AU2003224025A1 - p38 kinase inhibitors for treating mucus hypersecretion - Google Patents

Description

WO 03/084503 PCT/EP03/03434 1 Method of treating Mucus hypersecretion The invention relates to the use of p38 kinase inhibitors for the preparation of a pharmaceutical composition suitable for inhalation for the treatment of mucus 5 hypersecretion. Furthermore the invention is directed to pharmaceutical compositions suitable for inhalation comprising p38 kinase inhibitors and to methods for the preparation thereof. Background of the invention o10 Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) have been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, 15 cytokines, UV radiation, and stress-inducing agents. One particularly interesting MAPK is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor CD14 20 and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stresses, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF. 25 Based upon this finding it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency 30 disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. 35 In the conducting airways of the respiratory system, the mucociliary system serves as the primary defence mechanism to move inhaled particles or infectious agents out of the airways in the lungs. In addition, substances present in airway fluids serve to limit the toxicity of the particles and the inactivate infective agents. The physical mechanism of coughing serves to expel the mucus from the airway passages (see WO 03/084503 PCT/EPO3/03434 2 e.g., "Foundation of Respiratory Care," Pierson and Kacmarek, eds. (1992) Churchill Livingstone Inc. New York, New York; "Harrison's Principles of Internal Medicine", Fauci et al., eds. (1997) 14th Edition, McGraw Hill, New York, New York). 5 The mucociliary system consists of ciliated epitelial cells, epithelial goblet cells, and serous and mucous cells located in submucosal glands. The cilia are surrounded by an aqueous layer (periciliary fluid) secreted into the lumen of the airway passage by the active transport of chloride and the passive movement of water across the epithelium. The cilia make contact with the mucus floating on this aqueous layer, and 10 via a unidirectional propelling motion provide for movement of mucus toward the glottis (see Pierson and Kacmarek). Mucus is produced by the epithelial goblet cells and submucosal gland cells and is secreted into the lumen of the airway after degranulation. 15 While mucus generally facilitates the clearence of inhaled particles or infectious agents, hypersecretion of mucus in the airways may cause progressive airway obstruction. In peripheral airways, cough is ineffective for clearing secretions. Futhermore, because of their small dimensions, small airways containing many goblet cells are especially vulnerable to airway plugging by mucus. Airway 20 hypersecretion affects a substantial number of individuals. Hypersecretion has for instance been implicated in cystic fibrosis, with is one of the most common, fatal, genetic diseases in the world. Cystis fibrosis is an autosomal recessive diseases that causes the airway mucosal cell to become unresponsive to 25 cyclic-AMP-dependent protein kinase activation of the membrane chloride ion channels (Pierson and. Kacmarek). The subsequent electrolyte imbalance reduces the level of hydration of the airway mucus, thus resulting in highly viscous mucus in the lungs of an individual afflicted with cystic fibrosis. Hypersecretion obstructs the air passages of individuals with cystic fibrosis, further compromising lung function. 30 As a result of the high levels of mucus in the lungs of patients with hypersecretory pulmonary diseases, mucosal clearence is reduced. Pathological agents such as bacteria, e.g. Pseudomonas aeruginosa, often establish colonies within the mucus, resulting in frequent lung infection. 35 Classical modalities of treating individuals afflicted with airway hypersecretion include antibiotic therapy, bronchodilators (e.g., methylxantines, sympathomimetics with strong 112 adrenergic stimulating properties, anticholinergics), use of systemic or inhaled corticosteroids, liquefaction of the mucus by oral administration of WO 03/084503 PCT/EPO3/03434 3 expectorants, and aerosol delivery of "mucolytic" agents, e.g. water, hyperonic saline solution (see Harrison's, supra). A newer therapy for cystic fibrosis is the administration of DNAse to target the DANN-rich mucus or sputum (Shak, et al. (1990) Proc. Natl. Acad. (USA) 87:9188-9192; Hubbard, R.C. et al. (1991) N. Engl. J. 5 Med. 326:812). In addition, chest physical therapy consisting of percussion, vibration and drainage are also used to facilitate clearence of viscous mucus. Lung transplantation may be a final option for those with severe to target the mucosal secretions is needed. Specifically, there is a need for a specific modality that will reduce the formation of mucus secretions in the airways. 10 Description of the invention Suprisingly it has been found that p38 kinase inhibitors administered via inhalation are suitable for the reduction of mucus hypersecretion. 15 Accordingly, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, in particular cystic fibrosis. p38 kinase inhibitors applicable within the scope of the invention are known in the 20 art. Suitable compounds are disclosed for instance in US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 25 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 30 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 35 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO WO 03/084503 PCT/EPO3/03434 4 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 5 01/21591, WO 0129041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and JP 2000 86657 whose o10 disclosures are all incorporated herein by reference in their entirety. Of particular interest for the use according to the invention are those p38 inhibitors disclosed in US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 15 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403. 20 In a preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 1I as disclosed in WO 99/01131 R /2

R

1 N I1/> 25 41 wherein

R

1 is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-Ra and optionally with 30 an additional independent substituent selected from C1-4 alkyl, halogen, hydroxyl, C 1

-

4 alkoxy, C,-4 akylthio, C1-4 aklylsulfinyl, CH 2 0R 1 2 , amino, mono and di- C1-,6 alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 , N(Rl 0 )C(O)Rb or NHRe; 35 Y is oxygen or sulfur; WO 03/084503 PCT/EPO3/03434 5

R

4 is phenyl, naphth-1-yl or naphth-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4naphth-1-yl, 5-naphth-2-yl or 6-naphth-2 yl substituent, is halogen, cyano, nitro, C(Z)NRR 7 , C(Z)OR 1 6 , 5 (CRoR 2 0)vCOR 1 2 , SR 5 , SORq, OR 12 , halo-substituted-C 1

.

4 alkyl, C14 alkyl,

ZC(Z)R

1 2 , NRI0C(Z)R, 6 , or (CRoR 2 0)vNROR 2 0 and which, for other positions of substitution, is halogen, cyano, C(Z)NR, 3

R

14 , C(Z)OR 3 , (CRIOR 2 0o)m,,COR 3 , S(O)mRs, OR 3 , halo-substituted-C 1 4 alkyl, C1.4 alkyl, (CRoR 2 o)mRioC(Z)R 3 , NRioS(O)mR 8 , NRiOS(O)mNR 7

R

17 , ZC(Z)R 3 or (CRoR 2 o)m,.NRi3Ri 4 ; 10 Z is oxygen or sulfur; n is an integer having a value of 1 to 10; m is 0, or integer 1 or 2; m' is an integer having a value of 1 or 2; m" is 0, or an integer having a value of 1 to 5; 15 v is 0, or an integer having a value of 1 to 2;

R

2 is -C(H) (A) (R 22 ); A is optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is substituted C01 -10 alkyl;

R

22 is an optionally substituted C,-,o alkyl; 20 Ra is aryl, arylC, ealkyl, heterocyclic, heterocyclylC 6 alkyl, heteroaryl, heteroarylC.ealkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C1.6 alkyl, C3_7 cycloalkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroarylC 1

.

