WO2008140420A2

WO2008140420A2 - Pyrimidine derivatives

Info

Publication number: WO2008140420A2
Application number: PCT/SG2008/000179
Authority: WO
Inventors: Haishan Wang
Original assignee: S*Bio Pte Ltd
Priority date: 2007-05-15
Filing date: 2008-05-14
Publication date: 2008-11-20
Also published as: WO2008140420A3

Abstract

The present invention relates to pyrimidine compounds that are useful as agents for the treatment of kinase related disorders such as proliferative disorders. More particularly, the present invention relates to 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 kinase related disorders such as proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with kinases.

Description

PYRIMIDINE DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to pyrimidine compounds that may be useful as agents for targeting kinase related disorders. More particularly, the present invention relates to substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of kinase related disorders such as proliferative disorders. These compounds may therefore be useful as medicaments for the treatment of a number of kinase related disorders such as proliferative disorders including tumours and cancers as well as other conditions or disorders associated with kinases.

BACKGROUND OF THE INVENTION

There are a number of kinase related disorders known at the present time with proliferative disorders being one of the best characterised. Proliferative disorders such as cancer are characterised by the uncontrolled growth of cells within the body. As such proliferative disorders generally involve an abnormality in the control of cell growth and/or division leading to the formation of tumour and ultimately death. Without wishing to be bound by theory it is thought that this is caused by the pathways that regulate cell growth and division being altered in cancer cells. The alteration is such that the effects of these normal regulatory mechanisms in controlling cell growth and division either fails or is bypassed.

The uncontrolled cell growth and/or division ultimately proves fatal for the patient as successive rounds of mutations on the part of the cell then typically lead to the cancer cells having a selective advantage over normal healthy cells in the body of the patient leading to the cancer cells predominating in the cell mass of the patient. The cancer cells then typically metastasize to colonize other tissues or parts of the body other than the part of origin of the cancer cell leading to secondary tumours which eventually lead to organ failure and the death of the patient. It is the difficulty in controlling the rapid cell growth and division that is characteristic of cancer cells that make it hard to come up with effective chemotherapeutic strategies.

A number of traditional treatments for proliferative disorders such as cancer seek to take advantage of their higher proliferative capacity and thus their higher sensitivity to DNA damage. Treatments that have been utilised include ionizing radiation (γ-rays, X- rays and the like) as well as cytotoxic agents such as bleomycin, cis-platin, vinblastine, cyclophosphamide, 5'-fluorouracil and methotrexate. These treatments all rely on causing damage to DNA and destabilisation of the chromosomal structure eventually leading to death of the cancer cells.

The problem with many of these approaches is that they are non-selective for cancer cells and healthy cells can and often will be 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 in cancer cells (although typically at slower rates) and merely serves to highlight the difficulty in achieving successful treatment of the cancer in the patient without causing irreparable harm to the healthy cells. As such with many of these treatments there can be devastating side effects which can not only significantly reduce the short term quality of life of the patient but may also have long term detriments on the health of the patient should they survive the cancer attack.

Whilst some of the above problems have substantially been 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 by the cancer cells in the patient. The development of drug resistance in the cancer cells of a patient tends to be class specific and therefore if the cancer cells of a patient develop drug resistance to a class of anti-cancer drugs then all compounds within that class are typically rendered ineffective in the further treatment of that patient. As such in improving clinical outcomes for patients the identification of alternative chemotherapeutic agents is essential in providing the oncologist with an arsenal of drugs that may be used in any given situation.

The development of different classes of therapeutic agents is therefore important as it can help avoid the development of drug resistance and can also be used in combination therapies. Such combination therapies typically involve the use of anticancer drugs with different properties and cellular targets which in turn tends to increase the overall effectiveness of any chosen chemotherapy regime and limits the possibility of drug resistance developing in the patient.

One of the major advances in cancer research has been the clinical validation of molecularly targeted drugs that inhibit the activity of protein kinases. Small-molecule kinase inhibitors that are now approved for oncology indications include imatinib, gefitinib, erlotinib, sorafenib, sunitinib and dasatinib [Baselga J., Science, 2006, 312, 1175-1178]. A number of kinases such as JAK2, FLT3 and CDK2 are promising kinase targets for pharmacological intervention in solid tumours, hematological malignancies, myeloproliferative disorders and non-malignant proliferative disorders like keloids.

The Janus kinases (JAK) are a family of cytoplasmic tyrosine kinases consisting of JAK1 , JAK2, JAK3 and Tyk2. They play a pivotal role in the signaling pathways of numerous cytokines, hormones and growth factors [Rawlings JS et al, J. Cell ScL, 2004, 117, 1281-1283]. Their intracellular substrates include the family of proteins called Signal Transducer and Activator of Transcription (STAT). The JAK-STAT pathways, through the proper actions of the ligands, regulate important physiological processes such as immune response to viruses, erythropoiesis, lactation, lipid homeostasis, etc. However, dysfunctional signaling caused by a myriad of factors result in pathophysiological conditions such as allergies, asthma, rheumatoid arthritis, severe combined immune deficiency, hematological malignancies, 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, Hematol. Oncol., 2005, 23, 91-93]. Importantly, the myeloproliferative disorders belong to an area of unmet medical need where some treatment modalities have not been updated over the past few decades [Schafer Al, Blood, 2006, 107, 4214-4222].

The myeloproliferative disorders (MPDs) belong to a group of hematological malignancies arising from clonal expansion of mutated progenitor stem cells in the bone marrow. The association of one MPD, chronic myeloid leukemia, with the Philadelphia chromosome has been well documented. The Philadelphia negative MPDs include Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Chronic Idiopathic Myelofibrosis (MF). No effective treatment is currently available. The recent discovery that a single acquired somatic mutation in JAK2 appears responsible for many of the features of these MPDs promises to impact the diagnosis and treatment of patients with these disorders and to spur additional research into the origins of dysregulated cell growth and function. Until recently, most MPDs have been considered to be rare or orphan diseases but studies underway suggest a much higher prevalence. Essential Thrombocythemia is a chronic MPD characterized by an increased number of circulating platelets, profound marrow megakaryocyte hyperplasia, splenomegaly and a clinical course punctuated by hemorrhagic or thrombotic episodes or both. Current treatment options include low dose aspirin, or platelet lowering agents such as anagrelide, interferon or hydroxyurea. These treatments have severe side effects that compromise the quality of life of patients.

Polycythemia Vera is a chronic progressive MPD characterized by an elevated hematocrit, an increase in the red cell mass, and usually by an elevated leukocyte count, an elevated platelet count and an enlarged spleen. The most common cause of morbidity and mortality is the predisposition of PV patients to develop life threatening arterial and venous thromboses. Treatment options include: phlebotomy with low dose aspirin or myelosuppressive therapy options such as hydroxyurea, interferon or anagrelide. Again, these treatments are not ideal due to severe side effects.

Chronic Idiopathic Myelofibrosis (MF) is a chronic malignant hematological disorder characterized by an enlarged spleen, varying degrees of anemia and low platelet counts, red cells in the peripheral blood that resemble tear drops, the appearance of small numbers of immature nucleated red cells and white cells in the blood, varying degrees of fibrosis of the marrow cavity (myelofibrosis) and the presence of marrow cells outside the marrow cavity (extramedullary hematopoiesis or myeloid metaplasia). Current treatment is directed at alleviation of constitutional symptoms, anemia and symptomatic splenomegaly. Treatment options include hydroxyurea, interferon, thalidomide with prednisone, and allogeneic stem cell transplant. MF has the worst prognosis among the Philadelphia negative MPD and represents an area of greatest unmet medical need.

In addition, due to its role in the angiotensin Il signaling pathway, JAK2 is also implicated in the etiology of cardiovascular diseases like congestive heart failure and pulmonary hypertension [Berk BC et al, Circ. Res, 1997, 80, 607-616]. Furthermore, a putative role for JAK2 has been demonstrated in keloid pathogenesis and may constitute a new approach for keloid management [Lim CP et al, Oncogene, 2006, 25, 5416-5425]. Yet another potential application for JAK2 inhibitors lies in the treatment of retinal diseases as JAK2 inhibition was found to offer protective effects on photoreceptors in a mouse model of retinal degeneration [Samardzija M et al, FASEB J., 2006, 10, 1096]. A family of Class III receptor tyrosine kinases (RTK), including c-Fms, c-Kit, fms- like receptor tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptors (PDGFRα and β), play an important role in the maintenance, growth and development of hematopoietic and non-hematopoietic cells. Overexpression and activating mutations of these RTKs are known to be involved in the pathophysiology of diverse human cancers from both solid and hematological origins [Hannah AL, Curr. MoI. 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 D835 coding sequence have been found [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 involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells [Tickenbrock L et al, Expert Opin. Emerging Drugs, 2006, 11, 1-13]. Several clinical studies have confirmed that FLT3/ITD is strongly associated with a poor prognosis. Because high-dose chemotherapy and stem cell transplantation cannot overcome the adverse effects of FLT3 mutations, the development of FLT3 kinase inhibitors could produce a more efficacious therapeutic strategy for leukemia therapy.

Cyclin-dependent kinases (CDKs) are serine-threonine kinases that play important roles in cell cycle control (CDK1 , 2, 4 and 6), transcription initiation (CDK7 and 9), and neuronal function (CDK5) [Knockaert M et al, Trends Pharmacol. Sci., 2002, 23, 417-425]. Aberrations in the cell cycle CDKs and their cyclin partners have been observed in various tumour types, including those of the breast, colon, liver and brain [Shapiro Gl, J. Clin. Oncol., 2006, 24, 1770-1783]. It is believed that the pharmacological inhibition of CDK1, 2, 4, 6 and/or 9 may provide a new therapeutic option for diverse cancer patients. In particular, the simultaneous inhibition of CDK1, 2 and 9 has recently been shown to result in enhanced apoptotic killing of lung cancer (H1299) and osteosarcoma cells (U2OS), compared with inhibition of single CDK alone [Cai D et al, Cancer Res, 2006, 66, 9270-9280].

Recent advances in biomedical research, including major breakthroughs such as genome-wide association studies, have uncovered new molecular pathways that may be pivotal in the initiation and progression of autoimmune and other inflammatory diseases. These discoveries provide a conceptual framework for the relentless efforts to search for better therapeutic modalities to treat these ailments. The signalling pathway involving JAKs (Janus kinases) and STATs (signal transducer and activator of transcription) is emerging as an important target for anti-autoimmune and anti-inflammatory drug discovery as it constitutes a pivotal signalling mechanism for many novel inflammatory cytokines. JAK2 for example is involved in numerous interleukin signaling pathways which may render it a suitable target for seeking new treatment modalities for inflammatory disorders including asthma, psoriasis, and rheumatoid arthritis [Leonard WJ, int. J. Haematol., 2001, 73, 271].

Inflammation, for example, is a natural biological response to microbial challenge and other forms of threats or breach of tissue integrity. It is characterized by increased vascular permeability accompanied by an infiltration of specialized blood cells (neutrophils, macrophages, lymphocytes and plasma cells) into the inflamed area. These cellular responses are mediated by the appearance of adhesion molecules on endothelia and the release of inflammatory mediators (cytokines and prostaglandins) from tissue cells and leukocytes. The cardinal signs of inflammation are pain, edema, redness and warmth at the affected site. When occurring in a self-limiting fashion within the context of bona fide foreign insults, inflammation is a physiological process that puts the tissues on the path to recovery and prevents further damage.

