WO2009029998A1 - Retrometabolic compounds - Google Patents

Abstract

The present invention relates to phenylaminopyrimidine compounds that are retrometabolic drugs or metabolites thereof. These compounds are also inhibitors of protein kinases including JAK kinases, in particular JAK2 kinases and can be used in the treatment of kinase associated diseases such as vascular diseases including pulmonary arterial hypertension (PAH), hypertension, hypertrophy and ischemia; immunological or inflammatory diseases including asthma and Chronic Obstructive Pulmonary Disease (COPD); and hyperproliferative diseases such as cancer including lung cancer.

Description

RETROMETABOLIC COMPOUNDS

FIELD OF THE INVENTION

This invention relates to phenylaminopyrimidine compounds that are retrometabolic drugs or metabolites thereof, pharmaceutical compositions thereof and uses for such compounds and compositions. These compounds are also inhibitors of protein kinases including JAK kinases, in particular JAK2 kinases and can be used in the treatment of kinase associated diseases such as vascular diseases including pulmonary arterial hypertension (PAH) hypertension and ischemia; immunological or inflammatory diseases including asthma and Chronic Obstructive Pulmonary Disease (COPD); and hyperproliferative diseases including cancers for example lung cancer.

BACKGROUND OF THE INVENTION

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease affecting the pulmonary arterioles resulting in an elevation in pulmonary artery pressure and pulmonary vascular resistance but with normal or only mildly elevated left-sided filling pressures. PAH is caused by a constellation of diseases that affect the pulmonary vasculature. PAH can be caused by or associated with collagen vascular disorders such as systemic sclerosis (scleroderma), uncorrected congenital heart disease, liver disease, portal hypertension, HIV infection, Hepatitis C, certain toxins, splenectomy, hereditary hemorrhagic teleangiectasia, and primary genetic abnormalities. In particular, a mutation in the bone morphogenetic protein type 2 receptor (a TGF-b receptor) has been identified as a cause of familial primary pulmonary hypertension (PPH). It is estimated that 6% of cases of PPH are familial, and that the rest are "sporadic." The incidence of PPH is estimated to be approximately 1 case per 1 million population. Secondary causes of PAH have a much higher incidence. The pathologic signature of PAH is the plexiform lesion of the lung which consists of obliterative endothelial cell proliferation and vascular smooth muscle cell hypertrophy in small precapillary pulmonary arterioles. PAH is a progressive disease associated with a high mortality. Patients with PAH may develop right ventricular (RV) failure. The extent of RV failure predicts outcome.

Until recently, the only effective long-term therapy for PAH in conjunction with anticoagulant therapy was continuous intravenous administration of prostacyclin, also known as epoprostenol (PGI2). Recently, the non-selective endothelin receptor antagonist, bosentan, has shown efficacy for the treatment of PAH. As the first orally bioavailable agent with efficacy in the treatment of PAH, bosentan represents a significant advance. However, a subset of patients treated with bosentan may continue to deteriorate and require the addition of PGI2. Conversely some patients on PGI2 can be weaned off this medication with the addition of bosentan. PGI2 has both anti-platelet, inotropic, and vasodilatory properties. Recent evidence suggests that PGI2 may have additional beneficial effects on vascular remodelling. In most cases, incremental dosing is needed because of apparent tachyphylaxis/resistance. The mechanism for this resistance is not known. Selective endothelin type A receptor antagonists are currently in development for the treatment of PAH. Sildenafil, a phosphodiesterase type V (PDE-V) inhibitor has recently been approved for the treatment of PAH. PDE-V inhibition results in an increase in cyclic GMP which leads to vasodilation of the pulmonary vasculature. Treprostinil, an analogue of PGI2, can be administered subcutaneously to appropriately selected patients with PAH. In addition, Iloprost, another prostacyclin analogue, can be administered in nebulized form by direct inhalation. These agents are used to treat PAH of multiple etiologies, including PAH associated with or caused by familial PAH (primary pulmonary hypertension or PPH), idiopathic PAH, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, HIV infection, toxins such as phentermine/fenfluramine, congenital heart disease, Hepatitis C, liver cirrhosis, chronic thrombo-embolic pulmonary artery hypertension (distal or inoperable), hereditary hemorrhagic teleangiectasia, and splenectomy.

The JAK/STAT pathway has recently been implicated in the pathophysiology of PAH. JAKs are kinases which phosphorylate a group of proteins called Signal Transduction and Activators of Transcription or STATs. When phosphorylated, STATs dimerize, translocate to the nucleus and activate expression of genes which lead to proliferation of endothelial cells and smooth muscle cells, and cause hypertrophy of cardiac myocytes. There are three different isoforms of JAK: JAKl, JAK2, and JAK3. Another protein with high homology to JAKs is designated Tyk2. An emerging body of data has shown that the phosphorylation of STAT3, a substrate for JAK2, is increased in animal models of PAH. In the rat monocrotaline model, there was increased phosphorylation of the promitogenic transcription factor STAT3. In this same study pulmonary arterial endothelial cells (PAECs) treated with monocrotaline developed hyperactivation of STAT3. A promitogenic agent or protein is an agent or protein that induces or contributes to the induction of cellular proliferation. Therefore, one effect of JAK2 inhibition would be to decrease proliferation of endothelial cells or other cells, such as smooth muscle cells. A contemplated effect of a JAK2 inhibitor would be to decrease the proliferation of endothelial cells or other cells which obstruct the pulmonary arteriolar lumen. By decreasing the obstructive proliferation of cells, a JAK2 inhibitor could be an effective treatment of PAH.

Potent and specific inhibitors of JAK2, will also be useful in vascular disease (additionally to those described above) such as hypertension, hypertrophy, cardiac ischemia, heart failure (including systolic heart failure and diastolic heart failure), migraine and related cerebrovascular disorders, stroke, Raynaud's phenomenon, POEMS syndrome, Prinzmetal's angina, vasculitides, such as Takayasu's arteritis and Wegener's granulomatosis, peripheral arterial disease, heart disease and PAH.

Hypertension is a disease largely of the vasculature with consequences including hypertrophy, heart failure, coronary heart disease and aortic disease. Hypertension usually occurs as result of resistance in the blood vessels to blood flow. The resistance may, for example, be due to structural or functional changes to the blood vessels (eg atherosclerosis, arteriolosclerosis and arteriolitis). Hypertension can be defined by an elevated diastolic and/or systolic blood pressure.

Hypertrophy is the enlarging of an organ, myocardial hypertrophy, for example, is enlarging of the heart which may be due to myocardial valve damage or hypertension. Hypertrophic damage may lead, for example, to myocardial infarction, congestive heart failure and cardiomyopathy.

Ischemia is the deficiency of an organ in oxygenated blood. The deficiency of oxygenated blood may, for example, be due to functional constriction or obstruction of a blood vessel. Ischemic heart disease is often caused by a reduction in coronary blood flow relative to myocardial demand. The reduction in blood flow may occur for a number of reasons, and typically occurs as a result of artherosclerosis.

Heart Failure is a clinical syndrome resulting from disturbances in cardiac output or from increased venous pressure. The disturbances in cardiac output or increases in venous pressure may be due to dilated cardio myopathy, myocardial fibrosis, deposition of an amyloid, constrictive periocarditis, hypertension, hypertrophy and/or ischemia.

As well as cardiovascular pathologies, the JAK/STAT pathway has been implicated in a number of other diseases. A review of the JAK/STAT literature offers strong support to the hypothesis that this pathway is important for the recruitment and marshalling of the host immune response to environmental insults, such as viral and bacterial infection.

Information accumulated from gene knock-out experiments have underlined the importance of members of the JAK family to the intracellular signalling triggered by a number of important immune regulatory cytokines, including IL-4 and IL-13. The therapeutic possibilities stemming from inhibition (or enhancement) of the JAK/STAT pathway are thus largely in the sphere of immune modulation, and as such are likely to be promising drugs for the treatment of a range of pathologies in this area. Specifically, inhibitors of JAKs could be used for immunological and inflammatory diseases including organ transplants, asthma and Chronic Obstructive Pulmonary Disease as well as autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, autoimmune vasculitides, multiple sclerosis, rheumatoid arthritis, Crohns disease, Type I diabetes and autoimmune thyroid disorders.

Asthma is a complex disorder characterized by local and systemic allergic inflammation and reversible airway obstruction. Asthma symptoms, especially shortness of breath, are a consequence to airway obstruction, and death is almost invariably due to asphyxiation. Airway Hyper Responsiveness (AHR), and mucus hyper secretion by goblet cells are two of the principle causes of airway obstruction in asthma patients. Intriguingly recent work in animal experimental models of asthma has underscored the importance of IL- 13 as a key player in the pathology of asthma. Using a specific IL-13 blocker, it has been demonstrated that IL- 13 acts independently of IL-4 and may be capable of inducing the entire allergic asthma phenotype, without the induction of IgE (i.e. in a non-atopic fashion). This and other models have pointed to an important second tier mechanism for elicitating the pathophysiology of asthma, that is not dependent on the production of IgE by resident B-cells or the presence of eonisophils. A direct induction of AHR by IL- 13, represents an important process that is likely to be an excellent target for intervention by new therapies. A contemplated effect of a JAK2 inhibitor to the lungs would result in the suppression of the local release of IL- 13 mediated IgE production, and therefore reduction in histaminine release by mast cells and eosinophils. This and other consequences of the absence of IL- 13 indicate that many of the effects of asthma may be alleviated through administration of a JAK2 inhibitor to the lungs.

Chronic Obstructive Pulmonary Disease (COPD) is a term which refers to a large group of lung diseases which can interfere with normal breathing. Current clinical guidelines define COPD as a disease state characterized by airflow limitation which is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases, particularly cigarette smoke and pollution. Several studies have pointed to an association between increased production of IL- 13 and COPD, lending support to the proposition that the potential alleviation of asthma symptoms by use of a JAK2 inhibitor, may also be achieved in COPD. COPD patients have a variety of symptoms including cough, shortness of breath, and excessive production of sputum. COPD includes several clinical respiratory syndromes including chronic bronchitis and emphysema.

Chronic bronchitis is a long standing inflammation of the bronchi which causes increased production of mucus and other changes. The patient's symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.

Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi. The lung looses its elasticity and therefore these areas of the lungs become enlarged. These enlarges areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood. The predominant symptom in patients with emphysema is shortness of breath. The central role played by the JAK family of protein tyrosine kinases in the cytokine dependent regulation of both proliferation and end function of several important cell types indicates that agents capable of inhibiting the JAK kinases are useful in the prevention and chemotherapeutic treatment of disease states dependent on these enzymes. Potent and specific inhibitors of each of the currently known four JAK family members will provide a means of inhibiting the action of the cytokines that drive immunological and inflammatory diseases, such as those discussed above. Additionally, there is evidence that STATs activation in malignant tumors, among them lung cancer, suggesting the treatment of hyperproliferative disorders such as cancers including multiple myeloma; prostate, breast and lung cancer; Hodgkin's Lymphoma; B-cell Chronic Lymphocytic Leukemia; metastatic melanoma; glioma; and hepatoma, by JAK inhibitors is indicated. JAK2 inhibitors will also be useful in myeloproliferatve disorders (MPD) such as polycythemia vera (PCV). Additionally the use of JAK kinase inhibitors for the treatment of viral diseases and metabolic diseases is indicated. Conversely, the consequence of the wide ranging systemic actions of the JAK2, and the consequential systemic effect of a JAK2 inhibitor, means that where it is desired to target a localised disorder such as cardiovascular disease, PAH, asthma, COPD, or lung cancer it is highly desirable to deliver a JAK2 inhibitor to the organ in a manner that does not enable significant quantities of the active drug to enter other organs. Thus local or topical application to the lung with minimal systemic absorption is desirable.

Topical administration of drugs has typically been applied to lung and airway disorders, eye diseases and skin disorders. For skin disorders, direct topical application of a drug which does not have a high degree of transdermal penetration is a suitable solution. For eye diseases, unique problems are encountered in delivering drugs as the eyelids, tear- flow and cornea itself act as an effective protection system for the eye from foreign matter. In addition systemically administered medications reach the eye in very small quantites due to the low permeability of the blood-retinal barrier.

Finally, delivering medications by inhalation presents a different set of problems to the two situations described above, despite the use of inhaled drugs for asthma since the 1950's, difficulties are still being resolved. Concerns regarding the long term systemic effects of these therapies have been recently raised, shifting the emphasis in developing these types of therapies to minimizing oral availability and maximizing clearance of any absorbed drug. Inhaled drugs carry the risk of significant systemic effects due to both the ability of many drugs to be systemically absorbed through the lungs, as well as the risk of swallowing large amounts of the drug. If the drug is bioavailable by either of these routes there is significant potential for systemic effects following long term use. As highlighted above, patients with pulmonary arterial hypertension rarely have systemic hypertension, and the absence of other health problems, systemic application of JAK2 inhibitors may cause significant concern in relation to potential side effects.

A type of therapy in which an active drug is metabolised into an inactive molecule after leaving the site of therapeutic need can be used to treat lung disorders. Such therapies are known as soft drugs, ante drugs or retrometabolic drugs. Retrometabolic drugs can be distinguished from prodrugs as the prodrug concept is the administration of an inactive molecule, which is systemically activated, compared with a soft drug where the compound administered is active, but is rapidly metabolised into an inactive molecule once it leaves the site of required activity. Thus the molecule is desirably relatively stable in the target tissue, but readily and simply degradable to an

- S - inactive molecule in other organs or tissues. Soft drugs can themselves be formulated as prodrugs, which are enzymatically activated in vivo and then subsequently enzymatically deactivated.

Although the inhibition of various types of protein kinases, targeting a range of disease states, is clearly beneficial, it has been to date demonstrated that the identification of a compound which is selective for a protein kinase of interest, and has good "drug like" properties such as high oral bioavailability, is a challenging goal. In addition, it is well established that the predictability of inhibition, or selectivity, in the development of kinase inhibitors is quite low, regardless of the level sequence similarity between the enzymes being targeted.

In addition, where the drug is required to be active only locally, properties which enable this specific action in a directed manner must also be designed into a compound with the above properties.