4 alkyl, heterocyclyl, or heterocyclylC

,

_

4 alkyl, wherein each of 25 these moieties may be optionally substituted;

R

3 is heterocyclyl, heterocyclyl C01l-10 alkyl or R.;

R

5 is hydrogen, C1_4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR 7

R

,7 , excluding the moieties SR, being SNRR 17 and SOR, being SOH;

R

6 is hydrogen, a pharmaceutically acceptable cation, C-10 alkyl, C37 cycloalkyl, 30 aryl, aryl C_4 alkyl, heteroaryl, heteroaryl C-.4 alkyl, heterocyclyl, aryl, or C01 -10 alkanoyl;

R

7 and R 7 is each independently selected from hydrogen or C14 alkyl or R 7 and R 17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom 35 selected from oxygen, sulfur or NR, 15 ;

R

8 is Co alkyl, halo-substituted C-10 alkyl, C210 alkenyl, C210 alkynyl, C03.7 cycloalkyl, C_7 cycloalkenyl, aryl, aryl C-10 alkyl, heteroaryl, heteroaryl C1,1o alkyl, (CRoR 2 O)0OR 1 , (CRioR 2 0 )nS(O)mR8, (CRoR 20 )nNHS(O) 2 Ra 8

,

WO 03/084503 PCT/EPO3/03434 6 (CRoR 2 0),NR,,R 1 4 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, C(Z) Rj or optionally substituted C-1.10o alkyl, S(O) 2

R

8 , optionally substituted aryl or optionally substituted aryl C1_ 4 alkyl; 5 Rlo and R 20 is each independently selected from hydrogen or C,.4 alkyl;

R

, is hydrogen, C01.10 alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclyl CI-10 alkyl, aryl, arylC-o 10 alkyl, heteroaryl or heteroaryl Cl-10 alkyl, wherein these moieties may be optionally substituted;

R

12 is hydrogen or R 1 6 . 10 R 13 an R 1 4 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted arylC.

4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR,; 15 R 15 is R 0 io or C(Z)-C,- 4 alkyl; Ri 6 is C-4 alkyl, halo-substituted-C.4 alkyl, or C 3 7 cycloalkyl;

R

1

,

8 is C-,, alkyl, C3.7 cycloalkyl, heterocyclyl, aryl, aryl.l- 1 0 alkyl, heterocyclyl, heterocyclyl- C 1 0 oalkyl, heteroaryl or heteroaryll- 10 alkyl; or a pharmaceutically acceptable salt thereof. 20 In the aforementioned compounds of formula 1 R 2 is a substituted alkyl derivative. It is recognised that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This ethylene group has two additional substituents, an R 22 moiety and an A moiety, -C(H)(A)( R22). Both A and R 22 may not 25 be unsubstituted C1-10 alkyl moiety. In a preferred embodiment, R 2 is a -C(AA,)(A) moiety, wherein AA, is the R 22 moiety, but is specifically the side chain residue (R) of an amino acid, as is further described herein. Suitably, A is an optionally substituted C 1 3-7 cycloalkyl, aryl, heteroaryl, or 30 heterocyclic ring, or A is a substituted C-10 alkyl moiety. When A is an aryl, heteroaryl and heterocyclic ring, the ring may be substituted independently one or more times, preferably, 1 to 3 times by C 1 1 0 alkyl; halogen; halo substituted C1-,10 alkyl such as CF 3 ; (CR 0

R

2 0 )tOR 1 ; (CRoR 2 0)tNR 1 2

R

14 , especially amino or mono-or di-C 1

-

4 alkylamino; (CRIoR 20 )tS(O)m R 18 , wherein m is 0, 35 1 or 2; SH; NRoC(Z)R 3 (such NHCO(CI.so alkyl)); or NRo 10 S(O)m R 8 (such as

NHSO

2 (C 1 1 0 alkyl)). Suitably, t is 0, or an integer of 1 to 4. When A is an optionally substituted cycloalkyl it is as defined below with the R 22 substitution.

WO 03/084503 PCT/EPO3/03434 i 7 When A is an optionally substituted heterocyclil ring, the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring. When A is an optionally substituted aryl moiety, it is preferably a phenyl ring. 5 When A is an optionally substituted heteroaryl ring, it is as defined below in the definition section. When A is a substituted C-1o alkyl moiety, the alkyl chain may be straight or branched. The chain is substituted independently 1 or more times, preferably 1 to 3 times by halogen, such as fluorine, chlorine, bromine or iodine; halosubstituted C1-10 10 alkyl, such as CF 3 ; C 3

.

7 cycloaklyl, C1.10alkloxy, such as methoxy or ethoxy; hydroxy substituted Cs-10 alkoxy; halosubstituted C-10 alkoxy, such as OCF 2

CF

2 H; OR,,; S(O)mR, 8 (wherein m is 0, 1 or 2); NR 13

R

14 ; C(Z)NR 3

R

1 4 ; S(O)mNR13R 4 ;

NR

23 C(Z)R,,; NHS(O) 2

R

8 ,,; C(Z)Rll; OC(Z)R,,; C(Z)OR,; C(Z)NR,,OR,;

N(OR)C(Z)NR

3 Rl, 4 ; N(OR 6 )C(Z)Rll; C(=NOR 6 )Rll; NR 23

C(=NR,

9

)NR

1 3

R

4 ; 15 OC(Z)NR 3

R

4 ; NR 23

C(Z)NR,

3

R

14 ; or NR 2 3C(Z)ORo. Preferably A is a C3.7 cycloalkyl, or a C.6 alkyl, more preferably a C1-2 alkyl, i.e. a methylene or ethylene moiety, more preferably a methylene moiety which is substituted by one of the above noted groups. Preferably, when A is a Clo- alkyl, it is substituted by OR,, where R 1 , 20 is preferably hydrogen, aryl or arylalkyl; NR,,Ri 4 ; OC(Z)Rll; C(Z)OR 1 . More preferably, A is substituted by OR,, where R 1 , is hydrogen. Suitably, R 22 is a C1, alkyl chain, which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably 1 to 3 times, by halogen, such as fluorine, chlorine or iodine; halo 25 substituted C-. 0 alkyl; C1~01 alkoxy, such as methoxy or ethoxy; hydroxy substituted

CI.-

10 alkoxy; halosubstituted CI-10 alkoxy, such as OCF 2

CF

2 H; OR,,; S(O)mR, 8 ;

NR,.R

14 ; C(Z)NR 1 3

R

14 ; S(O)mNR13R4; NR2,C(Z)R,; NHS(O)RS; C(Z)R 1 ; OC(Z)OR 1 ;

