WO2008087437A1 - Treatment of corticoid-resistant asthma or copd with p38 map kinase inhibit (eg. sb2035809) - Google Patents

Abstract

The use of an inhibitor of ρ38 MAP kinase like for instance SB 203580 in the treatment of severe corticosteroid resistant asthma and/or chronic obstructive pulmonary disease. The treatment may be for reducing side effects and morbidity associated with prolonged corticosteroid use and for reducing corticosteroid insensitivity in patients by improving the therapeutic effects of corticosteroids.

Description

TREATMENT OF CORTICOID-RESISTANT ASTHMA

OR COPD WITH P38 MAP KINASE INHIBIT

(EG. SB2035809)

The present invention relates to the treatment of severe respiratory disease.

Corticosteroids are the most effective anti-inflammatory therapy for inflammatory diseases such as asthma The vast majority of patients with asthma control their symptoms well with inhaled corticosteroids (ICS) and long-acting p₂-agonists, but a minority of patiems continue to have uncontrolled asthma despite these treatments. These latter patients with severe (or uncontrolled) asthma suffer greater morbidity and face a greater risk of asthma-associated death despite taking high doses of ICS (sometimes together with oral corticosteroids). Severe asthmatics do not display absolute resistance to the therapeutic effects of corticosteroids, as ceasing therapy exacerbates their symptoms. Instead the}- show a reduced responsiveness to corticosteroids, and as a result, high does of corticosteroid are required to adequately control their asthma. This is described as corticosteroid-dependcnf (CD) asthma.

Chronic obstructive pulmonary disease (COPD)₅ which presents with an active airway and lung inflammation, is one of the primary causes of morbidity and mortality in developed countries. Although large doses of oral corticosteroids are now used as a standard therapy for patients with COPD exacerbations, inhaled corticosteroids provide relatively little therapeutic benefit in COPD. ICS also fail to reduce the progressive decline in lung function that is the major characteristic of COPD This may, in part, be a result of the fact that inflammation in COPD is only reduced by a small extent or not at all by corticosteroids. Moreover, there is now evidence for steroid resistance mechanisms in COPD. In ex vivo studies of alveolar macrophages from patients with COPD, cytokine release has been shown to be distinctly resistant to the anti-infiammatoiy effects of corticosteroids in comparison with alveolar macrophages from smokers with normal lung function.

Lear tctrα administration oϊ^'orai corϋcoRtcicids cϊcyrϊy effects the hyopo(b-ua!ru>- P'Uiitii.'-v-adren;.'! tixir. n - r,d m-: ' ciuis-.; side e rfcri.^; i Mri t/.dmζ skin and Υ,- 'r,r]c, atrophy, delayed wound healing and increased vsk of infection, osteoporosis and bone necrosis, glaucoma and cataracts, behaviouraϊ changes, hypertension, peptic ulcers and s;asvromtestinal bleedms,. Cushmg^'s svndrome and diabetes.

Although corticosteroid therapy offers clear benefits to sufferers of severe asthma and COPD in the short term, the development of corticosteroid resistance is a very serious setback for these patients. Clearly there is ε need to develop therapies that will increase the effectiveness of corticosteroids in the treatment of these diseases. Developments such as these may be able to overcome corticosteroid insensitivity in severe asthma and COPD and as a result reduce corticosteroid-associated side effects by reducing the dosage of corticosteroids required for effective therapy.

There are several mechanisms for resistance to the effects of corticosteroids in asthma, which differ between patients. An elevation in the expression of inflammatory cytokines (Inferleukin (IL)-2. IL -4 and IL- 13) has been seen in bronchial biopsies of patients with corticosteroid-resistant asthma. This can lead to a reduction in affinity of glucocorticoid receptor in. inflammatory cells, such as T-lymphocytes and monocytes, resulting in resistance in these cells to the antiinflammatory actions of corticosteroids. Through in vitro studies mis reduction in sensitivity to corticosteroids has been linked with the activation of p38 mitogcn- activated protein (KlAP) kinase, which phosphorylates glucocorticoid receptors thereby reducing corticosteroid binding affinity and steroid-induced nuclear translocation of glucocorticoid receptors (Irusen e( α/., (2002) Journal Allergy Clinical Immunology 109: 649-657). A therapeutic implication of this proposed mechanism of corticosteroid resistance is the administration of p3S AiAP kinase inhibitors to reduce corticosteroid resistance in affected patients. Adcock, Chung, Caramon and Ito have indicated in a review article that p3S MAP kinase inhibitors may be useful as a therapeutic drug in severe asthma and COPD at inhibiting airway inflammation (J Allergy Clinical Immunology (2006) 533: 1 18-132). A lthough the

of Irusen el nl published in 2004 suggested that p38 MAP kinase inOiMlVs could rev^rtx- *.< C' H.αi:ttκr,'j resistance, wo ύn :/J evidence for this use of the compound has been forthcoming so far (J Allergy Can Immunol. 2002: 109: 649-57).

The use of p38 MAP kinase inhibitors in the treatment of COPD has been disclosed as a means of reducing the inflammatory response mediated by cytokine release (WO 2005/018624 A2). However, WO 2005/01 S624 A2 does not disclose the use of p38 MAP kinase inhibitors in conjunction with corticosteroids, or for reducing corticosteroid resistance, in patients with asthma or COPD.

The combination of a p38 MAP kinase inhibitor, a Tumour Necrosis Factor (TNF)-C production inhibitor and a steroid for the treatment of inflammatory diseases such as rheumatism and arthritis has been disclosed previously (US 2004/0097555 Al). There is nothing to suggest that the use of such a formulation could be useful for treating or reversing corticosteroid resistance in sufferers of severe asthma or COPD.

Methods for the treatment of IL-I mediated diseases were disclosed in US 2006/001 S904 Al that described the administration of an agent selected from a sulfasalazine, a statin, a glucocorticoid agent an inhibitor of p3S kinase, an anti- IL-6-receptor antibody, anakinra, an IL-I monoclonal antibody, an inhibitor of JAK3 protein tyrosine kinase, a M-CSF monoclonal antibody or a humanised anti- CD20 monoclonal antibody and a benzamide inhibitor of the P2X₇ receptor for the treatment of inflammatory diseases including asthma and COPD. US 2006/0018904 Al focuses on the inhibition of the P2X₇ receptor by a number of disclosed compounds that are co-administered with one or more of the compounds listed above. The compounds at the centre of the invention in US 2006/0018904 Al are the inhibitors of the P2X₇ receptor.

The current invention provides the use of p38 MAP kinase inhibitor in cases of severe asthma and COPD where corticosteroid resistance is present. This approach in considered to be particularly beneficial to the patient in: cases of corticosteroid resistance, where large doses of corticosteroids are required by the patient in these cases there is the poieπuai for the patient to suffer from the broad range of side effects caused by overuse of corticosteroids (listed above). The use of the current invention is considered to allow reduction of the dose of corticosteroids needed for a therapeutic effect and thus reduce side effects. This 5 may save a great deal of morbidity associated with severe asthma and COPD and may even reduce mortality associated with these diseases.

By the term 'severe asthma^' is included any disease of the respirator}' tract that is brought about by a chronic inflammatory disorder of the airways associated with

10 bronchial hyperresponsiveness, that leads to loss of control of symptoms of recuiient wheezing, brealhlessness. chest tightness and coughing despite utilising reliever and controller medications thai include corticosteroids. These patients .are also referred to as difficult to control asthma patients and are usually Ihe Step 4 and Step 5 of asthma treatment as defined in the Global Initiative for control of

15 Asthma (GINA) 2006 Asthma guidelines (http://www.gniastfnna.com). Other definitions of severe asthma have been provided previously (Chung at ah, (2000) Am. J. Rcspir. CrIt. Care. Med. 162: 2341-51 ; Chung el al._s Eur.Respir.J. (1999) 13: 1198-208).

20 By chronic obstructive pulmonary disease (COPD) is meant a disease characterised by airflow limitation that is not fully reversible but usual!}' progressive, associated with an abnormal inflammatory response of the lung to noxious particles or gases (Global initiative for Obstructive Lung Disease (GOLD) guidelines; http://goldcopd.com). In classification by severity, those patients with 5 more severe COPD such as at Stage III and Stage IV, when corticosteroid therapy is usually used, may be the target of this therapy.

The term 'corticosteroid' as used in describing the current invention is interchangeable with the term 'glucocorticoid'. It may be understood that these

;<! τei iTir rrfer ιc, t?tc rani:; cι:ιsr. of compounds hi clinical practice ihe term coi LiGCslεjoid is often wwά.. and may be used i<f;; -:>. Alternative!}', the term glucocorticoid is often used when describing the use of these compounds in the context of the laboratory for in vitro analysis and may also be used herein.

A first aspect of the invention provides the use of a p38 MAP kinase inhibitor in the manufacture of a medicament for the treatment of severe or corticosteroid- resistant asthma or chronic obstructive pulmonary disease (COPD). It is considered that such a use may be able to decrease or potentially even reverse corticosteroid resistance in patients. This may lower the dose of corticosteroid required, and thus reduce the unwanted side effects associated with taking said corticosteroid over prolonged periods of time.

It is preferred that the patient is selected on the basis of inadequate control of the asthma or COPD (with either recurrent symptoms or recurrent exacerbations) at a corticosteroid dose of 2000 μg or more of inhaled beclomethasone or equivalent corticosteroid per day, with or without the use of systemic corticosteroid therap}' (usually administered orally) such as prednisolone. In addition, this would be suitable particularly if the patient is experiencing significant side-effects from the corticosteroid therapy. However, it is envisaged that any patient who requires any dose of corticosteroid for the treatment of severe asthma or COPD will benefit from die use of the invention. The benefits of the invention may be more marked in patients requiring said dose of corticosteroid.