Many pathological conditions in humans, however, involve inflammatory processes that were inadvertently dys-regulated and exaggerated. This can lead to chronic pain, severe morbidity, or even fatal consequences. Symptoms of inflammation are often present in many autoimmune diseases, which are pathological states caused by the body producing an inappropriate immune response against its own tissues. In such cases, the immune system ceases to recognize one or more of the body's normal constituents as "self and generates auto-antibodies - antibodies that attack its own cells, tissues, and/or organs. This results in inflammation and other concomitant damage which together constitute the symptoms of autoimmune diseases.

The exact cause of autoimmune diseases, as to why normal cellular components or products become auto-antigens that elicit robust immunologic reactions, is unknown. There appears to be a genetic basis underlying susceptibility to many autoimmune conditions and the initiating role played by microbial infections is strong in other cases. Autoimmune disorders fall into two general types: those that affect many organs (systemic) and those where only a single organ or tissue is directly damaged by the autoimmune process (localized). However, the distinction becomes blurred as the effect of localized autoimmune disorders frequently extends beyond the targeted tissues, indirectly affecting other organs and systems.

A number of traditional treatments for autoimmune and other inflammatory diseases, such as corticosteroids, azathioprine, methotrexate, cyclosporine A, rely on the potent non-specific immunosuppressive effects of these agents to mitigate the disease symptoms. These treatments are not satisfactory due to the side effects that will compromise the health of the patients over the long term, such as dysfunctional glucose homeostasis, osteoporosis, susceptibility to opportunistic infections, etc. While some of the above problems have been overcome by the development of new biological therapies (such as TNF-α blockers), about 30% of patients are not responsive to these new agents. As such, there is a need to provide further therapeutic options that would enable the autoimmune specialists to customise treatments for the individual patients. Following the identification of the potential importance of JAK kinases in mediating signalling in these conditions kinase inhibitors provide a potential source of therapeutics for these conditions.

There are therefore a number of kinase targets that have been identified as being involved in a number of disorders and compounds that target these kinases should display interesting biological activity. Accordingly, compounds that are kinase inhibitors have the potential to meet the need to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of kinase related conditions or disorders such as cancer and other proliferative disorders.

SUMMARY OF THE INVENTION The present invention provides compounds of formula (I):

Formula (I) wherein:

R¹ is selected from the group consisting of: H, halogen, OH, OCH₃, OCF₃, OCH₂CH₃, NO₂, NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, SH, SCH_3, optionally substituted C₁- C₄ alkoxy and optionally substituted d-C₄alkyl;

Ar¹ and Ar² are each independently selected from the group consisting of optionally substituted C₆-Ci₈aryl, and optionally substituted monocyclic C_rC₅heteroaryl; and

L is a group of formula:

-X¹-Y-X²-

wherein X¹ is attached to Ar¹ and X² is attached to Ar², and wherein X¹, X² and Y are selected such that the group L has between 3 and 15 atoms in the normal chain,

X¹ and X² are each independently selected from the group consisting of a bond, optionally substituted C₁-C_1OaIKyI and optionally substituted C₂-C₁₀ alkenyl, with the proviso that at least one of X¹ or X² must be optionally substituted alkenyl;

Y is selected from the group consisting of O, S, and N(R²);

R² is selected from the group consisting of H, optionally substituted Ci-Ci₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C^C^heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted CτC₁₈heteroaryl, and acyl;

or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of the Formula (I), are particularly useful in their end use application. In certain embodiments of the invention R¹ is selected from the group consisting of H, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, and amino.

In a specific embodiment R¹ is H.

Ar¹ and Ar² are each independently selected from the group consisting of optionally substituted C₆-Ci₈aryl, and optionally substituted monocyclic d-C₅heteroaryl. In certain embodiments each of Ar¹ and Ar² is a monocyclic or bicyclic moiety. In certain embodiments each of Ar¹ and Ar² are a monocyclic moiety.

In one embodiment of the invention Ar 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(R³); W is selected from the group consisting of O, S and N(R⁴);

W¹ and W² are each independently selected from the group consisting of N and

C(R³);

each R³ is independently selected from the group consisting of H₁ halogen, OH, NO₂, cyano, NH₂, optionally substituted CVC^alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted CrC₁₀heteroalkyl, optionally substituted C₃-d₂cycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted CrC₁₂alkyloxy, optionally substituted Ci-Ci₀heteroalkyloxy, optionally substituted Ci-i₂alkylamino, SR⁴, SO₃H, SO₃NH₂, SO₃R⁴, SONH₂, SOR⁴, COR⁴, COOH, COOR⁴, CONHR³, NHCOR⁴, NHCOOR⁴, NHSO₃R⁴, NHCONHR⁴, NR⁴R⁵, and acyl;

each R⁴ and R⁵ is independently selected from the group consisting of H, optionally substituted C_rC₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted CrC₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-Ci₂cycloalkenyl, optionally substituted C_rC₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-Ci₈aryl, optionally substituted C_rCi₈heteroaryl, and acyl.

In certain embodiments Ar is selected from the group consisting of:

wherein V¹, V², V³, V⁴, W₁ W¹, W², R³, R⁴, and R⁵ are as defined above.

In certain embodiments Ar is selected from the group consisting of:

wherein R³ is as defined above, m is an integer selected from the group consisting of 0, 1 , 2, 3, and 4; and n is an integer selected from the group consisting of 0, 1, 2, and 3.

In yet an even further embodiment Ar¹ is selected from the group consisting of:

wherein R³ is as defined above.

In certain embodiments Ar is selected from the group consisting of:

wherein R³ is as defined above, and p is an integer selected from the group consisting of 0, 1 , and 2.

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar is selected from the group consisting of:

In certain embodiments Ar¹ is a group of the formula:

wherein R³ is as defined above; and m is an integer selected from the group consisting of 0, 1 , 2, 3 and 4.

In certain embodiments of the invention m is 0.

In certain embodiments of the invention m is 1.

In certain embodiments of the invention R³ is selected from the group consisting of F, Br₁ Cl, I, OH, OCH₃, OCF₃, OCH₂CH₃, NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, N(CH₃)CH₂CH₃, SH, and optionally substituted d-C₄alkyl.

In certain embodiments of the invention Ar² is a group of the formula:

wherein V⁵, V⁶, V⁷ and V⁸ are independently selected from the group consisting of N, and C(R⁶);

wherein each R⁶ is independently selected from the group consisting of H, halogen, OH, NO₂, cyano, NH₂, optionally substituted C_rC₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁- Cioheteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃- C₁₂cycloalkenyl, optionally substituted C_rC₁₂ heterocycloalkyl, optionally substituted C₁- C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁- C₁₈heteroaryl, optionally substituted CrC₁₂alkyloxy, optionally substituted C₂- C₁₂alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁- C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂cycloalkyloxy, substituted C₃- C₁₂cycloalkenyloxy, optionally substituted CrC₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted CrC^heteroaryloxy, optionally substituted Cπ_∑alkylamino, SR⁷, SO₃H₁ SO₃NH₂, SO₃R⁷, SONH₂, SOR⁷, COR⁷, COOH, COOR⁷, CONHR⁷, NHCOR⁷, NHCOOR⁷, NHSO₃R⁷, NHCONHR⁷, NR⁷R⁸, acyl and a group of the formula:

wherein

A is selected from the group consisting of a bond, O, C=O, SO₂, NR¹⁵ and CH₂;

B is selected from the group consisting of a bond, O, C=O₁ SO₂, NR¹⁶, C=ONR¹⁶, C(=0)0, NR¹⁶C=O₁ SO₂NR¹⁶ and NR¹⁶SO₂;

D is selected from the group consisting of N and CR¹⁷;

q is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R¹¹ and R¹² are independently selected from the group consisting of H and optionally substituted C₁-C₆ alkyl;

each R¹³ and R¹⁴ are independently selected from the group consisting of H, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ ' alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C^C^heteroaryl, or

R¹³ and R¹⁴ when taken together with the atom to which they are attached form an optionally substituted cyclic moiety;

R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the group consisting of H and Ci-C₆-alkyl,

each R⁷ and R⁸ is independently selected from the group consisting of H, optionally substituted C_rCi₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted CrC^heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted CrCi₈heteroaryl, and acyl.

In a certain embodiment of the invention Ar² is a compound of the formula:

wherein R is as defined above; and

o is an integer selected from the group consisting of O₁ 1 , 2, 3 and 4.

In certain embodiments of the invention o is 0.

In certain embodiments of the invention o is 1.

In certain embodiments Ar² is selected from the group consisting of:

wherein each R⁶ is as defined above.

In an even further embodiment Ar² is selected from the group consisting of:

In one embodiment of the invention the compound is of the formula:

wherein R\ Fr₁ R^b, X¹, X^z, Y₁ m and o are as defined above.

In one embodiment of the invention the compound is of the formula:

wherein R , R³, R⁶, X¹, X^z, Y, p and o are as defined above.

In one embodiment of the invention the compound is of the formula:

wherein R¹, R^J, R⁶, X¹, X^z, Y, p and o are as defined above.

In one embodiment of the invention the compound is of the formula:

wherein R¹, R³, R⁶, X¹, X², Y, p and o are as defined above.

In one embodiment of the invention the compound is of the formula:

wherein R¹, R³, R⁶, X¹, X², Y₁ p and o are as defined above.

In one specific embodiment R⁶ is a group of formula:

wherein A, B₁ D₁ q, R¹¹, R¹², R¹³ and R are as defined above. In one form of this embodiment A is selected from the group consisting of CH₂, C=O and NH. In one specific embodiment A is CH₂. In one specific embodiment A is C=O. In one specific embodiment A is NH.

In one form of this embodiment B is selected from the group consisting of a bond, and C=O. In one specific embodiment B is a bond. In another specific embodiment B is C=O. In another specific embodiment B is NH.

In this embodiment q is an integer selected from the group consisting of 0, 1, 2, 3,

4, 5, and 6. In one specific embodiment q is 0. In one specific embodiment q is 1. In one specific embodiment q is 2. In one specific embodiment q is 3. In one specific embodiment q is 4. In one specific embodiment q is 5. In one specific embodiment p is 6.

In one form of this embodiment D is N.

In one form of this embodiment D is CH.

In one form of this embodiment R¹¹ and R¹² are H or methyl.

In one form of this embodiment R¹³ and R¹⁴ when taken together with the atom to which they are attached form an optionally substituted cyclic moiety. The optionally substituted cyclic moiety may be any suitable cyclic moiety including a C₁-C₁₀ cycloalkyl or a C₁-C₁₀ heterocycloalkyl moiety.

In one form of the invention R¹³ and R¹⁴ when taken together with the atom to which they are attached form an optionally substituted piperidinyl moiety. In one specific embodiment R¹³ and R¹⁴ when taken together form 4-methyl-piperidin-1-yl.