The challenges in developing a therapeutically appropriate JAK2 inhibitor for use in treatment of PAH include developing an active drug which specifically inhibits JAK2 and which has metabolic weak points resulting in a rapid and predictable degradation to an inactive metabolite. In addition the compound is required to be relatively stable in the target tissue, and degradation ideally occurs at a site distant to the required target.

There is therefore a continuing need to design and/or identify compounds which specifically inhibit the JAK family of kinases, and particularly compounds which may preferentially inhibit one or more of the JAK kinases relative to the other JAK kinases. There is a need for such compounds for the treatment of a range of disease states, including PAH, asthma and COPD.

There is also a continuing need to deliver a retrometabolic drug to the site of therapeutic need, to effect its action locally, however which have a short lived pharmacological effect.

SUMMARY OF THE INVENTION

In a first aspect, there is provided a compound of formula I

wherein

R¹ is independently selected from halogen, R², OR², R⁴, CN, NO₂, R²R⁴, SO₂R⁴, NR²SO₂R³, COR⁴, NR²COR³, NR²COR⁴, R²CN, R²OH₅ R²OR³ and OR⁵R⁴; R² is substituted or unsubstituted C_1-6 alkyl or C_1-6alkylene;

R³ is R² or substituted or unsubstituted aryl;

R⁴ is selected from NHR², N(R²)₂, morpholino, thiomorpholino, thiomorpholino- 1- oxide, thiomorpholino- 1,1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which may be optionally substituted with C_1-8 alkyl wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NR^Y and/or optionally substituted with halogen, C_4-10 lactone, COSR^Y or COOR^Y;

R⁵ is substituted or unsubstituted C_2-4 alkylene;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently selected from H, R^XCN, halogen, substituted or unsubstituted C_1-6alkyl, NR^YSO₂R^Y and SO₂N(R^Y)₂; where R⁷ and R⁸ are optionally joined with the carbon atoms to which they are attached to form a C_4-6 substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

R^γis H or substituted or unsubstituted d-βalkyl, R^x is C_1-6 alkyl wherein up to 3 carbon atoms are optionally replaced with CO,

NR^Y, CONR^Y, S, SO₂, O or NSO₂R^Y and/or substituted with CF₃;

R¹¹ is selected from H, halogen, C_1-6 alkyl , C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, N(R^Y)₂, NHR^Y, COR^Y NO₂, C00R^γ, CON(R^Y)₂, OC_1-6 alkyl, CN, CH₂F, CHF₂ and CF₃; R¹² is H, P(O)(OR²)₂, OR¹³, COOR¹³, COSR¹³, CONHR⁴ or CON(R⁴)₂;

R¹³ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, CN, C_1-6alkyl OC_1-6 alkyl, or heterocyclyl; m is 1 to 3; and n is 1 or 2, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from O, N and S; with the proviso that when R is H, then R is morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which is substituted with at least one C_1-8 alkyl wherein 1 to 4 carbon atoms are replaced with CO, O, S, C(O)S or C(O)O and/or optionally substituted with halogen, C_4-10 lactone, COSR^Y or COOR^Y; and wherein the compound is a stereoisomer thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof.

In a second aspect, there is provided a process for the preparation of the compound of formula I defined above which comprises the step of coupling a compound of formula II

II

wherein

R¹¹ and n are as defined above and X is a leaving group with compounds of formulae III and IV

III IV

wherein

R¹, R⁶ -R¹⁰, R¹² and m are as defined above and M is a metal.

The compounds of formula I are retrometabolic drugs or metabolites thereof, and kinase inhibitors, preferably JAK inhibitors, more preferably JAK2 inhibitors. These compounds are useful in the treatment of a kinase associated disease, preferably a JAK kinase associated disease such as vascular diseases including cardiovascular diseases and pulmonary vascular diseases, for example, PAH; immunological diseases such as asthma and COPD; and hyperproliferative diseases such as lung cancer.

In a third aspect, there is provided a retrometabolic drug or metabolites thereof comprising the compound of formula I defined above. There is also provided use of the compound of formula I as a retrometabolic drug or metabolites thereof.

There is further provided the compound of formula I defined above for use as a retrometabolic drug or metabolites thereof.

In a fourth aspect, there is provided a kinase inhibitor comprising the compound formula I defined above.

There is also provided use of the compound of formula I defined above as a kinase inhibitor.

There is further provided the compound of formula I defined above for use as a kinase inhibitor. It is a surprising finding that kinase inhibitors can also act as retrometabolic drugs.

In a fifth aspect, there is provided the use of a kinase inhibitor as a retrometabolic drug.

The compound of formula I may also be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier. In a sixth aspect, there is provided a pharmaceutical composition comprising the compound of formula I defined above and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition also comprises one or more additional therapeutic agents.

The compound of formula I may be contained within or attached to an implant, such as a drug eluting stent. For example, when the compound is used for the treatment of PAH, the compound may be contained within or attached to a pulmonary artery stent, which may act locally, or be released from the stent into the pulmonary circulation where the compound exerts its therapeutic activity in the pulmonary vasculature. The compound of formula I may be contained within a pressurised pack with a suitable propellant. For example, when the compound is used as for the treatment of asthma, COPD, or lung cancer the compound may be contained within an inhaler for oral inhalation, such as a "Diskhaler"

(trade mark of Glaxo Group Ltd) or a meter dose aerosol inhaler.

In a seventh aspect, there is provided an implant which comprises the compound of formula I defined above. In a eighth aspect, there is provided a method for the treatment of a kinase associated disease such as a vascular or immunological disease which comprises administering an effective amount of the compound of formula I or a pharmaceutical composition defined above to a subject in need thereof. There is also provided use of the compound of formula I or a pharmaceutical composition as defined above in the manufacture of a medicament for use in the treatment of a kinase associated disease state such as a vascular, hyperproliferative disease or immunological or inflammatory disease.

There is further provided use of the compound of formula I or a pharmaceutical composition as defined above in the treatment of a kinase associated disease state such as a vascular, hyperproliferative or immunological or inflammatory disease.

There is still further provided the compound of the formula I or a pharmaceutical composition defined above for use in the treatment of a kinase associated disease state such as a vascular, hyperproliferative or immunological or inflammatory disease. In a ninth aspect, there is provided a method for the treatment of a kinase associated disease such as a vascular or immunological or inflammatory disease which comprises administering an effective amount of a kinase inhibitor which acts as a retrometabolic drug to a subject in need thereof.

There is also provided use of a kinase inhibitor which acts as a retrometabolic drug in the manufacture of a medicament for use in the treatment of a kinase associated disease such as a vascular, hyperproliferative or immunological or inflammatory disease.

There is further provided use of a kinase inhibitor which acts as a retrometabolic drug in the treatment of a kinase associated disease such as a vascular, hyperproliferative or immunological or inflammatory disease. There is still further provided kinase associated disease, a kinase inhibitor which acts as a retrometabolic drug for use in the treatment of a kinase associated disease such as a vascular, hyperproliferative or immunological or inflammatory disease.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a Western Blot of incremental concentrations of compound 29 incubated with rat lung microvascular endothelial cells with IL-6 at 10 ng/ml and the STAT3 phosphorylation at tyrosine 705 was determined compared with total STAT3 (+positive control; - negative control; v vehicle); and Figure 2 shows a graph of the results from duplicate experiments described for Figure 1 , comparing the effect of concentration of compound 29 on IL-6 induced phosphorylation of STAT3.

DETAILED DESCRIPTION

The present invention relates to compounds of formula I that inhibit kinases, in particular JAK kinases such as JAK2 kinases and are useful in the treatment of kinase associated diseases such as vascular diseases, hyperproliferative diseases or immunological diseases.

The present invention further relates to salts, isomers and/or prodrugs of a compound of formula I:

wherein R¹ is independently selected from halogen, R², OR², R⁴, CN, NO₂, R²R⁴, SO₂R⁴,

NR²SO₂R³, COR⁴, NR²COR³, NR²COR⁴, R²CN, R²OH, R²OR³ and OR⁵R⁴; R² is substituted or unsubstituted C_1-6 alkyl or C_1-6alkylene; R³ is R² or substituted or unsubstituted aryl;

R⁴ is selected from NHR², N(R²)₂, morpholino, thiomorpholino, thiomorpholino-1- oxide, thiomorpholino- 1 , 1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which may be optionally substituted with C_1-8 alkyl wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NR^Y and/or optionally substituted with halogen, C_4-10 lactone, COSR^Y or C00R^γ; R⁵ is substituted or unsubstituted C_2-4 alkylene;

R⁶, R⁷, R⁸ R⁹ and R¹⁰ are independently selected from H, R^XCN, halogen, substituted or unsubstituted Ci.₆alkyl, NR^YSO₂R^Y and SO₂N(R^Y)₂; where R⁷ and R⁸ are optionally joined with the carbon atoms to which they are attached to form a C_4-6 substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

R^γ is H or substituted or unsubstituted Cj-ealkyl,

5 R^x is C_1-6 alkyl wherein up to 3 carbon atoms are optionally replaced with CO,

NR^Y, C0NR^Y, S₅ SO₂, O or NSO₂R^Y and/or substituted with CF₃;

R¹¹ is selected from H₅ halogen, C_1-6 alkyl , C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, N(R^Y)₂, NHR^Y C0R^Y, NO₂, COOR^Y, C0N(R^Y)₂, OCi_-6 alkyl, CN, CH₂F, CHF₂ and CF₃; 0 R¹² is H, P(O)(OR²)₂, OR¹³ _, COOR¹³, COSR¹³, CONHR⁴ or CON(R⁴)₂;

R¹³ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, CN, C]_-6alkyl OC_1-6 alkyl, or heterocyclyl; m is 1 to 3; and n is 1 or 2, 5 wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from

O, N and S; with the proviso that when R¹² is H, then R¹ is morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino- 1, 1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which is O substituted with at least one C_1-S alkyl wherein 1 to 4 carbon atoms are replaced with CO,

O, S, C(O)S or C(O)O and/or optionally substituted with halogen, C_4-I0 lactone, COSR^Y or C00R^γ; and wherein the compound is or a stereoisomer thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof. 5 Preferably the at least one substituent on morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino-1, 1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine contains at least one C(O)S, C(O)O, halogen, C_4-10 lactone, COSR^Y or C00R^γ group.

In one preferred embodiment are compounds of formula I, and pharmaceutically O acceptable salts thereof wherein:

R¹ is preferably morpholino or piperidine substituted with Ci-βalkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-10 lactone, COSC_1-4alkyl or CO₂C_1-4alkyl. Preferably R¹ is in the 4-position. R⁶, R⁹ and R¹⁰ are preferably H.

R⁷ is preferably SO₂NHR^Y or NHS0₂R^Y in which R^γ is C_1-6alkyl.

R⁸ is preferably R^XCN in which R^x is C_1-6alkyl wherein up to 2 atoms can be optionally replaced with CO, NR^YSO and/or substituted with C].₆alkyl or NHSO₂R^Y wherein R^γ is H or C_1-6alkyl. Alternatively, R⁷ and R⁸ are optionally joined together with carbon atoms to which they are attached to form optionally substituted heterocyclyl.

R¹¹ is preferably methyl or trifluromethyl and is in the 5 position.

R¹² is preferably in the 3 or 5 position and is OR¹³,COOR¹³, COSR¹³ or P(O)(OR²)₂ wherein R² is C^alkyl and R¹³ is H, C_1-6alkyl, C_3-6 cycloalkyl or heterocyclyl each of which may be optionally substituted with halogen, C_1-6alkyl or OC_1-6alkyl.

In another embodiment are compounds of formula I, wherein

R¹ is morpholino or piperidine substituted with C^alkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-10 lactone, COSC_1-4alkyl or CO₂C_1-4alkyl; R⁷ is S0₂NHR^γ or NHSO₂R^Y;

R^γ is H or C_1-6alkyl;

R⁸ is R^XCN wherein R^x is C_1-6alkyl wherein up to 2 atoms can be optionally replaced with CO, NR^YS0 and/or substituted with C_1-6alkyl or NHSO₂R^Y ; or

R and R are optionally joined together with the carbon atoms to which they are attached to form a substituted or unsubstituted heterocyclyl;

R¹¹ is C^alkyl or trifluoromethyl; and

R¹² is OR¹³, COOR¹³, COSR¹³ or P(O)(OR²)₂ wherein R² is C_1-4alkyl and R¹³ is H, C_1-6alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, C_1-6alkyl or OC_1-6alkyl. In one embodiment, the compounds of formula I have the formula Ia

Ia wherein R'_a is morpholino or piperidine substituted with Q-salkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-10 lactone, C0SC_1-4alkyl or CO₂C_1-4alkyl;

R⁷a is S0₂NHR^Y or NHS0₂R^Y in which R^γ is C_1-6alkyl; R⁸a is R^XCN in which R^x is C_1-6alkyl wherein up to 2 atoms can be optionally replaced with CO, NR^YSO and/or substituted with Ci_-6alkyl or NHSO₂R^Y wherein R^γ is H or C_1-6alkyl;

R _a and R _a are optionally joined together with the carbon atoms to which they are attached to form optionally substituted heterocyclyl; Rⁿ _a is C_1-4alkyl or trifluoromethyl;

R¹² is OR¹³, COOR¹³, COSR¹³ or P(O)(OR²)₂ wherein R² is C_1-4alkyl and R¹³ is H, Ci-βalkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, Ci_-6alkyl or OC_1-6alkyl.

xamples of compounds of formula I include, but are not limited to, the following:

In a particularly preferred embodiment the compound is selected from the following: methyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)ρyrimidin-2-ylamino)-2- morpholinobenzoate; ethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate; propyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; isopropyl 5~(4~(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylammo)-2- moφholinobenzoate; tert-butyl 5-(4-(4-(cyanomethylcarbamoyl)ρhenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; cyclopropyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; cyclobutyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; cyclopentyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; cyclohexyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ;

2-methoxyethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; methyl 5 -(4-(4-(cyanomethylcarbamoyl)phenyl)-5 -methylpyrimidin-2-ylamino)-2- morpholinobenzoate; ethyl 5 -(4-(4-(cyanomethylcarbamoyl)phenyl)-5 -methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; propyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methyIpyrimidin-2-ylamino)-2- niorpholinobenzoate; isopropyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; cyclohexyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate; tetrahydro-2H-pyran-4-yl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2- ylamino)-2-moφholinobenzoate; l-methylpiperidin-4-yl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-niethylpyrimidin-2- ylamino)-2-morpholinobenzoate;