A further aspect of the invention provides a method of treating severe or corticosteroid-resistant asthma or COPD. comprising administering to the patient a therapeutically effective amount of a p38 MAP kinase inhibitor.

The therapeutically effective dose of p38 MAP kinase inhibitor for a particular patient ma}' be determined by the medical practitioner. A desired end point in clinical treatment may be improvement in symptoms and lung function and quality of πfe, with the possibility of a rs<iιxtion in the dosage of corticosteroid required bv the patient. A yεt further aspect of the invention provides thai said medicament comprises, along with said p3S MAP kinase inhibitor, a corticosteroid. It is envisaged that while the provision of a p38 MAP kinase inhibitor will benefit the patient m ierms of reducing the dose of corticosteroid administered, the co-provision of a pharmaceutical]}' acceptable dose of both a p3S MAP kinase inhibitor and a corticosteroid may bε of even greater benefit to the patient. This benefit is as a result of the synergistic effect of the two compounds in the treatment of severe asthma and COPD. The administration of a corticosteroid as well as a p3S MAP kinase inhibitor is also intended to be an aspect of said method of treating a patient with either severe asthma or COPD.

It is preferred that the p3S MAP kinase inhibitor of said use and/or method is selected from, but not limited to. any of the following compounds:

SB203580; 3-[3-bromo-4-(2.4-difluoro-benzΛ'loxy)-6-mεthyl-2-oxo-2H-p>τidin-l -yl]-4.N- dimethyl-bεnzam ide;

3-[5-chloro-4-(2.4-difiuoro-benz3'loxy)-6-oxo-6H-pyrimidiii-l -yl]-N-(2-hydrox3'- ethyl)-4-meth3'l-benzamide;

3-[5-bromo-4-(2.4~difluoro-beiαz>'loxy)-6-oxo-6H-p3τimidin-l-yI]-N-(2-hydrox3'- 1 -mem3'l-emyl)-4-iner.hyl-bεnzannde:

3 -[5-chloro-4-(2,4-difluoiO-benz3'loxy)-6-oxo-6H-pyrimidin-l-yl]-N-(2 -hydroxy- l -memyl-cmy])-4-inethyl-bεnzamide;

1- (4-[5-(4-chloro-2-f]uoiO-phenyI)-4-p3'rimidiu-4-yl-2H-p3'razol-3-3^/l]-piperidin-

1 -yl }-2-h}'droxy-cthanone; 1 - {4-[5-(4-chloro-phenyl)-4-pyrimidin-4-y]-2H-p3'razol-3-yl]-piperidin-l -yl J -2- hydroxy-εthanone;

6-[4-(2,5-difluoro-phen\'l)-oxazol-5-3'I]-3-isoprop3'I-[l,2.4]triazolo[4.3-a]p3'7idmε;

3-tert-butyl-6-[4-(2,4.5-trifluoro-phenyl)-oxazol-5-yl]-[L2,4]tτiazolo[4_>3- a]pyridine; 1 -[5-iert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4--(4- (moφholin-4-y]) phenyl) naphthoVvi-i yjj \ιrcy: 1-(5-tert-Butyl--22-p-tolyi-2H-p\τa2ol-3-ylj-.:-[4-(4-(moipholm-4-yl-me&yI) phenyl) naρhthalεn-1-yl] urea;

1-(5-tert-Butyl-2-p-to]yl-2H-ρyrazol-3-γl]-3-[4-(4-(2-(τπonpholin-4-yIJ ethyl) phenyl) naphthalen-1 -yl] urea: l-[54ert-buτ}-1-2-p4o!yl-2H-p>'razol-3-y3]-3-[4-(4-dimεthylamiQθphenyl) κaphthalen-1-yl] urea; l-[5-tert-butyI-2-p-toJ}'l-2H-pyrazo]-3-yl]-3-[4-(3-(morphoiin-4-yl) pheny])naphthalen-l-yl] urea; l-[5-tert-but3'l-2-p-tolyl-2H-pyrazol-3-yl}o-[4-(3-(morphoIin-4-yl-tnethyl) phenyl)naphtlialen-l-yl] urea;

1-[5-tert-but3'l-2-p-tolyl-2H-pyr£-zol-3-yl]-3-[4-(6-morpholin-4-3'hnethyl'pyridirj-

3-yl) naphthalen-1-yl] urea; l -[5-tt^-butyl-2-p4ol3d-2H-p>τazol-3-3^/l]-3-[4-(5-morpholin-4-ylmeth3'l-pyridin-

2-yl)naphthalen-l-yl] urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyra2θ]-3-3'l]-3-[4-(5-morpholin .-4-ylτnethyl-fur-2-}'l) naphthalen-1-yl] urea;

1-[5-tert-Butyl-2-(6-inethyl-p3τidin-3-yl)-2H-pyrazol-3-y]]-3-[4-(6-morpholin }-4- yimethyl-pyridin-3-j'l) naphthalan- i-yl] urea;

1-[5-tert-Butyl-2-methyl-2H-p3τazo]-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin 3-yl) naphthalen-1 -yl] urea;

1-[5-tert-Butyl--22-phen3'l-2H-ρyrazol-3-yl]-3-[4-(4-piperidin-1-methyl- phenyl)naphthalen-l-yl] urea;

1 -[5-tcrt-butyI-2-phen3'2-2H-p3τazol-3-3']]-3 -[4-(4-(4-methylpiperazin- 1 -3']) methylphenyl) naphthalcn-l-yl] urea; l-[5-tert-butyl-2-p-tolyl-2H-p3τazol-3-yl]-3-[4-(3, 4-ώ (morpholin-4-yl-mεtb3'l) phenj'l) naphthalen-1-yl] urea; l -[5-tert-butyl-2-(6-rneth3^rl-p3τidin-3-yl)-2H-p3τazol-3-3'l]-3-[4-(6-pyriQiri-4- ylmethy]-p3τidin-3-yl) naphtiialen-l-yl] urea;

1-[5-tert-Butyl-2-(6-methy3-pyridin-3-yl)-2H-pyrazol-3-3']]-3-[4-(6-(l-oxo- tbiυinoφholm-4-ykrietby]) pyridin-3-yl) naρhthaleπ-1 -yϊ] urea;

1-[5-tert-Butyl-2-p-to]yl-2?I-p3τazol-3-3'i]-3-[4-(6-( ] "θxo-lliiomorpholiπ-4- ybπsiϊiy!) ρyτidii>3-yl) naphώalen-l-ylj urea; 1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] 3-[4-(6- tetrahydropyran-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(6-(l-oxo- tetrahydrothiophen-3-ylmethyl) pyridin-3-yl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(6-(imidazol 1-} - ylmethyl) pyridin-3-yI) naphthalen-1-yl]-urea ;

1 -[2-(3-dimethylaminomethylphenyl)-5-( 3 -methyl-cyclohexyl)-2H-pyrazol-3-yI]-

3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y]) naphthalen-1-yl]-urea ;

1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl}-2H-pyrazol-3-yl]-3-[4- (6-morpholin-4-ylmethy!-pyridin-3-y]) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(2-morpholin-4-yimethyl- pyrimidin-5-y]) naphthalen-1-yl] urea:

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(3-methoxy -5-(2- morpholin-4-yl -ethoxy) phenyl ) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(3-(2-morpholin- 4-yl-ethoxy) phenyl) naphthalen-1-yl] urea: 1 -[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl]-3-[4-3- (dimethylamino) phenyl) naphthalen-1-yl]-urea ; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl}-2H-pyrazol-3-yl]-3-[4-3- (methylsulfonyl) phenyl) naphthalen-1-yl]-urea ;

5-tert-butyl-3-f-3-[4-(6-morpholin-4-ylmethyl -pyridin-3-yl) naphthalen-1-yl]- ureido} thiophene-2-carboxylic acid methyl ester;

5-tert-butyl-3- {3-[4-(6-morpholin -4-ylmethyl -pyridin-3-yl) naphthalen-1-yl] ureido } thiophene-2-carboxylic acidmethylamide; 5-tert-butyl-1-rnethyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen- 1-yl]ureido}-1H-pyrrole-2-carboxylic acid methyl ester,

5-tert-butyl -1-methyl -3-f-3-[4-(6-morpholin-4-y]methy]-pyridin-3-yl) naphthalen- 1 -yl]ureido}-1H-1-pyrrole-2-carboxylic acid methyl amide; 2-acetylaminoN-(5-tert-butyl -3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl]ureido} thiophen-2-ylmethyl) acetamide;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3 -[4-(3-morpholin-4-yl-cyclohex-1- enyl) naphthalen-1-yl]-ureaa; 1-[5-tert-Butyl-2-p-tolyl^H-pyrazol-^-j-IJ^-^S-muiplioIiri-ⁱ-vl-cylohept-l-enyl} naphtha! en- 1 -yl] urea;

1-[5-tert-Butyl-2-p-mlyl-2H-pyrazal-r>-y^]l-3-[4-(3-(2-morphoim-4-y!-ethylamirio) cyclohex- 1 -enyl) naphthalεn- ! -yl] ursa: l-[5-tert-butyl-2-p-toly]-2H-pyrazo]-3-yl]-3-[4-(3-moipholin-4-yl-cΛ'clohept-l- enylj napht]ialen-l-yl] itrea;