In the compounds of the invention X¹, X² and Y are chosen such that there are between 3 and 15 atoms in the normal chain. In one embodiment of the compounds of the invention X¹, X² and Y are chosen such that there are between 3 and 7 atoms in the normal chain. In one specific embodiment of the compounds of the invention X¹, X² and Y are chosen such that there are 4 atoms in the normal chain. In one specific embodiment of the compounds of the invention X¹, X² and Y are chosen such that there are 5 atoms in the normal chain. In another specific embodiment of the compounds of the invention X¹, X² and Y are chosen such that there are 6 atoms in the normal chain.

X¹ and X² are each independently selected from the group consisting of a bond, optionally substitutedC^doalkyl and optionally substituted C₂-C₁₀ alkenyl;

In certain embodiments of the invention X¹ is a bond.

In certain embodiments of the invention X¹ is an optionally substituted C₁-C₅ alkyl group.

In certain embodiments X¹ is selected from the group consisting of:

(a) -CH₂-

(b) -CH₂CH₂-, (C) -CH₂CH₂CH₂-,

(d) -CH₂CH₂CH₂CH₂-; and

(Θ) — Cyπi2C/ri2v-/H2V-Η2θrl2~_ι

In certain embodiments of the invention X² is an optionally substituted C₁-C₅ alkyl group.

In certain embodiments X² is selected from the group consisting of:

(a) -CH₂-

(b) -CH₂CH₂-, (C) -CH₂CH₂CH₂-,

(d) -CH₂CH₂CH₂CH₂-; and

(e) -CH₂CH₂CH₂CH₂CH₂-;

In one specific embodiment X² is -CH₂CH₂CH₂CH₂-; and

In certain embodiments of the invention X² is an optionally substituted C₂-C₅ alkenyl group.

In certain embodiments of the invention X² is selected from the group consisting of (a) -CHCH-, (E configuration) (b) -CHCH-, (Z configuration) (C) -CHCHCH₂-, (E configuration)

(d) -CHCHCH₂-, (Z configuration)

(e) -CH₂CHCH-, (E configuration)

(f) -CH₂CHCH-, (Z configuration) (g) -CH₂CH₂CHCH-; (E configuration)

(h) -CH₂CH₂CHCH-; (Z configuration)

In certain compounds of the invention X² is selected from the group consisting of:

In a specific embodiment of the invention X² is selected from the group consisting of:

In a specific embodiment of the invention Y is O.

Many if not all of the variables discussed above may be optionally substituted. If the variable is optionally substituted then in certain embodiments the optional substituent is selected from the group consisting of halogen, =0, =S, CN, NO₂, CF₃, OCF₃, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyi, 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, alkoxyalky, COOH, COR⁹, C(O)OR⁹, SH, SR⁹, SO²R⁹, OR⁹ and acyl, each of which may be optionally substituted, wherein

R⁹ is H, optionally substituted d-C^alkyl, optionally substituted C₂-Ci₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C^C^heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-Ci₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted

C₆-C_1βaryl, optionally substituted CrC^heteroaryl, and acyl.

In certain embodiments the substituents are selected from the group consisting of: halogen, =0, =S, -CN, -NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyi, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl,

-C(O)OR⁹, SO²R⁹, COOH₁ SH₁ and acyl. In addition to compounds of Formula I₁ the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.

The invention also relates to pharmaceutical compositions including a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient.

In a further aspect the invention provides a method of inhibiting one or more protein kinase(s) including exposing the one or more protein kinase(s) and/or co-factor(s) thereof to an effective amount of a compound of the invention.

The compounds disclosed herein may act directly and solely on the kinase molecule to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors that are involved in the phosphorylation process. For example, where the kinase is cyclin-dependent, a co-factor such as cyclinA is involved in the transfer of phosphate from ATP (also considered a co-factor in itself) to the substrate molecule. Other kinase co-factors include ionic species (such as zinc and calcium), lipids (such as phosphatidylserine), and diacylglycerols.

In one embodiment of the method the 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. In one embodiment the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. In a specific embodiment the Group I CMCG kinase is CDK2 or a functional equivalent thereof.

In another embodiment of the method the one or more protein kinase(s) is a protein tyrosine kinase. In one form of this embodiment the protein tyrosine kinase is a Group VII protein tyrosine kinase. In one embodiment the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof. In one form of the method, the JAK2 includes a recurrent unique acquired clonal mutation. This mutation is observed in a majority of polycythemia vera (PV) patients and a significant proportion of patients with other myeloproliferative disorders, including, essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF). In one form of the method the mutation is a valine to phenylalanine substitution at position 617 (V617F). The incidence of this mutation in PV patients is very high (around 78% of patients).

The JAK2 mutation is somatic and occurs at the level of a hematopoietic stem cell. Studies have demonstrated that the mutated JAK2 was found in myeloid cells, i.e., bone marrow cells, granulocytes, platelets and erythroblasts derived from CD34+ cells, but not in T cells. In addition, mutant JAK2 was found in hematopoietic colonies derived from hematopoietic progenitor cells. Applicant has demonstrated that kinase inhibitors described herein are capable of inhibiting the activity of wild type and mutant JAK2.

In another embodiment of the method the protein tyrosine kinase is a Group XIV protein tyrosine kinase. In one form of this embodiment the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. In one specific embodiment the Group XIV protein tyrosine kinase 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 FLT3 tyrosine kinase activity and can transform factor-dependent hematopoietic cells as evidenced by conversion to factor-independent growth and formation of tumours in immunodeficient mice. In addition, retroviral transduction of primary murine bone marrow with an AML patient-derived FLT3 ITD (internal tandem duplication) cDNA results in a lethal myeloproliferative syndrome. Furthermore, retroviral transduction of bone marrow derived from promyelocytic leukemia/retinoic acid receptor (PML-RAR) transgenic mice with FLT3 ITD results in a marked increase in the incidence of acute prog ran ulocytic (APL)-like leukemia in such mice when compared with mice that received a transplant of mock- transduced bone marrow. Applicants have demonstrated that kinase inhibitors described herein are capable of inhibiting FLT3 including an ITD where there is a duplication of amino acids VDFREYEYDH at amino acid position 592-601. In an even more specific embodiment of the method the FLT3 includes an internal tandem duplication. In an even more specific embodiment the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601. In one embodiment of the method exposing the one or more protein kinase(s) to the compound includes administering the compound to a mammal containing the one or more protein kinase(s).

In one embodiment the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof. In one form of this embodiment the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.

In an even 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 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.

In one embodiment the Group I CMCG kinase is selected from the group consisting of

CDC2HS, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3,

CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK₁ LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+,

CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R and functional equivalents thereof. In a specific embodiment the Group I CMCG kinase is CDK2 or a functional equivalent thereof.

In another embodiment the one or more protein kinase(s) is a protein tyrosine kinase. In one form of this embodiment the protein tyrosine kinase is a Group VII protein tyrosine kinase. In one embodiment the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof. In a more specific embodiment the JAK2 includes a V to F mutation at position 617.

In another embodiment the protein tyrosine kinase is a Group XIV protein tyrosine kinase. In one form of this embodiment the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. In one specific embodiment the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof. In an even more specific embodiment FLT3 includes an internal tandem duplication. In an even more specific embodiment the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

In an even further aspect the invention provides a method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) and/or co- factors) thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of a therapeutically effective amount of a compound of the invention.

In one embodiment of the method the 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. In one embodiment the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. In a specific embodiment the Group I CMCG 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, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.

In another embodiment of the method the one or more protein kinase(s) is a protein tyrosine kinase. In one form of this embodiment the protein tyrosine kinase is a Group VII protein tyrosine kinase. In one embodiment the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof. In a more specific embodiment the JAK2 includes a V to F mutation at position 617. In one embodiment the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration. In another embodiment the condition is an inflammatory disorder and/or an autoimmune disorder. . Examples of potential disorders of this type that may be treated include acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressier^ syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter"s syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosisΛ

In one specific embodiment the inflammatory disorder is selected from the group consisting of ankylosing spondylitis, Graves' disease, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), multiple sclerosis, psoriasis and rheumatoid arthritis.

In another embodiment of the method the protein tyrosine kinase is a Group XIV protein tyrosine kinase. In one form of this embodiment the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1 R, c-kit, Flk2,

FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. In one specific embodiment the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof. In an even more specific embodiment FLT3 includes an internal tandem duplication. In an even more specific embodiment the internal tandem duplication is a duplication of 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, acute T-cell leukemia, myeloproliferative disorders, and chronic myelomonocytic leukemia.

In an even 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 inhibition of one or more protein kinase(s) can prevent, inhibit or ameliorate the pathology or symptomology of the condition.

In one embodiment the 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. In one embodiment the Group I CMCG kinase is selected from the group consisting of

CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. In a specific embodiment the Group I CMCG 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, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.

In another embodiment the one or more protein kinase(s) is a protein tyrosine kinase. In one form of this embodiment the protein tyrosine kinase is a Group VII protein tyrosine kinase. In one embodiment the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In a specific embodiment the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof. In a more specific embodiment the JAK2 includes a V to F mutation at position 617. In one embodiment the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration. In another embodiment the condition is an inflammatory disorder and/or an autoimmune disorder. . Examples of potential disorders of this type that may be treated include acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophil, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi- Harada syndrome and Wegener's granulomatosis.

In another embodiment the protein tyrosine kinase is a Group XIV protein tyrosine kinase. In one form of this embodiment the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. In one specific embodiment the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof. In an even more specific embodiment FLT3 includes an internal tandem duplication. In an even more specific embodiment the internal tandem duplication is a duplication of 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, acute T-cell leukemia, myeloproliferative disorders, and chronic myelomonocytic leukemia.

In an even 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 kinase-related disorder is a proliferative disorder. In a specific embodiment the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of

^• breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

In one embodiment the proliferative disorder is a myeloproliferative disorder. In a specific embodiment 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 embodiment the cancer is a solid tumour. In one embodiment the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.

In one embodiment the cancer is a hematological cancer. In a specific embodiment the hematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

In another embodiment the condition is an inflammatory disorder and/or an autoimmune disorder. . Examples of potential disorders of this type that may be treated include acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

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 embodiment the neurodegenerative disorder is Alzheimer's disease.

In an even further aspect the invention provides a method of treating or preventing a kinase-related disorder including administration of a therapeutically effective amount of a compound of the invention to a patient in need thereof.

In one embodiment the kinase-related disorder is a proliferative disorder. In a specific embodiment the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

In another embodiment the condition is an inflammatory disorder and/or an autoimmune disorder. Examples of potential disorders of this type that may be treated include acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressier^ syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

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.

The invention also provides a method for inhibiting cell proliferation including administration of an effective amount of a compound according to formula (I).

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined. As used herein, the term unsubstituted means that there is no substituent or that the only substituents are hydrogen.

The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =O, =S, -CN, -NO₂, -CF₃, -OCF₃, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR⁹, -C(O)OR⁹, CONHR⁹, NHCOR⁹, NHCOOR⁹, NHCONHR⁹, C(=NOH)R⁹, -SH, -SR⁹, -OR⁹ and acyl.