C(Z)OR

1 ; C(Z)NR 1 0R ,; N(OR 6

)C(Z)NR

1 3

R

14 ; N(OR,)C(Z)Rll; C(=NOR,)R,;

NR

2

,C(=NR,,)NR

1 3

R

14 ; OC(Z)NR 13

R

1 4 ; NR 23 C(Z)NRj 3

R

14 ; NR 2 3

C(Z)OR

1 0 ; optionally 30 substituted C3.7 cycloalkyl; optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an optionally substituted heterocyclic. The optional substituents on these cycloalkyl, aryl, heteroaryl, and heterocyclic moieties are as defined herein below. It is noted that those R 22 substituent groups which contain carbon as the first 35 connecting group, i.e. C(Z)OR 1 ; C(Z)NR,, OR 9 , C(Z)R,,, C(Z)NR,,R 14 , and C(=NOR)Rl, may be the sole carbon in alkyl chain. Therefore, the R22 group may, for instance, be a carboxy, an aldehyde, or an amide, as well as being a substituent of a methylene unit, such as carbamoylmethyl, or acetamidomethyl.

WO 03/084503 PCT/EPO3/03434 8 Preferably R 22 is a C eunsubstituted or substituted alkyl group, such as a C.

3 alkylene such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted by one of the above noted moieties, or as noted above those substituent groups which contain a carbon may substituent for the first methylene unit of the 5 alkyl chain, such as carboxy, C(O)OR,; C(O)NR, 3

R

1 4 or R 22 is an optionally substituted aryl group, such as a benzyl or phenethyl. In other words, R 2 2 can be an optionally substituted alkyl group, or R 22 can be C(Z)ORl; C(Z)NR,,OR 9 , C(Z)R,,

C(Z)NR

1 3

R

1 4 , or C(=NOR)Rll. Preferably R 22 is C, 6 unsubstituted or substituted alkyl group, more 10 preferably a C- 2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene. Preferably the alkyl chain is substituted by OR,, 11 , where R 1 , is preferably hydrogen, aryl or arylalkyl; S(O)mR, where m is 0 and R, 8 is a C 1 6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety. 15 More preferably, R22 is phenyl, benzyl, CH 2 OH, or CH 2 -O-aryl. Preferably, one or both of A and R 22 contain hydroxy moieties, such as in

C

1

_

6 alkyl OR,,, wherein R 11 is hydrogen, i.e. CH 2

CH

2 OH. Suitably, when AA 1 is the (R) side chain residue of an amino acid, it is a C_ alkyl group, which may be straight or branched. This means the R group of the 20 core amino acid of the structure R-C(H)(COOH)(NH 2 ). The R residue term is for example, CH 3 for alanine, (CH 3

)

2 CH- for valine, (CH,) 2

CH-CH

2 -for leucine, phenyl

CH

2 - for phenylalanine, CH 3

-S-CH

2

-CH

2 - for methionine, etc. All generally recognised primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, 25 glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other naturally accurring amino acids not found in proteins, such as 13-alanine, y-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and 3-cyanoalanine, or other naturally occurring non-mammalian 30 amino acids. Preferably AA 1 is the residue of phenylalanine, or alanine. Preferably A is a hydroxy substituted CI-10 alkyl and R 22 is a C 1

,-

10 alkyl or a hydroxy substituted Cll0 alkyl. 35 In a further preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds disclosed in WO 99/01131: WO 03/084503 PCT/EPO3/03434 9 1 -(1,3-Dihydroxyprop-2-yl)-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; trans-1 -(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)5-[(2-methoxy)pyrimidin-4 yl]imidazole; 1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole; 5 (4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-imidazole; In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 10 selected from the compounds of formula 2 as disclosed in.US 6,277,989 R I"-(CH 2 )nAr N Rm2 N

NR

2 2 and the pharmaceutically acceptable salts thereof, wherein 15 R 1 is H, alkyl(1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR 2 , SR, -OOCR, -NROCR, RCO, -COOR, -CONR 2 , -SO 2

NR

2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); each R 2 is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, 20 CONR 2 , SO 2

NR

2 , CN, CF 3 or NO 2 , wherein each R is independently H or lower alkyl (1-4C); each of I, m, and n is independently 0, 1 or 2; and Ar is phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, or benzimidazolyl, each optionally substituted with optionally substituted alkyl, alkenyl, alkynyl, aryl, N 25 aryl, NH-aroyl, halo, OR, NR 2 , SR, -OOCR, -NROCR, RCO, -COOR, CONR 2 , SO 2

NR

2 , CN, CF 3 , or NO 2 , wherein each R is independently H or alkyl (1-4C); Preferably the invention relates to the use of p38 kinase inhibitors for the preparation 30 of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 2 as disclosed in US 6,277,989 , wherein

R

1 is H; WO 03/084503 PCT/EPO3/03434 10

R

2 is halo, m is 0, 1, or 2, and I is 1 or 2; Ar is 4-pyridyl. In a particularily preferred embodiment the invention relates to the use of p38 kinase 5 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the follwoing compounds disclosed US 6,277,989: 2-phenyl-4-(4-pyridylamino)-quinazoline; 2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline; 10 2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline; 2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(3-methoxyanilyl)-4-(4-pyridylamino)-quinazoline; 15 2-(2,6-dichlorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2,6-dibromophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2,6-difluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline; 2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline; 20 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino -6-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-7-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methoxybenzylamino)-quinazoline; 25 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(2-isobutylamino)-quinazoline; and 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methylmercaptobenzylamino)-quina zoline; and the pharmaceutically acceptable salts thereof.

WO 03/084503 PCT/EPO3/03434 11 In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 3a, 3b, 3c, or 3d as disclosed in US 5 6,340,685

R

3 Z2 R3 2 R3 Z 2 R

R

, 3a, R 2 3b, 3c, or

R

1 1 2

R

3 R 3d 10 and the pharmaceutically acceptable salts thereof, wherein each of Z 1 and Z 2 is independently CR 4 or N; where each R 4 is independently selected from H and alkyl(1-6C); wherein said alkyl optionally includes one or more heteroatoms selected from O, S and N, and wherein said alkyl is optionally substituted by one or more 15 substituents selected from halo, OR, SR, NR 2 , RCO, COOR, CONR 2 , OOCR, NROCR, ON, =0, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1 2 N heteroatoms, wherein R in the foregoing optional substituents is H or alkyl (1-6C); 20 R 1 is (Y)n 1 3 23 -X-N Z3 -X2Ar wherein

X

1 is CO, SO, CHOH orSO2; m is 1; 25 Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is 0, 1 or 2;

Z

3 is N; WO 03/084503 PCT/EPO3/03434 12

X

2 is CH or CH 2 ; and Ar consists of one or two phenyl moieties directly coupled to X 2 , said one or two phenyl moieties being optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF 3 , RCO, COOR, CONR 2 , NR 2 , 5 OR, SR, OOCR, NROCR, (wherein R in the foregoing is H or 1-6C alkyl), and phenyl, itself optionally substituted by the foregoing substituents;

