 1H), 8.17 (dd, 1H), 7. 73 (dd, 1H), 7.57 (t, 1H), 4.85 (s, 2H), 2.07 (s, 1H). 1-allyloxymethi1-3-nitrobenzene (XXIIb) (XXI b) (XVII b) To a mixture of (XXIb) (5 g, 32.6 mmol) and allyl bromide (11.3 ml, 130.4 mmol) at room temperature is added KOH (3.65 g, 65.2 mmol) and TBAI (602). mg, 1.63 mmol) and the resulting mixture is stirred at 40 ° C overnight. The reaction mixture is cooled and quenched with H20. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried with Na2SO4 and concentrated under reduced pressure to obtain an oil, which is purified by column (EtOAc / Hexane: 9/1 ) to obtain 6.3 g of (XXIIb). LC-MS (ESI positive mode) m / z 194 ([M + H] +). XH NMR (CDC13) d 8.27 (s, 1H), 8.18 (dd, 1H), 7.73 (dd, 1H), 7.57 (t, 1H), 6.01 (m, lH), -5.38 (m, 1H), 5.29 (m, 1H), 4.65 (s, 2H), 4.13 (dt, 2H). 3-allyloxymethyl-phenylamine (XVIbl) (XVIIb) (XVIbl) To a solution of (XXIIb) (10 g, 51.75 mmol) in MeOH / CH2Cl2 (1: 1, 150 ml) at room temperature is added SnCl2-2H20 (46.7 g, 207 mmol) and the mixture The resulting mixture is stirred overnight. The reaction mixture is cooled to 0 ° C and quenched with saturated Na 2 CO 3. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried with Na 2 SO 4 and concentrated under reduced pressure to obtain an oil, which is purified by column (EtOAc / Hexane: 5/1) to obtain 6.80 g of (XVIbl) in 80% yield. LC-MS (ESI positive mode) m / z 164 ([M + H] +). XH NMR (CDC13) d 7.17 (t, 1H), 6.79 (m, 2H), 6.68 (d, 1H), 5.95-6.06 (m, 1H), 5.33 (m, 1H), 5.29 (m, 1H), 4.49 (s, 2H), 4.06 (m, 2H), 3.38 (s, 2H). (3-Allyoxymethyl-phenyl) - [4- (3-but-3-enyloxy-phenyl) -pyrimidin-2-yl] -amine (XVIIbl) (XVal) (XVIbl) (XVIIbl) To a mixture of (XVal) (100 mg, 0.38 mmol) and (XVIbl) (93.9 mg, 0.57 mmol) in n-butanol (15 ml) at room temperature, add 1 N HCl (1.0 ml) and the resulting mixture Stir at 100 ° C overnight. The reaction mixture is cooled to 0 ° C and quenched with H20. The product is extracted with CH2C12 three times and the combined organic extracts are washed with saturated NaHCO3 followed by brine, dried with Na2SO4 and concentrated under pressure. reduced to obtain an oil, which is purified by column (EtOAc / Hexane) to obtain 70 mg of (XVIIbl) by 47%. XH NMR (CDC13) d 8.38 (d, 1H), 7.59-7.62 (m, 3H), 7.58 (d, 1H), 7.41 (s, 1H), 7.32 (t, 1H), 7.26 (t, 1H), 7.08 (d, 1H), 6.96-6.98 (m, 2H), 5.80-5.94 (m, 2H), 5.25 (m, 1H), 5.10-5.15 (m, 2H), 5.06 (m, 1H), 4.48 (s, 2H), 4.04 (t, 2H), 3.99 (m, 2H), 2.50 (m, 2H).

EXAMPLE OF MACROCICLO 1 (Compound 1) (XVIIbl) (i) To a degassed solution of (XVIIbl) (20 mg, 0.05 mmol) and TFA (14 mg, 0.125 mmol) in CH2C12 (200 ml) at room temperature is added second generation Grubbs catalyst (7 mg, 0.005 mmol). The resulting mixture is stirred at 50 ° C overnight. The reaction mixture is cooled and concentrated under reduced pressure to obtain an oil, which is purified by preparative HPLC to obtain 9 mg of (1). Purity HPLC at 254 nm: 95%.

LC-MS (ESI positive mode) m / z 360 ([M + H] +). X H NMR (CDCl 3) d 11.75 (s, 1 H), 8.38 (m, 1 H), 8.18 (d, 1 H), 7.92 (m, 1 H), 7.41-7.42 (m, 1 H), 7.30 (t, 1 H), 7.23 (d, 1H, CH), 7.10-7.20 (m, 3H), 5.61-5.73 (m, 2H, Jtrans = 16.0 Hz), 4.51 (s, 2H), 4.11 (t, 2H), 4.08 (d, 2H), 2.48 (q, 2H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIIc) l-allyloxy-3-nitro-benzene (XXIIc) (XXc) (XVIIc) The compound (XXIIc) is obtained using the same procedure described for the compound (XXIIb). LC-MS (ESI positive mode) m / z 180 ([M + H] +). 3-allyloxy-phenylamine (XVIcl) (XVIIc) (XVIcl) The compound (XVIcl) is obtained using the same procedure described for the compound (XVIbl). LC-MS (ESI positive mode) m / z 150 ([M + H] +). (3-allyloxyphenyl) - [4- (3-but-3-enyloxy-phenyl) -pyrimidin-2-yl] -amine (XVIIcl) (XVal) (XVIcl) (XVIIcl) The compound (XVIIcl) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 374 ([M + H] +).