"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Ci-Ci₄ alkyl, more preferably CrCi₀ alkyl, most preferably Ci-C₆ unless otherwise noted. Examples of suitable straight and branched C_rC₆ alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.

"Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified.

"Mono-alkylamino" means a -NH-Alkyl group, in which alkyl is as defined above. "Dialkylamino" means a -N(alkyl)₂ group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C₁-C₆ alkyl group.

The group may be a terminal group or a bridging group.

"Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein. di-arylamino means a group of formula (aryl)₂N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group.

"Acyl" means an alkyl-CO- group in which the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a C₁-C₆ alkyl group. The group may be a terminal group or a bridging group.

"Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.

"Alkoxy" refers to an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a CrCealkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

"Alkenyloxy" refers to an -O- alkenyl group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups. The group may be a terminal group or a bridging group.

"Alkynyloxy" refers to an -O-alkynyl group in which alkynyl is as defined herein.

Preferred alkynyloxy groups are C₁-C₆ alkynyloxy groups. The group may be a terminal group or a bridging group.

"Alkoxycarbonyl" refers to an -C(O)-O-alkyl group in which alkyl is as defined herein. The alkyl group is preferably a C₁-C₆ alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group.

"Akylsulfinyl" means a -S(O)-alkyl group in which alkyl is as defined above. The alkyl group is preferably a C₁-C₆ alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group.

"Alkylsulfonyl" refers to a -S(O)₂-alkyl group in which alkyl is as defined above. The alkyl group is preferably a Ci-C₆ alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group.

"Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

"Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which alkylamino is as defined above. The group may be a terminal group or a bridging group.

"Cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group.

The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.

"Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group.

"Halogen" represents chlorine, fluorine, bromine or iodine.

"Heterocycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4- oxazepane, and 1 ,4-oxathiapane. The group may be a terminal group or a bridging group.

"Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond. The group may be a terminal group or a bridging group.

"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The group may be a terminal group or a bridging group.

"Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein reference to the normal chain when used in the context of a bridging group refers to the direct chain of atoms linking the two terminal positions of the bridging group.

"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C_5-7 cycloalkyl or C_5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group.

"Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group.

"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci_-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. The group may be a terminal group or a bridging group.

"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms.

Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, A-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. The group may be a terminal group or a bridging group.

"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group.

"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a bridging group. It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to 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. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.

In addition to compounds of the Formula (I), the compounds of the various embodiments include pharmaceutically acceptable salts, prodrugs, N-oxides and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987).

The term "therapeutically effective amount" or "effective amount" is an amount ^■ sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

The term "normal chain" refers to the direct chain joining the two ends of a linking moiety. In reference to the present compounds an alkoxyalkyl group is a heteroalkyl group containing a heteroatom in the normal chain (in this case an oxygen atom). An amide group is also a heteroalkyl group but it does not contain an oxygen atom in the normal chain (it has a nitrogen atom in the normal chain).

The term "functional equivalent" is intended to include variants of the specific protein kinase species described herein. It will be understood that kinases may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given kinase isoform is different to the protoypical kinase, the molecule maintains biological activity as a protein kinase. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term "functional equivalent" are variants generated at the level of transcription. Many kinases (including JAK2 and CDK2) have isoforms that arise from transcript variation. It is also known that FLT3 has an isoform that is the result of exon-skipping. Other functional equivalents include kinases having altered post-translational modification such as glycosylation.

Specific compounds of the invention include the following:

The compounds of the invention have the ability to inhibit the activity of certain protein kinases. The ability to inhibit kinase activity may be a result of the compounds of the invention acting directly and solely on the kinase molecule to inhibit biological activity. However, it is understood that the compounds may also act at least partially on co-factors of the kinase in question that are involved in the phosphorylation process. For example, where the kinase is cyclin-dependent, a co-factor such as cyclinA is involved in the transfer of phosphate from ATP (also considered a co-factor in itself) to the substrate molecule. Other kinase co-factors include ionic species (such as zinc and calcium), lipids (such as phosphatidylserine), and diacylglycerols.

The compounds may have activity against a wide range of protein kinases. One suitable family of protein kinases are the cyclin-dependent protein kinases. An example of the cyclin-dependent kinases is the Group I CMCG kinases. Examples of Group I CMCG kinases include CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK₁ LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R. A Group I CMCG kinase of particular interest is CDK2.

Another family of protein kinases are protein tyrosine kinases. An example of protein tyrosine kinases is a Group VII protein tyrosine kinase. Examples of Group VII protein tyrosine kinase include TYK2, JAK1, JAK2 and HOP. A protein kinase of particular interest is the Group VII protein tyrosine kinase is JAK2. The JAK2 protein kinase may include a recurrent unique acquired clonal mutation. As stated previously this mutation is observed in a majority of polycythemia vera (PV) patients and a significant proportion of patients with other myeloproliferative disorders, including, essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF). A typical mutation is a valine to phenylalanine substitution at position 617 (V617F). The incidence of this mutation in PV patients is very high (around 78% of patients).

Another example of protein tyrosine kinases is the Group XIV protein tyrosine kinases. Examples of the Group XIV protein tyrosine kinase include PDGFR-b, PDGFR- a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4. A Group XIV protein tyrosine kinase of particular interest is FLT3. The FLT3 kinase may include a mutation. 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 FLT3 tyrosine kinase activity and can transform factor-dependent hematopoietic cells as evidenced by conversion to factor-independent growth and formation of tumours in immunodeficient mice. In addition, retroviral transduction of primary murine bone marrow with an AML patient-derived FLT3 ITD (internal tandem duplication) cDNA results in a lethal myeloproliferative syndrome. Furthermore, retroviral transduction of bone marrow derived from promyelocytic leukemia/retinoic acid receptor (PML-RAR) transgenic mice with FLT3 ITD results in a marked increase in the incidence of acute progranulocytic (APL)^like leukemia in such mice when compared with mice that received a transplant of mock- transduced bone marrow. Applicants have demonstrated that kinase inhibitors described herein are capable of inhibiting FLT3 including an ITD where there is a duplication of amino acids VDFREYEYDH at amino acid position 592-601. In an even more specific embodiment of the method the FLT3 includes an internal tandem duplication. In an even more specific embodiment the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

The inhibition of the protein kinase may be carried out in any of a number of well known ways in the art. For example if inhibition of the protein kinase in vitro is desired an appropriate amount of the compound of the invention may be added to a solution containing the kinase. In circumstances where it is desired to inhibit the activity of the kinase in a mammal the inhibition of the kinase typically involves administering the compound to a mammal containing the kinase. Accordingly the compounds of the invention may find a multiple number of applications in which their ability to inhibit protein kinases of the type mentioned above can be utilised. For example the compounds may be used to inhibit protein kinases. The compounds may also be used in treating or preventing a condition in a mammal in which inhibition of a protein kinase and/or co-factor thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition.

Examples of conditions that may be treated by inhibition of protein kinases include prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's

Disease.

Other conditions that may be treated by inhibition of protein kinases include conditions such as Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.

Other conditions that may be treated by inhibition of 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, myeloproliferative disorders, and chronic myelomonocytic leukemia.

The compounds of the invention may also be used the preparation of a medicament for treating a condition in an animal in which inhibition of a protein kinase can prevent, inhibit or ameliorate the pathology or symptomology of the condition. The compounds of the invention may also be used in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.

One example of a kinase-related disorder is a proliferative disorder. In a specific embodiment the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

One example of a proliferative disorder is cancer. The cancer may be a solid tumour. The solid tumour may be a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.

Another example of a cancer is a hematological cancer. Examples of hematological cancers include acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

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 may be Alzheimer's disease.

Another example of a kinase related disorder are inflammatory disorders and/or an autoimmune disorders. Examples of disorders of this type that may be treated include acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis. In one specific embodiment the inflammatory disorder is selected from the group consisting of ankylosing spondylitis, Graves' disease, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), multiple sclerosis, psoriasis and rheumatoid arthritis.

The compounds disclosed have the ability to be used in the treatment of proliferative disorders. An example of such a disorder is cancer.

Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose. In various embodiments the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. cancerous tumours, than to normal cells.

As used herein the term 'cancer' is a general term intended to encompass the vast number of conditions that are characterised by uncontrolled abnormal growth of cells.

It is anticipated that the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasma, gastrointestinal cancers including stomach cancer, oesophageal cancer, small intestine cancer, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostrate cancer, gynaecological cancers including cervical cancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer, vulva cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers including oral cavity cancer, lip cancer, salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynx cancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemias including childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocyte leukemia, plasma cell leukemia, myelomas, hematological disorders including myelodysplasia syndromes, myeloproliferative disorders, aplastic anaemia, Fanconi anaemia, Waldenstroms 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, eye cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma, non-melanoma skin cancer, merkel cell cancer, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumour, bladder cancer, urethral cancer, and transitional cell cancer. Exemplary cancers that may be treated by compounds of this invention include Hematologic cancer such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculoskeletal neoplasm; Squamous cell carcinoma and fibroid tumour.

Exemplary cancers that may be treated by compounds of this invention include but are not limited to bladder cancer, breast cancer, cervical cancer, colorectal cancer, colon cancer, gastric cancer, neuroblastoma, retinoblastoma, ovarian cancer, pancreatic cancer, leukemia, lymphoma, prostate cancer and lung cancer.

Exemplary cancers that may be treated by compounds of this invention are colon cancer, colorectal cancer, pancreatic cancer and cervical cancer. Even further exemplary cancers that may be treated by 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), cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma.

Even further exemplary cancers that may be treated by compounds of the present invention include solid tumours and hematologic malignancies.

It is anticipated that, by virtue of their JAK2 inhibition, the compounds of the invention will also be useful in treating various myeloproliferative disorders which may include polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis.

In using the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19^th edition, Mack Publishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.

The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. As such in a further embodiment the present invention provides a pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in manners well known in the art.

The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found a container having a unit dosage of the agent (s). The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

The compounds of the invention may be used or administered in combination with one or more additional drug (s) that are anti-cancer drugs and/or procedures (e.g. surgery, radiotherapy) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one or more additional drugs that include anti-cancer drugs, the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.

Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. 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 preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may 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 isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium 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.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid 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, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution 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 may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. 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 acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

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 carriers 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 needed preservatives, buffers, or propellants which may be required.

The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration,- the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.

As discussed above, the compounds of the embodiments may be useful for treating proliferative diseases. Examples of such cell proliferative diseases or conditions include cancer (include any metastases), psoriasis, and smooth muscle cell proliferative disorders such as restenosis. The inventive compounds may be particularly useful for treating tumours such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and/or neck cancer, or renal, gastric, pancreatic cancer and brain cancer as well as hematologic malignancies such as lymphoma and leukemia. In addition, the inventive compounds may be useful for treating a proliferative disease that is refractory to the treatment with other anti-cancer drugs; and for treating hyperproliferative conditions such as leukemias, psoriasis and restenosis. In other embodiments, compounds of this invention can be used to treat pre-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

SYNTHESIS OF COMPOUNDS OF THE INVENTION

The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list- of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3^rd, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

GENERAL SYNTHETIC SCHEME

Scheme 1 is a general synthetic scheme outlining the procedures for the manufacture of compounds of the invention of general formula (I) (L = X¹ -Y-X²) which is represented by two types of compounds (IV) and (V) being compounds of the invention wherein X is derived from X¹-Y-X³, where X³ is C_1-7. Ar¹ is an aryl or heteroaryl, and Ar² is phenylene. This general procedure can be modified to produce other compounds of the invention with different values for X₁ Ar¹ and Ar² by appropriate modification of the reagents and starting materials used. A skilled addressee would readily be able to make these changes. The compounds of formula (IV)/(V) may be reacted with appropriate reagents to produce the associated saturated macrocycle (Vl).