2-methoxyethyl 5 -(4-(4-(cyanomethylcarbamoyl)phenyl)-5 -methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; propyl 5-(4-(4-(2-cyanoacetamido)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ;

S-ethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzothioate;

S-fluoromethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzothioate ; propyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate; isopropyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ;

5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid;

5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid; l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)pb.enyl)piperidine-4- carboxylic acid; l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylic acid; ethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylate; ethyl l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylate; methyl 2-(l -(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)acetate;

2-methoxyethyl l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxylate;

N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3-yloxy)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide;

N-(cyanomethyl)-4-(2-(4-(4-((2-oxotetrahydrofiiran-3-yloxy)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide;

5-(4-{4-[l-(Cyanomethyl-amino)-2,2,2-trifluoro-ethyl]-phenyl}-pyrimidin-2-ylamino)-2- morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester;

5-[4-(2-Ethyl- 1 , 1 ,3-trioxo-2,3-dihydro- 1 H- 1 λ⁶-benzo[d]isothiazol-6-yl)-pyrimidin-2- ylamino]-2-morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester;

5-[4-(2-Cyanomethyl- 1 , 1 ,3-trioxo-2,3-dihydro- IH- 1 λ⁶-benzo[<f]isothiazol-6-yl)-pyrimidin-

2-ylamino]-2-morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester; l-(4-{4-[4-(Cyanomethyl-carbamoyl)-phenyl]-pyrimidin-2-ylamino}-phenyl)-piperidine-4- carbothioic acid S-fluoromethyl ester;

N-(cyanomethyl)-4-(2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)ρiperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide;

S-fluoromethyl 2-(l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)ethanethioate;

S-fluoromethyl 2-( 1 ~(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)ethanethioate;

N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)piperidin-l- yl)phenylamino)pyrimidin-4~yl)phenyl)methanesulfonamide;

S-fluoromethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate;

S-fluoromethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- niorpholinobenzothioate;

S-ethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzothioate ; ethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate; ethyl 2-(5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzamido)acetate ;

S-propyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carbothioate; ethyl 2-( 1 -(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxamido)acetate;

S-ethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carbothioate;

5-{4-[4-(Cyanomethyl-methanesulfonyl-amino)-phenyl]-pyrimidin-2-ylamino}-2- morpholin-4-yl-benzoic acid;

S-fluoromethyl 5-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2- ylamino)-2-morpholinobenzothioate;

S-fluoromethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzothioate ;

N-(cyanomethyl)-N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3 -ylthio)methyl)piperidin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide;

N-(cyanomethyl)-4-(5-methyl-2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide;

2-(2,2,2-trifluoro- 1 -(4-(2-(4-(4-((2-oxotetrahydrofuran-3 -ylthio)methyl)piperidin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)ethylamino)acetonitrile;

[l,l,3-Trioxo-6-(2-{4-[4-(2-oxo-tetrahydro-furan-3-ylsulfanylmethyl)-piperidin-l-yl]- phenylamino}-pyrimidin-4-yl)-l,3-dihydro-lλ⁶-benzo[d]isothiazol-2-yl]-acetonitrile;

S-fluoromethyl l-(4-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate;

S-fluoromethyl l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate;

S-fluoromethyl 1 -(4-(4-(4-(I -(cyanomethylamino)-2,2,2-trifluoroethyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate ; and

1 - {4- [4-(2-Cyanomethyl- 1 , 1 ,3-trioxo-2,3-dihydro- 1 H- 1 λ⁶-benzo [d] isothiazol-6-yl)- pyrimidin-2-ylamino] -phenyl }-piperidine-4-carbothioic acid S-fluoromethyl ester.

The term "C_1-6alkyl" refers to straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.

The term "Ci_-6alkylene" refers to the divalent equivalents of Ci-βalkyl defined above.

The term "C_2-6alkenyl" refers to straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl and 2- methyl-2-propenyl . The term "C_2-6alkynyl" refers to straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 4 carbon atoms. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3- butynyl and methyl-2-propynyl.

The term "C3_-6cycloalkyl" refers to non-aromatic cyclic hydrocarbon groups having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" refers to single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenxanthracenyl and phenanthrenyl.

The term "heterocyclyl" refers to saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing at least one heteroatom atom selected from the group consisting of nitrogen, sulphur and oxygen.

Suitable heterocyclyls include N-containing heterocyclic groups, such as, unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to

3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

Preferred heterocyclyls are N-containing heterocyclyls such as morpholino, piperidinyl and l,2-benzisothiazol-3(2H)-one 1,1 -dioxide.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine.

The term "optionally substituted" refers to a group that may or may not be further substituted with one or more groups selected from C_1-6 alkyl, CF₃, C_3-6 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, heterocyclyl, halo, haloC_1-6alkyl, haloC_3-6cycloalkyl, haloC_2- βalkenyl, haloC_2-6alkynyl, haloaryl, haloheterocyclyl, hydroxy, C_1-6 alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, aryloxy, heterocyclyloxy, carboxy, haloC_1-6alkoxy, haloC_2-6alkenyloxy, haloC₂-₆alkynyloxy, haloaryloxy, nitro, nitroC_1-6,alkyl, nitroC_2-6alkenyl, nitroaryl, nitroheterocyclyl, azido, amino, Cμgalkylamino, C_2-6alkenylamino, C₂.₆alkynylamino, arylamino, heterocyclamino acyl, Ci_-6alkylacyl, C₂-₆alkenylacyl, C_2-6alkynylacyl, arylacyl, heterocyclylacyl, acylamino, acyloxy, aldehydo, C_1-6alkylsulphonyl, arylsulphonyl, C_{1- 6}alkylsulphonylamino, arylsulphonylamino, C_1-6alkylsulphonyloxy, arylsulphonyloxy, C_1- βalkylsulphenyl, C_2-6alklysulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, Ci_-6alkylthio, arylthio, acylthio, cyano and the like. Preferred optional substituents are selected from the group consisting of C_1-4 alkyl, CF₃, C_3-6 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, heterocyclyl, halo, haloaryl, haloheterocyclyl, hydroxy, C_1-4 alkoxy, aryloxy, carboxy, amino, arylacyl, heterocyclacyl, acylamino, acyloxy, arylsulphonyl and cyano.

The leaving group may be any suitable known type such as those disclosed in J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure" 4^th Edition, pp 352-357, John Wiley & Sons, New York, 1992 which is incorporated herein by reference. Preferably, the leaving group is halogen, more preferably chlorine.

The compounds of the invention may also be prepared as salts which are pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric, isethionic and orotic acids. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.

The salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

Where a compound possesses a chiral center the compound can be used as a purified enantiomer or diastereomer, or as a mixture of any ratio of stereoisomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, 97.5% or 99% of the preferred isomer.

This invention also encompasses prodrugs of the compounds of formula I. This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of protein kinases, such as JAK comprising administering drugs or prodrugs of compounds of the invention. For example, compounds of formula I having free amino, amido, hydroxy or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of the invention. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of compounds of the present invention through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I. Prodrugs may also include N-oxides, and S-oxides of the appropriate nitrogen and sulphur atoms in compounds of formula I.

Process of making compounds

Compounds of the general formula I are generally prepared from a dichloropyrimidine . The first step of the process typically begins with a cross-coupling reaction between a dichloropyrimidine and a suitably functionalised coupling partner. Typical coupling partners are organoboronic acids or esters (Suzuki coupling: see for example Miyaura, N. and Suzuki, Chem Rev. 1995, 95 2457), organostannanes (Stille coupling: see for example Stille, J.K., Angew. Chem., Int. Ed. Engl, 1986, 25, 508), Grignard reagents (Kumada coupling: Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1988, Coll. Vol.6, 407.) or organozinc species (Negishi coupling: Negishi, E.; J. Organomet. Chem. 2002, 653, 34). The Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THF, DMF, ethanol, propanol, toluene, acetonitrile or 1,4-dioxane, with or without added water, in the presence of a base such as sodium or potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate. The reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh₃)₄, Pd(OAc)₂, [PdCl₂(dppf)], Pd₂(dba)₃/P(t-Bu)₃. The second step of the process involves a nucleophilic aromatic substitution reaction of the derived above with a suitably substituted aniline. The nucleophilic aromatic substitution is typically carried out by addition of the aniline to monohalo heterocyclic intermediate obtained from the first in a solvent such as ethanol, n-propanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene. The reaction is typically performed at elevated temperature in the presence of an acid such as HCl or p-toluenesulfonic acid or in the presence of base such as a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.

Alternatively, the aniline substituent may be introduced through a transition metal catalysed amination reaction. Typical catalysts for such transformations include Pd(OAc)₂/ P(t-Bu)₃, Pd₂(dba)₃/BINAP and Pd(OAc)₂/BINAP. These reactions are typically carried out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux (e.g. Hartwig, J.F., Angew. Chem. Int. Ed. 1998, 37, 2046). The anilines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art.

The products formed from either reaction step may be further derivatised using techniques known to those skilled in the art. Alternatively, derivatisation of the mono-halo intermediate may be undertaken prior to displacement of the halo substituent. Those skilled in the art will appreciate that the order of the reactions described for the syntheses above may be changed in certain circumstances and that certain functionalities may need to be derivatised (i.e. protected) in certain instances for the reactions described above to proceed with reasonable yield and efficiency. The types of protecting functionality are well-known to those skilled in the art and are described for example in Greene (Greene, T., Wuts, P. (1999) Protective Groups in Organic Synthesis. Wiley-Interscience; 3rd edition.).

Retrometabolic drugs The compounds of formula I are retrometabolic drugs or metabolites thereof. The term "retrometabolic drug" refers to an active drug which is metabolised into an inactive drug after leaving the site of therapeutic need. Such drugs are also known as "soft drugs" or "ante drugs".

Retrometabolic drugs can be distinguished from pro-drugs which are administered as inactive drugs and then systematically activated. Retrometabolic drugs are desirably relatively stable in the target tissue, but readily and simply degradable to an inactive drug in other organs or tissues.

Retrometabolic drugs can themselves be formulated as prodrugs, which are enzymatically activated in vivo and then subsequently enzymatically deactivated. Without wishing to be bound by any theory, it is believed that the retrometabolic activity of the compounds of formula I is provided by including a substituent on the periphery of the compound which has metabolic weak spot. In a preferred embodiment this is provided by substituents R¹ and/or R¹² which may be attached to the phenyl ring on the right hand side of the compounds of formula I. Specific examples of such substituents include:

but it will be appreciated that variations of these substituents will provide similar effects.

JAK Inhibition The compounds of formula I have activity against protein kinases, particularly the

JAK kinases and most particularly JAK2 kinases. A JAK2 inhibitor is any compound that selectively inhibits the activity of JAK2. One activity of JAK2 is to phosphorylate a STAT protein. Therefore an example of an effect of a JAK2 inhibitor is to decrease the phosphorylation of one or more STAT proteins. The inhibitor may inhibit the phosphorylated form of JAK2 or the non-phosphorylated form of JAK2.

The present invention also provides the use of kinase inhibitors such as JAK kinase inhibitors, in particular JAK2 inhibitors as retrometabolic drugs.

Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising at least one of the compounds of the formula I and a pharmaceutically acceptable carrier. The carrier must be "pharmaceutically acceptable" means that it is compatible with the other ingredients of the composition and is not deleterious to a subject. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation (See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins).

The compounds of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intra(trans)dermal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray or insufflation; topically, such as in the form of a cream or ointment ocularly in the form of a solution or suspension; vaginally in the form of pessaries, tampons or creams; or rectally such as in the form of suppositories; in dosage unit formulations containing nontoxic, pharmaceutically acceptable vehicles or diluents. The compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.

The pharmaceutical compositions for the administration of the compounds of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. These methods generally include the step of bringing the compound of formula I into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the compound of formula I into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions containing the compound of formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents such as sweetening agents, flavoring agents, coloring agents and preserving agents, e.g. to provide pharmaceutically stable and palatable preparations. Tablets contain the compound of formula I in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the compound of formula I is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the compound of formula I is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the compound of formula I in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound of formula I in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example poly oxy ethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable formulations.

For administration to the respiratory tract, including intranasal administration, the active compound may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract. Thus in general the active compound may be administered in the form of a solution or a suspension or as a dry powder.

Solutions and suspensions will generally be aqueous, for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol or polyethylene glycols such as PEG 400).

Such solutions or suspensions may additionally contain other excipients for example preservatives (such as benzalkonium chloride), solubilising agents/surfactants such as polysorbates (eg. Tween 80, Span 80, benzalkonium chloride), buffering agents, isotonicity-adjusting agents (for example sodium chloride), absorption enhancers and viscosity enhancers. Suspensions may additionally contain suspending agents (for example microcrystalline cellulose and carboxymethyl cellulose sodium).

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided. In the case of a dropper or pipette this may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray this may be achieved for example by means of a metering atomising spray pump. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of active compound may be controlled by provision of a metered valve,

Alternatively the active compound may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges of eg. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the active compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

When desired, formulations adapted to give sustained release of the active compound may be employed. The active compound may be administered by oral inhalation as a free-flow powder via a "Diskhaler" (trade mark of Glaxo Group Ltd) or a meter dose aerosol inhaler.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)

For application to the eye, the active compound may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle. Additives, for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride, or chlorohexidine and thickening agents such as hypromellose may also be included.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.

Efficacy of this class of compounds may be applicable to drug eluting stents. Potential applications of drug eluting stents with these compounds include pulmonary artery stenosis, pulmonary vein stenosis, as well as coronary artery stenosis. Drug eluting stents may also be used in saphenous vein grafts or arterial grafts or conduits. Drug eluting stents that release this class of compounds may also be applicable for treating stenoses of the aorta or peripheral arteries, such as the iliac artery, the femoral artery or the popliteal artery. The compound may be bound to the drug eluting stent by any of various methods known in the field. Examples of such methods include polymers, phosphoryl choline, and ceramics. The compound may also be impregnated into a bioabsorbable stent.