EXAMPLE OF MACROCYCLE 2 (Compound 12) (XVIId) (12) The compound (12) is obtained using the same procedure described for the compound (1).

Purity HPLC at 254 nm: 99%. LC-MS (ESI positive mode) m / z 346 ([MH-H] +). XH NMR (CDC13) d 11.30 (s, 1H), 8.29 (d, 1H), 8. 21 (t, 1H), 8.11 (t, 1H), 7.57 (d, 1H), 7.48 (t, 1H), 7.32-7.35 (m, 2H), 7.22-7.25 (m, 1H), 6.95 (dd, 1H), 6.82 (dd, 1H), 6.02-6.08 (m, 1H, CH =, JtranS = 11 Hz), 5.87-5-93 (m, 1H, CH =, Jtrans = 11 Hz), 4.78 (d, 2H), 4.29 (t, 2H), 2.63-2.68 (m, 2H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIId) [3- (2-chloro-pyrimidin-4-yl) -phenyl] -methanol (XIIIa2) (la) (XIIIa2) The compound (XIIIa2) is obtained using the same procedure described for the compound (XlIIal). LC-MS (ESI positive mode) m / z 221 ([M + H] +). 4- (3-Allyloxymethyl-phenyl) -2-chloro-pyrimidine (XVa2) (XIIIa2) (XVa2) The compound (XVa2) is obtained using the same procedure described for the compound (XVal). LC-MS (ESI positive mode) m / z 271 ([M + H] +). 2- (2-chloro-ethoxy) -5-nitro-benzaldehyde (XXId) (XXd) (XXId) To a mixture of (XXd) (1.0 g, 5.98 mmol) and bromochloroethane (996 μL, 11.96 mmol) in dry DMF (15 mL) at room temperature is added potassium carbonate (1.64 g, 11.96 mmol) and the resulting mixture it is stirred at 60 ° C overnight. The reaction mixture is cooled to 0 ° C and quenched with H20. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried over Na2SO4 and concentrated under reduced pressure to obtain 1.29 g of a colored solid. yellow (XXId) with 94% yield. LC-MS (ESI positive mode) m / z 229 ([M + H] +). X H NMR (CDC13) d 10.56 (s, 1H), 8.78 (d, 1H), 8.50 (dd, 1H), 7.15 (d, 1H), 4.54 (t, 2H), 3.99 (t, 2H). [2- (2-chloro-ethoxy) -5-nitro-phenyl] -methanol (XXIId) The compound (XXIId) is obtained using the same procedure described for the compound (XXIb). LC-MS (ESI positive mode) m / z 232 ([M + H] +). 2-Allyoxymethyl-1- (2-chloro-ethoxy) -4-nitro-benzene (XXIIId) (XXIId) (XXIIId) The compound (XXIIId) is obtained using the same procedure described for the compound (XXIIb). LC-MS (ESI positive mode) m / z 272 ([M + H] +). 1- [2- (2-Allyloxymethyl-4-nitro-phenoxy) -ethyl] -pyrrolidine (XXIVd) (XXIIId) To a solution of (XXIIId) (1 g, 3.68 mmol) in DMA (10 mL) is added pyrrolidine (0.61 mL, 7.36 mmol) and the resulting mixture is stirred overnight at 60 ° C. The reaction mixture is quenched with water. The product is extracted with CH2C12 three times and the combined organic extracts are washed with H20 followed by brine, dried with Na2SO and concentrated under reduced pressure to obtain 750 mg of compound (XXIVd) in 70% yield without purification. LC-MS (ESI positive mode) m / z 307 ([M + H] +). 3-Allyoxymethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (XVIb2) The compound (XVIb2) is obtained using the same procedure described for the compound (XVIb).

LC-MS (ESI positive mode) m / z 277 ([M + H] +). [4- (3-Allyoxymethyl-phenyl) -pyrimidin-2-yl] - [3-allyloxymethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amine (XVIIdl) (XVIIdl) The compound (XVIIdl) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 501.

EXAMPLE OF MACROCICLO 3 (Compound 13) (XVIIdl) (13) The compound (13) is obtained using the same procedure described for the compound (1). Purity HPLC at 254 nm: 99%. LC-MS (ESI positive mode) m / z 473 ([M + H] +).