Formula (I)

As can be seen in scheme 1 an appropriately substituted pyrimidine (I) is reacted with a suitably functionalized aniline (II) under standard conditions affords terminal alkene (III), a key intermediate ready for ring closing reaction via Heck reaction. Once again selection of the appropriately substituted aniline (Vl) allows entry into a wide range of possible X groups contemplated by the present invention. Employing Heck reaction furnishes (IV) or (IV) together with (V) in some cases. The alkenes (IV)/(V) could be saturated to give (Vl).

Scheme 1

Alternatively, pyrimidine (I) reacts with halide (VII) first to provide an alkene (VIII) as product of Heck reaction. The Nitro group is subsequently reduced and the resulting aniline (IX) is cyclized to afford the cyclic alkene (IV) or (IV)/(V). Scheme 2.

By varying the identities of the starting materials a number of different combinations of R¹, R³, R⁶ and X can be envisaged and produced as can a number of differentially substituted forms of Ar¹ and Ar². In the scheme shown Ar² are represented as phenyl moieties, however other aryls or heteroaryls can be accessed by employing analogous chemistry as depicted in Scheme 1. Synthetic procedures for the synthesis of a number of analogs of the compounds of formula (IV) or (IV)/(V) and (Vl) are detailed below.

EXAMPLES

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 indicated otherwise.

Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and Λ/./V- dimethylformamide (DMF) were purchased from Aldrich in SureSeal bottles and used as received. All solvents were purified by using standard methods in the art, unless otherwise indicated. The reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying guard tube, at ambient temperature (unless otherwise stated). Analytical thin-layer chromatography (TLC) was performed on glass-backed silica gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v/v). The TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodine chamber.

The reactions were assayed by TLC, LC-MS, and HPLC and terminated as judged by the consumption of starting material.

Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] was conducted using Silica gel 60 (Merck KGaA, 0.040-0.063 mm, 230-400 mesh ASTM) and a silica gekcrude material ratio of about 20:1 to 50:1, unless otherwise stated. Hydrogenolysis was done at the pressure indicated or at ambient pressure.

Reverse-phase preparative HPLC: a column (Luna 5μ C18 (2) 100A 150x21.2 mm 5 micron) with adjustable solvent gradients at flow rate of 20 mL/min were used for routine purification. Solvent A: H₂O with 0.1% trifluoroacetic acid (TFA); Solvent B: acetonitrile with 0.1% TFA.

Mass spectra were obtained using LC-MS in ESI positive mode.

NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operating at 400 MHz for ¹H NMR and 100 MHz for ¹³C-NMR. NMR spectra are obtained as CDCI₃ solutions (reported in ppm), using chloroform as the reference standard (7.26 ppm and

77.14 ppm) or CD₃OD (3.3 and 49.3 ppm), or DMSO-</₆ (2.50 and 39.5 ppm) or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants (J), when given, are reported in Hertz. All final products had greater than 90% purity (by HPLC at wavelengths of 220 nm and 254 nm), unless otherwise stated. Analytical HPLC conditions for routine purity check: Xterra® RP18 3.5 μm 4.6 mm x 20 mm IS column; 2.0 mL/min, gradient 5-65% B over 4 min, then 65-95%b over 1 min and 95%B for additional 0.1 min; Solvent A: H₂O with 0.1% TFA; Solvent B: acetonitrile with 0.1% TFA. For those compounds not suitable for the above HPLC method either due to too polar or poor peak separation, a longer column (Phenomenex® Gemini 5 micron C18, 110A₁ 4.6 x150 mm), together with suitable solvent gradients, were used for their HPLC analyses.

Example 1

Representative procedures for the synthesis of compounds of type (I)

Some examples of compounds (la-d) of type (I) are shown in Scheme 3.

Scheme 3.

Ia Ib

The synthesis of compounds of formula (la-d) is described in Scheme 4. The pyrimidine (X) is reacted with boronic acid (Xl, L¹ = OH, CH₂OH; p = 0) via Suzuki coupling to provide the biaryl (XII), which is further alkylated with alkene halide (XIII, L² = Br, q = 0, 1) to furnish alkene (la-d). Scheme 4.

la-d

Example 1a Preparation of 4-(3-But-3-enyloxy-phenyl)-2-chloro-pyrimidine (Ia)

XIM Ia

Step 1 : 3-{2-Chloro-pyrimidin-4-yl)-phenol (XIM)

To a degassed solution of X-1 (1.0 g, 6.71 mmol) and XI-1 (1.1 g, 8.05 mmol) in 1 ,2-dimethoxy ethane (10 ml_) was added sequentially, aqueous Na₂CO₃ (1.06 g, 10.06 mmol) and Pd(PPh₃)₄ (0.387 g, 0.335 mmol). The resultant mixture was stirred at 80-85⁰C for 4 h, cooled to O⁰C and quenched with saturated aqueous NH₄CI solution The product was extracted with CH₂CI₂ thrice and the combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (EtOAc/Hexane) to furnish 0.450 g of XIM.

LC-MS m/z: 207 ([MH]⁺). ¹H NMR (CDCI₃) δ 9.74 (s, 1H), 9.23 (d, 1 H), 8.83 (d, 1H), 8.01

(dd, 1 H), 7.60-7.65 (m, 1H), 7.35 (t, 1 H), 6.94-6.99 (m, 1 H).

Step 2: 4-{3-But-3-enyloxy-phenyl)-2-chloro-pyrimidine (Ia) To a mixture of XIM (2.0 g, 9.68 mmol) and 4-bromo-but-1-ene (XIIM₁ 7.8 g, 5.80 mmol) in dry DMF (10 mL) at ambient temperature was added cesium carbonate (14.19 g, 43.55 mmol) and the resulting mixture was stirred at 4O⁰C for 6 h. The reaction mixture was cooled to O⁰C and quenched with H₂O. The product was extracted with CH₂CI₂ (x3) and worked up, the resulting residue was purified by flash column chromatography (EtOAc/Hexane) to obtain Ia (1.61 g). LC-MS m/z: 261 ([MH]⁺). ¹H NMR (DMSO-Cf₆) δ 8.82 (d, 1H), 8.12 (d, 1 H), 7.77 (d, 1 H), 7.70 (br s, 1H), 7.48 (t, J = 8.0 Hz, 1H)₁ 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).

Example 2

Preparation of compound (II)

Synthesis of 3-amino-5-bromo-W-(2-(pyrrolidin-1-yl)ethyl)benzamide (Ha).

Step i:

To a pre-stirred solution of 3-bromo-5-nitrobenzoic acid (0.400 g, 1.7 mmol), in DCM (5 mL), were added thionyl chloride (0.477 mL, 6.5 mmol). The mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and dissolved in toluene and evaporated to dryness again. The dried mixture was dissolved in 5mL of DCM and added with 2-(pyrrolidin-1-yl)ethanamine (0.310 mL, 2.5 mmol) and stirred for another 5 minutes. The reaction mixture was washed with saturated NaHCO_3, and the organic layer was collected and evaporated to dryness to obtain 3-bromo-5-nitro-Λ/-(2- (pyrrolidin-1-yl)ethyl)benzamide (0.531 g, 95%). HPLC purity at 254nm: 100.0%; LC-MS m/z: 344 ([M+H]⁺). ¹H NMR (CDCI₃) δ 8.66 (t, 1H, J = 1.7), 8.40 - 8.42 (m, 2H), 8.04 (bs, 1H), 3.66 (q, 2H, J = 5.6), 2.94 (t, 2H, J = 5.5), 2.88 (bs, 4H), 1.88 - 1.98 (m, 4H).

Fe reduction

To a pre-stirred solution of 3-bromo-5-nitro-Λ/-(2-(pyrrolidin-1-yl)ethyl)benzamide (0.531 g, 1.6 mmol), in 20ml of 1N HChMeOH (1:1), were added iron, Fe, (0.261 g, 4.7 mmol), The solution was warmed to 70 ⁰C for 2-4 hours. The mixture was filtered through celite and was added with DCM. The filtrate was evaporated to dryness. The mixture was basified with saturated NaHCO_3, and extracted with DCM (x3). After workup, the tilted compound Ha was obtained. HPLC purity at 254 nm: 100.0%; LC-MS m/z: 314 ((M+H]⁺).

The following compounds (lib) to (He) were prepared according to the procedures described for (Ha), by using appropriate starting materials.

Table 1.

Example 3 Preparation of compound (III) Example 3a Synthesis of [4-(3-But-3-enyloxy-phenyl)-pyrimidin-2-yl]-(3-iodo-phenyl)-arnine (HM)

To a 100 mL flask, 4-(3-But-3-enyloxy-phenyl)-2-chloro-pyrimidine (Ia) (0.146 g, 0.558 mmol), 3-iodoaniline (0.156 g, 0.710 mmol), MeOH (12 mL) and 6 N HCI (0.33 mL, 1.98 mmol) were added. The above solution was heated in an 8O⁰C oil bath for 34 h, and then evaporated to dryness. The residue was dissolved into MeOH and subjected to reverse-phase prep-HPLC for purification. The desire fractions were pooled and evaporated to remove organic solvents, then basified with saturated aqueous NaHCO₃, extracted with dichloromethane (DCM x2), dried (Na₂SO₄) and removed the solvent to afford the title compound as white solid (0.149 g, 60%). HPLC purity at 254 nm: 99.7%; LC-MS (m/z) 444 ([M+H]⁺). ¹H NMR (CDCI₃) δ 8.43 (1H, d, J = 5.3), 8.28 (1H, t, J = 1.8), 7.96 (1H, b s, NH), 7.66 (1 H, t-like, J = 2.0), 7.58 (1H, dt, J = 7.8, 1.1), 7.48 (1H, ddd, J = 8.2, 2.1, 0.7), 7.36 (1H, t, J = 8.0), 7.33 (1H, m), 7.13 (1H, d, J = 5.2), 7.01 (1H, ddd, J = 8.2, 1.7, 1.6), 6.99 (1H, t, J = 8.0), 5.92 (1H, ddt, J = 17.1, 10.3, 6.8), 5.17 (1 H, ddt, J = 17.2, 1.7, 1.6), 5.11 (1H₁ ddt, J = 10.3, 1.7, 1.4), 4.10 (2H, t, J = 6.6), 2.56 (2H, qt-like, J = 6.7, 1.2); ¹³C NMR (CDCI₃) δ 164.8, 159.5, 158.6, 141.1, 138.2, 134.5, 131.1, 130.3, 129.9, 128.0, 119.6, 118.4, 117.8, 117.2, 112.8, 109.0, 94.4, 67.5, 33.7.