R

2 is selected from H, and alkyl (1-6C); wherein said alkyl optionally includes one or more heteroatoms which are selected from O, S and N, and wherein said alkyl is optionally substituted by 10 one or more substituents selected from halo, OR, SR, NR 2 , RCO, COOR, CONR2, OOCR, NROCR, (where R in the foregoing is H or 1-6C alkyl) CN, =O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1-2 N heteroatoms;

R

3 is H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR 2 , RCO, COOR, 15 CONR 2 , OOCR, or NROCR where R is H or alkyl (1-6C). In a particularily preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 20 selected from the follwoing compounds disclosed US 6,340,685: 4-(2,6-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(2,3-d ifluorobenzyl)-pi perazinyl-benzimidazole-5-carboxamid e; 4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 25 4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-carboxymethyl benzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-trifluoromethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-methylbenzyl)-piperazinyl-benzimidazole-5arboxamide; 30 4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(3,4-dichlorobenzoylm)piperazinyl-benzinidazole-5-carboxamnide; 4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxm ide; 4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide; 4-benzomethylbenzoylpiperazyl-benzimidazole-5-carboxamide; 35 4-(2-trifluoromethylbenzoyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-methxybenzoyl)-piperazinyl-benzimidazole-5-carboxamid e; 4-(3,4-dichlorophenyl)-piperazinyl-benzimnidazole-5-carboxamide; 4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxamide; 4-trans-I1-cinnamyl piperazinyl-benzimidazole-5-carboxamide; WO 03/084503 PCT/EPO3/03434 13 4-(4-chlorophenyl)-piperazinyl-benzimidazole-5-carboxamide; 4-[bis(4-fluorophenyl)-methyl]-piperazinyl-benzimidazole-5-carboxamide; 4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 5 4-benzylpiperazinyl-benzinudazole-5-carboxamnide; 4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(3,4,5-trimethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(2-naphthylmethyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 10 4-(biphenylmethyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-phenoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-quinolinylmethyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(4-chlorobenzyl)-piperazinyl-1 -(2-propyl)-indole-5-carboxamide; 4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 15 4-(3-chlorobenzyl)-piperazilnyI-N-(2-propyl)-benzimidazole-5-carboxamide; 4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-6-carboxamide; 4-(3-chlorobenzyl)-piperaziny-N-methyl-benzimidazole-5-carboxamide; 4-(3-chlorobenzyl)-piperaziny-N-methyl-benzimidazole-6-carboxamide; 4-(3-chlorobenzyl)-piperazilnyl-N-ethyl-benzimidazole-5-carboxamide; and 20 4-(3-chlorobenzyl)-piperazi nyl-N-ethyl-benzimidazole-6-carboxamide. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 25 selected from the compounds of formula 4 as disclosed in WO 00/43384 X Arl N'A NAr 2- L -Q 1 I H H 4 wherein 30 Ar, is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein Ar, may be substituted by one or more R 1

,R

2 or R 3 ; Ar 2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, 35 tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, WO 03/084503 PCT/EPO3/03434 14 indanyl, indenyl or indole each being optionally substituted with one to three

R

2 groups; L, a linking group, is a 5 CI-10 saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C1-4 branched or unbranched alkyl which may be substituted by 10 one or more halogen atoms; Q is selected from the group consisting of: a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, 15 benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5 b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C16 alkyl, C, alkoxy, hydroxy, mono- or di-(C 1

-

3 alkyl)amino, C16 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally 20 substituted with one to two groups consisting of halogen, C16 alkyl and C_ 6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4 dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, 25 cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of C,-., alkyl, Cj., alkoxy, hydroxy, mono- or di-(C 1

.

3 alkyl)amino-C, 1

-

3 alkyl, phenylamino-C, 3 30 alkyl and C1.3 alkoxy-C 1

-

3 alkyl; c) C16 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1.3 alkyl and C 5 ,,alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C, alkoxy, 35 hydroxy or mono- or di-(C 1

.

3 alkyl)amino, C1_ alkyl-S(O)r, phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C-.6 alkoxy, hydroxy or mono- or di-(Cl_ 3 alkyl)amino; WO 03/084503 PCT/EPO3/03434 15

R

1 is selected from the group consisting of: (a) C3.10 branched or unbranched alkyl, which may optionally be partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of 5 pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C1. branched or unbranched alkyl which is optionally partially or 10 fully halogenated, C 3 cycloalkyl, C . cycloalkenyl, hydroxy, cyano, C,.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(O) and di(C, 1 4)alkylaminocarbonyl; (b) C37 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, 15 bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C_ 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, >C=0, >C=S and NH; 20 (C) C3-10 branched alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three C-5. branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, 25 imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, C-.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, 30 bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or di(C,-)alkylaminocarbonyl; (d) C5.7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 35 bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C1.3 alkyl groups; (e) cyano; and, (f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; WO 03/084503 PCT/EPO3/03434 16

R

2 is selected from the group consisting of: a C 1 , branched or unbranched alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and 5 phenylsulfonyl;

R

3 is selected from the group consisting of: a) a phenyl, naphthyl or heterocyclic group selected from the group 10 consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, 15 purinyl and indazolyl; wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a C66 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C 1 6 branched or unbranched alkyl which is optionally partially or fully halogenated, 20 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cl,_salkyl, naphthyl C_ alkyl, halo, hydroxy, cyano, C,3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove 25 described, nitro, amino, mono- or di-(C, 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di

(C,

3 )alkyl aminocarbonyl, C ,_ alkyl-C(O)-C 1 4 alkyl, amino-C 1 . alkyl, mono or di-(C,.

3 )alkylamino-C 1

-

5 alkyl, amino-S(O) 2 , di-(C 1 3 )alkylamino-S(O) 2 , R 4 30 C,.

5 alkyl, R 5

-C

1 ., alkoxy, R.-C(O)-C,- 5 alkyl and R 7 -Cj., alkyl(R,)N; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, 35 cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, WO 03/084503 PCT/EPO3/03434 17 cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, 5 naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, Cj., branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, Cs, alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, 10 heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C.