1-[5-tert-Butyl-2-(6-mεthj']-p}τidiπ-3-yl)-2H-p)τa2θl-3-3'l]-3-[4-(3-(pyridm-4-yl- methylamino)cyclohex-l-enyl) naphthalen-l -ylj urea:

1-[5-tert-Butyl-2-(6-mcthy]-p>'ridin-3-yl>2H-pyrazDl-3-yl]-3-[4-(3-

(dimethylaminoethyiammo)cyclohex-l-εm'l) jiaphthalen-l-yl] urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-j'l)-2H-p}τa2ol-3-yI]-3-[4-(3-(ρyridin-3-yl- methylamino)cyclohex-l-enyl)naphthalc]>l-yl] urea;

I-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phcnyl- methylamino)cyclohex-l-enyl) aaphtlialcn-1 -yl] urea;

1-[5-tert-Butyl-2-(6-msthyl-p3τidm-3-yl)-2H-pyrazol-3-ylj-3-[4-(3-(2- phsnylethylaniino)cyclohex-] -en3']) naphthalen-1 -yl] urεa;

1-[5-tert-Butyl-2-(6-methyl-p3'ridir3-3-yl)-2H-pyra2ol-3-yl]-3-[4-(3-(^'furan-2-yl- methylamino)cyclohex-i-en3']) naphthalen-i-j'lj urea; l-[5-tert-butyl-2-(6-meώyI.pyridm-3-yl)-2H-p>τazol-3-yl]-3-[4-(3-(2-pyπdiii-2- yl-ethylamino)cyclohex- 1 -enyl) naphtha! en- 1 -y 1] urea;

1-[5-tert-Butyl-2-Cό-raethj'l^Tidm-S-ylJ^H-pyrazol-S-ylj-S-M-CS^-piperdin-l - yl-ethylaτnino)cycjθhex-l-en3'i) naphthalεn- 1 -yl] urea;

1-(5-tert-Butyl-2-(^melhyi-pyiidin-3-yl)-2H-p>τazol-3-3'l]-3-[4-(3-(2-iiΩidazcl-4- yl-ethylamiαo)c}'clohex-] -enyl) naphthalen-1-yl] urea;

1-(5-tert-Butyl-2-(ό-raethyl-pyridin-3-yl)-2K-pyrazol-3-yl]-3-[4-(3-(pyridin-2-yl- rπetlij'lamino)cyc]ohex-l -enyl) naphtlialen-1 -yl] urea;

1-(5-tert-Butyl-2-(6-raεthyl-pyridin-3-yl)-2K-p3τazol-3-yl]-3-[4-(3-(2-(4- rnethox3φheny]) eth3'lamjno)cyclohex-l -eπyl) naphtha] en- 1 -yϊ\ urea;

1-(5-tert-Butyl-2-p-to]yl-2H-pyrazo]-3-yl]-3-[4-(4-rnαrpholiii-4-y]methy]-3-oxo-- cyclohex-1 -enyl) naphthalcn-l-yl] urea,

1-(5-tert-Butyl-2-:vtolyl~2J-l-pγrrι2βIO-3'l]-3-[4-(4-(i -oxo-tcfrrώydrothJop^*tierι-3- ylmcthy])-3-υΛθ-!:ycIohex-1 -enyl) aaphthaiw.-l-y]] urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(.<-(l -o;;o-thiomo:-pholin--1~ ylmethylj-3-oxo-cyclohcx-] -εnyl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(4-nisthylpiperazin-l -yIiτiethy?)'-3- oxo-cyclobex-l-enyl) naphthalen-1-yl]-urea :

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4- (6-Dxo-l-

(tetrahydro-pyran-4-ylmethy])-1.2) 3. 6-tctrahydro-pyridin-4-yl} naphthalan- 1-yl] urea:

1 -[5-tert-butyl-2-(6-methy]-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo- 1 -pyridir.-

4-γlmethyl-piperdin-4-yl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(ό-oxo-l-pyndin-4-yl-1 ,2,3.6- tetraliydro-pyridin-4-yl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(6-oxo-l-pyridiii- 4-yl-l,2,3,6-tetrahγdro-p3'ridin-4-yl) naphthalen-1 -yl] urea; 5-tert-butyl-3-{3-t4-(6-oxo-l -pyridin-4-yl-ls2,3>6-tetrahydro-pyτidin-4-yl) naphthalen-l-yl]urcido} thiophene-2-carboxylic acid methyl ester:

5-teιt-butyl-l-methyl)-3-{3-[4-(6-oxo-l-pyridin-4-yl--1.2,3,6-tetrahy dro-pyridm-4- yl) naphthalen-l-yl]ureido} pyrrole-2-carboxy!ic acid methyl ester: 5-tert-butyl-l-methy]-3- (3-[4-(6-oxo-l -pyridin-4-yl-l. 2.3, 6-tetrahydro-pyrJ.din-4- j'l)naphthalen-l-yl] ureido} pyrrole-2-carboxylic acid methj'l ainide; 5-tert-butylo-{3-[4-(3-morphoiin-4-yl-cyclohex-l -enyl) naphthalsn-1-yl] ureido} t]iiophεne-2-carboxylic acid methyl ester;

5-tert-but}'l-l-metb)'l-3-{3-[4-(3-morpholin-4-yl-cyclohex-l-en.yl) naphthalen-1- yl] ureido} pyrrole-2-carboxylic acid methyl ester;

5-tert-bυry]-l -methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-l-enyl) naphthalen-1- yl]ureido} pyrrole-2-carboxyiic acid methyl ainide;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(4-morpholin-4-yl-metliylphenyl)- naphthalen-1-yl] -urea:

3-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[3-(4-morpholin-4-yl-rnethylphεnyl)-naphthalen-1-yl]-urea ;

3-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(5-iτioφholin-4-yl-:ϊietbylfui-an-2- yi)-naphthalen-1-yl]-urea : 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl) cychloexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(2-(4-(morpholin-4-yl)ethylphenyl)

-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphenyl)-- naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(5-(morpholin-4-yl-methyl) pyridin-2-1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-γl]-3-[4-(4-(3, 4'dimethoxyphenylmethyl) -3-hydroxyphenyl)naphthalen-1-yl]-urea ; 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo- 1 ,6-dihydro-pyridin-3yl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-r4-(4-(morpholin-4- yl-methyl) phenyl)naphthalen-1-yl]-urea:

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(4-(morpholin-4- yl-methyl) imidazol- 1 -yl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(4-(morpholin-4-yl-methyl) imidazol-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(4-(furan-3- ylmethyl) -3-hydrophenyl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(6-(4- hydroxybutylamino)pyridin-3--yl)-naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(4-(pyridin -3-yI- methyl) -3-hydroxyphenyI)naphthalen-1-yl]-urea ; l-[5-tert-bury}-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl) pyridin-3-yl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(4-(imidazol-2- ylmethyl) -3-hydroxyphenyl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl] -3-[4-(4-(3- hydroxymorpholin-4-yl-methy]) phenyl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2- methoxyethy-N-methylaminomethyl) phenyl)naphthalen-1-yl]-urea : 1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4-(4- hydrox3;morphohn-4-j'l-raetbyl) phenyl )naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(3-(morpholin-4- yl-methyl) cycloheχeny])-naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4- (teti-ahydvofuran-3-yl-metb.yl) -3-hydroxyphsnyl) naphthalen-1-yl]-urea ; 1 -[5-tert-bυty]-2-(6-methyl-pyridin-3-yl)-2H-pyrazo]-3-yl]-3-[4-(4-(N, N-di-(2- methoxyeth3'l) aminomethyl) pheny'l)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(6-(3- cyanopropoxy) pyridin-3-yI) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4-morpbolin-4- yl-msthyl-piperdinyl) naphthalen-1 -yl]-ursa:

1-[5-tert-bulyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N! N-di-

(2cyanoethyl) aminoinethyl) phenyl) naphlhalen-1-yl] -urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(l-moτpholin-4-yl-indan-5- yI )naphthalen-1-yl]-urea:

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl]]-3-[4-(4-(fliran-2-yl- methyl) -3-hydroxyphenyl) naphthalen-1-yl]-urea :

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4- (thiomorphoIin-4-3'l-methyl) phenyl) naphthalcn-l-yl]-urea;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4-(3- carboxarnidomoi-pholin-4-yl- methyl ) phenyl)naphtb.alen-l-yl]-urea;

1-[5-tert-butyl-2-(6 methyl-pyridin-3-yl)-2H-pyrazol -3-yl] -3-[4-(4-(2-met}iyl-3- oxo-piperzin-1 -y]-methyl ) phenyl)naphthalen-l-yl]-urea;

1-[5-tert-but>'l-2-(2-methylpyrimidin-5-yl)-2H-pyrazo!-3-yl]-3-[4-(6-(moipholiri- 4-3'1-methy]) p3τidin-3-yl) naphthalen-1-yl]-urea ; 1-[5-tert-bulyl-2-(6-ineth}'l-pyridin -3-yl)-2H-pyrazol-3-3'l]-3-[4-(6- (4hydroxybut3'loxy) pyridin-3-yl) -naphthalan- 1 -yl]-urea;

1 -[3-tert-butyl-l'H-[l , 4']bip3τazol-5-yi]-3-[4-(6-(morpholm-4-yl-metliyl) pyridin 3-yI) naphthalen-1-yl]-urea ;