XH NMR (Me0D-d4) d 8.79 (d, 1H), 8.46 (d, 1H), 8.34-8.31 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.49 (m, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 1H), 7.07-7.02 (m, 1H), 5.98-5.75 (m, 2H, 2x = CH), 4.67 (s, 2H), 4.67 (s, 2H) , 4.39-4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88-3.82 (m, 2H), 3.70 (t, 2H), 2.23-2.21 (m, 2H), 2.10 -2.07 (m, 2H).

EXAMPLE OF MACROCICLO 4 (Compound 53) (13) (53) To a solution of (13) (0.02 g) in mixture of CH2C12 (2 ml) dioxane (1 ml) at 0 ° C is added 5 mol% of Pd (OAc) 2. Then fresh ethereal solution of CH2N2 is added slowly. The resulting mixture is stirred at 0 ° C for 3 hours. The reaction mixture is then concentrated under reduced pressure to obtain an oil, which is purified by preparative HPLC to obtain 0.005 g of (53). (CDC13) d 8.78 (br s, 1H), 8.63 (br s, 1H), 8.42 (d, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.18 ( d, 1H), 6.83 (m, 2H), 5.12 (d, 1H), 4.87 (d, 1H), 4.72 (d, 1H), 4.61 (d, 1H), 4.14-4.19 (m, 2H), 4.03-4.07 (m, 2H), 2.99 (t, 2H), 2.81-2.86 (m, 1H), 2.74 (br s, 4H ), 2.66-2.71 (m, 1H), 1.81-1.86 (m, 4H), 1.04-1.15 (m, 2H,), 0.28-0.33 (m, 1H), 0.15-0.20 (m, 1H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIIe) - (2-chloro-pyrimidin-4-yl) -thiophen-2-carbaldehyde (XHIel) (Xllel) (XIHel) To a solution of 1,4-dioxane, 2,4-dichloropyrimidine is added and the reaction is evacuated and purged with N 2. Then add dppf catalyst ([1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium (II) and the system is evacuated and purged again with N2, then added sequentially (Xllel) and saturated bicarbonate solution and the solution is stirred at 85 ° C under N2 for 1 hour, the solution is cooled and filtered through celite and washed with DCM three times. extract with water. The aqueous layer is extracted with DCM and all DCM layers are dried with Na2SO4 and removed in vacuo. The crude product is purified by flash chromatography eluting with 40% ethyl acetate in hexane to obtain a pale yellow solid (XHIel) (50%). LC-MS (ESI positive mode) m / z 225 ([M + H] +). X H NMR (CDC13) d 10.64 (s, 1 H), 8.68 (d, 1 H), 7.66 (m, 2 H), 7.57 (d, 1 H). [5- (2-chloro-pyrimidin-4-yl) -thiophen-2-yl] -methanol (XIIIe2) The compound (XIIIe2) is obtained using the same procedure described for the compound (XXIb) with a yield of 90%. LC-MS (ESI positive mode) m / z 227 ([M + H] +). X H NMR (CDCl 3) d 8.62 (d, 1H), 7.55 (m, 2H), 7.25 (d, 1H), 4.83 (s, 2H), 4.68 (bs, 1H). 4- (5-Allyloxymethyl-thiof en-2-yl) -2-chloropyrimidine (XVel) (XIIIe2) (XVel) The compound (XVel) is obtained using the same procedure described for the compound (XXIIb) with a yield of 80%. LC-MS (ESI positive mode) m / z 267 ([M + H] +). [3-allyloxymethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - [4- (5-allyloxymethyl-thiophen-2-yl) -pyrimidin-2-yl] • amine (XVIIel) (XVel) (XVIb2) (XVIIel) The compound (XVIIel) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 507.

EXAMPLE OF MACROCICLO 5 (Compound 48) (XVIIel) (48) The compound (48) is obtained using the same procedure described for the compound (1). HPLC purity at 254 nm: 100%. LC-MS (ESI positive mode) m / z 479 ([M + H] +). XH NMR (MeOD-d4): d 8.66 (d, 1H), 8.32 (d, 1H), 7.81 (d, 1H), 7.27 (d, 1H), 7.12 (dd, 1H), 7.07-7.02 (m, 2H), 6.08 (dt, 1H, CH, J = 4.4 Hz, Jtrans = 15.6 Hz), 5.98 (dt, 1H, CH, J = 4.6 Hz, Jtrans = 15.6 Hz), 4.61 (s, 2H), 4.38 ( t, 2H), 4.18 (d, 4H), 3.81 (br s, 2H), 3.69 (t, 2H), 3.37-3.35 (m, 2H), 2.22-2.08 (m, 6H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIIF) - (2-chloro-pyrimidin-4-yl) -furan-2-carbaldehyde (XlIIfl) The compound (XlIIfl) is obtained using the same procedure described for the compound (XlIIel). LC-MS (ESI positive mode) m / z 209 ([M + H] +). [5- (2-chloro-pyrimidin-4-yl) -furan-2-yl] -methanol (XIIIf2) The compound (XIIIf2) is obtained using the same procedure described for the compound (XXIb). LC-MS (ESI positive mode) m / z 211 ([M + H] +). 4- (5-Allyoxymethyl-furan-2-yl) -2-chloro-pyrimidine (XVfl) (XIIIf2) (XVfl) The compound (XVfl) is obtained using the same procedure described for the compound (XXIIb). LC-MS (ESI positive mode) m / z 251 ([M + H] +). [4- (5-Allyoxymethyl-furan-2-yl) -pyrimidin-2-yl] - [3-allyloxymethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amine (XVIIfl) (XV fl) (XV I b2) (XVII fl) The compound (XVIIfl) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 491.