Example 3b

Synthesis of 3-bromo-5-<4-(3-(but-3-enyloxy)phenyl)pyrimidin-2-ylamino)-N-(2-

(pyrrolidin-1-yl)ethyl)benzamide (III-2)

To a pre-stirred solution of 3-amino-5-bromo-Λ/-(2-(pyrrolidin-1-yl)ethyl)benzamide

(Ha) (0.100 g, 0.32 mmol), Ia (0.100 g, 0.39 mmol) in MeOH (4 mL), was added 4N HCI (0.220 mL). The mixture was heated to 75°C overnight. After neutralization, the mixture was extracted and worked up. The residue was purified by flash chromatography (50% - 100% EtOAc in Hexanes with 2% Et₃N, then 5% MeOH in EtOAc with 2% Et₃N) to afford the product 111-2 (0.113 g, 66%). HPLC purity at 254nm: 100.0%; LC-MS m/z: 536/538 ([M+H]⁺); ¹H NMR (CDCI₃) δ 8.49 (d, 1H, J = 5.3), 8.43 (t, 1H, J = 1.8), 7.85 (t, 1H, J = 1.7), 7.69 (t, 1H, J = 1.7), 7.61 (d, 1H, J = 6.8), 7.53 (t, 1H, J = 1.6), 7.47 (bs, 1 H), 7.40 (t, 1H, J = 8.0), 7.22 (d, 1H, J = 5.3), 6.98 (bs, 1H), 5.88 - 6.00 (m, 1H), 5.19 (dd, 1H, J = 15.6, 1.7), 5.12 (dd, 1H, J = 10.2, 1.7), 4.15 (t, 2H, J = 6.6), 3.57 (q, 2H, J = 6.0), 2.74 (t, 2H, J = 6.0), 2.53 - 2.60 (m, 4H), 1.77 - 1.86 (m, 4H).

The following compounds (lll-3~9) were prepared according to the procedures described for (111-1 and III-2), by using appropriate starting materials.

Table 2.

Example 4

Preparation of compound (IV & V) Example 4a. Synthesis of compound (IV-1 A & IV-1 B) (1 &2)

To a 100 mL flask, MM (0.099 g, 0.222 mmol) and 1,2-dichloroethane (10 mL) were added, followed by saturated aqueous NaHCO₃ (10 mL), and equipped with condenser and the system was flushed with N₂. Pd[P(Ph)₃J₄ (0.042 g, 0.036 mmol) was added to the above mixture under N₂. The flask was heated in an 80⁰C oil bath overnight, and then added Pd[P(Ph)₃J₄ (0.076 g, 0.066 mmo!) and heated for additional two days. The reaction mixture was extracted with DCM (x2), after workup, the residue was purified by flash chromatography (silica, 0-5% MeOH in DCM). The product was further purified by preparative TLC (silica, EtOAαHexanes = 1:2) to afford the title compound (0.011 g, 15%). HPLC purity at 254 nm: 97.1% (two isomers of ratio 38%:62%); LC-MS m/z: 316 ([M+H]⁺). ¹H NMR indicated two sets of signals in a ratio of 44%:59%. ¹H NMR (CDCI₃) typical signals for 44% isomer (IV-1B, 2): δ 6.59 (1H, d, J = 12.1, Ar-CH=), 5.57 (1 H, dt, J = 12.1, 6.0, Ar-CH=CH-), 4.35 (2H, overlapped), 3.07 (2H, m); typical signals for 56% isomer (IV-1A, 1): δ 6.77 (1H), 4.33 (2H, overlapped), 2.70 (2H, dt-like, J = 3.4, 6.3). ¹³C NMR (CDCI₃) δ (two sets of signals) 164.0, 163.8, 161.9, 160.0, 159.9, 159.2, 159.1, 158.6, 140.2, 139.9, 139.7, 139.2, 138.2, 137.8, 132.7, 132.4, 132.0,129.8, 129.7, 128.9, 128.5, 125.3, 125.1, 122.8, 120.9, 120.7, 119.7, 119.0 (C x2), 118.9, 117.0, 116.2, 111.6, 107.9, 107.7, 76.7, 67.2, 35.4, 27.8.

Example 4b. Synthesis of compound (IV-2 and V-2) (3 and 4)

Above compound III-2 (0.096 g, 0.18 mmol) dissolved in 1 ,2-dichloroethane (DCE) (10 mL) was added with Pd[PPh₃J₄ (0.017 g, 0.01 mmol). The mixture was degassed before heating to 8O⁰C overnight. The mixture was extracted with DCM and worked up. The resulting residue was purified by preparative TLC (silica, 6% MeOH in EtOAc) to afford a 1:1 mixture of IV-2 (3) and V-2 (4). HPLC purity at 254nm: 97.9%; LC-MS m/z: 456 ([M+HD; ¹H NMR indicated ¹H NMR (CDCI₃) (two sets of signals) typical signals for IV-2 (3): δ 6.52 (d, 1H, J = 12.4), 5.61 (dt, 1 H, J = 11.9, 8.5), 4.29 (m, 2H), 2.88 (m, 2H); typical signals for V-2 (4): δ 6.00 (dt, 1H, J = 15.7, 7.2), 5.83 (dt, 1H, J = 15.5, 4.7), 4.82 (d, 2H, J = 4.6), 3.44 (d, 2H, J = 7.3); Other signals for both: 9.98 (s, 1H), 9.85 (s, 1H), 9.76 (S₁ 1H)₁ 9.65 (s, 1H), 9.00 (s, 1H), 8.41 - 8.54 (m, 7H), 8.13 - 8.32 (m, 6H), 8.07 (s, 1H), 7.50 - 7.64 (m, 9H), 7.30 - 7.41 (m, 7H), 7.20 - 7.22 (m, 3H), 6.90 - 7.10 (m, 3H), 6.55 - 6.69 (m, 2H), 4.06 - 4.31 (m, 10H), 2.81 - 2.88 (m, 2H), 1.08 - 1.17 (m, 6H)

Example 4c. Synthesis of compound (IV-3) (5)

(IV-3) was prepared according to the procedures described for (IV-1 and IV-2), by using appropriate starting materials. HPLC purity at 254 nm: 97.7%; LC-MS m/z: 456 ([M+H]⁺). ¹H NMR (CDCI₃) δ 9.36 (s, 1 H), 8.92 (bs, 1 H), 8.53 (bs, 1 H), 7.80 - 7.81 (m, 1 H), 7.76 (S₁ 1 H)₁ 7.67 (s, 7H), 7.44 (d, 2H, J = 4.8), 7.30 (d, 2H, J = 5.2), 6.70 (d, 1 H, J = 16.0), 6.32 - 6.39 (m, 1H₁ J = 15.9), 4.46 (s, 2H), 4.27 (d, 2H, J = 6.2), 3.95 - 3.98 (m, 2H), 3.44 - 3.49 (m, 2H), 1.21 - 1.30 (m, 4H), 0.86 - 0.88 (m, 4H).

Example 4d. Synthesis of compound (IV-4, V-4A and V-4B) (6, 7, and 8)

IV-4 (6) V-4A (7) V-4B (8)

Compound III-6 (0.101 g, 0.175 mmol) dissolved in DMF (23 mL) was added with Pd(OAc)₂ (0.023 g, 0.103 mmol), P(O-ToI)₃ (0.059 g, 0.183 mmol), and K₂CO₃ (0.085 g, 0.613 mmol). The mixture was heated at 100⁰C overnight under nitrogen. DMF was removed under reduced pressure and the residue was mixed with DCM and purified by flash chromatography (silica, DCM-EtOAc, EtOAc, and 5% MeOH in DCM with 1% Et₃N). After removing solvents, the fractions provided the crude product (0.043 g, 49%) which was further washed with EtOAc-hexanes (1:2) to afford the titled compounds. HPLC purity at 254 nm = 94.5% (two major peaks, regional isomers; the 2nd peak containing trans/cis isomers of V-4); LC-MS m/z: 500 ([M+H]⁺). Compound IV-4 and V-4 are separable. ¹H NMR (CDCI₃) δ three compounds in a ratio of IV-4:V-4A:V-4B = 51:(34+15).Typical data NMR data assignment:

The following compounds (9~21) were prepared according to the procedures described for (1~8), by using appropriate starting materials.

In general, the regional isomers of compound IV and V are separable, the ratio of IV V in the isolated product depends on the reaction conditions and purification methods used. Some of the fractions from the chromatography do contain almost pure either IV or V, which may also contain trans and cis isomers.

Table 3. Examples made by the above procedures.

sets d, 7.9), 4.61 J =

δ m,

LC- 3H), (m, (d,

(m, (d, 1 H, 2H, (t,

8.33 J = 1 H, = 2.70

The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. The compounds outlined in Table 3 were synthesized following the procedures outlined above. Additional compounds, other than those described in Table 3, may be prepared using the described reaction scheme or appropriate variations or modifications thereof. Such compounds are depicted in Table 4. Table 4

Cmpd Structure Cmpd Structure No No

22 23

24

26

28

Cmpd Structure Cmpd Structure No No

30 31

32

34

36

38

0

BIOLOGICAL TESTING

In vitro kinase activity assay

The recombinant enzymes (CDK2/CyclinA, FLT3, JAK2 and JAK2 V617F) were purchased from Invitrogen (Cat # PV3267, 3182, 4210 and 4347 respectively). All assays were carried out in 384-well white microtiter plates using the PKLight assay system from Cambrex (East rutherford, New Jersey). This assay platform is essentially a luminometric assay for the detection of ATP in the reaction using a luciferase-coupled reaction. For CDK2/Cyclin A assay, the reaction mixture consisted of the following components in 25 μL assay buffer (50 mM Hepes pH 7.5, 10 mM MgCI₂, 5 mM MnCI₂, 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 μg/mL of CDK2/Cyclin A complex, 0.5 μM of RbING substrate (Invitrogen, Cat # PV2939) and 0.5 μM of ATP. The compounds were tested at 8 concentrations prepared from 4-fold serial dilution starting at 10 μM. The reaction was incubated at room temperature for 2 hr. 13 μL of PKLight ATP detection reagent was added and the reaction was incubated for 10 min. Luminescence signals were detected on a multi-label plate reader (Victor² V 1420, Perkin-Elmer). The other kinase assays were identical except for the following differences in reagents. For FLT3 assays, the reaction contained 2.0 μg/mL FLT3 enzyme, 5 μM of poly(Glu,Tyr) substrate (Sigma, Cat # P0275) and 4 μM of ATP. For JAK2 assays, the reaction contained 0.6 μg/mL of JAK2 enzyme, 2 μM of poly(Glu,Ala,Tyr) substrate (Sigma, Cat # P3899) and 0.2 μM of ATP. For JAK2 V617F mutant assays, the reaction contained 8.0 μg/mL of JAK2 mutant enzyme, 2 μM of poly(Glu,Ala,Tyr) substrate (Sigma, Cat # P3899) and 0.2 μM of ATP.