1 -[5-tc-rt-butyl-2-(6-methyl-pyridin-3-y1)-2H-pyrazol -3-yl}-3-[4-(4-(furan-2--y!-- methyl)-3-methoxyphenyl) naphthalen-1-yl]-urea ; l-[5-t5π-butΛ'l-2-(6-metiiyl-pyridin-3-)'i)-2I]-pyrazo]-?-y!]-3-[4-(5-(morpholin- 4carbonyl) pyraziπ-2 -yl )naphthalen- ] -3'!] - urea: l-[5-icrt4iutyl-2-(6-raethyi-pyrirlin-3-yπ-2H-pyrazol-3-yl]-3-[4-(6- (tctrahydrothiopyran-4-)'l-amino)pyridin-3-γl)-iiaphthalen-l-3'i]-urea; l-[5-tεrt-butλ'l-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[^/!-(6-(morpholin-4-yl- methyl }pyridin-3-yl)-naphthalen-l -yl]-υrεa: l-[5-tert-butyl-2-(6-mcthyi-pyridm-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2_: 6- dimethylmorphoIin-4-yl-methy]) pyridin-3-yl)-napb.lhalen-l -yl]-urea: l -[5-teπ-butyl-2-(2-methoxyp3'ridm-5-yl)-2H-pyrazoI-3-yl]-3-[4-(6-(rαθφholJπ-4~ yl-methyi) pyridin-3-j'l)-naphthalen-l-yl]-urea; l -[5-τert-butyI-2-{2-aminoypyridin-5-)'l)-2H-pyrazol-3-yl]-3-[4-(6-(mGipholJn-4- yl-metliyl) pyridin-3-}'l)-Jiaphthalen-I-y]]-urea: l -[5-tcrt-butyI-2-(6-oxo-1.6-dihydropyridin-3-yI)-2H-pyrazol-3-yl]-3-[4-(6-

(inorpholin-4-y]-mεthyl) pyridin-3-yl)-napbthaiεn-l-yl]-urea; l -|^'54ert-but3'l-2-(6-methλ'¹ι-pyπdin-3-yl)-2H-pyrazoI-3--yl]-3-[4-(6-(moφholin-4- γ]-4-carbony3) p3τidin-3-)'l)-naphtbalεn- 1 -y]]-urea; l -[54ε:1-butyl-2~(6-mεthyl-pyridi-n-3-yl)-2H-pyrazo]-3-yl]-3-[4-(6-(2-oxa-5-aza- bicyclo [2.2.1] liept-5-y3-inelhyl) pyridin-3-yl)-naphthalen-l -yl]-urea; l -[5-ιert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbam\'lphenyl) naphlhalεn- I yl] -urea; l -[5-tcrt-butyl-2K6-methyl-pyridin-3-yl)-2H-ρ>'razol-3-yl]-3-[4-(4-(N-(2-yl- propyl) pyridm-3-yl)-iiaphthalεn-l-yl]-^'urεa; l -[5-tert-butyl-2^6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3- πiethoxypropyl) amino) p}τidin-3-yl)-naphth.alen-l -yl]-urea: ] -[5-lεrt-bυtyl-2-(6-methyi-pyridin-3-yl)-2H-pyτazol-3-yl]-3-[4-(6-(N-(3- lΩethoxypropyl) -N-methylamino) pyridin-3-y])-naρhthalen-] -y I] -urea;

] -[3-tert-butyl-r-mcthyl-l ¹H-[1 ,4']bipyrazol-5-y]]-3-[4-(5-(morpholin-4-yl- methy])

naphthalen-1-yl] -urea; i -[5-tert-bul)'l-2-bεnzΛ'l-2H-p3τazol-3-yl]-3-[4-(6-(morpho3iιi-4-y]-methyl) p}'ridin-3-yl)-naphthalen-l -yl]-υrca; l -fi -^.i-bπtyl^-Cβ-mcLbyl-pyridir.-j-yl^H-pyra/oi-:-:/]] 3 -[J-(^i-(N-N-rli-("

£.minomcih3'i) ρiκ:ny])-napbthaleu-l-yl]-urea; ^] -[5-teπ-hu¹.yl-2-p-tolyl-2H-p}τazo!-3-\'l]-3-[4-(4-(4-carbaJD}']phenyI) naphihalen- Iy]] -ursa; l -[5-ιsπ-but3'l-2-(^'6-me-thyl-pyπdin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(t-oxo- ietr ahy droth i opj'ran -4jd - amino ) p yri cb n - 3 -y ! ) -n aphtb al en - ϊ -yl ] -urea; !-[5--terι-butyl-2-(.6-methyl-pyπdin-3-yr)-2H-pyrazol-3-yl]-3-[4-(6- (lctrahydroρyran-4yl-amino) pyriάin-3-yl)-naphtiia]εr!-l-yl]-urea; 1 -[3-tεrl -butyl- 1 '-(3-cyanopropyl)-l 'H-[I. 4'] bipyrazoI-5-yl]-3-[4-(ό-(morρholin- 4-yi-methyl) pjτiαin-3-yl) naphthalan- l -yl]-urea; l-[5-teit-buiyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(3-mctliancsulfinylpbenyl) naphthal en-l-yl]-urea: l -[5-tcrt-bui^d-2-p-toM-2H-pyrazo]-3-yl]-3-[4-(3-rnctliai-iesulfonylphen}'l) naphthal en- 1 - γl]-urea; l-[5-ιert-buty]-2-p-Lθlyl-2H-p)τa7_Jol-3-yl]-3-[4-(3-sulfonatrddophenyl) naphthalan- 1 -3'1] -urea: l-[5-tεπ-butyl-2-p-toiyl-2H-pyra2ol-3-yl]-3-[4-(3-(inorpho!in-4yI) carboirylpheπyl) naphthalen-l-3'l] -urea: l-[5-teπ-butyl-2-(6-methyl-pyridin-3-yl)-2H-p5τazol-3-y!]-3-[4-(5- (tεtrahydiOthiopyran-4λ''l-ami2io) pyrazin-2-yl)-naρhthalen-l -yi]~urεa; I-[5-tert-butyl-2-(6-mεtliyl-pyridin-3-yl)-2H-p3'razol-3-y]]-3-[4-(6- (methylcarboiiyiamino) pyridm-3-yl)-naphthalen-l -yl]-urca; l -[5-tεrt-buiyl-2-p-tolyl-2H-pyrazol-3-yI]-3-[4-C6-(morphoIin-4-y]-4-carbonyl) ph enyl ) -1 iaphthal en -1 -yl] -urea; l-[3-tert-but3/]-r-(3-methylsuifanylpiOpyl)-rH-[l,4']bipyT£zol-5-y!]-3-[4-(6- (morphoIin-4-3'l-raetli3'l) p3τidm-3-:v'l) naphthalan- l-}^rl]-urea; l-[5-tert-but3'l-2-p-tol34-2H-pyra2ol-3-yl]-3-[4-(5-(morpholin-4-yl-carbonyl) p3'ridin-3 -yl)-naphtha] en- 1 -yl] -urea; l-[5-tert-but3'l-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-3d]-3-[4-(5-(morpholin-4- yl-methy]) pyra2in-2-3'3)-rjaphtlialcn-] -yl]-urea; l-[5-tcrt-butyi-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-3'l]-3-[4-(6-araiiiopyridin- 3-y!) nόipliihalen-l -yl] -urea; l-f'^"-tort-hL'iyl-2-(6-mcthyl-pyridJn-3^»y];-?H-pyra7_Jol-3--yl]- 3- f4-(6-- (lnieth/JoJ|K'idijv4-vl -amino) ρyridin-3-yl) naphthal en-] -yl] -iircM: 1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] 3-[4-(6-C2-rnethyJ-3- oxo-pipsrzin- 1 -yl-methyi) pyridin-3-yl)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(2 methylparimidin-5-yl)-2H-pyrazol -3-yl] -3-[4-(6-(moipholin- 4-yl-carbonyl) p\τidin-3-3'l)naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-r4-(6-(K, N-di-(2- methoxyethyl) aiiiir.omethylj pyridin-3-y]) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-[4--(6-( 1-oxo- thiomorpholiri-4-yl-mcthyl) pyridin-3-yl)naphthalen-l -yl]-urea;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-[4-(6- (tetrahydropyran-4-yl-amino) pjτidin-3-yl) naphthalen-l-yl]-urea;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-(4-(5-(moφholii> 4yi-methyl) p3τa7.in-2-yl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-[4-(6- (moφh'oliπ-4-yl-methyI) pyridin-3-3'1) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-r4-(6-(2-msthyl-3-QXO-piperzin-l-yl~ methyl) pyridin-3-yl) naphthalen-l-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-[4-(6-(pyridin-3-y]-oxy) pyridin-3-yl) naphthalen-1 -yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(p3'ridin-3-yl-amino) pyridin-3- yl)naphthalen-l-yl]-urea; l-[5-tert-but34-2-(2-methoxypyrimidin-5-yl)-2H-pyra2ol-3-yl]-3-[4-(6- (morpholin-4-3'l-methyl) p3τidin-3-3'l) naphthalen-1-yl]-urea ; ]-[5-tert-butyl-2-p-tolyl-2H-pyrazoI-3-yl]-3-[4-(5-carbamylpyridin-3-3'l) naphthal en-l-yl] -urea;

1 -[5-tert-but3'l-2-(2-aminopyrimidin-5-yl)-2H-ρyra2ol-3-3'l]-3-[4-(6-(morpholin-4- yl-methyl) p3τidiπ-3-yl) naphthalen-1-yl]-urea ;