3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(Cl_ 3 )alkyl aminocarbonyl, C 1 ,4 alkyl-OC(O), 15 C 1 , alkyl-C(O)-C 1 4 branched or unbranched alkyl, an amino-Cl-s alkyl, mono- or di-(C,- 3 )alkylamino-C. alkyl, Rg-C 5 alkyl, Rlo-C.- 5 alkoxy, Rll-C(O)-C 1 , alkyl, and R 12 -C _ alkyl(R 13 )N; c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and 20 bicycloheptanyl, which the cycloalkyl may optionally be partially or fully halogenated and which may optionally be substituted with one to three

C

1 3alkyl groups; d) C 5

-

7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 25 bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three Cl3alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; f) C 1

,

6 branched or unbranched alkyl which may optionally be partially or fully halogenated; 30 or R, and R 2 taken together may optionally form a fused phenyl or pyridinyl ring, and wherein each R 8 , R 13 is independently selected from the group consisting of: hydrogen and C 4 branched or unbranched alkyl which may optionally be 35 partially or fully halogenated; each R 4 , R 5 , R 6 , R 7 , R 9 , Ro 10 , R 1 , and R 12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; WO 03/084503 PCT/EPO3/03434 18 m = 0, 1,2; r=0, 1,2; t = 0, 1,2; 5 X = O or S and physiologically acceptable acids or salts thereof. In a preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of 10 mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 4 as disclosed in WO 00/43384 wherein Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl. A more preferred subgeneric aspect of the invention comprises the use of 15 compounds of the formula 4 wherein Ar 2 is naphthyl. A yet more preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4, as described in the immediate previous paragraph, wherein: 2o Arl is thiophene or pyrazole; Ar 2 is 1-naphthyl; L is C 1

,

6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and 25 wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C,4 branched or unbranched alkyl which may be substituted by one or more halogen atoms; R, is selected from the group consisting of C 1 ,alkyl branched or unbranched, cyclopropyl and cyclohexyl which may optionally be partially or fully 30 halogenated and which may optionally be substituted with one to three C 13 alkyl groups;

R

3 is selected from the group consisting of C 1 4alkyl branched or unbranched, cyclopropyl, phenyl, pyridinyl each being optionally substituted as described above, alkoxycarbonylalkyl; C, 6 alkyl branched or unbranched; cyclopropyl or 35 cyclopentyl optionally substituted as described above. A yet further preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4, as described in the immediate previous paragraph, wherein Arl is pyrazole.

WO 03/084503 PCT/EPO3/03434 19 A still yet further preferred subgeneric aspect of previous the invention comprises the use of compounds of the formula 4, as described in the immediate paragraph, wherein L is C1. saturated carbon chain wherein one or more methylene groups are 5 optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C14 branched or unbranched alkyl which may be substituted by one or more halogen atoms; 10 Particularly preferred embodiments of L are propoxy, ethoxy, methoxy, methyl, propyl, C 3 -5 acetylene or methylamino each being optionally substituted are described herein. A more particularly preferred embodiment of L is ethoxy optionally substituted. 15 The following compounds are representative of the compounds of formula 4 and are of particular interest according to the invention: 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yil]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1 20 yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4 yl)ethoxy)naphthalen-1 -yl]-urea; 25 1-[5-tert-Butyl-2-p-toly-2H-pyrazol-3-y]-3-[4-(2-(trans-2 ,6-dimethylmorpholin-4 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4 yl)ethoxy)naphthalen-1 -yl]-urea; 30 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2 oxoethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2 35 methylethoxy)naphthalen-l1-yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-I methylethoxy)naphthalen-l1-yl]-urea; WO 03/084503 PCT/EPO3/03434 20 1 -[5-tedt-But 2ptli2-przl3y]3[4(-hoopoin-4-yl ethoxy)naphthalen-1 -yI]-urea; I -[5-terd-ButyI-2-p-tolyI-2H-pyrazoI-3-yl]-3-[ 4

-(

2 -(l -oxoth iomorpholin-4 5 yI)ethoxy)naphthalefl-1 -yl]-urea; I 5tr-uyl2ptll2-przl3y]3-4(-opoin-4-yI-ethoxy)-3 methylnaphthalen-I -yI]-urea; 10 1 -[5-teit-B utyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(2-p ipe rid i n-4-yI-eth oxy)nap htha Ienl- 1 yI3-u rea; I -[5-tert-Butyl-2-p-tolyi-2H-pyrazoI- 3 -y]- 3

[

4

(

2 -(I -acetyl piperid in-4 yI)ethoxy)naphthalefl-1 -yl-urea; 15 I -[5-tert-Butyl-2-p-tolyI-2 H-pyrazoI-3-yl]-3-[4-(2-thiazolid in-3-yI-ethoxy)naphthalefl-1 yI]-urea; I -[5-ted-B utyl-2-p-tolyl-2 H-pyrazoI-3-yI]-3-[4-(2-(morphoI in-4-yI 20 carbonyloxo)ethoxy)flaphthalefl-l -yI]-urea; I 5tr-utl2ptly-Hprzo--l--[-2(erhyd ropyran-4 yi)ethoxy)naphthalefl-1 -yII-urea; 25 1 -[5-tert-Butyl-2-p-tolyI-2 H-pyrazol-3-ylU-3-[4-(2-(N-methyl-2 methoxyethylamino)ethoxy)faphthalefll -yi]-urea; I -[5-tert-Butyl-2-p-tolyI-2H-pyrazo-3-Y]- 3