For PDK1 FlashPlate assays, the kinase reactions were initiated by adding 25 μL of 2x substrate solution (2 μM biotin-casein, 4 μM ATP, 10 μCi/mL [γ-³³P] ATP in 1x assay buffer: 30 mM Hepes pH 7.5, 5 mM MgCI₂, 30 mM KCI, 1 mM DTT and 0.2 mg/mL BSA) to 25 μL of 2X enzyme solution (100 nM PDK1 in 1x assay buffer). After 1 hour's incubation at room temperature, the reaction was terminated with 25 μL of stop buffer (45 mM EDTA, 50 mM ATP, 0.1% Triton-X, 30 mM Hepes pH 7.5) and 60 μL of the stopped reaction were transferred to a 384-well Streptavidin FlashPlate HTS PLUS (Perkin Elmer Cat # SMP410). After minimum 30 min incubation at room temperature, the FlashPlate was washed 3x with 90 μL/well of H₂O/0.02% Tween 20, air-dried and counted on a Wallac MicroBeta (Perkin Elmer) scintillation counter.

The analytical software, Prism 4.0 (GraphPad Software Pte Ltd) was used to generate IC₅₀ values from the data. IC₅₀ is defined as the concentration of compound required for 50% inhibition of kinase enzyme activity. IC₅₀ values are shown below in Table 5.

Table 5 - In vitro kinase activity assay IC₅₀ data

*when a mixture was used, the ratio (%) of compounds was given in the bracket as determined by ¹H NMR or HPLC.

NT = not tested

IC₅₀ < 0.1 μM +++

0.1 μM < IC₅₀ < 1 μM ++

1 μM < IC₅o< 1O μM +

IC₅₀> 10 μM

Cell lines

The cell lines used in the studies are summarized in Table 6 below:

Table 6. Characteristics of human cell lines used

Cell-based proliferation assay for determination of GUn values The biological efficacy of the invention was demonstrated by the following assay.

Human cancer cell lines HL60 (acute myeloid leukemia cell line), HEL92.1.7 (erythroleukemia cell line) and MV4-11 (acute myeloid leukemia cell line) were obtained from ATCC. They were cultivated in the media according to the ATCC work instructions. HEL92.1.7 and MV4-11 cells were seeded at 6000 cells per well while HL60 cells were seeded at 8000 cells per well in 96 well plate. The plates were incubated at 37⁰C, 5% CO₂, for 24 h. Cells were treated with compounds at various concentrations for 96 h. Cell growth was then monitored using Celltiter96 Aqueous One Solution Cell Proliferation Assay from Promega (Madison Wisconsin). Dose response curves were plotted to determine Gl₅₀ values for the compounds using XL-fit (ID Business Solution, Emeryville, CA). Gl₅₀ is defined as the concentration of compound required for 50% inhibition of cell growth. The compounds of this invention inhibited cell proliferation as shown in Table 8 below. The data indicated that the compounds of this invention are active in the inhibition of tumour cell growth.

NT = not tested

GI₅₀ < 1 μM +++

1 μM < GI₅₀< 5 μM ++

Gl₅₀ > 5 μM +

The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

What is claimed is:

1. A compound of formula I:

Formula (I)

wherein:

R¹ is selected from the group consisting of: H, halogen, OH, OCH₃, OCF₃, OCH₂CH₃, NO₂, NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, SH, SCH_3, optionally substituted C₁- C₄alkoxy and optionally substituted C₁-C₄SIlCyI;

Ar¹ and Ar² are each independently selected from the group consisting of optionally substituted C₆-Ci₈aryl, and optionally substituted monocyclic C^Csheteroaryl; and

L is a group of formula:

_χⁱ_γ_χ²-

X¹ and X² are each independently selected from the group consisting of a bond, optionally substitutedC^C^alkyl and optionally substituted C₂-C₁₀ alkenyl; with the proviso that at least one of X¹ or X² must be optionally substituted alkenyl; Y is selected from the group consisting of O, S, and N(R );

R² is selected from the group consisting of H, optionally substituted d-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C_rCi₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted

optionally substituted CrC^heteroaryl, and acyl;

or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

2. A compound according to claim 1 wherein R¹ is H.

3. A compound according to claim 1 or 2 wherein 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(R³);

W is selected from the group consisting of O, S and N(R⁴);

W¹ and W² are each independently selected from the group consisting of N and C(R³);

each R³ is independently selected from the group consisting of H, halogen, OH₁ NO₂, cyano, NH₂, optionally substituted C_rC₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted CrC₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted Ci-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C_1βaryl, optionally substituted Ci-C₁₈heteroaryl, optionally substituted CrC^alkyloxy, optionally substituted C₂-C₁₂alkenyloxy, optionally substituted

C₂-C₁₂alkynyloxy, optionally substituted C_rC₁₀heteroalkyloxy, optionally substituted C₃-

C₁₂cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy, optionally substituted C₁-

C₁₂heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted Ci-C₁₈heteroaryloxy, optionally substituted C_ri2alkylamino, SR⁵, SO₃H, SO₃NH₂, SO₃R⁵, SONH₂, SOR⁵, COR⁵, COOH,

COOR⁵, CONHR⁵, NHCOR⁵, NHCOOR⁵, NHSO₃R⁴, NHCONHR⁵, NR⁴R⁵, and acyl;

each R⁴ and R⁵ is independently selected from the group consisting of H, optionally substituted Ci-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted CrC^heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted d-C^heteroaryl, and acyl.

4. A compound according to any one of the preceding claims wherein Ar¹ is a group of the formula:

wherein R³ is as defined in claim 3;and

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4.

5. A compound according to claim 4 wherein m is 0.

6. A compound according to claim 4 wherein m is 1.

7. A compound according to claim 3, 4 or 6 wherein R³ is selected from the group consisting of F, Br, Cl, I₁ OH, OCH₃, OCF₃, OCH₂CH₃, NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, N(CH₃)CH₂CH₃, SH, and optionally substituted C_rC₄alkyl.

8. A compound according to any one of claims 1 to 7 wherein Ar² is selected from the group consisting of:

wherein V⁵, V⁶, V⁷ and V⁸ are independently selected from the group consisting of

N₁ and C(R⁶);

wherein each R⁶ is independently selected from the group consisting of H, halogen, OH, NO₂, cyano, NH₂, optionally substituted C_rCi₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted C₁-

C₁₀heteroalkyl, optionally substituted C₃-Ci₂cycloalkyl, optionally substituted C₃- Ci₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted Ci- C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C₁- C₁₈heteroaryl, optionally substituted CrC₁₂alkyloxy, optionally substituted C₂- C₁₂alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy, optionally substituted C₁- C₁₀heteroalkyloxy, optionally substituted C₃-C₁₂cycloalkyloxy, optionally substituted C₃- C₁₂cycloalkenyloxy, optionally substituted C^C^heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy, optionally substituted

SR⁷, SO₃H, SO₃NH₂, SO₃R⁷, SONH₂, SOR⁷, COR⁷, COOH, COOR⁷, CONHR⁷, NHCOR⁷, NHCOOR⁷, NHSO₃R⁷, NHCONHR⁷, NR⁷R⁸, acyl and a group of the formula:

wherein

A is selected from the group consisting of a bond, O₁ C=O, SO₂, NR¹⁵ and CH₂;

B is selected from the group consisting of a bond, O, C=O, SO₂, NR¹⁶, C=ONR¹⁶,

C(=0)0, NR¹⁶C=O, SO₂NR¹⁶ and NR¹⁶SO₂;

D is selected from the group consisting of N and CR¹⁷;

q is an integer selected from the group consisting of O₁ 1 , 2, 3, 4, 5, and 6;

each R¹³ and R¹⁴ are independently selected from the group consisting of H, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted Crdβheteroaryl, or

R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the group consisting of H and d-Ce-alkyl,

each R⁷ and R⁸ is independently selected from the group consisting of H, optionally substituted CrC₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionally substituted d-doheteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted CrC^heteroaryl, and acyl.

9. A compound according to claim 8 wherein Ar² is a compound of the formula:

wherein R⁶ is as defined in claim 8; and

o is an integer selected from the group consisting of 0, 1 , 2, 3 and 4.

10. A compound according to claim 9 wherein o is 0.

11. A compound according to claim 9 wherein o is 1.

12. A compound according to claim 9 or 11 wherein R⁶ is and a group of the formula:

wherein

A, B₁ D, p, R¹¹, R¹², R¹³ and R¹⁴ are as defined in claim 8.

13. A compound according to claim 12 wherein A is C=O.

14. A compound according to claim 12 or 13 wherein B is NH.

15. A compound according to any one of claims 12 to 14 wherein q is an integer selected from the group consisting of 0, 1 , 2, and 3.

16. A compound according to any one of claims 12 to 15 wherein each R¹¹ and R¹² is independently selected from the group consisting of H and methyl.

17. A compound according to any one of claims 12 to 16 wherein D is N.

18. A compound according to any one of claims 12 to 17 wherein each R¹³ and R¹⁴ are independently selected from the group consisting of H and optionally substituted C₁-C₁₂ alkyl.

19. A compound according to any one of claims 12 to 17 wherein R¹³ and R¹⁴ when taken together with the atom to which they are attached form an optionally substituted cyclic moiety.

20. A compound according to any one of claims 1 to 19 wherein X¹ is a bond.

21. A compound according to any one of claims 1 to 19 wherein X¹ is CH₂.

22. A compound according to any one of claims 1 to 21 wherein Y is O.

23. A compound according to any one of claims 1 to 22 wherein X² is an optionally substituted C₂-C₅ alkenyl group.

24. A compound according to any one of claims 1 to 23 wherein X² is selected from the group consisting of:

25. A compound according to any one of the preceding claims wherein X² is selected from the group consisting of:

26. A compound according to any one of claims 1 to 25 wherein the optional substituent is selected from the group consisting of: halogen, =0, =S, CN, NO₂, CF₃, OCF₃, 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, alkoxyalky, COOH, COR⁹, C(O)OR⁹, SH, SR⁹, 0R⁹and acyl, each of which may be optionally substituted, and

R⁹ is H, optionally substituted C_rC₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-Ci₂alkynyl, optionally substituted CrCioheteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionally substituted C^C^heteroaryi, and acyl.

27. A compound according to claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

28. A pharmaceutical composition including a compound according to any one of claims 1 to 27 and a pharmaceutically acceptable diluent, excipient or carrier.

29. A method of inhibiting one or more protein kinase(s) including exposing the one or more protein kinase(s) and/or co-factor(s) thereof to an effective amount of a compound according to any one of claims 1 to 27.

30. A method according to claim 29 wherein the one or more protein kinase(s) is a cyclin-dependent protein kinase.

31. A method according to claim 30 wherein the cyclin-dependent kinase is a Group I CMCG kinase.

32. A method according to claim 31 wherein the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.

33. A method according to claim 31 or 32 wherein the Group I CMCG kinase is CDK2 or a functional equivalent thereof.

34. A method according to claim 29 wherein the one or more protein kinase(s) is a protein tyrosine kinase.

35. A method according to claim 34 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase.

36. A method according to claim 35 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof.

37. A method according to claim 35 or 36 wherein the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.

38. A method according to claim 37 wherein the JAK2 includes a V to F mutation at position 617.

39. A method according to claim 34 wherein the protein tyrosine kinase is a Group XIV protein tyrosine kinase.

40. A method according to claim 39 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-D, PDGFR-D, CSF1R, c-kit, Flk2, FLT1,

FLT2, FLT3 and FLT4 or a functional equivalent thereof.