1-[5-tert-butyl-2-(2 methylpyrimidin-5-yl)-2H-pyrazol -3-yl] -3-[4-(4-(inorpholiD- 4-yl-methyl) phen3'l)naphthalen-1-yl]-urea ;

1 -[3-tert-butyl-l '-mefhyl-l 'H-[I !4l]bipyra2»l-5-yl]-3-[4-(6-(moipholin-4-y]- methyl) phenyl)naphthalen-1-yl]-urea ;

1 -[5-tert- butyl-2-(2-cyclopropylpyrimidin-5-y]) -2ϊJ-pyrazol-3-yl]-3-[4-(δ- (morpholin-4-yl-methyl) p3τidjn-3-yl)naphthalen-1-yl]-urea ; 1 -[5-tert-butyl -2-p-ιol>-I-2i-i-p},τazol-5-y!]-3-[4-(2-φ>iidin-3->'l-amino) pyrimidin-

5-y!)naphthalen-l -yl]-urea; l-[5-tεrt-butyl-2-p-to]}^rl-2H-pyrs2θ]"3-γ]]-3-[4-(6-(i-oλo-tεtrahydrothiopyran-4- ylamino) pyridin-3-yl) naphtalen 1-yl] -urea; l-[5-tsri-butyl-2-p-toly]-2H-pyrazo]-3-yl]-3-[4-(6-(ftiomorpholin -4-ylnietliyl) pyridin-3-3'I) naphthalen- 1-yl] -urea; l-[5-tert-but}(']-2-p-to]\'l-2H-pyi-azol-3-yl]-3-[4-(3-ben2yl-3H-imidazo [4,5-b] ρyridin-l-[5-tert-butyl-2-p-to]yl-2H-pyrazol-3-y]j-3-[4-(2-(morpholin-4-yl- methyl) pyrimidin-5-yl)naphtalen-l -yl]-urea; l-[5-tert-but>^rl-2-p-tol3'l-2H-p\'razol-3-y]]-3-[4-(3-aτnino-4-carbainylpheπyl) naphtalen- 1 -yl]-urea; l-[5-terf-buty]-2-p-tolyl-2H-pyi-azol-3-yl]-3-[4-(6-(l-oxo-tbiomorpholin-4-yl- methyl) pyridin-3-3'])naphtalen-l -}'l]-urea:

1-[5-teit-butyl-2-p-tolyi-2H-pyrazol-3-yl]-3-[4-(6-(pyridiri-3-yl-inetb.yl) pv.-idin-3- yl)naphthalen- 1 -yl]-urea;

1-[5-tert-but5'l-2-p-toly]-2H-p3'i-azol-3-yl]-3-[4-(6-(hydiOxy-pyrLdiii-3-yl-methyl} p)τidin- 3 -yl)naphtalen- 1 -y] ]-urea; l-[5-tert-but3'l-2-(2-metli3']pγrimidin-5-yl)-2H-p\τazol-3-yljo-[4-(2-(morpholin -4- yl-mεthyl) pyrirαidin-5-yl) naphtalen-l-ylj-ursa;

1 -(3-Cyano-pheny])-3-[4-(6-morpholin-4-ylniethyl-pyridm-3-yl)-naphthalen- 1 - yl]-urea; l-(3-Fluoro-phenyl)-3-[4-(6-morpbolin-4-ylinethyl-pyridiπ-3-3'l)-naphthalen-l - ylj-urca;

1-(4-Cliloro-2-trifluoromethyl-phenyI)-3-[4-(6-inorphoIin-4-ylmelhyl-pyridin-3-

3'l)-naphthalen-l-yl] -urea;

1 -(2-Chloro-5-trifluoromsth3'l-phenyl)-3-[4-(6-morpho]in-4-3'hnethyl-pyridiii-3- yl)naphthalen-l-yl] -urea;

1-(3. 4-Dimethyl-phsny])-3-[4~(6-morpholin-4-3'Lmε±yl-pyridin-3-yl)-naphthalen- l13'i] -urea;

1-(3-Iodo-phenyl)-3-[4-(6-morpholin-4-ylmcthy]-pyi-Jdύ>3-y])-naphtalen -] -yI]- ui-ea:

-[4-(6-Mmorpholin-4"ylme(hyI-py]idin-3-yl)-naphtalen-i-y]l-3-m-to^'Jyl-ui^"ea; l-{4-MεthylsulfanyI-piieriy!)-?-[4-(6-morpholin -4-yiraethyi-pyridin-3-y!}- naphtalen-l-yl]-urea;

I-(3-Chloro-4-metliy]-pheπyl}-3-[4-(6-morphoIin-4-ylmcthyl-pyπdin-3-

3'l)naphtalen-l-y3] -urea; l-(4-Cliloro-3-nitro-pheny3)-3-[4-(6-morpholin -4-ylirict}iyl-pyridir:-3-yI)- naphtalen-l-y]]-urea: l-(2. S-Dichloro-phenylJ-S-^-fό-morpholin -ylmcthyl-pyridm-S-yll-naphtalen-

IyIJ -urea; l-[4-(6-Morpholin-4-yknetl'iyl-pyridin-3-yl)-naphthalen-l-yl]-3-naphthaien-2-yl- urea; l-[4-(6-Morpholin-4-ylmethyl-pyridir!-3-yl)-naphthaien-l-γl]-3-pben3'l-urea;

1-(3-Chloro-phenylj-S-^-fό-morpholin ylmetliyl-pyridJDo-ylJ-naphtalen-l - ylj-urea:

1 -(4-Chloro-3 -tri fluorometh)'] -pbenyI)-3 -[4-(6-morpholin-4-ylmethy l-pyridin -3 - yl)-naphthalen-i-yl]-urea; l-[4-(6-Morpholiπ-4-ylrnethyl-p}'ridia-3-yI)-naphtalen-l-yi]-3 -(2,4,6-trichloro- phenyl) -urea;

1-(2-Me(hyl-3-mtro-phεny])-3-[4-(6-morpholin -4-3'lmethyl-pyτidin-3-yl)- naphthalen-l-yl]-urea;

1-(4-Methy]-2-nitiO-phen3'l)-3-[4-(6-morpholin-4-ylmethyl-pj'ridiii-3-y])- naphthalen-l-yl]-urea: l-(2. 3-Dichloro-phenyl)-3-[4-(6-morpholin -4-3'kneth3'l-pyj-idiD-3-}']}-naphtalen-

IyI] -urea:

1-(2-Methoxy-5-msthyl-phemyl)-3-[4-(6-morpholin-4-ylrnethyi-pyridiii-3-yl)-- naphthaleπ -1-yl] -urea;

] -(2-CWoro-6-rnethyI-phenyl)-3-[4-(6-rnorpholin-4-ylrnethyl-p}τidiii-3-yl)-naphtalen-l -yl]-urea;

1 -(2, 4-Dichloro-pbenyI)-3-[4-{6-morpholin -4-ylrnethyl-ρyridin-3 -yl)-naphtalen-

] yl] -urea:

1-(4-Mcthy]-3-Ωitro-phenyl)-3-[4-(6-morpholin -4-ylmet]iyl-p)τidiπ-3-yl)- naphtha^'ier,-! -yl]-urεa; l -(2. 4-DinieLhyl-i)hen\1)-3-[4-(6-morpholin -4-ylrnetny:-pyridin-3-y])-naphtalen-

]-yl]-urea; l-(2. 3-Dimethyl-phεnyl)-3-[4-(6-morpholin >-4^ylmεthyl-p3'ridin-3-γl)-naphtalen-

1 yl] -urea;

1 -(4-Cyano-phenyi)-3-[4-(6-morpholin 4-ylmethyl-pyπdin-3-3i)-naphtalen- 1 -

3'l]-urea: l-[4-(6-MoτphoIin-4-ylmethyl-pyridin-3-y])-naphtalen-l-yl]-3-(3_:4,5- tπmethoxj'-phcnyl} -urea; l-BJphenyl-4-yl-3-[4-(6-morpholin -4-ylmeth}i-pyridin-3-yl)-naphthalen-l-yl]- urea;

1 -(2, 5-Difluoro-ρhenyI)-3-[4-(6-morpholin-4-3άmsthy]-pyridijj-3 -yl)-naphtalen-

IyI] -urea; l-(3-Chloro-2-τmethoxy-pheny'l)-3-[^-(6-morpholin -4-ylmethyl-pyridin-3-yl)- naphtalen-1-yl] -urea; l-(2-Fluoro-3-l-ifluoromcthyl-phenyI)-3-[4-(6-morpholin -4-ylinethyl-pyndino- yl)naphtalen-l -}']] -urea; l-(4-Benzy]oxy-phenyl}-3-[4-(6-morpholirι-4-ylraethyl-pyridin-3-yl)-naphtalen-

IyI] -urea; l-(2-Methylsulfaiiyl-phenyI)-3-[4-(6-morpholin--Φ-ylrnethyl-pyridin-3-3'l)-naphtalen-l-yl]-urea; l-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-3'-lineth3d-p\'iidin-3- yl)-naphtalen-l-yl] -urea; l-(4-Fluoro-3-trifluoromethy]-plienyi}-3-[4-(6morpholin -4-ylmeth>-]-pyridin-3- yl)-naphtalen-]-γ!] -urea: l-[4-(6-Morpholin -4-yltnεthyl-p>'ridin-3-yl}-rιaphthalen-l-yl]-3-(2_:4.5-triniet>iyl- phenyl) -urea;