The active compounds may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for:

(a) oral administration, external application, for example drenches (e.g. aqueous or nonaqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;

(b) parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;

(c) topical applications, e.g. as a cream, ointment or spray applied to the skin; or

(d) rectally or intravaginally, e.g. as a pessary, cream or foam. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

Examples of other therapeutic agents include the following: endothelin receptor antagonists (eg ambrisentan, bosentan, sitaxsentan), PDE-V inhibitors (eg sildenafil, tadalafil, vardenafil), Calcium channel blockers (eg amlodipine, felodipine, varepamil, diltiazem, menthol), prostacyclin, treprostinil, iloprost, beraprost, nitric oxide, oxygen, heparin, warfarin, diuretics, digoxin, cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80₅ anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CDl 54), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen, leflunomide, deoxyspergualin, azathioprine and cyclooxygenase inhibitors such as rofecoxib and celecoxib, steroids such as prednisolone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine, VP- 16, etoposide, fludarabine, doxorubin, adriamycin, amsacrine, camptothecin, cytarabine, gemcitabine, fluorodeoxyuridine, melphalan and cyclophosphamide, antimetabolites such as methotrexate, topoisomerase inhibitors such as camptothecin, DNA alkylators such as cisplatin, kinase inhibitors such as sorafenib, microtubule poisons such as paclitaxel, TNF- α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, hydroxy urea and rapamycin (sirolimus or Rapamune) or derivatives thereof.

When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

Methods of Treatment

The compounds of formula I may be used in the treatment of kinase associated diseases including JAK kinase associated diseases such as vascular or immunological diseases. Generally, the term "treatment" means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and include: (a) preventing the disease from occurring in a subject that may be predisposed to the disease, but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.

The term "subject" refers to any animal having a disease which requires treatment with the compound of formula I.

In addition to primates, such as humans, a variety of other mammals can be treated using the compounds, compositions and methods of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the invention can also be practiced in other species, such as avian species (e.g., chickens). The term "administering" should be understood to mean providing a compound of the invention to a subject in need of treatment.

The term "kinase associated diseases" refers to a disorder or disorders that directly or indirectly result from or are aggravated by aberrant kinase activity, in particular JAK activity and/or which are alleviated by inhibition of one or more of these kinase enzymes.

In a preferred embodiment the kinase associated disease state involves one or more of the JAK kinases, JAKl, JAK2, JAK3 or TYK2. In a particularly preferred embodiment, the diseases involves JAK2 kinase. Such diseases include, but are not limited to, those listed in the Table below. Activation of the JAK/STAT pathway in various pathologies

The term "immunological and inflammatory disease" refers to an immunological, inflammatory or autoimmune disease, including but not limited to rheumatoid arthritis, polyarthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowl disease, irritable bowl syndrome, mucous colitis, ulcerative colitis, diabrotic colitis, Crohn's disease, autoimmune thyroid disorders , gastritis, esophagitis, hepatitis, pancreatitis, nephritis, psoriasis, eczema, acne vulgaris, dermatitis, hives, multiple sclerosis, Alzheimer's disease, Motor Neurone Disease (Lou Gehrig's disease), disease, Paget's disease, sepsis, conjunctivitis, neranl catarrh, chronic arthrorheumatism, systemic inflammatory response syndrome (SIRS), polymyositis, dermatomyositis (DM), Polaritis nodoa (PN), mixed connective tissue disorder (MCTD), Sjoegren's syndrome, Crouzon syndrome, achondroplasia, systemic lupus erythematosus, scleroderma, vasculitis, thanatophoric dysplasia, insulin resistance, Type I diabetes and complications from diabetes and metabolic syndrome. The term "hyperproliferative diseases" includes cancer and myeloproliferative disease states such as cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, WiIm' s tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostrate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfrorna (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal glands: neuroblastoma; and Myeloproliferative diseases such as polycythemia vera, primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), agnoneic myeloid metaplasia (AMM), also referred to as idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML).

The term "vascular disease" refers to diseases including but not limited to cardiovascular diseases, hypertension, hypertrophy, hypercholesterolemia, hyperlipidemia, thrombotic disorders, stroke, Raynaud's phenomenon, POEMS syndrome, angina, ischemia, migraine, peripheral arterial disease, heart failure, restenosis, atherosclerosis, left ventricular hypertrophy, myocardial infarction, ischemic diseases of heart, kidney, liver and brain, and pulmonary arterial hypertension. Preferred diseases for JAK2 selective inhibitors include immunological and inflammatory diseases such as asthma, COPD, auto-immune diseases such as atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis, thanatophoric dysplasia and diabetes; vascular diseases such as hypertension, hypertrophy, stroke, Raynaud's phenomenon, POEMS syndrome, angina, ischemia, migraine, peripheral arterial disease, heart failure, restenosis, atherosclerosis and pulmonary arterial hypertension; hyperproliferative disorders such as cancer for example prostate cancer, colon cancer, breast cancer, head and neck cancer, leukemia and lymphoma. As it has been found that the compounds of the present invention or metabolites thereof and kinase inhibitors in general are also retrometabolic drugs they are particularly useful in a the treatment of PAH in which the effect of the drug is only required locally. Dosages

The term "therapeutically effective amount" refers to the amount of the compound of formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

In the treatment or prevention of conditions which require kinase inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient. The dosage may be selected, for example to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the patient to be treated. The compounds will preferably be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

In order to exemplify the nature of the present invention such that it may be more clearly understood, the following non-limiting examples are provided.

EXAMPLES

Compound Synthesis

The compounds of the invention may be prepared by methods well known to those skilled in the art, and as described in the synthetic and experimental procedures shown below for selected compounds. Definition of Abbreviations:

PyBOP benzotriazole- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate DMF N,iV-dimethylformamide n-PrOH n-propanol ACN acetonitrile EDCHCl 1 -ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride HOBT iV-hydroxybenzotriazole TEA triethylamine DIPEA diisopropylethylamine ^-TsOH j>-toluene sulfonic acid HATU o-(7-azabenzotriazol-l-yl)--YN,N',NM:etramethyluronium hexafluorophosphate

Generalised reaction schemes

(a) 2 M Na₂CO₃ (aq), Pd(PPh₃)₄, toluene, n-PrOH, 100°C, N₂ atm; (b) 2 M Na₂CO₃ (aq), Pd(PPh₃)₄, ACN, 90⁰C₅ N₂ atm; (c) 0.8-0.97 eq;?-TsOH, 1,4-dioxane, 80-130°C; (d) K₂CO₃, dioxane, 100°C; (e) H₂, 1 :1 MeOH:EtOAc, 10% Pd on C (5% w/w); (e) K₂CO₃, ACN, R³-Br, rt. Alternative synthetic route for compound synthesis

(b)

(a) 2M Na₂CO₃ (aq), Pd(PPh₃)₄, toluene, n-PrOH, N₂ atm., 100°C; (b) 4-morpholinoaniline, ^-TsOH.H₂O, dioxane, 100°C; (c) 2M NaOH (aq), DMF₅ 60°C; (d) PyBOP, aminoacetonitrile hydrochloride, DIPEA, DMF; (e) EDCHCl, HOBt, aminoacetonitrile hydrochloride, TEA, DMF; (f) HATU, THF:DMF (2:3), rt, N₂ atm, sonication, 10 min, followed by aminoacetonitrile hydrochloride, rt, N₂ atm.

Note: the above coupling conditions (d, e or f) can also be used to install appropriate R¹ or R² functionalities as used in the generalised reaction schemes above.

Preparation of Key intermediates:

Intermediate 1 : (4-(2-chloropyrimιdin-4-yl)-N-(cyanomethyl)benzamide

To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0°C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 4O⁰C for 3 h by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0⁰C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 rnL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na₂SO₄) filtered and concentrated under reduced pressure to afford 4-

(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). ¹HNMR (J₆-DMSO, 300 MHz) δ 9.18 (IH, br. t, J= 5.1Hz), 7.8-7.9 (4H, m), 4.31 (2H, d, J= 5.4 Hz). LC-MS: rt 0.9 min.; m/z 203.3 [M-H]^". To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and A- (cyanomethylcarbamoyi)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine)palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 9O⁰C for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na₂SO₄) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate in petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-7V- (cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). ¹H NMR (J₆-DMSO, 300 MHz) δ 9.40 (IH, t, J= 5.4 Hz), 8.88 (IH, d, J= 5.2 Hz), 8.32 (2H, d, J= 8.7 Hz), 8.23 (IH₃ d, J= 5.1 Hz), 8.05 (2H, d, J= 8.7 Hz), 4.36 (2H, d, J= 5.4 Hz). LC-MS: rt 5.3 min.; m/z 273.2/275.2 [M+H]⁺.

Intermediate 2: (4-(2-chloro-5-methylpyrimidin-4-yl)-N-(cyanoτnethyl)benzamide

(4-(2-Cliloro-5-methylpyrimidin-4-yl)-iV-(cyanomethyl)benzamide can be prepared by Suzuki coupling of 4-(cyanomethylcarbamoyl)phenylboronic acid and 2,4-dichloro-5- methylpyrimidine by analogous procedures to that described for the preparation of Intermediate 1. ¹H NMR (^-methanol, 300 MHz) δ 8.68 (IH, s), 8.07 (2H, d, J = 8.7 Hz), 7.34 (2H, d, J = 8.7 Hz), 4.59 (IH, brs), 4.42 (2H, s), 2.43 (3H₅ s).

Intermediate 3: N-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide

A round bottomed flask was charged with 4-methanesulfonylaminophenylboronic acid (4.3Og, 20 mmol) and 2,4-dichloropyrimidine (5.97 g, 40 mmol, 2 eq), toluene (75 mL), n- propanol (25 mL) and 2 M sodium carbonate solution (18 mL, 1.8 eq). The reaction vessel was then evacuated and backfilled with nitrogen three times before adding tetrakis(triphenylphosphine) palladium (0) catalyst (1.02 g, 4.4 mol%). The reaction vessel was again evacuated and backfilled with nitrogen three times before being heated at 100°C under a nitrogen atmosphere for 66 hours. The reaction mixture was then cooled and stirred at room temperature for several hours during which time the product precipitated from the reaction mixture. The fine yellow solid (3.45 g, 61% yield) was collected by vacuum filtration washed with methanol and dried under high vacuum. ¹H NMR and LC MS data confirmed this to be the desired iV-(4-(2-chloropyrimidin-4- yl)phenyl)methanesulfonamide. ¹H NMR tø-DMSO, 300 MHz) δ 10.26 (IH, brs), 8.75 (IH, d, J= 5.5 Hz)₅ 8.17 (2H, d, J= 9.1 Hz), 8.05 (IH, d, J= 5.5 Hz), 7.35 (2H, d, J= 8.7 Hz), 3.10 (3H₅ s). LC-MS: rt 5.54 min (br) m/z 284.2/286.1 [M+H]⁺.

Intermediate 4: ^'N-(4-(2-chloropyrimidin-4-yl)phenyl)-^~N- (cyanomethyl)methanesulfonamide

iV-(4-(2-chloropyrimidm-4-yl)phenyl)methanesulfonamide (750 mg 2.64 mmol) and potassium carbonate (730 mg, 2 eq) were placed in a round bottomed flask and suspended in acetone (50 niL). The mixture was stirred for several minutes before adding bromoacetonitrile (368 μL, 2 eq). The reaction mixture was then stirred at room temperature for 48 hour. The crude reaction mixture was then concentrated in vacuo and the residue taken up in ethyl acetate (200 mL) and washed with water (2 x 100 mL), brine (100 mL) and then dried (Na₂SO₄). The organic phase was concentrated in vacuo to give N-(4-(2-chloropyrimidin-4-yl)phenyl)-N-(cyanomethyl)methanesulfonamide (762 mg, 89% yield) as a beige solid. ¹H NMR fø-DMSO, 300 MHz) δ 8.86 (IH, d, J= 5.0 Hz), 8.28 (2H, d, J= 8.7 Hz)₅ 8.18 (IH, d, J= 5.5 Hz), 7.66 (2H, d, J= 8.7 Hz), 4.97 (2H, s), 3.22 (3H, s). LC-MS: rt 5.94 min m/z 323.2/325.2 [M+H]⁺.

Intermediate 5: 2-(l-(4-(2-chloropyrimidin-4-yl)phenyl)-2,2,2- trifluoroethylamino)acetonitrile

Intermediate 5 can be made according to the synthesis paths shown in Example 8 Intermediate 6: 6-(2-Chloro-pyrimidin-4-yl)-l , 1 -dioxo-1 ,2-dihydro-l λ⁶- benzo[d]isothiazol-3-one

Intermediate 6 can be prepared from 4-bromosaccharin via conversion to the corresponding pinacol boronate and subsequent Suzuki coupling (analogous to that described above) as outlined in the general scheme below.

Intermediate 7: \6-(2-Chloro~pyrimidin-4-yl)-l , 1 ,3-trioxo-l ,3-dihydro-l λ - benzo[ά]isothiazol-2-yl]-acetonitrile (and related alkylated analogues of intermediate 6).

6-(2-Chloro-pyrimidin-4-yl)-l , 1 -dioxo-1 ,2-dihydro-lλ⁶-benzo[cf|isothiazol-3-one may be alkylated using appropriate alkyl halides and procedures similar to those described above for alkylation of N-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (Intermediate 4).

Preparation of anilines

Those anilines which cannot be purchased from commercial sources can generally be prepared by reaction of appropriate secondary amines to the required nitrofluorobenzene and subsequent reduction of the nitro moeity. Elaborated anilines may be coupled to the chlorides described above under acidic conditions (as per example 1) or Buchwald-Hartwig coupling conditions. Alternatively anilines may be coupled using the described procedures and then further elaborated subsequently using methods familiar to those skilled in the art (as indicated in various examples below).