41. A method according to claim 39 or 40 wherein the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.

42. A method according to claim 41 wherein the FLT3 includes an internal tandem duplication.

43. A method according to claim 42 wherein the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

44. A method according to any one of claims 29 to 43 wherein exposing the one or more protein kinase(s) to the compound includes administering the compound to a mammal containing the one or more protein kinase(s).

45. A method according to claim 29 wherein the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof.

46. A method according to claim 45 wherein the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.

47. Use of a compound according to any one of claims 1 to 27 to inhibit one or more protein kinase(s).

48. A use according to claim 47 wherein the one or more protein kinase(s).is a cyclin- dependent protein kinase.

49. A use according to claim 48 wherein the cyclin-dependent kinase is a Group I CMCG kinase.

50. A use according to claim 49 wherein the Group I CMCG kinase is selected from the group consisting of, CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI , PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.

51. A use according to claim 49 or 50 wherein the Group I CMCG kinase is CDK2.

52. A use according to claim 47 wherein the one or more protein kinase(s).is a protein tyrosine kinase.

53. A use according to claim 52 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase.

54. A use according to claim 53 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof.

55. A use according to claim 53 or 54 wherein the Group VII protein tyrosine kinase is JAK2 or a functional derivative thereof.

56. A use according to claim 55 wherein the JAK2 includes a V to F mutation at position 617.

57. A use according to claim 52 wherein the protein tyrosine kinase is a Group XIV protein tyrosine kinase.

58. A use according to claim 57 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof.

59. A use according to claim 58 wherein the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.

60. A use according to claim 59 wherein the FLT3 includes an internal tandem duplication.

61. A use according to claim 60 wherein the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

62. A use according to claim 47 wherein the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof.

63. A use according to claim 62 wherein the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.

64. A method of treating or preventing a condition in a mammal in which inhibition of one or more protein kinase(s) and/or co-factor(s) thereof prevents, inhibits or ameliorates a pathology or a symptomology of the condition, the method including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 18.

65. A method according to claim 64 wherein the one or more protein kinase(s) is a cyclin-dependent protein kinase.

66. A method according to claim 65 wherein the cyclin-dependent kinase is a Group I CMCG kinase.

67. A method according to claim 66 wherein the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.

68. A method according to claim 66 or 67 wherein the Group I CMCG kinase is CDK2 or a functional equivalent thereof.

69. A method according to any one of claims 64 to 68 wherein the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.

70. A method according to claim 64 wherein the one or more protein kinase(s) is a protein tyrosine kinase.

71. A method according to claim 70 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase.

72. A method according to claim 71 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TΥK2, JAK1 , JAK2 and HOP or a functional equivalent thereof.

73. A method according to claim 72 wherein the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.

74. A method according to claim 73 wherein the JAK2 includes a V to F mutation at position 617.

75. A method according to any one of claims 70 to 74 wherein the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.

76. A method according to any one of claims 71 to 75 wherein the condition is an inflammatory disorder or an autoimmune disorder selected from the group consisting of acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophil, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressier^ syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

77. A method according to claim 76 wherein the disorder is selected from the group consisting of ankylosing spondylitis, Graves' disease, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), multiple sclerosis, psoriasis and rheumatoid arthritis...

78. A method according to claim 70 wherein the protein tyrosine kinase is a Group XIV protein tyrosine kinase.

79. A method according to claim 78 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof.

80. A method according to claim 79 wherein the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.

81. A method according to claim 80 wherein the FLT3 includes an internal tandem duplication.

82. A method according to claim 81 wherein the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

83. A method according to any one of claims 78 to 82 wherein 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.

84. A method according to claim 64 wherein the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof.

85. A method according to claim 84 wherein the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.

86. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for treating a condition in an animal in which inhibition of one or more protein kinase(s) can prevent, inhibit or ameliorate the pathology or symptomology of the condition.

87. A use according to claim 86 wherein the one or more protein kinase(s) is a cyclin- dependent protein kinase.

88. A use according to claim 87 wherein the cyclin-dependent kinase is a Group I CMCG kinase.

89. A use according to claim 88 wherein the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1,

PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKI, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof.

90. A use according to claim 88 or 89 wherein the Group I CMCG kinase is CDK2 or a functional equivalent thereof.

91. A use according to any one of claims 87 to 90 wherein the condition is selected from the group consisting of prostate cancer, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, musculoskeletal neoplasms and Alzheimer's Disease.

92. A use according to claim 86 wherein the one or more protein kinase(s) is a protein tyrosine kinase.

93. A use according to claim 90 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase.

94. A use according- to claim 93 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof.

95. A use according to claim 94 wherein the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof.

96. A use according to claim 95 wherein the JAK2 includes a V to F mutation at position 617.

97. A use according to any one of claims 93 to 96 wherein the condition is selected from the group consisting of Myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, congestive heart failure, ischemia, thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinal degeneration.

98. A use according to any one of claims 93 to 96 wherein the condition is an inflammatory disorder or an autoimmune disorder selected from the group consisting of acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressle^s syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

99. A use according to claim 98 wherein the disorder is selected from the group consisting of ankylosing spondylitis, Graves' disease, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), multiple sclerosis, psoriasis and rheumatoid arthritis...

100. A use according to claim 92 wherein the protein tyrosine kinase is a Group XIV protein tyrosine kinase.

101. A use according to claim 100 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof.

102. A use according to claim 101 wherein the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof.

103. A use according to claim 102 wherein the FLT3 includes an internal tandem duplication.

104. A use according to claim 103 wherein the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

105. A use according to any one of claims 100 to 104 wherein 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.

106. A use according to claim 86 wherein the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2 or functional equivalents thereof.

107. A method according to claim 106 wherein the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2 or functional equivalents thereof.

108. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for the treatment or prevention of a kinase-related disorder.

109. A use according to claim 108 wherein the kinase-related disorder is a proliferative disorder.

110. A use according to claim 109 wherein the proliferative disorder is selected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B- cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

111. A use according to claim 110 where the proliferative disorder is a myeloproliferative disorder.

112. A use according to claim 111 wherein the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis.

113. A use according to claim 109 wherein the proliferative disorder is cancer.

114. A use according to claim 113 wherein the cancer is a solid tumour.

115. A use according to claim 114 wherein the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.

116. A use according to claim 115 wherein the cancer is a hematological cancer.

117. A use according to claim 116 wherein the hematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

118. A use according to claim 108 wherein the kinase-related disorder is a cardiovascular disorder.

119. A use according to claim 118 wherein the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis.

120. A use according to claim 108 wherein the kinase-related disorder is a neurodegenerative disorder.

121. A use according to claim 120 wherein the neurodegenerative disorder is Alzheimer's disease.

122. A use according to claim 108 wherein the condition is an inflammatory disorder or ^• an autoimmune disorder selected from the group consisting of acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cel! lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressler"s syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter's syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

123. A use according to claim 122 wherein the disorder is selected from the group asthma, psoriasis, inflammatory bowel disease and rheumatoid arthritis.

124. A method of treating or preventing a kinase-related disorder including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 27 to a patient in need thereof.

125. A method according to claim 124 wherein the kinase-related disorder is a proliferative disorder.

126. A method according to claim 125 wherein the proliferative disorder is selected from the group consisting of wherein the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

127. A method according to claim 126 where the proliferative disorder is a myeloproliferative disorder.

128. A method according to claim 127 wherein the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis.

129. A method according to claim 125 wherein the proliferative disorder is cancer.

130. A method according to claim 129 wherein the cancer is a solid tumour.

131. A method according to claim 130 wherein the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.

132. A method according to claim 129 wherein the cancer is a hematological cancer.

133. A method according to claim 132 wherein the hematological cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, chronic myelomonocytic leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

134. A method according to claim 124 wherein the kinase-related disorder is a cardiovascular disorder.

135. A method according to claim 134 wherein the cardiovascular disorder is selected from the group consisting of congestive heart failure, ischemia, thrombosis, cardiac hypertrophy and restenosis.

136. A method according to claim 134 wherein the kinase-related disorder is a neurodegenerative disorder.

137. A method according to claim 136 wherein the neurodegenerative disorder is Alzheimer's disease.

138. A method according to claim 124 wherein the kinase related disorder is an inflammatory disorder or an autoimmune disorder selected from the group consisting of acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma, allergic encephalomyelitis, allergic rhinitis, alopecia areata, alopecia senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid antibody syndrome, aortitis syndrome, aplastic anemia, atopic dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune oophoritis, BaIo disease, Basedow's disease, Behcet's disease, bronchial asthma, Castleman's syndrome, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythrema multiforme, dermatomyositis, Dressler's syndrome, dystrophia epithelialis corneae, eczematous dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosing alveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease, Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura, inflammatory bowel diseases, Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lyme disease, linear IgA disease, megaloblastic anemia, Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis, myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis, pernicious anemia, pollen allergies, polyglandular autoimmune syndrome, posterior uveitis, primary biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma, Reiter"s syndrome, reversible obstructive airway disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis, urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and Wegener's granulomatosis.

139. A method according to claim 138 wherein the disorder is selected from the group consisting of ankylosing spondylitis, Graves' disease, inflammatory bowel diseases

(Crohn's disease, ulcerative colitis), multiple sclerosis, psoriasis and rheumatoid arthritis...

140. Use of a compound according to any one of claims 1 to 27 in the treatment of a proliferative disorder.

141. A use according to claim 140 wherein the proliferative disorder is selected from the group consisting of wherein the proliferative disorder is elected from the group consisting of myeloproliferative disorders (chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukaemia), myeloid metaplasia, chronic myelomonocytic leukaemia, acute myeloid leukaemia, juvenile myelomonocytic leukaemia, acute promyelocytic leukaemia, acute lymphocytic leukaemia, acute erythroblastic leukaemia, acute B-cell leukaemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukaemia, breast carcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma, myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasm of breast, malignant tumour of colon, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloid leukaemia, cervical carcinoma, fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletal neoplasms.

142. A use according to claim 140 where the proliferative disorder is a myeloproliferative disorder.

143. A use according to claim 142 wherein the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis.

144. A use according to claim 140 wherein the proliferative disorder is cancer.

145. A use according to claim 144 wherein the cancer is a solid tumour.

146. A use according to claim 145 wherein the solid tumour is a tumour present in or metastasized from an organ or tissue selected from the group consisting of breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel, bladder and muscle.

147. A use according to claim 146 wherein the cancer is a haematological cancer.

148. A use according to claim 147 wherein the haematological cancer is selected from the group consisting of acute myeloid leukaemia, acute promyelocytic leukaemia, acute lymphocytic leukaemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukaemia, acute B-cell leukaemia, chronic myeloid leukaemia, acute T-cell leukaemia, chronic myelomonocytic leukaemia, myeloid metaplasia, chronic myelomonocytic leukaemia, acute erythroblastic leukaemia, Hodgkin's disease, and B-cell lymphoma.