3 -[4-(6-Morpholin -4-ylmethyl-p>τidin-3-yl)-naphtalen-l -yl]-3-(4- irifluoromethyl-phenyl) -urea; l -(3-Methylsulfanyl-pheDy!)-3-[4-(6-morpholin -4-yimethyl-pyridin-3-3'J)-naphtalen-l-yl] -urca; l -(?-M.eϋiϋxy-ρhαπyl)-3-[4"(6-morpholin -4-ylnicthyl"pyridin*3-yj}-nεiyιil->aieβ-l- y I] -urea; ] -(2-Fluoro-5-rπfluoromstIiyl-phεnyl)-3-[4-(6-morpholin !-4-ylmεthy]-ρ>'ridin-3- yl)-naplithaieτ>l -yl]-urea: l -(4-Methoxy-2-iτιethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyτidin-3-Λ'lV naphthalεn-l-yl]-ureε; l-(2-FlL3oro-5-nitro-pheπyl)-?-[4-(6-morpholin -4-ylraethy!-p3τidin-3~yl)- naphthaien-1 -ylj-urea;

]-(4-Ethoxy-phenyl)-3-[4-(D-morpholin -4-yImethyi-pyridin-3-y])-naphtalen-l- y]]-urea; l-Cl^-Dimethoxy-phenyπ-S-^-Cό-morpholin ^-ylmcthyl-pyTidin-S-yl)- naphthalen-lyl]-urea;

]-(4,5-Dimethyl-2-nifro-phenyl)-3-[4-(6-morpholin-4-ylmslh)'l-pyridiii-3-yl)- naphthalen- 1 -yl]-ursa; l-(5-Chjoro-2-methyl-phcnyl)-3-[4-(6-morpholin -4-yb-iethyI-pi'ridin-3- yl)πaphthalen- 1 -yl]-urea; l -(2-lsopropyl-6-msthyl-phenyl)-3-[4-(6-morpholin -4--ylrnothyl-pyridin-3- yl)iiapbthalen- 1 -yl]-urea; i-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-34methyl-pyτidin-3-

}'l)naphtbalen- 1 -yl]-urea; l -(4-Isopropyl-phenyl)-3-[4-(6-morpholin -4-ylrnethyl-pyrid-nr3-yl)-naphthalen-l- ylj-urea; l-(4-Methox5'-pheEyI)-3-[4-(6-morpholin -4-ylmεthyl-p)'iiώn-3-yl)-naphtalen-l- yl]-urea:

I-(4-Butoxy-phεnyl)-3-[4-(6-moτpholin-4-ylmethyl-p3'ridin-3-yl)-naphtalen-] - yl]-urea; 4- {3-[4-(6-Moτpholin-4-ylτne(h3'l-pyridin-3-yl)-naphthalεn-l -yl]-ureido } -benzoic acid ethyl estεr;

] -(4-But)'l-2-methyl-phenyl)-3-[4-(6-morpholin -4-yItneth3'l-pyridin-3-yl)- πaphthalen- 1 -yl]-urεa;

J -(2.6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmetliyl-pyridin-3-yl) naρ]i.t]]alen- )-y]]-urea,

1 -(3-Methϋλ-y-phenyl)-3-[4-(ό-morpholin -4-)'ln]efhyJ-pvτidin-3-yl}-naphtalen -J - yl]-υrca; l-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholm-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea 1-Benzothiyzol-6-yi-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-] - y]]-urea;

N-(2,5-Disthoxy-4- 3-[4-(6-moirpholin-4-ylmethyl-pyridino-yl)-naphthalen- 1 - yl] -urei do } -phen)'l)-benzamide:

1 -[4-(6-Morphαlin-4-ylrne-byl -pyri din -3 -yl )-naphthalen- 1 -y I]-3 -(3 -phenoxy- phenyl) -urea: l-(4-Chloro-2-nitro-phenyl)-3-[4-(6-inorpho]iri-4-ylmehtyl-pyridin-3-3'-l)- naphtlialcn-]-y]]-urea;

1 -(5-Chloro-2-msthox:y-phenyl)-3 -[4-(6-niorpholin-4-}'lmethyl-pyτidin-3 - y])naphthalen-l -yl]-urea; l-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyI-pyridin-3-3'l)- naphthalen- 1 yl]-urea; 1 -[4-(6-Morpholiri-4-ylmeth}'l-pyridin-3-y])-naphthalen-l -yl]-3 -(4- trifluoromethox3'pheπyl)-urea;

] -[4-(6-Moτpholin-4-ylmetiiyl-pyiidm-3-yl}-naphthalen-l -yl]-3-

(3trifluoromcthylsulfanyl-phenyl)-urea: l-[4-(6-Morpholin-4-34methyl-pyridin-3-yl}-naphthalen-l-yl]-3-(2-phenoxy- phenyl)-υrea: l-(2-Mcthoxy-5-nitro-phenyl)-3-[4-(6-moφholm-4-ylmethyl-pyridin-3-yl)-l-(5-

Chloro-2.4-dimethoxy-phenyl)-3-[4-(6-raorpholin-4-ylmetbyl-pj'ridin-3-yl)-l- p3iidin-3-yl)-naphtbalen-I-yl]--urea; l-[5-tert-Bu(yl-3-(3-hydrcxy-prop-l-yiiyl)-2-methyl-pherιyl]-3-[4-(6-nioφholin-4- yhnethyl-pyridin-3-yl)-naphthalen-1-yl]-urea ;

1 -[5-terl-Butyi-2-(3-hydroxy-prop- 1 -yny])-phenyl]-3-[4-(6-moipho!in-4-ylmethy]- pyridin-3-y])-naphthalen-l-yl]-urea;

1 -[5-teit-Butyl-3-(2,2-dimethyl-[ 1.. 3]dioxolan-4-3^1metliyl)-2-metboxy-pheπyl]-3-

[4-(6-moφho!in-4-ylmethyl-p\τidm-3-yl)-naphthalen-1-yl]-ureaa; l -[5-tert-βMty!-3-(2,3-dLhydroxy-propy])-2-metboxy-phenyl]-3-[4-(6-vnoφholin-

4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-uτea; l-(5-teπ-Buτoxy-2-mεtiioxy-phenyl)-3-[4-(6-ino:^"phoIiii-4-yhτisthy^]-ρyridin-3-y]J- naphtha] en-I -y]] -urea: i-f5-(i-Cyano-cyclαpropy3)-2-methoxy-phεny]j-3-[4-(6-raorpholm-⁴-yli-ne¹.hy]- pyridin-3 -)'l)-naphtbal en- 1 -yl]-urεa:

5 l -[5-tsπ-Butyl-3-(2-dieth34amiiio-ethy])-2-raethoxy-phεnyi]-3--[4-(6--raorpholin-4- yhneth3'3-pyriάin-3-\d)-naphthaien-l-3'lJ-urea; l-(5-tεrt-Buty:-2-metlioxy-pben3'l)-3-[4-(6-[1.3]dio.xolan-2-)'I-pyridi:v3-yl)- naphthalan- 1 -yl] -urea; l-(5-teπ-Bulyl-2-pyrrolidin-l-yl-phεnyl)-3-[4-(6-morpholir.-4-yhnethyl-p3τidin-3- 10 yl) -naphthalen-1-y]] -urea; l-(5-tsrl-Butyl-2-dimethylaiτiino-phen}'l)-3-[4-(6-moipholm-4-ylinethyl-pyridin- 3-yl)-naphthalen- 1 -yl]-urea: i-(5-tsτt-Bur3'l-2-propoxy-phenyl)-3-[4-(6-morpholin-4-y]ixιcthyl-p>'ridiii-3-yl)- naphthalan- 1-yl] -urea;

15 l-(5-tert-Butyl-2-mεtho?:y-phenyI)-3-[4-(6-hydro.\}'metliy]-pyridin-3-yl)- naphtha! en-]-yl]-urea: l-(5-tert-Buty3-2-methoxy-phenyl)-3- (4-[6-(2. 6-dimethyl-morpholin-4-y]mεlhyl) -pyridm-3-yI]-naphthalen- 1 -yl} -urea; l-(5-Cyclohexyi-2-metlioxy-phenyl)-3-[4-(6-nioφholin-4-)'lmethyl-pyridin-3-yl)- 20 naphthal εn- 1 -y 1] -urea: l-(2.4-Dimethoxy-5-trifluorometh)'l-phcr)yl)-3-[4~(6-morpholm-4-ylraeth}'l- pyridin-3-yl)-naphthalen-l-yl]-urea;

]-(5-tcrt-But)']-2-methoxy-3-nitro-phei;yJ)-3-[4-C6-morpholin-4-j'lmethyl-pyridin- 3-)'l)-naphthaIsn- 1 -yl]-urea;

25 l-(3-Amino-5-tert-bur}'l-2-methoxy-phenyl)-3-[4-(6-mefe3^-p)'ridin-3-}^;l)- naphthal en-l-yl]-urca;

N-Acetyl-N-(5-tert-burs'l-2-3iiethoxy-3- [3-[4-(6-morpholiii-4-3'lniethyl-p}'τidu>3- y])-naphthalen-l-yl]-ureido}-phenyl)-acetaπiidε; l-(6-tert-Butyl-4-merh3']-3-oxo-3.