Intermediate 8: (l-(4-aminophenyl)piperidin-4-yl)methanol

4-piperidinemethanol (882 mg, 7.66 mmol), 1 -fluoro-4-nitrobenzene (1.485 g, 10.52 mmol, 1.4 eq) and potassium carbonate (2.15 g, 15.56 mmol, 2 eq) were placed in a round bottomed flask, suspended in 1,4-dioxane (22 mL) and heated at 100°C under a nitrogen atmosphere for 108 hours. The reaction mixture was diluted with water (40 mL) and the product collected by filtration and washed with diethyl ether to remove the excess 1 -fluoro- 4-nitrobenzene starting material. (l-(4-Nitrophenyl)piperidin-4-yl)methanol was thus obtained as a yellow solid (1.3 g, 72% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (2H, d, J = 9.5 Hz), 6.81 (2H, d, J= 9.5 Hz), 3.98 (2H, m), 3.55 (2H, m), 2.99 (2H, dm, J= 2.7 Hz), 1.72-1.92 (3H, m), 1.29-1.42 (3H, m). LC-MS: rt 5.75 min (br) m/z 237.2 [M+H]⁺. A fluted flask was charged with l-(4-nitrophenyl)piperidin-4-yl)methanol (595 mg, 2.52 mmol) in 1 : 1 ethyl acetate methanol (25 mL: 25 mL). The reaction vessel was evacuated and backfilled with nitrogen three times before adding 10% Pd/C (36 mg, 6% w/w). The reaction vessel was again evacuated and backfilled with nitrogen three times. The reaction was then placed under a hydrogen balloon and stirred at room temperature overnight. TLC 2:8 petroleum spirits: ethyl acetate showed the reaction had gone to completion (the product was apparent as a new baseline spot staining with ninhydrin dip). The reaction mixture was filtered through Celite with methanol and concentrated in vacuo to afford the desired aniline (478 mg, 92% yield). ¹H NMR tø-DMSO, 300 MHz) δ 6.67 (2H, d, J= 8.7 Hz), 6.46 (2H, d, J= 8.7 Hz), 4.49 (2H₃ brs), 4.41 (IH, br), 3.25 (m) overlapping H₂O resonance, 2.42 (2H, dm, J= 2.7 Hz), 1.70 (2H, brd), 1.37 (IH₅ m), 1.26 (2H, m). LC-MS: rt 0.90 min m/z 207.2 [M+H]⁺.

Intermediate 9: (l-(4-aminophenyl)piperidin-4-ol

Intermediate 9 was prepared by methods analogous to those for intermediate 8. ¹H NMR

(CDCl₃, 300 MHz) δ 6.82 (2H₅ d, J= 8.6 Hz), 6.64 (2H₅ d, J= 8.6 Hz), 3.80 (IH, m), 3.37

(4H, m), 2.77 (2H₅ m), 1.99 (2H, m), 1.73 (2H₅ m).

Intermediate 10: ethyl l-(4-aminophenyl)piperidine-4-carboxylate

Ethyl isonipecoate (764 μL, 4.96 mmol), l-fluoro-4-nitrobenzene (1.03 g, 6.55 mmol, 1.3 eq) and potassium carbonate (1.42 g, 10.27 mmol, 2.1 eq) were placed in a round bottomed flask, suspended in 1,4-dioxane (15 mL) and heated at 100°C under a nitrogen atmosphere for 108 hours. The reaction mixture was diluted with water (40 mL) and allowed to stand at room temperature. The product solidified and was collected by filtration and washed with diethyl ether to remove the excess l-fluoro-4-nitrobenzene starting material. Ethyl 1- (4-nitrophenyl)piperidine-4-carboxylate was thus obtained as a yellow solid (582 mg, 42% yield) and used without further purification. A round bottomed flask was charged with ethyl l-(4-nitrophenyl)piperidine-4-carboxylate (582 mg, 2.09 mmol) in 1:1 ethyl acetate methanol (20 mL : 20 mL). The reaction vessel was evacuated and backfilled with nitrogen three times before adding 10% Pd/C (29 mg, 5% w/w). The reaction vessel was again evacuated and backfilled with nitrogen three times. The reaction was then placed under a hydrogen balloon and stirred at room temperature overnight. TLC 2:8 petroleum spirits:ethyl acetate showed the reaction had gone to completion, (the product was apparent as a new baseline spot staining with ninhydrin dip). The reaction mixture was filtered through Celite with methanol and concentrated in vacuo to afford the desired aniline with essentially quantitative conversion. ¹H NMR (W₆-DMSO, 300 MHz) δ 6.67 (2H, d, J= 9.0 Hz), 6.47 (2H, d, J = 9.0 Hz), 4.46 (2H, s), 4.07 (2H, q, J= 7.2 Hz), 3.27 (2H₅ m), 2.55 (2H, m), 2.35 (IH, m), 1.87 (2H, m), 1.68 (2H, m), 1.18 (3H, t, J= 7.2 Hz). LC-MS: rt 5.70 min m/z 249.3 [M+H]⁺.

Intermediate 11: (4-aminophenyl)piperidine-4-carboxylic acid

Isonipecotic acid (328 mg, 2.54 mmol), 1 -fluoro-4-nitrobenzene (500 mg, 1.4 eq) and potassium carbonate (705 mg, 5.1 mmol, 2 eq) were placed in a round bottomed flask, suspended in 1,4-dioxane (7.5 mL) and heated at 100°C for 108 hours. The reaction mixture was concentrated in vacuo. The residue washed with petroleum spirits (25 mL), chloroform (25 mL) and ethyl acetate (20 mL) to afford the crude product as a yellow solid containing residual potassium carbonate. ¹H NMR and LC-MS data was consistent with the desired product which was used without further purification. ¹H NMR (cfe-DMSO, 300 MHz) δ 7.99 (2H, d, J= 9.7 Hz), 6.94 (2H, d, J= 9.7 Hz), 3.82 (2H, m), 3.05 (2H, m), 1.99 (IH, m), 1.72 (2H, m), 1.56 (2H, m). LC-MS: rt 5.91 min m/z 251.2 [M+H]⁺. A round bottomed flask was charged with the crude (4-nitrophenyl)piperidine-4-carboxylic acid above ( ~ 2.5 mmol) in ethyl acetate : methanol : water (35 mL : 20 mL : 5 mL). The reaction vessel was evacuated and backfilled with nitrogen three times before adding 10% Pd/C (27 mg). The reaction vessel was again evacuated and backfilled with nitrogen three times. The reaction was then placed under a hydrogen balloon and stirred at room temperature overnight. The hydrogen balloon was then replaced and the mixture stirred at room temperature for a further 3 h. The reaction mixture was then filtered through Celite and concentrated in vacuo to afford the desired aniline as a beige solid. Formation of the crude product was confirmed by LC-MS and the product was then used without further purification or characterization. LC-MS: rt 0.89 min m/z 219.4 [M-H]^'. eneral scheme for preparation of fluoromethylthioesters

Conversion of the carboxylate to thioacid is mediated by the action of tetramethylthiourea, hydrolysis, and alkylation with the appropriate fluoromethyl halide, indicated for illustrative purposes in this case as chlorofluoromethane. Analogous methods are well known to those skilled in the art and include those reported for the production of the marketed drug product fluticasone propionate (for example see patent applications WO 03/013427 A2; and US 2006/009435 Al)

General scheme for conversion of heteroalkyl groups to butyrolactone derivatives

X = O₁ S₁ Or NH

Benzyl alcohols, thiols or amines of the general type A can be converted to the corresponding heteroalkyl linked butyrolactones according to the general scheme above. This chemistry is well known to those skilled in the art and can be performed according to literature precedents (J Med. Chem. 2000, 43, 19-21; J Chem. Soc. Perkin Trans. 1, 2002, 831-839; J Med. Chem. 2001, 44(4), 602-612) or as described in example 10 below. Intermediate 12 : N- (4- (2- (4- (4- (hydroxymethyl)piperidin- 1 -yl)phenylam inoyrim idin-4- yl)phenyl)methanesulfonamide

N-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (50 mg, 0.18 mmol), (l-(4- aminophenyl)piperidin-4-yl)methanol (54 mg, 0.26 mmol, 1.4 eq) and />-toluene sulfonic acid monohydrate (32 mg, 0.95 eq) were suspended in dioxane (4 mL) and the mixture heated at 12O⁰C under a nitrogen atmosphere for ~ 90 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (30 mL) and water (10 mL). The two phases were mixed and separated. The aqueous phase was subjected to C₁₈ cartridge chromatography (step-wise gradient: 100% water, then 50:50 wateπmethanol) to afford the desired product as its hydrochloride salt (27 mg green solid, 31% yield). ¹H NMR (c/₆-DMSO, 300 MHz) δ 10.10 (IH, s), 9.31 (IH, s), 8.43 (IH, d, J= 5.5 Hz), 8.11 (2H, d, J= 8.7 Hz), 7.63 (2H, brd, J= 9.1 Hz), 7.33 (2H, d, J= 8.7 Hz), 7.25 (IH, d, J= 5.0 Hz), 6.93 (2H, brd, J= 7.8 Hz), 4.45 (IH, brs), 3.59 (2H, m), 3.07 (3H, s), 2.58 (2H, m), 1.75 (2H, brm), 1.46 (IH, br), 1.25 (3H, brm). LC- MS: rt 6.19 m/z 454.0 [M+H]⁺.

Intermediate 13 : N- (4- (2 -(4- (4-hydroxypiperidin- 1 -yl)phenylam ino)pyrim idin-4- yl)phenyl)methanesulfonamide

Intermediate 13 was prepared by procedures analogous to those used for intermediate 12 (isolated as the tosylate salt). ¹H NMR (^-methanol, 300 MHz) δ 8.46 (IH, d, J= 6.0 Hz), 8.21 (2H, d, J= 9.0 Hz), 7.95 (2H, d, J= 9.2 Hz), 7.73 (2H, d, J= 9.2 Hz)₅ 7.70 (2H, d₅ J= 8.1 Hz), 7.57 (IH, d, J= 6.0 Hz), 7.40 (2H, d, J= 9.0 Hz), 7.22 (2H₅ d, J= 9.0 Hz), 4.11 (IH, m), 3.86 (2H₅ m), 3.64 (2H, m), 3.07 (3H, s), 2.35 (3H, s), 2.32-2.22 (2H, m), 2.09- 1.99 (2H, m). LC-MS: rt 0.9 and 5.4 min m/z 440.3 [M+H]⁺.

Intermediate 14: ^~N-(cyanomethyl)-4-(2-(4-(4-hydroxypiperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide

Intermediate 14 can be prepared by procedures analogous to those used for intermediate 12 ¹H NMR (300 MHz, J₆-DMSO): δ 9.44 (s, IH), 9.38- 9.30 (m, IH), 8.52 (d, J= 5.1, IH), 8.26 (d, J= 8.4 Hz, 2H), 8.02 (d, J= 8.7 Hz₅ 2H)₅ 7.61 (d, J= 9.3 Hz, 2H), 7.38 (d, J= 5.1 Hz, IH), 6.91 (d, J= 9.3 Hz, 2H), 4.69 (d, J= 4.2 Hz, IH), 4.35 (d, J= 5.4 Hz₅ 2H)₅ 3.68- 3.50 (m, 2H)₅ 2.82- 2.68 (m, 2H), 1.93- 1.74 (m, 2H), 1.58- 1.39 (m, 2H). LC-MS m/z 429.3 [M+H]⁺

Intermediate 15: ^'N-(cyanomethyl)-4-(2-(4-(4-hydroxypiperidin-l-yl)phenylamino)-5- methylpyrimidin-4-yl)benzamide

Intermediate 15 can be prepared by procedures analogous to those used for intermediate 12 ¹H NMR (300 MHz₅ CD₃OD): δ 8.27 (s, IH), 7.95 (d, J= 8.4 Hz₅ 2H), 7.75 (d, J= 8.7 Hz₅ 2H), 7.52 (d, J= 9,1 Hz, 2H), 6.94 (d, J= 9.0 Hz₅ 2H)₅ 4.34 (s, 2H), 3.78-3.68 (m, IH)₅ 3.45-3.41 (m, 2H), 2.80-2.75 (m, 2H), 2.21 (s, 3H), 1.93-1.91 (m, 2H), 1.65-1.62 (m, 2H). LC-MS m/z 443.3 [M+H]⁺

Intermediate 16: ^'N-(cyanomethyl)-4-(2-(4-(4-hydroxymethylpiperidirι-l- yl)phenylamino)pyrimidin-4-yl)benzamide

Intermediate 16 can be prepared by procedures analogous to those used for intermediate 12 ¹H NMR (300 MHz, CD₃OD): δ 8.44 (d, J= 5.4 Hz₅ IH)₅ 8.25 (d, J= 8.4 Hz₅ 2H)₅ 7.98 (d, J= 9.0 Hz₅ 2H)₅ 7.60 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 5.4 Hz, IH), 7.03 (d, J= 9.3 Hz, 2H), 4.53 (brs, IH)₅ 4.36 (s, 2H)₅ 3.68- 3.60 (m, 2H)₅ 3.46 (d, J= 6.3 Hz₅ 2H), 2.73- 2.64 (m, 2H), 1.92- 1.82 (m, 2H)₅ 1.68- 1.52 (m, IH)₅ 1.48- 1.32 (m, 2H). LC-MS m/z 443.4 [M+H]⁺

Intermediate 17: Η-(cyanomethyl)-4-(2-(4-(4-hydroxymethylpiperidin-l-yl)phenylamino)- 5methylpyrimidin-4-yl)benzamide

Intermediate 17 can be prepared by procedures analogous to those used for intermediate 12 ¹H NMR (300 MHz₅ CDCl₃): δ 8.30 (s, 3H)₅ 7.89 (d, J= 8.2 Hz₅ 2H)₅ 7.73 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.9 Hz₅ 2H)₅ 6.94 (d, J= 8.6 Hz₅ 2H), 6.49 (t, J= 6.1 Hz₅ IH), 4.43 (d, J= 5.9 Hz, 2H), 3.63 (d, J= 12.0 Hz, 2H)₅ 3.55 (t, J- 5.7 Hz₃ 2H), 2.72-2.63 (m, 2H), 2.23 (s, 3H), 1.85 (d, J= 13.2 Hz, 2H), 1.48-1.39 (m, 2H), 1.35-1.31 (m, IH). LC-MS m/z 457.4 [M+H]⁺

Alternative method for aniline coupling - Buchwald-Hartwig conditions:

An oven dried Schlenck flask with a stirrer bar was assembled under an atmosphere of nitrogen and heated under vacuum with a heat gun for several minutes and allowed to cool to ambient temperature under a positive flow of nitrogen. Under a stream of nitrogen the catalyst, (Pd₂(dba)₃) (16 mg, 0.0175 mmol, 0.05 eq.), ligand (DBPB (2-(Di-t- butylρhopshino)biphenyl)) (10.5 mg, 0.035 mmol, 0.1 eq) and the base (K₃PO₄) (104 mg, 0.49 mmol, 1.4 eq.) were added in sequence. This was followed by iV-[4-(2-Chloro- pyrimidin-4-yl)-phenyl]-methanesulfonarnide (99 mg, 0.35 mmol, 1.0 eq.) and the required aniline (0.315 mmol, 0.9 eq). The flask was sealed, evacuated and backfilled with nitrogen twice. The solvent (1,2-dimethoxyethane, 3.0 mL) was introduced by needle through one of the taps capped with a suba-seal under a positive flow of nitrogen from the other tap. The flask was then sealed and vigorous stirring commenced. The flask was again evacuated and backfilled with nitrogen six times before being placed to the level of the solvent in a thermostatted oil bath heated to 100°C. A blast shield was placed around the reaction and it was stirred at this temperature for 48 hrs before being allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered through a sintered funnel. The residue was washed with ethyl acetate (30 mL) and diethyl ether (30 mL) and the combined organics were evaporated to dryness in vacuo to give the crude product which was purified by trituration with DCMMeOH 90:10 and subsequent washing with DCM or alternatively by silica column chromatography. Intermediate 18: Y\-(4-{2-[3-(4-Hydroxy-piperidin-l-ylmethyl)-phenylamino]-pyrimidin- 4-yl} -phenyl) -meihanesulfonam ide

Intermediate 18 was prepared by coupling Intermediate 3 and l-(3-aminobenzyl)piperidin- 4-ol using the general Buchwald-Hartwig conditions described above. ¹H NMR (CDCl₃, 300MHz) δ 8.41 (IH, d, J= 5.1 Hz), 8.07 (2H, d, J= 8.7 Hz), 7.70-7.76 (IH, m), 7.58 (IH, ddd, J= 0.9, 2.1, 8.1 Hz), 7.36 (2H, d, J= 9.0 Hz), 7.30 (IH, d, J= 8.1 Hz), 7.13 (IH, d, J = 5.4 Hz), 7.01 (IH, d, J= 7.5 Hz), 3.65-3.71 (IH, m), 3.55 (2H, s), 3.04 (3H, s), 2.79-2.93 (2H, m), 2.20-2.32 (2H, m), 1.84-1.96 (2H, m), 1.57-1.67 (2H, m). LC-MS: rt 5.53 min (br) m/z 454.0 [M+H]⁺.

Example 1. Compound 26 - 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- yIamino)-2-morphoIinobenzoic acid

iV-(4-(2-Chloropyrimidin-4-yl)phenyl)methanesulfonamide (151 mg, 0.53 mmol), 5-amino- 2-morpholinobenzoic acid (142 mg, 0.64 mmol, 1.2 eq) and j»-toluene sulphonic acid monohydrate (98 mg, 0.97 eq) were all placed in a round bottomed flask fitted with a condenser. The reagents were dissolved in 1,4-dioxane (8 mL) and the reaction mixture was heated at 100⁰C overnight. The reaction mixture was then cooled to room temperature and filtered to afford the crude product which was then washed with methanol (~3 mL) and dried under vacuum. The resulting mustard solid (199 mg, 59% yield) was identified as the 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid tosylate salt by ¹H NMR and LC-MS analyses. Example 2. Compound 47 - ethyl 5-(4-(4-(methylsuIfonamido)phenyl)pyrimidin-2-

iV-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (77 mg, 0.27 mmol), 5-amino- 2-morpholinobenzoic acid (73 mg, 0.33 mmol, 1.2 eq) and /Holuene sulphonic acid monohydrate (49 mg, 0.97 eq) were all placed in a round bottomed flask fitted with a condenser and CaCl₂ drying tube. The reagents were dissolved in 1,4-dioxane (4 mL) and absolute ethanol (2 mL) and the reaction mixture was heated at 12O⁰C overnight. The reaction mixture was then cooled to room temperature, concentrated in vacuo. The residue was taken up in ethyl acetate (60 mL) and water (30 mL). The organic phase was further washed with bicarbonate solution (20 mL) and brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. LC-MS revealed a significant amount of the carboxylic acid intermediate remained thus the residue was re-dissolved in ethyl acetate (30 mL) and washed with 2 M aqueous sodium carbonate solution (10 mL) then brine (10 mL). The organic phase was dried (Na₂SO₄) and concentrated in vacuo to afford ethyl 5-(4-(4- (methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate (75 mg, 56% yield) as a yellow solid.

Example 3. Compound 23 - propyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- yIamino)-2-morpholinobenzoate

iV-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (755 mg, 2.66 mmol), 5-amino- 2-morpholinobenzoic acid (714 mg, 3.21 mmol, 1.2 eq) and /7-toluene sulphonic acid monohydrate (490 mg, 2.57 mmol , 0.97 eq) were all placed in a round bottomed flask fitted with a condenser. 1,4-Dioxane (40 mL) was added and the reaction mixture was heated at 100⁰C for 72 h. n-Propanol (15 mL) was added to the reaction mixture and the reaction continued at 12O⁰C for a further 48 h (note: power was cut to reaction for ~ 16 hours during this time) . The reaction mixture was then allowed to stir at room temperature overnight. The resulting precipitate was collected by filtration and the crude product was then washed with methanol (~ 3 rnL) and dried under reduced pressure. The resulting solid was then taken up in ethyl acetate (150 niL) and washed with water (50 mL). The organic phase was dried (Na₂SO₄) and concentrated in vacuo to afford the propyl ester product (447 mg, yellow solid) in sufficient purity for subsequent reactions. A portion of this material (42 mg) was taken up in aqueous sodium carbonate solution (2 M, 10 mL) and ethyl acetate (20 mL). The phases were mixed and separated. The organic phase was concentrated in vacuo to afford propyl 5-(4-(4- (methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate (22 mg) as a creme solid of sufficient purity for biological screening.

Example 4. Compound 46 - S-ethyl 5-(4~(4-(methylsulfonamido)phenyl)pyrimidin-2- ylamino)-2-morpholinobenzothioate

A round bottomed flask was charged with 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin- 2-ylamino)-2-morpholinobenzoic acid tosylate salt (67 mg, 0.1 mmol) and PyBOP (62 mg, 0.12 mmol, 1.2 eq) and ΛζiV-dimethylformamide (4 mL). Diisopropylethylamine (70μL, 4 eq) was added to the reaction mixture, followed by ethane thiol (15μL, 2.6 eq). The reaction mixture was then stired at room temperature overnight under a nitrogen atmosphere, before being diluted with ethyl acetate (50 mL) and washed with diluted brine solution (25 mL) followed by saturated brine solution (15 mL). The organic phase was dried (Na₂SO₄) and concentrated in vacuo and subjected to silica column chromatography (20%, 30%, 40% and 50% ethyl acetate in dichloromethane) followed by Sephadex (LH- 20, methanol) chromatography to afford S-ethyl 5-(4-(4-

(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzothioate (7.1 mg, yellow glass). Example 5. Compound 48 - ethyl 2-(5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- yIamino)-2-morpholinobenzamido)acetate

5-(4-(4-(Methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid hydrochloride salt (68 mg, 0.14 mmol), PyBOP (62 mg, 0.12 mmol) and glycine ethyl ester hydrochloride (38 mg, 0.27 mmol, 1.9 eq) were placed in a round bottomed flask. Anhydrous ΛζiV-dimethylformamide (4 rnL) was added, followed by diisopropylethylamine (105μL, 4.3 eq). The reaction mixture was stirred at room temperature overnight before being diluted with ethyl acetate (20 mL) and washed with diluted brine solution (25 mL), bicarbonate solution (25 mL) and saturated brine solution (20 mL). The organic phase was then dried (Na₂SO₄) and concentrated in vacuo. The residue was triturated with methanol (~2 mL), the suspension was sonicated and then allowed to stand overnight. The precipitate was collected and confirmed by LC-MS and ¹H NMR to be the desired ethyl 2- (l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxamido)acetate (21 mg, dull yellow solid, 27% yield).

Example 6. Compound 29 - ethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxylate

Ethyl l-(4-aminophenyl)piperidine-4-carboxylate, iV-(4-(2-chloropyrimidin-4- yl)phenyl)methanesulfonamide and p-tohienε sulfonic acid monohydrate (61 mg, 0.32 mmol, 0.84 eq) were placed in a reaction vessel, suspended in dioxane (4 mL) and heated at 100°C under a nitrogen atmosphere for 66 hours. The reaction mixture was transferred to a polypropylene tube and centrifuged. The liquid was decanted and the residue washed with methanol (2 x 3 mL). The resulting cream solid was dried under vacuum and confirmed by LC-MS and ¹H NMR to be the desired ethyl l-(4-(4-(4- (methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4-carboxylate isolated as its tosylate salt (125 mg, 49% yield).

Example 7. Compound 27 - l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidm-2- ylamino)phenyl)piperidine-4-carboxylic acid

Ethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylate tosylate salt (28.5 mg) was suspended in EtOAc (20 mL), treated with concentrated ammonia solution (1 mL) and washed with water (20 mL) then brine (20 mL).

The organic phase was dried (Na₂SO₄ ), filtered and concentrated in vacuo to provide compound 29 a free base. This material was then dissolved in aqueous 2 M HCl solution and heated at 6O⁰C for 24 hours. The reaction mixture was treated with a small volume of toluene and concentrated in vacuo to give l-(4-(4-(4-

(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4-carboxylic acid hydrochloride salt as a yellow solid in quantitative yield.

Example 8. Compound 35 - 5-(4-{4-[l-(cyanomethyl-amino)-2,2,2-trifluoro-ethyl]- phenyl}-pyrimidin-2-ylamino)-2-morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester

Preparation of substituted trifluoroethylamines can be accomplished as indicated by several different paths. In path 1, the reductive animation of 4-bromo- 1,1,1, -trifluoroacetophenone with aminoacetonitrile, followed by optical resolution methods well known in the art, can afford either enantiomer of A. Subsequent conversion of the bromide to boronate B is achieved by palladium-catalyzed cross-coupling with bis-pinacolatodiboron, and Suzuki- type coupling with 2,4-dichloropyrimidine, followed by elaboration via nucleophilic heteroaromatic displacement of the 2-chloride with the relevant aniline. In path 2, cross- imination of 4-methoxy- 1,1,1, -trifluoroacetophenone with benzophenone imine followed by reduction and cleavage under hydrogenolysis conditions would be expected to yield the free trifluoroethylbenzylamine, which upon conversion to the triflate and Pd-catalyzed cross-coupling as indicated in path 1, followed by alkylation using bromoacetonitrile, would yield B. A modification to this route would be available through reduction of a benzyl imine (formed by the reaction of benzylamine/TiCl₄) and reduction of the intermediate with NaCNBH₃ to give the same intermediates. Path 3 offers an alternative method to introduce the trifiuoromethyl group on an aldimine formed by the reaction of 4- bromobenzaldehyde and aminoacetonitrile, using the Motherwell-Storey reagent C as described.

In path 4, 4-bromo-l,l,l,-trifluoroacetophenone is converted to the corresponding trifluoromethylamine, either racemically as shown or in a chirally selective manner according to literature procedures {Org. Lett. 2005, 7(2), 355). The resulting amine can then be alkylated and converted to the corresponding boronate (or converted to the boronate and subsequently alkylated) using conditions similar to those as shown to afford B. Suzuki coupling with 2,4-dichloropyrimidine using the conditions described above then affords the desired 2-(l-(4-(2-chloropyrimidin-4-yl)phenyl)-2,2,2- trifluoroethylamino)acetonitrile (D).

General scheme for synthesis of components of compound 35

Path i

Path 2

Path 3 (for preparation of C see. Motherwell, W.B., Storey, L.J., J. Fluorine Chem. (2005) 126(4), 489-496.;

Path 4:

Example 9. Compounds 37 and 38 - 5-[4-(2-ethyl-l,l,3-trioxo-2,3-dihydro-lH-lλ⁶- benzo [d] isothiazol-6-yl)-py rimidin-2-ylamino] -2-morpholin-4-yl-thiobenzoic acid S- fluoromethyl ester and 5-[4-(2-Cyanomethyl-l,l,3-trioxo-2,3-dihydro-lH-lλ⁶- benzo[</]isothiazol-6-yl)-pyrimidm-2-ylammo]-2-morphoIin-4-yl-thiobenzoic acid S- fluoromethyl ester

The use of 4-bromosaccharin provides a pathway into the synthesis of compounds 37 and 38 as shown. Palladium-catalyzed cross-coupling methods can be used to attach the saccharin ring to the dichloropyrimidine, which can then be elaborated further with the trisubstituted aryl group under acidic conditions described elsewhere. Upon alkylation with, for example, ethyl bromide or bromoacetonitrile, followed by conversion to the fluoromethylthioester, the final products can be delivered.

General scheme for the preparation of compounds 37 and 38

Example 10. Compound 33 - iV-(4-(2-(4-(4-((2-oxotetrahydrofuran-3- yloxy)methyl)piperidin-l-yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide

A round bottomed flask was charged with iV-(4-(2-(4-(4-(hydroxymethyl)piperidin-l- yl)phenylaminoyrimidin-4-yl)phenyl)methanesulfonamide (Intermediate 12; ~ 0.35 mmol), potassium carbonate (80 mg, 0.58 mmol, 1.65 eq) anhydrous tetrahydrofuran (4 mL), and α-bromo-γ-butyrolactone (48 mL, 1.5 eq). The reaction mixture was heated at 6O⁰C overnight under a nitrogen atmosphere to afford the desired product (46% conversion by LC-MS). LC-MS (column: Alltima HP C_]8 2.1 x 150 mm, 5 μm): rt 7.15 min m/z 538.4 [M+H]⁺.