[

4

(

2 -(I -oxo-tetra hydroth iophen-3 yI)ethox y)naphthalefl-1 -yI]-u rea; 30 1 -[-etB tl2ptll2 -yao--l--4(-opoi--lpoy~~ptae - yI]-urea; I -[5-ted-B utyl-2-p-tolyl-2 H-pyrazoI-3-y]-3-[4-(morpholin-4-yI-methyl)flaphthaiefl I -yI] 35 urea; I -[5-tet-B utyI-2-p-tolyI-2 H-pyrazoI-3-y]-3- 4 -(3-th iazol id in-3-yI- pro pyl)n aphth alefn-I1 yi]-u rea; WO 03/084503 PCT/EP03/03434 21 1 -[-etB tl2ptli2 -ya o--l--4(-tta y o ya -- l oxy)propyl)naphthalen-1 -yI]-urea; 1 -15-tert-ButyI-2-p-tolyI-2H-pyrazoI-3-y1-3-[4-(2-pyrid in-4-yI-ethylna phthalen-1 -yII 5 urea; I -[5-tert-B utyl-2-p-tolyl-2 H -pyrazol-3-yI]-3-[4-(2-pyrid i n-4-yi-ethenyl)n ap hth ale n- 1 -yI] urea; 10 1 -[5-tett-Butyl-2-p-tolyl-2 H-pyrazol-3-y]-3-[4-(3-(morphoI in-4-yI)propyn-I yI)naphthalen-1 -yI]-urea; I -[5-tert-Butyl-2-p-tolyl-2 H-pyrazoI-3-yI]-3-II4-(3-(tetrahyd ropyran-2-yl-oxy)propyn-1 yI)naphthalen-1 -yI]-urea; 15 I -[5-teft-Butyl-2-p-tolyl-2 H-pyrazo-3-y]-3-[4-(3-(methoxymethyIoxy)prQpyn yI)naphthalen-1 -yl]-urea; I 5tr-utl2ptly-Hprzl--i--4-3(opoin-4-yI)-3-methylpropyn-1 20 yI)naphthalefl-I-yI-urea; I 5tr-utl2ptly-Hprzl--l--4-3 o oi n-4-yI )-3,3-d imethyipropyn 1 -yI)naphthalen-1 -yi]-urea; 25 1 [-etBtl2ptoy-Hprzl3y -- 4(-ttayropyran-2-yI-oxy)butyn- 1 yI)naphthalen-1 -yll-urea; I -[5-tert-ButyI-2-p-toli-2H-pyrazo-3-yi]-34-( 3 -(furan-2-ylcarbonyloxy)propyn- 1 yI)naphthalen-1 -yi]-urea; 30 I -[5-tert-Butyl-2-p-tolyI-2 H-pyrazo-3-yIl-3-[4-(3-(pi perd in-I -yl)propyn-1 -yI )naphthalen I -yI]-urea; I 5tr-uyl2ptli2Hprzl3yi--4(-2-ehxmtymorpholin-4 35 yI)propyn-1 -yI)naphthalen-1 -yI]-urea; I -[5-tert-ButyI-2-p-tolyl-2H-pyrazoI-3-yl]-3-[4-(pyrid in-4-yI-methoxy)flaphthalel-1 -yI] urea: WO 03/084503 PCT/EP03/03434 22 I -[5-tert-Butyl-2-p-tolyl-2 H-pyrazol-3-yi]j-3-[4-(2-pyrid in-4-yI-ethoxy)naphthalel-1 -yI] urea; I -[5-tert-ButyI-2-p-tolyi-2H-pyrazoI-3-yI1-3-[4-(3-pyrid in-4-yI-propoxy)naphthalen-1 -yI] 5 urea; I 5tr-uy---tll2-yao--i]3[-2iiao- -yi-ethoxy)naphthalen-I -yI] urea; 10 1 -[5-tert-Butyl-2-p-tolyl-2 H-pyrazov-3-yI-3-[4-(2-belzimidazol-1 -yi-ethoxy)naphthalen 1 -yI]-u rea; I -15-tert-Butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(2-(3 ,4-d imethoxyphenyl ) ethoxy)naphthalen-I -yI]-urea; 15 I 5tr-uy---oli2 -yao--i-3[-prdn4y-etya ionptae - yll-urea; I -[5-tedt-Butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(pyrid in-4-yl-carbonyla mino)naphthalen 20 1-yII-urea; I 5tr-uy---oy-H-yao--l--4(opoin4y-ctmd~ahhln 1 -yI]-urea; 25 1 -[5-tert-Butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(pyrid in-3-yI-methylamino)naphthalel-I 1 yI]-urea; I -[5-tert-Butyl-2-p-tolyl-2 H-pyrazoI-3-yI]-3-[4-(pyridin-3-yI-carboflamlifo)flaphthalel I -yI]-urea; 30 1-5IsoPoy--hnl2-yaz 3y]3[-2mrhli--lehx~ahhi 1 -yi]-urea; I -[5-(Tetrahyd ropyran-3-yI )-2-phenl-2 H-pyrazo-3-yl]-3-[4-(2-morpholi n-4-yI 35 ethoxy)naphthalen-I -yII-u rea; 1 -[5-cyclohexyI-2-phenyl-2 H-pyrazol-3-yIII-3-[4-(2-niorphoI in-4-yI-ethoxy)naphthalen I -yi]-urea; WO 03/084503 PCT/EP03/03434 23 1 -[5-(2 ,2 ,2-trifluoroethyI)-2-phenyl-2H-pyrazo-3-ylI-3-[4-(2-morphQI in-4-yI ethoxy)naphthalen-1 -yi]-urea; 1 -[5-( I -methylcycloprop-1 -yI)-2-phenyl-2H-pyrazol-3-y]-3-[4-(2-morpholil-4-YI 5 ethoxy)naphthalen-1 -yi]-urea; 1 -[5-ethoxyca rbonyl-2-phenyl-2H-pyrazol-3-yI-3-[4-(2-morphoil- 4 -yI ethoxy)naphthalen-1 -yi]-urea; l0 1 -[5-(lI -methylcyclohex-I -yI)-2-phenyl-2H-pyrazo-3-y1-3-[4-(2-mo'rphoil-4-yI ethoxy)naphthalen-1 -yI]-urea; I 5tr-uy--ehy-Hprzl3y]3-4(-opoi--l-toynpta -1 yI]-urea; 15 I 5ti-utl2bnyl2-yaol3y]3[4(-opoin-4-yI-ethoxy)naphthalen- 1 yII-urea; I 5t/-uyl2(-hoopey)2-yrzl3y]3-4(-o oi n-4-yI 20 ethoxy)naphthalen-1 -yI]-urea; I 5tr-uyl2btl2-yrzl3y]3-4(-opoin-4-yi-ethoxy)naphthalen-1 -yI] u rea; 25 1 [-etbtl2(toyab nleh l-2 -yao--l--4(- opoi--l ethoxy)naphthalen-1 -yi]-urea; I -[5-tert-butyl-2-(4-methyl-3-carbamylphelyl)-2 H-pyrazol-3-yI]-3-[4-(2-morphOlil-4-YI ethoxy)naphthalen-1 -yI]-urea; 30 I -[5-tert-butyl-2-(4-.methyl-3-(2-ethoxycarboflylviflyl )phenyl)-2H-pyrazol-3-yI]-3-[4-(2 morpholin-4-ylkethoxy)naphthalefl-1 -yIII-u rea; I -I5-tet-butyI-2-(4-methyI-3-(morpholifl- 4 -yI)methyI phenyl )-2H-pyrazol-3-yU]-3-[4-(2 35 morpholin-4-yi-ethoxy)naphthalefl-l-yI]-urea; I -[5-tert-butyl-2-(4-methyl-3-dimethylamiflomethyl phenyl)-2 H-pyrazol-3-YI-3-[4-(2 morpholin-4-yI-ethoxy)naphthalefl-l -yl]-urea; WO 03/084503 PCT/EP03/03434 24 I 5tr-utl2(-2-opoi-4y ty)phenyl)-2 H-pyrazoI-3-yiI-3-[4-(2-morpholifl 4-yi-ethoxy)naphthalel-1 -yiI-u rea; I -[5-tedt-butyl-2- (3-(tetra hyd ro pyran-4-yl amino) phe nyl )-2 H-pyrazol-3-y]-3-14-(2 5 morpholin-4-yl-ethoxy)flaphthalefl-I -yl]-urea; I -[5-tert-butyl-2-(3-d imethylaminomethylPhel)-2 H-pyrazoI-3-yI]-3-I4-(2-morpholi n-4 yl-ethoxy)naphthalefl-I -yI]-urea; 10 1 -[5-tert-butyl-2-(4-(tetrahyd ropyran-4-ylamli no)phenyl )-2H-pyrazol-3-yI]-3-[4-(2 morpholin-4-yI-ethoxY)naphthalefl-I -yI]-urea; I -[5-tert-butyl-2-(4-(3-belu reido)phenyl)-2H-pyraZOI-3-YI]-3-[4-(2-morpho i n-4-yI ethoxy)naphthalefl-I -yI]-urea; 15 I -[5-tert-butyl-2-(2-ch loropyrid in-5-yI)-2 H-pyrazol-3-yI-3-[4-(2-morphoI in-4-yI ethoxy)naphthalefl-I -yI]-urea; I -15-tert-butyl-2-(2-methyl pyridin-5-yI )-2 H-pyrazo-3-yIII-3-[4-(2-morphoifl-4-yI 20 ethoxy)naphthalen-I -yI]-urea; I -[5-tert-buty-2-(2-methoxypyrid in-5-yI)-2H-pyrazoI-3-yI]-3-[4-(2-morpholif-lAY ethoxy)naphthalefl-I -yI]-urea; 25 1 -[5-tert-butyl-2-(pyrid in-3-yi)-2H-pyrazoI-3-yI]-3-[4-(2-morpholi n-4-yl ethoxy)naphthalen-1 -yII-urea; I -[5-tert-butyl-2-(2-methyl pyridin-5-yI)-2 H-pyrazol-3-y]-3-14-(2-pyrid in-4-yI ethoxy)naphthalefl-1 -yI]-urea; 30 I -[5-tert-butyl-2-(2-methyl pyrid in-5-yl)-2 H-pyrazol-3-yI]-3-[4-(2-(trafls- 2 ,6 dimethylmorpholil-4-y)ethoxy)flaphthalefl-I -yI]-u rea; I -[5-tert-butYl-2-(2-methylpyrid in-5-yI)-2H-pyrazol-3-yi]-3-[4-(3-morphoI in-4-yl-propyn 35 1 -yl)naphthalefl-1 -yI]-urea; I -[5-tert-ButyI-2-p-toIyi-2H-pyrazoI-3-yi]-3-[4-(2-(2-d imethylaminomethylmorphol in-4 yI)ethoxy)flaphthalefll -yII-urea; WO 03/084503 PCT/EP03/03434 25 I 5tr-uy--s-roy-Hprzl3y]3-4(-opoi--i ethoxy)naphthalen-1 -yi]-urea; I -[5-tert-butyIl.2-cyclopropy-2H-pyrazoI-3-yI]-3-[ 4