[1. 4]oxazin-S-y])-3-[4-(6- ''O mcrpholin-4-ylιr.etiiyl--pyridirι-3-yl)-naρritba]ei]-l -3_'l]-r.rea; i-(3-[θιt-Butyl-2-cι]iυxy pl!C'iiyl)-3-[4"(fi -:τ\orpiϊυIiii-4-yinielJiyl-pyridiu-j -y]> r.iφhtlialci-] -yl]-τjrca; 1-(5-tert-Butyl-2-isopropoxy-phenyl )-3-[4-(6-morpholin--4-ylmethyl-pyridin-3- yl)naphthalen-l-yl] -urea:

1 -(5-tert-Buτyl-2-imidazo^]-l -yl-phsnyl}-3-[4-(6-ιnoiphσlin-4-ylnietbyl-pyridin-3 - y!)-naphthalen-l -yl]-urea;

1-(5-tert-Butyl--32-ethy]£uτiino-2-rnethoxy-phei:yI)-3-[4-(6-morpholir!-4-3'lniεthyI- pyridin-3-yl)-naphthalen- 1 -y]]-urea:

N-(5-tert-Butyl--22-methox3'-3-{3-[4-(6-rnoφholin-4-ylmelhy]-pyτidin-3-yl)- naphthalen-l-yl]-ureido}-phenyl)-bis (methanesulfoπ) amide;

1-(5-tert-Butyl--22-(l-mεthy]-lH-p)'ra2θl-4-yl)-pheπyl]-3-[4-(6-morpholiπ-4- ylmethγl-pyridino-yl)-naphthalsn-l-yl]-υrea; l-(2-lvJethanesulfύiy]-5-lrifluoτomεthy3-plienyI)-3-[4--(6-rnorpholin-4-ylrπcthyl- pyridin-3 -)'l)-naphthal en- 1 -yl]-urea; l-[4-(6-{ [Bis-(2-me1iioxy-etliyl}-ajnino]-meth3'l}-p\'ridin-3-yl)-naphthalen-l-yI]-

3 -(5teπ-but3'l-2 -methoxy -phenyl) -urea;

N-[] ~(5-f 4-[3-(5-tert-Buty]-2-rnethoxy-phenyl)-ureido]-naphthalcai-l-yl}-pyridin-

2-l-(l-A∞tyl-3p-dimethyl-2,3-dihydro-lH-iπdol-5-yl)-3-[4-(6-morphoIin-4- ylraetliyl-pyridin-3-}'l)-naρhthalcn- 1 -yl]-urea;

N-(5-tert-Butyl--22-rnethoxy-3- f3-[4-(6-morpho!in-4-ylrneώyi-p)'τidin-3-yl)- naphthalon-l -yl]-υreido}-phsnyl)-propionamide ;

1-(5-tert-Butyl--22-methyl-benzooxazoi-7-yl)-3-[4-(6-morpholm-4-3'lmethyl- pyridin-3 -yl)-naphthalsn- 1 -yl]-urεa;

] -[4-(6-Morpholin-4-}'li-nethyl-pyridin-3-yl)-naphthaIen-l-y3]-3-(3- tτifluorometiianesulfony]-phenyl)-urea;

N-(5-tert-Butyl-2-methoxy-3-f3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-

Daphthalen-l-}'l]-ui-eido}-phenyl)"isobutyramids ;

2-f4-tcrt-Butyl-2-{3-[4-(6-morpholiπ-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urcido}~phenoxy)-acetamide ;

1-(5-terl-Butyl-2-oxo-2,3-dihydro-ben2θθxa2θl-7-y])-3-[4-(6-mθφholin-4- yInιetli}'l-pyi"idin-3-yl)-naphtlialcn-l-yl]-urea:

1-(5-tert-Butyl-3-cyano-2-raethoxy-phenyl)-3-[4-f6-morphπϊin-4-ylmetby]- pyridiii -3-yi)-napbtha]en-l-yl \-v.ma, l-(5-tert-But>']-bcnzooxα-iθi-7-yl)-?-[4-( D-moηihoIin-4-}.']meth5']-pyπcin-3-ylj- nεphthaien-1 -ylj -urea;

N-(5-leπ-Buly]-2-mcthoxy-?- f3-['^:i-(6-moφholin-4-3']ineth3'l-p;.τiάin-3-yl)- naphthalan ] -yl]-ureido J -phenyO-benzenesulfonamide ; Ethan esuifon ic sad (5-tei1-bulyl-2-methoxy-3- (3-[4-(ό-morpholin-4-ylmethyl- p)τid]n-3 -yl)-naphthalen- 1 -yl]-urcido \ -phenyl )-amide , l -(5-tcπ-Butλ']-2-rnethox}'-phen)'I)-3-[4-(2-morpholin-4-ylmetkyl-p}'rimidin-5- yl}-naphώalen-i -3'1] -urea;

3 -(5-iert-Bυt3'l-2-met}i>4sulfanyI-phεnyI)-3-[4-(6-morphϋlin-4-ylrnetJiyl-pyridin- 3 -yl)-naphthalcn- 1 -yϊ]- area; l-(5-tert-Bul3'l-2-mcllioxy-pyridin-3-\'l)-3-[4-(6-iiiorphohn-4-ylmεthyl-pyridin-3- 3'^"l)-naρhthalcn-l -yl] -urea;

2,2.2-Trifluoro-cthanesulfonic acid(5-tcπ-but3'l-2-metboxy-3- [3-[4-C6-moipholiπ- 4-ykncthyl-p3'πdin-3 -yl)-naphthal en- 1 -yX\ -ureido } -phenyl) -ami de : N-(5- [4-[3-(5-tei1-Butyl-2-methyI-phen\4}-ureido]-naphthalen-1 -3⁷I¹, -p\τazin-2- yl)-methanesuifonamide;]-[4-(6- [ [Bis-(2-cyano-εthyl)-amino]-methylj-p3τidiii-3- yI)-naphthalen-3-yl]-3-(5tsrt-but3^?3-2-]χiclho>:y-phenyI) -urea; l-(5-tert-Bυt3'l-2-methoxy-ρhenyl)-3- (4-[6-(4-raetlw]-ρiperazin-l -yliiiethyI)- pyri din-3 -yl] -naphthal en-l-3^rl } -urea: l -(5-tert-Buτyl-2-raethox3^/-phen3'l)-3-[4-(6-lhiomoipholiii-4-3^'lixιeth3'l-p3αidin-3- yl)naphthalcn-] -yl] -urea;

1 -(5-tert-Buty]-2-raethoxy-phenyl)-3- [4-[6-(2. 6-dimethyl-piρeridin-l -ylmethyl)- pyridin-3-yl]-naphthalen-l-y3}-urea;

1 -(5-tert-Buτ3'l-2-methoxy-phen3'l)-3- [4-[6-(l -oxo-tetraliydro-tliiopyran-4- 3'lamino)-pyndin-3-3'l]-naphthalen~] -yl}-urea: l -(5-tert-Butyl-2-methoxy-phεnyl)-3- (4-[6-(tctrahydro-pyran-4-ylammo)-pyridm- 3-yl]-naphthalen-] -3'l}-urea; l-(5-lert-Buiyl-2-mcthoxy-pheny!)-3-[4-(ό-f [(2-cyano-eth3'l)-(teti-ahydro-furan-2- 3']methγI)-amniθ]--nieth3'l}-p3'ridin-3-yl}-naphtbalen-l -yl]-urea: I -(5-tcrt-Bι;iy]-2 nicthoxy-phc,nyl)-3- {A ^•f6-(?.-iτⁱclho>:ymsthyl-τjυπ->bolin-4-

iu M . -3-y ij-naphthalcn- J -y! <- ; ur-.u; l-(5-ιεrt-Butyϊ-2-melbαxy-pheπγl)-3- !4-[o-(2-rnethyl-3-oxo-piperazin- 3 - y]methyl)p)τidm-3-yl] ~naphthalen-l -yl] -urea: i -(5- !4-[3-(5-tcrt-Butyl-2-methoxy-phεnyl)-ureido]-naphthalen-l -yl ppyridin-2- }imethyl) -piperidine-3-caτboxyIic acid amide; 1 -(5-teπ-Butyl-2-methoxy-pheiiyl)-3- 14-[6-(l -03,Ό-11⁴-tJriornorpholrn-4- ylmethyl)pyridin-3-y]] -naphtha! er>- I -yl } -urea; l -(3,3-Dimethy]-2-oxo-2.3-dihj'diO-lH-indol-5-yl)-3-[4-(6-moτpholin-4-ylmethyl- l-(5-tert-Bυtyl-2-rnethoxy-phcn)4j-3-(4- (6-[(tetrahydro-furan-3-3-^r]aiT!ii-io)- methyl]-pyridin-3-yl J -naphtlialen-l-yl)-urca; l-(5-tert-But}']-2-methoxy-phenyl)-3-[4-(6-{[(2-c3'aπo-ethyl)-pyridin-3-ylmeth}'l- amino] -methyl } -pyridin-3 -yl)-naphtha] en- 1 -yl] -urea; l-(5-tert-But}'l-2-mcthoxy-phenyl)-3- [4-[6-(2-oxa-5-aza-bicyclo [2.2. 1 ] hept-5- y]methyl)-pyridiiϊ-3-yl]-naphthalen- 1 -yl [-urea: l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2.6-dimethyl-morpholin-4-ylmeth)'l)- pyridii)-3-yl]-naρhthalen- 1 -ylj -urea; l-(5-tert-But3'l-2-merhoxy-phenyl)-3-(4- (6-[4-(3-methoxy-ph.enyl)-pipe:-azrn-l- 3'lmeth}'] ] -pyri din-3 -yl J -naphthalen-1-yl) -urea: l-(5-terL-BuM-2-msthoxy-phen3^fl)-3- [4-[6-(rrLθrpholine-4-carbonyl)-pyridiri-3- yl]naphthalen-l -yl} -urea; 1 -(5-tert-Butyl-2-methox3'-phen3'l)-3 - [4- (5 -morph olin-4-ylmetb.34-pyi-aziii-2-yl)- naphthalen-] -yl]-urea; l-(6-teri-Butyl-3-oxo-3,4-di]iydro-2H-bcnzo[l_J4]oxazin-8-y])-3-[4-(6-moφhoIin- 4-yimetliyl-pyridm-3 ~yl)-naphthaϊen- 1 -yl]-urea; l -(3-Amino-5-tcrt-butyl-2-methoxy-phenyl)-3-f4-(6-πiorpholin-4-ylmerhyl- pyridin-33^/]) -naphdialen-1-yl] -urea;