EXAMPLE OF MACROCYCLE 6 (Compound 38) (XVIIfl) (38) The compound (38) is obtained using the same procedure described for the compound (1). Purity HPLC at 254 nm: 99%. LC-MS (ESI positive mode) m / z 463 ([M + H] +). X H NMR (MeOD-d 4) d 8.90 (d, 1 H), 8.33 (d, 1 H), 7.37 (d, 1 H), 7.17 (d, 1 H), 7.14-7.11 (m, 1 H), 7.04 (d, 1 H) ), 6.67 (d, 1H), 6.04 (dt, 1H, CH, J = 5.2 Hz, Jtrans = 15.8 Hz), 5.96 (dt, 1H, CH, J = 5.0 Hz, Jtrans = 15.8 Hz), 4.65 (s) , 2H), 4.62 (s, 2H), 4.37 (t, 2H), 4.14 (d, 2H), 4.09 (d, 2H), 3.81 (br s, 2H), 3.66 (t, 2H), 3.33 (s) , 2H), 2.21-1.98 (m, 4H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIIgl) 4- (2-chloro-pyrimidin-4-yl) -thiophen-2-carbaldehyde (XlIIgl] (xpgi) The compound (XlIIgl) is obtained using the same procedure described for the compound (XlIIel). LC-MS (ESI positive mode) m / z 225 ([M + H] +). [4- (2-chloro-pyrimidin-4-yl) -thiophen-2-yl] -methanol (XIIIg2) The compound (XIIIg2) is obtained using the same procedure described for the compound (XXIb). LC-MS (ESI positive mode) m / z 227 ([M + H] +). 4- (5-Allyloxymethyl-thiophen-3-yl) -2-chloro-pyrimidine (ygi) The compound (XVIgl) is obtained using the same procedure described for the compound (XXIIb). LC-MS (ESI positive mode) m / z 267 ([M + H] +) [3-allyloxymethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - [4- (5-allyloxymethyl-thiophen-3-yl) -pyrimidin-2-yl] -amine (XVIIgl) (xvgi) (XVIb2) (XVIIgl) The compound (XVIIgl) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 507.

EXAMPLE OF MACROCICLO 7 (Compound 52) (XVIIgl) The compound (52) is obtained using the same procedure described for the compound (1). Purity HPLC at 254 nm: 99%. LC-MS (ESI positive mode) m / z 479 ([M + H] +). X H NMR (MeOD-d 4): d 9.03 (d, 1 H), 8.86 (d, 1 H), 8.81 (d, 1 H), 8.26 (s, 1 H), 7.81 (d, 1 H), 7.59. (dd, 1H), 7.56-7.51 (m, 1H), 6.38 (dt, 1H, CH, J = 5.7 Hz, Jtrans = 15.7 Hz), 6.31 (dt, 1H, CH, J = 5.4 Hz, Jtrans = 15.7 Hz), 5.24 (s, 2H), 5.14 (s, 2H), 4.86 (t, 2H), 4.65 (d, 2H), 4.54 (d, 2H), 4.29 (br s, 2H), 4.18 (t, 2H), 3.84-3.83 (m, 2H), 2.80-2.48 (m, 4H).

REPRESENTATIVE PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS OF TYPE (XVIIIhl) 4- (2-chloro-pyrimidin-4-yl) -furan-2-carbaldehyde (XlIIhl) The compound (XlIIhl) is obtained using the same procedure described for the compound (XIIIel). LC-MS (ESI positive mode) m / z 209 ([M + H] +). [4- (2-chloro-pyrimidin-4-yl) -furan-2-yl] -methanol (XIIIh2) The compound (XIIIh2) is obtained using the same procedure described for the compound (XXIb). LC-MS (ESI positive mode) m / z 211 ([M + H] +). 4- (5-Allyoxymetfuran-3-yl) -2-chloro-pyrimidine (XVhl) The compound (XVhl) is obtained using the same procedure described for the compound (XXIIb). LC-MS (ESI positive mode) m / z 251 ([M + H] +). [4- (5-Allyoxymetfuran-3-yl) -pyrimidin-2-yl] - [3-allyloxymet4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amine (XVIIhl) (XVhl) (XVIb2) (XVIIhl) The compound (XVIIhl) is obtained using the same procedure described for the compound (XVIIbl). LC-MS (ESI positive mode) m / z 491.