-(

2 -morpho i n-4-yI 5 ethoxy)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(thio phen-3-yI)-2 H-pyrazol-3-yI]-3-[4-(2-morphQI in-4-yI ethoxy)naphthalen-I -yi]-urea; 10 1 -[5-tert-butyl-2-cyclopentyl-2 H-pyrazo-3-yI]-3-[4-(2-morphoil- 4 -yi ethoxy)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-iso-propyl-2 H-pyrazol-3-yl]-3-[4-(tetrahyropyra n-4-yI ethoxy)naphthalen-1 -yI]-urea; 15 I -[5-tert-butyl-2-cyclopropyl-2 H-pyrazol-3-y]-3-[4-( I -oxo-tetrahyd roth iophen-3-yi ethoxy)naphthalen-1 -yII-urea; I -[5-tert-butyl-2-(th io phen-3-yI )-2 H-pyrazol-3-yI]-3-[4-(2-pyrid inyl-4-yI 20 ethoxy)naphthalen-I -yi]-urea; 1 -[5-tert-butyl-2-cyclope ntyl-2 H -pyrazol -3-yI]-3-[4-(pyrid in -4-yi-methoxy)n ap hth ale n- 1 yI]-u rea; 25 1 -[5-tert-Butyl-2-p-tolyI-2H-pyrazoI-3-y]-3-[4-(3-(pyrid in-4-yI)propyn-I -yI)naphthalen I -yI]-urea; 1 -[5-tert-Butyl-2-p-tolyl-2 H-pyrazoI-3-yI]-3-[4-(3-(2-mlethylamiflopyrid in-4-yI )propyn- I yl)naphthalen-1 -yI]-urea; 30 1 -[5-tedt-B utyl-2-p-tolyl-2H-pyrazoI-3-yI]-3-[4-(3-(l -oxo-tetrahydoth iophen-3 yI)propyn-l -yI)naphthalefl-1 -yI]-urea; I -[5-tert-Butyl-2-p-toIYI- 2 H-pyrazol-3-yI]-3-[4-(3-(th iazolid in-3-yI)propyn-1 35 yl)naphthalen-1 -yI]-urea; I -[5-tert-Buty-2-p-toIyi- 2 H-pyrazol-3-yI]-3-[4-(3-(tetrahydropyra n-4-yI)propyn- 1 yI)naphthalen-1 -yI]-urea; WO 03/084503 PCT/EPO3/03434 26 I -[5-ted-But 2ptll-Hprzl3-i--4(-mtyaioyimin-4-yI methoxy)naphthalen-1 -yI]-urea; I 5tr-utl2ptli-Hprzl3-i--4(-(-ehlmnopyrimid in-4 5 yI)ethoxy)naphthalen-1 -yI]-urea; I -[5-ted-B utyl-2-p-tolyl-2H H-pyrazoI-3-yl]-3- [4-(2- (4- methoxybeflzi mid azol- I yI)ethoxy)naphthalen-1 -yI]-urea; 10 1 -[-etB tl2ptli2 -yao--l]3[-2(-ehlmn b niia -1 yI)ethoxy)naphthalel-1 -yil-urea; 1 [-etBtl---oy-H-yao-- ]3[-2(-midazo[4 ,5-b]pyrid in-I yI)ethoxy)naphthalen-1 -yI]-urea; 15 I -[5-tedt-Butyl-2-p-toly-2H-pyrazo-3-YI]- 3 4-( 2 {l ,8]na phthyrid in-4 yI)ethoxy)naphthalen-1 -yI]-urea; I -[5-tert-ButyI-2-p-tolyl-2H-pyrazoI- 3 -yiI- 3

-[

4

-(

2

-(

3 ,4-dihyd ro-2 H-pyrano[2 ,3-b] pyrid in 20 5-yI)ethoxy)naphthalel-1 -yI]-urea; I -[5-tert-B utyl-2-pyrid in-3-y-2 H-pyrazoI-3-yI]-3-[4-(2-methyl am i nopyri mid in-4-yI methoxy)naphthalen-1 -yl]-urea; 25 1 -[5-tert-Butyl-2-(2-methylpyrid in-5-yI) -2H-pyrazol-3-yII-3-[4-(2-( 2 methylaminopyrimidin-4-yI)ethoxy)faphthalefll -yI]-urea; 1 -[5-tert-Butyl-2-(2-nlethYl pyrid in-5-yI)-2 H-pyrazol-3-yII-3-[4-(2-( 4 methoxybenzimidazol-1 -yI)ethoxy)naphthalen-1 -yI]-urea; 30 I -[5-tert-Butyl-2-(2-methyl pyridi n-5-yI)-2 H-pyrazol-3-yI]-3-[4-(2-( 4 methylaminobenzimidazol- I -yI)ethoxy)naphthalen-1 -yl]-urea; I -[5-tert-Butyl-2-(2-methyl pyridin-- -Hpyao--i]3[-2 2iiao45 35 b]pyridin-1 -yI)ethoxy)naphthalefl-l -yI]-u rea; 1 -[5-ted-B utyl-2-(2-methyl pyridin-5-ylD-2H-pyrazol-3-yi]-3-[ 4