N-(5- [4-[3-(5-tert-Bulyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yl} -p3τidin-2- yl)-acetamidc;

N-(5-tert-Bulyl-2-iriethox3'-3- [3-[4-(6-moipholin-4-ylmethyI-pyridin-3-yl}- πaphthalen-1 -yl]-ureido} -phenyl)-N-methyl-acciamide ; TN-(5-tci1-ButyI-2-mt;fhox3_''-3- {3-[4-(6-moη")ho]in-4-yliτicthy]-pyridin-3-yl}- luiphthaleii- J -yl]-υroido^'; -])hcn3'i)-2_; 2,2-lrifiuL)jO--riC(.:ιr-u',jide : l-(5-terL-But}']-2-msthoxy-phenylV3- ;4-[6-(pyrjdin-5-ylox}')-p3'ridi!i-3-)'l]-- n aphtha! en - 1 -yl j -urea;

[4-(6-Morpholin-4-}'liiieth}'l-pyπd.in-3-}'l}-i!Jjphthalen-l -yi]-carbamic acid 3-tert- butyl-phenyl ester; and

J N-(5-tert-Butyi-2-methoxy-3- |^'5~[4--(6-iτiθφholiri-4-γ3πielhy]-p>ⁱridin-3-y!)- naphthalsn-l -yl]-ureido}-pheπyl)-mefhanesulfonamide (these compounds are described in US 2006/0018904 Al and WO 2005'Ol 8624 A2) or any pharmaceutically acceptable salts thereof.

] 0 It ic particularly preferred that the p38 MAP kinase inhibitor of said use or method 1S .SB2035S0.

It is preferred that the corticosteroid (or glucocorticoid) of the invention is selected from any one or more of hydrocortisone, prednisolone, roεthylprednisoloπe. 5 triamcinolone, dexamethasone. beclomethasone. budesonide. fluticasone, ciclesonide, mometasone. and any derivative or form thereof. It is particularly preferred mat said corticosteroid is dexamethasone.

In a preferred embodiment fnc medicament is a combination of a p3S IvLAP kinase0 inhibitor and a corticosteroid as denned above used for treatment of corticosteroid resistant severe asthma and COPD. In a further embodiment the use of said combination is for the manufacture of a medicament to reduce the side effects associated with the use of high dosages of corticosteroids used in the treatment of corticosteroid resistant severe asthma and COPD. The synergistic action of said5 combination is of particular benefit to the patient. It is therefore an. aspect of the invention to provide the use of a p38 MAP kinase inhibitor, as defined above, in the manufacture of a medicament to reduce the side effects associated with the treatment of corticosteroid resistant severe asthma and COPD and moderate to severe asthma. 0

Jt is αNo preferred that a possible aspect of the invention provides the use of a p3.^c: h^: A P kir,a?e. inhibitor, as dofi-xv] nbove, in the marmiactui o of a medicament Io overcome corticosteroid irisensitivity in the treatment of severe asthma . and COPD. It is envisaged that over a period of time, the- use of the invention will lead to a decrease in the patient's resistance to corticosteroids (in instances of corticosteroid resistance).

It is intended that the patient be a mammalian patient It is preferred that said mammalian patient be a human, but said patient can also be any one of, but not limited to, a dog. cat. horse, cow, rai, mouse_; ape or monkey.

All documents referred to herein are incorporated herein,, in their entirety, by reference.

The listing or discussion of a prior-published document in this specification should nov necessarily be taken as an acknowledgment that the document is part of the state of the art or is common general knowledge.

The invention is now described in more detail by reference to the following., non- limiting, Figures and Examples.

Figure 1. A) Suppression of Lipopolysaccharide (LPS)-induced IL-6 release from peripheral blood mononuclear monocytes (PBMCs) from severe asthmatics by p38 MAP kinase inhibitor (p38i) SB203580 (SB) and dexamethasone (Dex) compared to dexamethasone alone. B) Comparison of IL-6 suppression between SB/Dex 10^-6 M and SB/Dex 10^-7 M. The percentage suppression of IL-6 release is shown at increasing concentrations of S3203580 on a log scale.

Figure 2. A) Suppression of LPS-induced IL-6 release from PBMCs from patients with COPD by p38 inhibitor SB2035S0 and dexamethasoneccompared to dexamethasone alope. B) Comparison of IL -6 suppression between SB/Dex 1 0^-6 M and SB/Dex 10^-7 M. The percentage suppression of IL-6 release is shown at increasing concentrations of SB203580 on a log scale. Example t: Isolation and Stimtiktikm of Peripheral Blood Mononuclear Monocytes (PBMCs).

5 Methods

Venous blood (SO ml) was diluted 1 :! with Hanks buffered saline solution (HBSS) and layered on Ficoll-Hypaquε-Plus (Amersham, UK). Following centπfugation (30 minutes; LlOO x g: IS ⁰C). PBMCs were collected, washed and centrifuged

10 (250 x g; 10 minutes). PBMCs were re-suspended in culture media and counted using Kimura dyε. They were plated (7.5 x 10^" ccllsΛvell) and stimulated with lipopolysaccaride (LPS, 10 μg/rnl) alone or pre-trcated for 30 τvΛn with dexamethasone (10^"6 M to 10^"10 M) and/or the p38 MAPK inhibitor SB203580 (10^~6 M to 10^"!0 M) before stimulation with LPS. Supεrnatants were removed 18 i -" hours later and analysed for IL-6 by ELlSA.

Results and Discussion

In PBMCs from severe asthmatics the SB203580 in combination with

20 Dexamethasone (10^"6 M) suppressed LPS-induced IL-6 release in a close dependant manner with maximal suppression of 80 % at an SB2035S0 concentration of 10^""' M (Figure IA). The maximal suppression obtained with

Dexamethasone (10^"ή M) alone was 40 % (Figure IA). Reducing the concentration of Dexamethasone to 10^"' M (Figure IB) had little effect on the

25 suppressive efficacy of the SB2035S0/Dexamethasone combination.

We showed that in PBMCs from patients with COPD.. SB203580 in combination with Dexamethasone (10^"6 M) suppresses LPS-induced IL-6 release in a dose dependant manner, with maximal suppression of 85 % at an SB20rό80 VJ concentration of 10^"6 M (Figure 2A). The maximal suppression obtained with DeN.amcthiis.ono (10^"'' M) alone was 5!^"! %. Reducing the concent rat ic-ri nf Dcxamethasone to 10" M (Figure 23) had little effect on the suppressive efficacy of the SB203580/Dexameth.»sone combination.

Together these data indicate that, for both severe asthma and COPD. ε combination of corticosteroid and a p3S inhibitor (SB203580) results in a greater suppression of the inflammatory response compared with corticosteroid alone.

Claims

1. Use of a p3 S MAP kinase inhibitor in the manufacture of a medicament for the treatment of severe or corticosleroid-resistant asthma or chronic obstructive pulmonary disease (COPD).

2. The use of claim 1 wherein the patient is selected on the basis of inadequate control of the asthma or COPD at a corticosteroid dose of 2000 μg or more of inhaled beciomethasone or equivalent corticosteroid per day with or without the use of oral prednisolone.

3. A method of treating severe or corticosteroid-resistant asthma or COPD, comprising administering to the patient a therapeutical!}' effective amount of a p38 MAP kinase inhibitor.

4. The use according to claim 1 or 2 wherein the medicament comprises a corticosteroid or the method of claim 3 wherein the patient is administered a corticosteroid.

5. The use of claim 1 wherein the p38 MAP kinase inhibitor is selected from, but not limited to, SB203580,

6. The use of claim 5 wherein the p38 MAP kinase inhibitor is SB2035S0.

7. The use of claim 4 wherein the corticosteroid is selected from, but not limited to, hydrocortisone, prednisolone, metlrylprednisolone, triamcinolone, dexamethεsone, beciomethasone, bndcsonide, betamethasone, fluticasone, ciclesomdc, moinetasone. and any derivative or form thereof.

8. The use of claim 7 wherein ⁺.hc corticosteroid is dexarnolbasonc.

9. The use of the p3S MAP kinase inhibitor as defined in am' of the preceding claims m the manufacture of a medicament to reduce the side effects associated with the use of high dosages of corticosteroids used in the treatrneut of corticosteroid resistant severe asthma and COPD.

10. The use of the p38 MAP kinase inhibitor as d εfined in an)^* of the preceding claims in the manufacture of a medicament to reduce the side effects associated with the treatment of corticosteroid resistant severe asthma and COPD.

11. The use of the p3S MAP kinase inhibitor as defined in any of the preceding claims in the manufacture of a medicament to overcome corticosteroid insensitivity in the treatment of severe asthma and COPD.