EXAMPLE OF MACROCICLE 8 (Compound 50) (XVIIhl) The compound (50) is obtained using the same procedure described for the compound (1). Purity HPLC at 254 nm: 99%. LC-MS (ESI positive mode) m / z 463 ([M + H] +). X H NMR (MeOD-d 4): d 8.56 (d, 1 H), 8.38 (d, 1 H), 8.29 (br s, 1 H), 7.17 (d, 1 H), 7.11-7.06 (m, 2 H), 7.03-7.01 (m, 1H), 5.99 (dt, 1H, CH, J = 6.0 Hz, Jtrans = 15.6 Hz), 5.84 (dt, 1H, CH, J = 5.8 Hz, Jtrans = 15.6 Hz), 4.66 (s, 2H2) , 4.57 (s, 2H), 4.37 (t, 2H), 4.18 (d, 2H), 4.09 (d, 2H), 3.79 (br s, 2H), 3.69 (t, 2H), 3.35-3.34 (m, 2H), 2.21-2.07 (m, 4H).

The compounds indicated in Table 1 are synthesized following the procedures outlined above.

TABLE 1 fifteen twenty fifteen twenty fifteen twenty 1 As previously indicated in one embodiment of the invention, the compounds are of the formula (III): Formula (III) By following procedures analogous to those described above and making appropriate modifications to the starting materials, the compounds listed in Table 2 can also be prepared.

TABLE 2 TABLE 2 (cont.) In each of the listed compounds, the geometry around the double bond can be cis or trans.

B The position of R10 and R11 may vary depending on the position of the corresponding substituent in the relevant starting material. In another embodiment of the invention, the compounds are of the formula (IV): Formula (IV) Following procedures analogous to those described above and making appropriate modifications to the starting materials, the compounds listed in Table 3 can also be prepared.

TABLE 3 TABLE 3 (cont.) In each of the listed compounds, the geometry around the double bond can be cis or trans B. The position of R10 and Rn can vary depending on the position of the corresponding substituent in the relevant starting material. In another embodiment of the invention, the compounds are of the formula (V): Formula (V) By following procedures analogous to those described above and making appropriate modifications to the starting materials, the compounds listed in Table 4 can also be prepared.

TABLE 4 TABLE 4 (cont.) TABLE 4 (cont.) In each of the listed compounds, the geometry around the double bond can be cis or trans B. The position of R1oU and R1i1 can vary depending on the position of the corresponding substituent in the relevant starting material. In another embodiment of the invention, the compounds are of the formula (VI): Formula (VI) By following procedures analogous to those described above and making appropriate modifications to the starting materials, the compounds listed in Table 5 can also be prepared.

TABLE 5 TABLE 5 (cont.) In each of the listed compounds, the geometry around the double bond can be cis or trans. B The position of R, 1? 0? and R > ? 1? 1 may vary depending on the position of the corresponding substituent in the relevant starting material. In another embodiment of the invention, the compounds are of the formula (VII): Formula (VII) Following procedures analogous to those described above and by making appropriate modifications to the starting materials, the compounds listed in Table 6 can also be prepared.

TABLE 6 TABLE 6 (cont.) ? In each of the listed compounds, the geometry around the double bond can be cis or trans. B The position of R, 1i0U and R11 may vary depending on the position of the corresponding substituent in the relevant starting material.

BIOLOGICAL EVALUATION 1. Testing for kinase activity in vi tro Recombinant enzymes (CDK2 / Cyclin A, FLT3, JAK2 and JAK2 V617F) are purchased from Invitrogen (Cat # PV3267, 3182, 4210 and 4347 respectively). All tests are performed on 384-well white microtiter plates using the Cambrex PKLight test system (East Rutherford, New Jersey). This test platform is essentially a luminometric test for the detection of ATP in the reaction using a reaction coupled with luciferase. For the CDK2 / Cyclin A test, the reaction mixture consists of the following components in 25 μl of buffer for testing (50 mM Hepes, pH 7.5, 10 mM MgCl2, 5 mM MnCl2, 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 μg / ml CDK2 / Cyclin A complex, 0.5 μM RbING substrate (Invitrogen, Cat # PV2939) and 0.5 μM ATP. The compounds are analyzed at 8 concentrations prepared from 4-fold serial dilution starting at 10 μM. The reaction is incubated at room temperature for 2 hours. 13 μl of the PKLight ATP detection reagent is added and the reaction is incubated for 10 minutes. The luminescence signals are detected in a multiple-brand plate reader (Victor2 V 1420, Perkin-Elmer). The other kinase tests are identical except for the following differences in the reagents. For the FLT3 tests, the reaction contains 2.0 μg / ml of FLT3 enzyme, 5 μM of poly (Glu, Tyr) substrate (Sigma, Cat # P0275) and 4 μM of ATP. For the JAK2 tests, the reaction contains 0.6 μg / ml of JAK2 enzyme, 2 μM of poly substrate (Glu, Ala, Tyr) (Sigma, Cat # P3899) and 0.2 μM of ATP. For tests of the JAK2 V617F mutant, the reaction contains 8.0 μg / ml of the JAK2 mutant enzyme, 2 μM of poly (Glu, Ala, Tyr) substrate (Sigma, Cat # P3899) and 0.2 μM of ATP. The analytical program, Prism 4.0 (GraphPad Software Pte Ltd) is used to generate the IC50 values from the data. IC 50 is defined as the concentration of compound required to inhibit the activity of enzyme kinase by 50%. The IC 50 values are shown below in Table 7.