Example 11. Compound 52 - 5-(4-(4-(N-

(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2-ylammo)-2-morpholinobenzoic acid

N-(4-(2-Chloropyrimidin-4-yl)phenyl)-iV-(cyanomethyl)methanesulfonamide ( 171 mg,

0.53 mmol), 5-amino-2-morρholinobenzoic acid (142 mg, 1.2 eq.) and/>-toluene sulfonic acid monohydrate (98 mg, 0.98 eq.) were suspended in 1,4-dioxane (8 mL) and heated at 10O⁰C overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was taken up in ethyl acetate (80 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was then dried and concentrated in vacuo. The residue was repeatedly triturated with methanol (5 mL then 3 mL) to afford, as a cream solid, 5-(4-(4-(iV-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoic acid (101 mg, 37%). ¹H NMR (300 MHz, <4-DMSO) δ 17.23 (IH, s) CO₂H, 9.99 (IH, s), 8.74 (IH, d, J= 2.7 Hz), 8.62 (IH, d, J= 5.0 Hz), 8.33 (2H, d, J= 8.7 Hz), 8.01 (IH, dd, J= 2.8, 8.7 Hz), 7.69 (IH, d, J= 9.1 Hz), 7.63 (2H, d, J= 8.7 Hz), 7.52 (IH, d, J= 9.1 Hz), 4.97 (2H, s), 3.81 (4H, m), 3.21 (3H, s), 3.06 (4H, m). LC-MS: rt 5.4 min.; m/z 509.3 [M+H]⁺. Summar of S nthetic Methodolo ies for Com ounds 1 to 21, 23 to 35 and 37 to 64

Compound Analysis

¹H NMR data was acquired on a Bruker 300 MHz NMR Spectrometer. LC MS data was acquired on a Waters LC MS system operating under Masslynx software control and consisting of 2695Xe HPLC, 2996 PDA detector and ZQ single quadrupole mass spectrometer over a m/z range of 100-650 with cone voltage of 30 V, with nitrogen desolvation gas (500 L/h) and cone gas (100 L/h), source temperature set to 120°C and desolvation temperature set to 140°C.

Unless otherwise stated all LC MS data was obtained using the following conditions: Column: XTerra MS Ci₈, 3.5 micron, 2.1 x 50 mm Flow rate : 0.25 mL/min Solvent Gradient : Time % MiIIiQ water % ACN Curve

0 90 10 1

5 0 100 6

6 0 100 6

7 90 10 6

10 90 10 6

Where method 2 is stated for LC MS conditions, the following conditions were used: Column: XTerra MS C₁₈, 3.5 micron, 2.1 x 50 mm Flow rate : 0.25 mL/min Solvent Gradient :

Time % MiIIiQ % % 0.5% formic acid Curve water ACN (aq)

0 90 0 10 1

0.5 90 0 10 6

5.5 0 90 10 6

7.5 0 90 10 6

8.5 90 0 10 6

11.5 90 0 10 6

Method 3 was used for compound 33

Column: Alltima HP C₁₈ 2.1 x 150 mm, 5 μm Flow rate : 0.25 mL/min Solvent Gradient:

Time % MiIIiQ water % ACN Curve

0 90 10

7 0 100 6

9 0 100 6

10 90 10 6

13 90 10 6

Example 12. Enzyme Screening Compound Dilution

For screening purposes, compounds (in 100% DMSO) were warmed at 37 degrees for at least 20 minutes before use. A 20 μm stock was initially made in assay buffer, where the final concentration of DMSO was 0.3%. The stocks were then diluted in 384 well Optiplates (Packard) where the final concentration of the compound was 5 DM. JAK Tyrosine Kinase Domain Production

JAK kinase domains were produced using the following procedures:

JAKl The kinase domain of human JAKl was amplified from U937mRNA using the polymerase chain reaction with the following primers: XHOI-Jl 5'-CCG CTC GAG ACT GAA GTG GAC CCC ACA CAT-3' [SEQ. ID. NO.

5]

Jl-KPNI 5'-CGG GGT ACC TTA TTT TAA AAG TGC TTC AAA-3' [SEQ. ID. NO. 6]

The JAKl PCR products were cloned into the pDest20 destination vector (Gibco). The JAKl plasmid was then transformed into competent DHlOBac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.

JAK2

The kinase domain of human JAK2 was amplified from U937mRNA using the polymerase chain reaction with the following primers:

SALI-jk2 5'-ACGCGTCGACGGTGC CTTTGAAGACCGGGAT-S' [SEQ. ID.

NO.7] jk2-N0TI 5'-ATAGTTTAGCGGCCGCTCAGAATGAAGGTCATTT-S' [SEQ.

ID. NO.8]

The JAK2 PCR products were cloned into the pDest20 destination vector (Gibco). The

JAK2 plasmid was then transformed into competent DHlOBac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.

JAK3

The kinase domain of human JAK3 was amplified from U937mRNA using the polymerase chain reaction with the following primers: XHOI- J3 5'-CCGCTC GAGTATGCC TGC CAAGACCCCACG-S' [SEQ. ID. NO.9]

J3-KPNI 5'-CGGGGTACCCTATGAAAAGGACAGGGAGTG-S' [SEQ. ID. NO.10] The JAK3 PCR products were cloned into the pDest20 destination expression vector (Gibco). The JAK3 plasmid was then transformed into competent DHlOBac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.

Large Scale Production of Kinase Domains

Baculovirus preparations from each of the JAK family members were infected into one litre of Sf9 {Spodoptera frugiperda) cells (Invitrogen) grown in SF900II serum free medium (Invitrogen) to a cell density of approximately 2 x 10⁶ cells/ml. Cells were infected with virus at a cell culture to virus stock ratio of 20:1. Cells were harvested and lysed 48 hours post infection. The GST-tagged JAK kinase domains were purified by affinity chromatography on a GSH agarose column (Scientifix).

Assay Protocols

Kinase assays were performed in 384 well Optiplates (Packard) using an Alphascreen Protein Tyrosine KinasePlOO detection kit The compounds were pre-incubated with affinity purified PTK domain in the presence of phosphotyrosine assay buffer (1OmM HEPES, pH 7.5, 10OmM MgCl₂, 25mM NaCl, 20OmM sodium vanadate and 0.1% Tween 20) for 20 minutes. The compounds were then incubated with substrate in the presence of either 80 or 625um ATP for 60 or 90 minutes. The substrate used was either susbtrate-1 with the sequence biotin-EGPWLEEEEEA YGWMDF-NH₂ [SEQ. ID. NO. 13] (final concentration 111 μM) or susbtrate-2 substrate with the sequence biotin- EQEDEPEGDYFEWLEPE (final concentration 133μM )., Alphascreen phosphotyrosine acceptor beads followed by streptavidin donor beads at a concentration of 1/100 in stop buffer were added to each well under subdued light and incubated for 2-3 hours. , The Alphascreen plates were read on a Packard Fusion Alpha instrument. Results

The enzyme assay results and structural data for selected compounds is given below in Table Ia, where +++ is <100nM, ++ is <500nM and + is <lμM and Table Ib: Table Ia. Compound characterization data. as

H

oo

U⁾

Table Ib. Compound activity data (ND= not determined).

Example 13. Cellular screening Compound Dilution

For screening purposes, compounds were diluted in 96 well plates at a concentration of 20μM. Plates were warmed at 37⁰C for 30 minutes before the assay was performed. Establishment of the TEL: JAK2 and TEL: JAK3 cell lines

The coding region encompassing nucleotides 1-487 of TEL was amplified by PCR using the oligonucleotides 5TEL (5' -GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC- 3') [SEQ ID NO 14] and 3TEL (5' -AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3') [SEQ ID NO 15] and U937 mRNA as a template. A BamHI restriction site was incorporated into the 5TEL primer, and a Sal I restriction site was incorporated into the 3TEL primer. The regions encompassing the kinase domain of JAK2 (nucleotides 2994- 3914; JAK2F 5'-ACGC GTC GAC GGT GCC TTT GAA GAC CGG GAT-3' [SEQ ID NO 16]; JAK2R 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3') [SEQ ID NO 17] and JAK3 (nucleotides 2520-3469; JAK3F 5'-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3') [SEQ ID NO 18] were generated by PCR using Taq DNA polymerase (Gibco/BRL) and U937 mRNA as a template. A Sal I restriction site was incorporated into the forward primer of JAK2 and JAK3, a Not I site was incorporated into the JAK2 reverse primer and a Xba I site was added to the reverse primer of JAK3. A TEL/Jak2 fusion was generated by digestion of the TELPCR product with BamH I/Sal I restriction enzymes, digestion of the JAK2 PCR product with Sal I/Not I restriction enzymes, followed by ligation and subcloning of the ligation product into the mammalian expression Vector pTRE 2 (Clontech), which was prepared by digestion with BamH I- Not I restriction enzymes, to give the the TEL/Jak2 fusion plasmid pTELJAK2. The TEL/Jak3 fusion was prepared by ligation of the JAK3 Sal I/Not I cleaved kinase domain PCR product with the BamH I/Sal I restriction digested TEL product, followed by ligation of the ligation product into the BamH I/Not I digested pTRE2, to give the TEL/Jak3 fusion plasmid pTELJAK3. The growth factor dependant myelomonocytic cell line BaF3 bearing the pTET-off plasmid (Clontech) was transfected with either pTELJAK2 or pTELJAK3, and the transfected cells were selected for growth-factor independent cell growth. The BaF3 wild-type cells were cultured in DMEM containing 10% FCS, 10% WEHI 3B conditioned medium. The BaF3 TELJAK cells (BafT_J2 or BafT_J2) were cultured in DMEM 10% Tet-System Approved FBS (without WEHI 3B conditioned medium).

Cellular assays were performed as follows:

Cell suspensions were prepared by harvesting cells from culture, (the cells used in this test were in late log phase growth with high viability.) Cells were diluted in the appropriate growth medium, as described above, to l.lx final concentration (from 50,000 cell/mL to 200,000 cell/mL, depending on cell line).

Compounds to be tested were added (lOμL, 1OX final concentration) to a flat bottomed 96- well plate. The cellular suspension (90μL per well) was then added, and the plate incubated for 40 hr at 37°C, 5% CO₂. Alamar Blue lOμL per well was added and the plates returned to the incubator for a further 4-6 hours. The plates were then read at 544 nm. Cellular Screening Results

Table 2. Compound activity data, where +++ is <lμM, ++is<5μM and +is <20μM

Example 14. Western Blots

Rat lung microvascular endothelial cells were grown in serum free media for 24 hours then exposed to IL-6 10 ng/ml with varying concentrations of compound 29. The cells were harvested after 30 minutes of exposure to IL-6 and the amount of STAT3 phosphorylation at tyrosine 705 was determined relative to total STAT3 with Western blots. An example of a Western blot from this experiment is shown in Figure 1. The primary antibody against pSTAT3was specific for phosphyorylation at Y705. The antibodies against pSTAT3 and STAT3 were from Cell Signaling (MA). Densitometric analysis was performed with Image J. Non-linear regression was performed with Graph Pad Prizm to obtain sigmoidal curves and calculate the EC50. Results shown in Figure 2 are from duplicate experiments.

Example 15. Metabolism of Compound 29 in human hepatic microsomes

Compound 29 was incubated at 37°C with human liver microsomes at a concentration of 1 μM. The reaction was initiated by the addition of an NADPH-regenerating system and quenched at various time points over the incubation period by the addition of acetonitrile. The relative loss of parent compound and formation of metabolic products was determined by LC/MS using a Micromass Q-TQF mass spectrometer.

Compound 29 exhibited rapid degradation in the incubation matrix containing human liver microsomes devoid of the cofactors required for CYP450-mediated metabolism. At the point of initiation of the assay, concentrations of test compound could not be detected, although a putative P-28 metabolite was detected. This indicates that compound 29 underwent non-NADPH dependent degradation in the microsomal matrix during the 10 minute incubation period which was likely to be due to hydrolysis of the ester bond by microsomal hydrolytic enzymes.

Example 16. Additional Compound Evaluation

The compounds of formula I can be tested in the dog model of pulmonary hypertension as described in Gust, R and Schuster, D. P. Experimental Lung Research, 27:1-12, 2001. They can also be tested in a rabbit model of monocrotaline induced pulmonary hypertension. The compounds of formula I can also be tested in humans with pulmonary arterial hypertension. The effect of the compounds of formula I can be tested in humans with pulmonary arterial hypertension by measurement of its acute effects on cardiopulmonary hemodynamics. The effect of the compounds on right ventricular pressures, pulmonary artery pressures, pulmonary vascular resistance, and cardiac output may be determined. The effect of the compounds on the six minute walk time, and maximal oxygen consumption may be determined in humans with PAH. The effect of the compounds on quality of life (as measured by a questionnaire), hospitalization, and survival may be determined in humans with PAH. In humans PAH may be caused by genetic abnormalities (i.e., primary or familial PAH) or secondary causes such as scleroderma, uncorrected congenital heart disease, mixed collagen vascular disorder, hepatitis C, or other liver disease, HIV infection, or hereditary hemorrhagic teleangiectasia. The effect of the compounds may also be tested on human endothelial cells, fibroblasts and/or smooth muscle cell lines: for example, determination of IC50 for STAT3 phosphorylation in human pulmonary artery smooth muscle cell lines. Cell lines from other species, ie, the rat may also be examined. The effect of the compounds on precontracted vascular rings from human blood vessels, or blood vessels from other species, i.e, the rat, may be examined. For example, rat pulmonary artery rings preconstricted with phenylephrine, or endothelin, or serotonin, or vasopressin, angiotensin II, or KCL may be studied to determine the dose response to the compounds for vasorelaxation. Other vasoconstrictors may be examined.

The effect of the compounds on hypoxia induced pulmonary vasoconstriction may be examined. A model of hypoxia induced pulmonary hypertension might include study of rats, such as the Fawn-Hooded rat exposed to low oxygen (i.e., 5 percent oxygen). Another model of hypoxia induced pulmonary hypertension might include the fetal calf maintained in a high altitude chamber.

The effect of the compounds may be examined in transgenic models of pulmonary hypertension: i.e., the BMPR2 knockout mouse treated with IL6, the caveolinl knock out mouse, or the vasoactive intestinal peptide knockout mouse.

The effect of the compounds on histopathologic changes that occur in both human and animal models of PAH may be measured. For example, the compounds may decrease the extent of plexiform lesions in the pulmonary arterioles of diseased lungs. The plexiform lesion consists of endothelial cells, smooth muscle cells, and fibroblasts which proliferate and obstruct to a varying degree, the pulmonary arteriolar lumen.