TABLE 7 IC50 data of the in vitro kinase activity test TABLE 7 (cont.) NA = not analyzed CI50 < lμM +++ lμM < IC50 < 5μM ++ IC50 5μM + 2. Cell lines The cell lines used in the studies are presented in summary form in the following table 8: TABLE 8 Characteristics of the human cell lines used 3. Cell-based proliferation test for determination of GI50 values The biological efficacy of the invention is demonstrated by the following test. HL60 cell lines of human cancer (acute myeloid leukemia cell line), Colo205 (colon adenocarcinoma cell line), HEL92.1.7 (erythroleukemia cell line) and MV4-11 (leukemia cell line) acute myeloid) are obtained from the ATCC. These are grown in the media in accordance with the ATCC work instructions. Colo205 cells are seeded in 96-well plates at 5000 cells per well. HEL92.1.7 cells and MV4-11 are seeded at 6000 cells per well while HL60 cells are seeded at 8000 cells per well in 96-well plates. The plates are incubated at 37 ° C, 5% C02, for 24 hours. The cells are treated with the compounds at various concentrations for 96 hours. Cell growth is then monitored using the cell proliferation assay "Celltiter96 Aqueous One Solution" from Promega (Madison Wisconsin). Dose-response curves are plotted to determine the GI50 values for the compounds using XL-fit (ID Business Solution, Emeryville, CA). GI50 is defined as the concentration of compound required for 50% inhibition of cell growth. The compounds of this invention inhibit cell proliferation as shown in the following table 9. The data indicate that the compounds of this invention are active in the inhibition of tumor cell growth.

TABLE 5 GI50 data of the cell-based proliferation test TABLE 5 (cont.) NA = not analyzed GI50 < lμM +++ lμM < GI50 < 5μM + + GI50 > 5μM + Antineoplastic (or antitumor) effect in vivo The efficacy of the compounds of the invention can then be determined using xenograft studies in vivo in animals. The animal xenograft model is one of the most commonly used in cancer models in vivo. In these studies, nude athymic female mice (Harian), 12-14 weeks of age, were implanted subcutaneously in the flank, 5 x 10 6 human biphenotypic myelomonocytic B-cell MV4-11 leukemia cells in Matrigel (BD Biosciences, in 1: 1). When the tumor reaches a size of 100 mm3, several treatment groups are formed with nude xenograft mice. The selected kinase inhibitors are dissolved in the appropriate vehicles and administered to nude xenograft mice intraperitoneally or orally daily for 21 days. The volume of the dose is 0.01 ml / g body weight. The volume of the tumor is calculated every second day or twice a week after the injection using the equation: Volume (mm3) = (w2 xl) / 2, where w = width and 1 = length in mm of a MV4 tumor -eleven. The compounds of this invention that are tested show a significant reduction in tumor volume relative to vehicle-only controls. Therefore the result indicates that the compounds of this invention are effective in treating a proliferative disease such as cancer. The details of the specific modalities described in this invention should not be considered as limitations. Various equivalents and modifications can be made without departing from the essence and scope of this invention, and it should be understood that such equivalent embodiments are part of this invention.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS 1. - A compound of the formula (I): Formula (I) wherein: R1 and R2 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, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, -COOH, -COR3, -COOR3, -CONHR3, -NHCOR3 , -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, ariisulfonilo, arylsulfinyl, aminosulfonyl, -SR3, R4S (0) R6-, RS (0) 2R6-, R4C (0) N (R5) R6- , R4S02N (R5) R6-, R4N (R5) C (0) R6-, R4N (R5) S02R6-, R 4 N (R 5) C (0) N (R 5) R 6 - and acyl, each of which may be optionally substituted; each R3, R4, and R5 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each one of which may be optionally substituted; each R6 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 can be optionally substituted; Z2 is selected from the group consisting of a bond, 0, S, -N (R7) -, -N (R7) -alkyl (C? -2) -, and -alkyl (d-2) -N ( R7) -; each R7 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 can be optionally substituted; Ar1 and Ar2 are independently selected from the group consisting of aryl and heteroaryl, each of which may be optionally substituted; L is a group of the formula: -X1-Y-X "- in which X1 is attached to Ar1 and X2 is attached to Ar2, and in which X1, X2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain, X1 and X2 are each independently a heteroalkyl group containing at least one atom from Oxygen in the normal chain, Y is a group of the formula -CRa = CRb- or an optionally substituted cycloalkyl group, characterized in that Ra and Rb are each 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, or Ra and Rb may be joined such that when taken together with the carbon atoms to which these are attached form a cycloalkenyl or cycloheteroalkenyl group; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.
2. A compound according to claim 1, characterized in that Z2 is -N (H) -.
3. A compound according to claim 1 or 2, characterized in that Ar1 is selected from the group consisting of: wherein V1, V2, V3 and V4 are each independently selected from the group consisting of N, and C (R10); W is selected from the group consisting of O, S and N (R10); W1 and W2 are each independently selected from the group consisting of N and C (R10); wherein each R10 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, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, -COOH, -COR3, -COOR3, -CONHR3, -NHCOR3, -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, aryisulfonyl,. arylsulfinyl, aminosulfonyl, -SR3, R4S (0) R6-, R4S (0) 2R6-, R4C (O) N (R5) R6-, R4S02N (R5) R6-, R4N (R5) C (0) R6-, R4N (R5) S02R6-, R4N (R5) C (0) N (R5) R6- and acyl, each of which may be optionally substituted, in which R3, R4, R5 and R6 are as defined in claim 1. 4. - A Composite according to any of claims 1 to 3, characterized in that Ar1 is selected from the group consisting of: wherein R10 is as defined in claim 3, k is an integer that is selected from the group consisting of 0, 1, 2, 3, and 4; n is an integer that is selected from the group consisting of 0, 1, 2, and 3; and q is an integer that is selected from the group consisting of 0, 1, and 2. 5. A compound according to any of claims 1 to 4, characterized in that Ar2 is a group selected from group consisting of: in which each R is selected independently 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, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylammo, -COOH, -COR3, -COOR3, -CONHR3, -NHCOR3 , -NHCOOR3, -NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, -SR3, R4S (0) R6-, R4S (0) 2R6 ~, R4C (O) N (R5) R6- , R4S02N (R5) R6-, R4N (R5) C (0) R6-, R4N (R5) S02R6-, R4N (R5) C (O) N (R5) Rd- and acyl, each of which may be optionally substituted. 6. A compound according to any of the preceding claims, characterized in that the compound is selected from the group consisting of: wherein R1, R2, R10, R11, k, X1, X2, Y, q and "o" are as defined above, or a pharmaceutically acceptable salt thereof. 7. A compound according to any of claims 1 to 6, characterized in that X1 and X2 are select each independently from the group consisting of: (a) -O-alkyl (C? _5) -, (b) -alkyl (C? -5) -0-, and (c) -alkyl ( C1-5) -O-C1-5 alkyl. 8. - A compound according to any of claims 1 to 7, characterized in that X1 is selected from the group consisting of: (a) -OCH2- (b) -CH20-, (c) -OCH2CH2-, (d) -CH2CH20-, (e) -CH2OCH2-, and ( f) -CH2CH2OCH2-. 9. A compound according to any of claims 1 to 8, characterized in that X2 is selected from the group consisting of: (a) -OCH2- (b) -CH2O-, (c) -OCH2CH2-, ( d) -CH2CH20-, (e) -CH2OCH2-, and (f) -CH2CH2OCH2-. 10. A compound according to claim 1, which is selected from the group that it consists of: wherein R1, R2, R10, R11, k, Y, q and "o" are as defined above; or a pharmaceutically acceptable salt thereof. 11. A compound according to any of claims 1 to 10, characterized in that R1 and R2 are H. 12. A compound according to any of claims 3, 4, 6 or 10, characterized in that R10 is 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. 13. A compound according to any of claims 12, characterized in that R10 is selected from the group consisting of H, hydroxyl, methoxy, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and phenyl. -morpholino-ethoxy, each of which may be optionally substituted. 14. A compound according to any of claims 5, 6 or 10, characterized in that each R11 is independently selected from the group consisting of H, alkoxy, heteroalkyl, heterocycloalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, and arylsulfonyloxy, each one of which may be optionally substituted. 