The effect of the compounds can also be evaluated in asthma models. Asthma is restricted to human species, but animal models are often used to investigate particular aspects of this human disease. Bronchial biopsies and bronchoalveolar lavage (BAL) fluid recovered from patients with asthma have been shown to contain an increased number of activated T cells, B cells, eosinophils and mast cells. Many patients with asthma are sensitized and have specific immunoglogulin E (IgE) antibodies to one or more inhalant allergens. Atopy is, considered to be a major cause of asthma. In atopic individuals, inhalation of allergens preferentially induces a T-helper 2 cell (Th2) response. In the majority of current models, mice are sensitized by itraperitoneal (ip) injection of ovalbumin (OVA), often together with a Th2 skewed adjuvant, such as alum. In the classical mouse model for asthma, C57/BL6 mice are actively sensitized on day 0 by ip injection of lOμg of OVA absorbed onto 1 mg of alum. From day 14-21 the mice are exposed daily to aerosolized OVA over a 30 minute period. On day 22, airway inflammation is apparent. BAL fluid recovered from these animals demonstrate an increase in peri-bronchiolar space consisting of mixed cellular infiltrates of mononuclear cells and eosinophils. OVA-specifϊc IgE antibodies can be demonstrated in the serum of sensitized animals. The mononuclear cell population consists mainly of cells of Th2 phenotype secreting cytokines IL-4 and IL- 5. IL-4 promotes isotype switching of B cells towards IgE synthesis and IL-5 influences the production, maturation and activation of eosinophils. AU publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before the priority date of each claim of this application.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims

WE CLAIM:

1. A compound of formula I :

wherein

5 R¹ is independently selected from halogen, R², OR², R⁴, CN, NO₂, R²R⁴, SO₂R⁴,

NR²SO₂R³, COR⁴, NR²COR³, NR²COR⁴, R²CN, R²OH, R²OR³ and OR⁵R⁴;

R² is substituted or unsubstituted C_1-6 alkyl or C_1-6alkylene;

R³ is R² or substituted or unsubstituted aryl;

R⁴ is selected from NHR², N(R²)₂, morpholino, thiomorpholino, thiomorpholino-1-0 oxide, thiomorpholino- 1,1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which may be optionally substituted with C_1-S alkyl wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NR^Y and/or optionally substituted with halogen, C_4-I0 lactone, COSR^Y or COOR^Y; 5 R⁵ is substituted or unsubstituted C_2-4 alkylene;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently selected from H, R^XCN, halogen, substituted or unsubstituted Ci_-6alkyl, NR^YS0₂R^Y and SO₂N(R^Y)₂; where R⁷ and R⁸ are optionally joined with the carbon atoms to which they are attached to form a C_4-6 substituted or unsubstituted aryl, substituted or unsubstituted O cycloalkyl or substituted or unsubstituted heterocyclyl;

R^γis H or substituted or unsubstituted Ci-₆alkyl,

R^x is C_1-6 alkyl wherein up to 3 carbon atoms are optionally replaced with CO, NR^Y C0NR^γ, S, SO₂, O or NSO₂R^Y and/or substituted with CF₃;

R¹¹ is selected from H, halogen, Ci_-6 alkyl , C_2-6 alkenyl, C_2-6 alkynyl, C_3-65 cycloalkyl, N(R^Y)₂, NHR^Y, C0R^Y, NO₂, COOR^Y, CON(R^Y)₂, OC_1-6 alkyl, CN, CH₂F, CHF₂ and CF₃;

R¹² is H, P(O)(OR²)₂, OR¹³, COOR¹³, COSR¹³, CONHR⁴ or CON(R⁴)₂;

R¹³ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, CN, Ci_-6alkyl OCj_-6 alkyl, or heterocyclyl; ni is 1 to 3; and n is 1 or 2, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from O, N and S; with the proviso that when R¹² is H, then R¹ is morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, NR²-piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine, each of which is substituted with at least one C_1-8 alkyl wherein 1 to 4 carbon atoms are replaced with CO, O, S₅ C(O)S or C(O)O, and/or optionally substituted with halogen, C_4-10 lactone, COSR^Y or COOR^Y; and wherein the compound is a stereoisomer thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein at least one substituent on morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, NR²- piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine contains at least one C(O)S, C(O)O, halogen, C_4-10lactone, COSR^Y or COOR^Y group.

3. The compound according to claim 1, wherein R¹ is morpholino or piperidine substituted with Cj.salkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-10 lactone, COSC_1-4alkyl or CO₂C_1-4alkyl; R² is H or C_1-4alkyl; R⁶, R⁹ and R¹⁰ are H; R⁷ is SO₂NHR^Y or NHS0₂R^Y in which R^γ is C_1-6alkyl;

R⁸ is R^XCN where R^x is C_1-6alkyl wherein up to 2 atoms are optionally replaced with CO, NR^YSO and/or substituted with C_1-6alkyl or NHS0₂R^Y wherein R^γ is H or Ci- ₆alkyl, where R and R are optionally joined together with carbon atoms to which they are attached to form a substituted or unsubstituted heterocyclyl; R¹¹ is H, methyl or trifluromethyl; and

R¹² is H, OR¹³, COOR¹³, COSR¹³ or P(O)(OR²)₂;

R¹³ is H, C_1-6alkyl, C_3-6 cycloalkyl or heterocyclyl each of which may be optionally substituted with halogen, Ci_-6alkyl or OCi_₆alkyl.

4. The compound according to claim 1, wherein

R¹ is morpholino or piperidine substituted with C_1-8alkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-io lactone, COSC^alkyl or CO₂Ci-₄alkyl; R⁷ is SO₂NHR^Y or NHSO₂R^Y;

R^γ is H or C_1-6alkyl;

R⁸ is R^XCN wherein R^x is C_1-6alkyl wherein up to 2 atoms can be optionally replaced with CO, NR^YSO and/or substituted with C_1-6alkyl or NHSO₂R^Y ; or

R⁷ and R⁸ are optionally joined together with the carbon atoms to which they are attached to form a substituted or unsubstituted heterocyclyl; R¹¹ is C_1-4alkyl or trifluoromethyl; and

R¹² is OR¹³, COOR¹³, COSR¹³ or P(O)(OR²)₂ wherein R² is C_Malkyl and R¹³ is H₅ C_1-6alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, C_1-6alkyl or OC_1-6alkyl.

5. The compound according to claim 1 which has the formula Ia

Ia wherein R*_a is morpholino or piperidine substituted with Ci-salkyl, wherein up to 4 carbon atoms are optionally replaced with CO, O, S, C(O)S, C(O)O or NH and/or optionally substituted with F, C_4-10 lactone, COSC_1-4alkyl or CO₂C_1-4alkyl; R⁷a is S0₂NHR^Y or NHS0₂R^Y in which R^γ is C_1-6alkyl;

R⁸a is R^XCN in which R^x is C_1-6alkyl wherein up to 2 atoms can be optionally replaced with CO, NR^YS0 and/or substituted with C_1-6alkyl or NHS0₂R^Y wherein R^γ is H or C_1-6alkyl;

R a and R _a are optionally joined together with the carbon atoms to which they are attached to form optionally substituted heterocyclyl; Rⁿ _a is Ci_-4alkyl or trifluoromethyl; R¹² is OR¹³, COOR¹³, COSR¹³ or P(O)(OR²)₂ wherein R² is C_halky, and R¹³ is H₃ Ci- ₆alkyl, C_3-6 cycloalkyl or heterocyclyl, each of which may be optionally substituted with halogen, C_1-6alkyl or OC_1-6alkyl.

6. A compound selected from: methyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; ethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; propyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; isopropyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ; tert-butyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate, cyclopropyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; cyclobutyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylarnino)-2- morpholinobenzoate; cyclopentyl 5-(4-(4-(cyanomethyIcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; cyclohexyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate;

2-methoxyethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate; methyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate; ethyl 5 -(4-(4-(cyanomethylcarbamoyl)phenyl)-5 -methylpyrimidin-2-ylamino)-2- morpholinobenzoate; propyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; isopropyl 5 -(4-(4-(cyanomethylcarbamoyl)phenyl)-5 -methylpyrimidin-2-ylammo)-2- morpholinobenzoate; cyclohexyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; tetrahydro-2H-pyran-4-yl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2- ylamino)-2-morpholinobenzoate; l-methylpiperidin-4-yl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2- ylamino)-2-morpholinobenzoate;

2-methoxyethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; propyl 5-(4-(4-(2-cyanoacetamido)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzoate ; S-ethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzothioate ;

S-fluoromethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2-ylamino)-2- morpholinobenzothioate; propyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate; isopropyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzoate ;

5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid;

5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid; l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylic acid; l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylic acid; ethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylate; ethyl l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxylate; methyl 2-(l -(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)acetate; 2-methoxyethyl 1 -(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)ρiperidine-4-carboxylate;

N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3-yloxy)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide;

N-(cyanomethyl)-4-(2-(4-(4-((2-oxotetrahydrofuran-3-yloxy)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide ;

5-(4-{4-[l-(Cyanomethyl-amino)-2,2,2-trifluoro-ethyl]-phenyl}-pyrimidin-2-ylamino)-2- morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester;

5-[4-(2-Ethyl-l,l,3-trioxo-2,3-dihydro-lH-lλ⁶-benzo[Λdisothiazol-6-yl)-pyrimidin-2- ylamino]-2-morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester; 5-[4-(2-Cyanomethyl-l,l,3-trioxo-2,3-dihydro-lH-lλ⁶-benzo[J]isothiazol-6-yl)-pyrimidin-

2-ylamino]-2-morpholin-4-yl-thiobenzoic acid S-fluoromethyl ester;

1 -(4- {4- [4-(Cyanomethyl-carbamoyl)-phenyl] -pyrimidin-2-ylammo } -phenyl)-piperidine-4- carbothioic acid S-fluoromethyl ester;

N-(cyanomethyl)-4-(2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide;

S-fluoromethyl 2-(l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)ethanethioate;

S-fluoromethyl 2-(l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carboxamido)ethanethioate; N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3 -ylthio)methyl)piperidin- 1 - yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide;

S-fluoromethyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2- ylarnino)phenyl)piperidine-4-carbothioate;

S-fluoromethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzothioate; S-ethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzothioate ; ethyl 5-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoate; ethyl 2-(5~(4~(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2- morpholinobenzamido)acetate;

S-propyl l-(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carbothioate; ethyl 2-( 1 -(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carboxamido)acetate ; S-ethyl 1 -(4-(4-(4-(methylsulfonamido)phenyl)pyrimidin-2-ylamino)phenyl)piperidine-4- carbothioate;

5 - {4- [4-(Cyanomethyl-methanesulfonyl-amino)-phenyl] -pyrimidin-2-ylamino } -2- morpholin-4-yl-benzoic acid;

S-fluoromethyl 5-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2- ylamino)-2-morρholinobenzothioate;

S-fluoromethyl 5-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-2~ylamino)-2- morpholinobenzothioate ;

N-(cyanomethyl)-N-(4-(2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)phenyl)methanesulfonamide; N-(cyanomethyl)-4-(5-methyl-2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)piperidin-l- yl)phenylamino)pyrimidin-4-yl)benzamide;

2-(2,2,2-trifluoro-l-(4-(2-(4-(4-((2-oxotetrahydrofuran-3-ylthio)methyl)ρiperidin-l- yl)phenylamino)pyrimidin-4-yl)phenyl)ethylamino)acetonitrile;

[l,l,3-Trioxo-6-(2-{4-[4-(2-oxo-tetrahydro-furan-3-ylsulfanylmethyl)-piperidin-l-yl]- phenylamino } -pyrimidin-4-yl)- 1 ,3 -dihydro- 1 λ⁶-benzo [d\ isothiazol-2-yl] -acetonitrile ;

S-fluoromethyl l-(4-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate;

S-fluoromethyl l-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)-5-methylpyrimidin-2- ylamino)phenyl)piperidine-4-carbothioate; S-fluoromethyl l-(4-(4-(4-(l-(cyanomethylamino)-2,2,2-trifluoroethyl)phenyl)pyrimidin-2- ylamino)pheny l)piperidine-4-carbothioate ; and

1 -{4-[4-(2-Cyanomethyl- 1 , 1 ,3-trioxo-2,3-dihydro- IH-I λ⁶-benzo|>f]isothiazol-6-yl)- pyrimidin-2-ylammo]-phenyl}-piperidme-4-carbothioic acid S-fluoromethyl ester or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.

7. A process for the preparation of the compound according to claim 1 comprising the step of coupling a compound of formula II

wherein R and n are as defined in claim 1 and X is a leaving group with compounds of formula III and IV

III IV wherein R¹, R⁶, R¹⁰, R¹² and m are as defined in claim 1 and M is a metal.

8. A compound according to claim 1 which is a retrometabolic drug or metabolite thereof.

9. The compound according to claim 1 which is a kinase inhibitor.

10. A pharmaceutical composition comprising the compound according to claim 1 or 6 and a pharmaceutically acceptable carrier.

11. An implant which comprises the compound according to claim 1 or 6 or the pharmaceutical composition according to claim 10.

12. A method for the treatment of a kinase associated disease comprising administering a therapeutically effective amount of the compound according to claim 1 or 6 or the pharmaceutical composition according to claim 10 to a subject in need thereof.

13. The method according to claim 12, wherein the kinase inhibitor acts as a retrometabolic drug.

14. The method according to claim 12, wherein the kinase associated disease is an immunological or inflammatory disease, hyperproliferative disease or vascular disease.

15. The method according to claim 12, wherein the kinase associated disease is selected from the group consisting of Pulmonary Arterial Hypertension, asthma, Chronic Obstructive Pulmonary Disease and lung cancer.

16. Use of the compound according to claim 1 or 6 or the pharmaceutical composition according to claim 10 in the manufacture of a medicament for the treatment of a kinase associated disease.

17. Use of the compound according to claim 1 or 6 or the pharmaceutical composition according to claim 10 in the treatment of a kinase associated disease.

18. The compound according to claim 1 or 6 or the pharmaceutical composition according to claim 10 for the use in the treatment of a kinase associated disease.