15. A compound according to any of claims 5, 6, 10 or 14, characterized in that each R11 is independently selected from the group consisting of: 16. - A compound in accordance with any of claims 1 to 15, characterized in that Y is selected from the group consisting of: Y 17. - A compound according to any of claims 1 to 16, characterized in that the optional substituent is selected from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl , alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy , heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, aryisulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) 0R5, -SH, -SR5 , -OR6 and acyl. 18. A compound according to claim 1, which is selected from the group consisting of: H H H H H H H H H H H or a pharmaceutically acceptable salt or prodrug thereof. 19. A pharmaceutical composition that includes a compound according to any of claims 1 to 18 and a pharmaceutically acceptable diluent, excipient or vehicle. 20. The use of a compound according to any of claims 1 to 18 to inhibit one or more protein kinase (s). 21.- Use in accordance with the claim 20, characterized in that said one or more protein kinase (s) is a cyclin-dependent protein kinase or a protein tyrosine kinase. 22. A use in accordance with the claim 21, characterized in that the cyclin-dependent kinase is a Group I CMCG kinase that is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKl, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. 23.- Use in accordance with the claim 22, characterized in that the CMCG kinase of Group I is CDK2. 24. Use according to claim 21, characterized in that the protein tyrosine kinase is a tyrosine kinase protein of group VII or a protein tyrosine kinase of group XIV. 25.- A use in accordance with the claim 24, characterized in that the protein tyrosine kinase of group VII is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. 26.- A use in accordance with the claim 24 or 25, characterized in that the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. 27. A use in accordance with the claim 26, characterized in that the JAK2 includes a mutation from V to F at position 617. 28.- A use in accordance with the claim 24, characterized in that the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. 29.- A use in accordance with the claim 28, characterized in that the protein tyrosine kinase of Group XIV is FLT3 or a functional equivalent thereof. 30.- A use in accordance with the claim 29, characterized in that the FLT3 includes an internal tandem duplication of the amino acids VDFREYEYDH at position 592-601. The use of a compound according to any of claims 1 to 18, in the preparation of a medicament for treating a condition in an animal in which the inhibition of one or more protein kinase (s) can prevent, inhibit or improve the pathology or symptomatology of the condition. 32. A use according to claim 31, characterized in that said one or more protein kinase (s) is a cyclin-dependent protein kinase or a protein tyrosine kinase. 33.- A use in accordance with the claim 32, characterized in that the cyclin-dependent kinase is a Group I CMCG kinase that is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK / M015, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKl, PfC2R, EhC2R, CfCdc2R, cdc2 +, CDC28, PH085, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. 34.- A use in accordance with the claim 33, characterized in that the CMCG kinase of Group I is CDK2 or a functional equivalent thereof. 35. Use according to any of claims 32 to 34, characterized in that the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatic cell carcinoma, malignant neoplasm of the pancreas, myeloid leukemia, cervical carcinoma, fibroid tumor, colon adenocarcinoma, T cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, musculoskeletal neoplasms and Alzheimer's disease. 36.- A use according to claim 32, characterized in that the protein tyrosine kinase is a protein tyrosine kinase of group VII or a protein tyrosine kinase of group XIV. 37. - A use in accordance with the claim 36, characterized in that the protein tyrosine kinase of group VII is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. 38.- A use in accordance with the claim 37, characterized in that the protein tyrosine kinase of group VII is JAK2 or a functional equivalent thereof. 39.- A use in accordance with the claim 38, characterized in that the JAK2 includes a mutation from V to F at position 617. 40.- A use according to any of claims 36 to 39., characterized in that the condition is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblast leukemia, Hodgkin, B cell lymphoma, acute T cell leukemia, breast tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and degeneration of the retina. 41.- A use in accordance with the claim 38, characterized in that the protein tyrosine kinase of Group XIV is selected from the group consisting of PDGFR-b, PDGFR-a, CSFIR, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. 42.- A use in accordance with the claim 41, characterized in that the protein tyrosine kinase of Group XIV is FLT3 or a functional equivalent thereof. 43.- A use in accordance with the claim 42, characterized in that the FLT3 includes an internal tandem duplication of the amino acids VDFREYEYDH at position 592-601. 44. A use according to any of claims 41 to 43, characterized in that the condition is selected from the group consisting of acute 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. 45.- The use of a compound according to any of claims 1 to 18 in the preparation of a medicament for the treatment or prevention of a kinase-related disorder. 46.- A use in accordance with the claim 45, characterized in that the kinase-related disorder is a proliferative disorder. 47.- A use in accordance with the claim 46, characterized in that the proliferative disorder is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocytopenia, 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 tissue carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast tissue, malignant colon tumor, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatic cell carcinoma, neoplasm malignant of the pancreas, myeloid leukemia, carci cervical noma, fibroid tumor, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, neoplasms of the bladder, and musculoskeletal neoplasms. 48. A use according to claim 46, characterized in that the proliferative disorder is cancer. 49.- A use in accordance with the claim 48, characterized in that the cancer is a solid tumor or a hematologic cancer. 50.- A use in accordance with the claim 49, characterized in that the solid tumor is a tumor present in or metastasized from an organ or tissue that is 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. 51. A use according to claim 49, characterized in that the haematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, cell leukemia Acute B, chronic myeloid leukemia, acute T cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute leukemia of erythroblast, Hodgkin's disease, and B-cell lymphoma. 52. A method for synthesizing a compound of formula I in accordance with claim 1, the method includes the steps of: (a) providing a compound of the formula wherein R1, R2, Ra, R, Z2, Ar1, Ar2, X1 and X2 are as defined in claim 1; (b) subjecting the compound to ring closure metathesis; (c) optionally reacting the double bond formed in this manner to form a cycloalkyl group. 53. A method according to claim 52, characterized in that step (b) involves treating the salt of trifluoroacetic acid (TFA) or hydrochloric acid (HCl) of the compound with 5-10 mole% of the second generation catalyst of Grubbs in dichloromethane at 40 ° C. 54. - A method according to claim 52 or 53, characterized in that step (c) includes treating the metathesis product with a freshly prepared ethereal solution of diazomethane (CH2N2) in dichloromethane / dioxane at 0 ° C.