-(

2 -[I ,8] naphthyrid in-4 yI)ethoxy)naphthalel-1-yi]-urea; WO 03/084503 PCT/EPO3/03434 27 1-[5-tert-Butyl-2-(2-methylpyridin-5-yl )-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1 -yl]-urea; 1 -[5-tert-Butyl-2-cyclopropyl -2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl 5 methoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yi]-3-[4-(2-(2-methylaminopyrimidin-4 yl)ethoxy)naphthalen-1 -yl]-urea; o10 1-[5-tert-Butyl-2-cyclopro pyl-2H-pyrazol-3-yi]-3-[4-(2-(4-methoxybenzimidaOl-1 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1 yl)ethoxy)naphthalen-1 -yl]-urea; 15 1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin- 1 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4 20 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-methyl-2H-pyral-3-yl]- 3

-[

4

-(

2

-(

3 ,4-dihydro-2H-pyrano[2,3-b]pyridin 5-yl)ethoxy)naphthalen-1 -yl]-urea 25 and their physiologically acceptable acids or salts thereof. In a particularily preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 30 selected from the follwoing compounds of formula 4 as disclosed in WO 00/43384: 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morph olin-4-yl-ethoxy)naphthalen-1 yl]-urea; 35 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yi]-3-[ 4 -(2-(cis-2 ,6-dimethylmorpholin-4 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[ 4 -(2-(trans-2 ,6-dimethylmorpholin-4 yl)ethoxy)naphthalen-1 -yl]-urea; WO 03/084503 PCT/EP03/03434 28 1 -[5-tert-Butyl-2-p-tolyl-2 H-pyrazo-3-yI-3-4-(2-(2-(ethoxymlethyI )morphol in-4 yl)ethoxy)naphthalen-1 -yI]-urea; 5 1 -[-etBtl2ptli2-yrz 3y]3[-2(opoin-4-yl)-2 oxoethoxy)naphthalefl-1 -yI]-urea; 1I5tr-ut 2ptly-Hprzi--i--4-2(opoin-4-yI)-2 methylethoxy)naphthalel-1 -yi]-urea; 10 I 5ti-uy-2ptll2-yrzl3y]3[4(-mrhln-4-yI)-1 methylethoxy)naphthalel-1 -yIJ-urea: I -[5-tedt-B utyl-2-p-tolyl-2H-pyrazoI-3-yI]-3-[4-(2-th omorphol in-4-yI 15 ethoxy)naphthalen-1 -yI]-urea; I -[5-tedt-B utyl-2-p-toly-2H-pyrazol-3-YII-3-[ 4

-(

2 -( I -oxothiomorpholin-4 yl)ethoxy)naphthalefl-I -yI]-urea; 20 1 -[5-ted-Butl2ptll2-yazl3y 3[-2mrpoi--lehx)3 methylnaphthalen-1 -yII-urea; I 5ti-utl2ptly-Hprzl--l--4-2(opoin-4-YI carbonyloxo)ethoxy)flaphthalel-I -yI]-urea; 25 I 5tt-uy-2ptli2-yrzl3yl3[4(-ttayropyran-4 yI)ethoxy)naphthalefl-I -yi]-urea; I -[5-tert-ButyI-2-p-toly-2H-pyrazoI-3-YI]- 3

-[

4

-(

2 -(l -oxo-tetrahydrothiophen-3 30 yI)ethoxy)naphthalel-1 -yl]-urea; I 5tr-uy---oy-H-yao--i--4(-opoln4y-rplnptae- yl]-u rea; 35 1 [-etBtl2ptli2-yao--i-3[-Mrhln4y-ehlnptae- -yfl urea; I -[5-tert-ButyI-2-p-tolyI-2H-pyraZbI-3-yi]--{ 4

-(

2 -pyrid in-4-yI-ethyl )naphthalen-1 -yi] urea; WO 03/084503 PCT/EP03/03434 29 I 5tr-utl2ptly-Hprzl--l--4-3(o oi n-4-yI)propyn-I yI)naphthalen-I -yfl-urea; 5 1 -[-etBuy---oll2Hpyao--l--4(-ttay ropyra n-2-yI-oxy) pro pyn- I yl)naphthalen-l -yI]-urea; I 5tr-uy---oli2-yao--l-3[-3(erhdoyrn2y-x~u - I yI)naphthalen-I -yI]-urea; 10 I 5ti-uyl2ptli2-przl3y]3-4(-pprin-I -yl)propyn-I -yI)naphthalen I -yl]-u rea; I 5ti-uy-2ptll2-yrzl3y]3[4(-2mtoymtymrhln-4 15 yI)propyn-I -yI)naphthalen-1 -yl]-u rea; I -[5-tert-ButyI-2-p-toly-2H-pyrazoI-3-yi]-3-I 4 -(pyrid in-4-yI-methoxy)nap hthalen-I -yI] u rea; 20 I 5tr-utl2ptly-Hprzo--l--[-2prdn-4-yl-ethoxy)n aphthalen- I -yI] u rea; I 5tr-uyl2ptli2Hprzl3yl -4(-yiin-4-yI-propoxy)naphthalen-I -yI] u rea; 25 I -[5-tert-B utyl-2-p-toly-2 H-pyrazo-3-yI1-3-I 4

-(

2 -i mid azol -I -yI-ethoxy)naphthalen-I -yI] u rea; I -r5-tert-Butyl-2-p-tolyI-2H-pyrazoI-3-yi]- 3

-[

4

-(

2

-(

3 ,4-di methoxyphenyl) 30 ethoxy)naphthalen-I -yI]-urea; I 5tr-uy---oll2-yao--i-3[-prdn4y-etyaionptae- yI]-urea; 35 1-5isoPoy--hnl2-yaz 3y]3[-2mrhli--iehx~ahhl I -yI]-urea; I 5ccoey--hey-Hpr zl3-i--4(-opoln4y-toynphthalen 1 -yI]-u rea; WO 03/084503 PCT/EP03/03434 30 I -[5-(2 ,2 ,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl-3-[4-(2-morphoI in-4-yI ethoxy)naphthalen-I -yI]-urea; 5 1 -[5-(1 -methylcycloprop-1 -yI)-2-phenyl-2H-pyrazol-3-y]-3-[4-(2-morphoil-4-y! ethoxy)naphthalen-1 -yI]-urea; 1 -[5-(l -methylcyclohex-1 -yI )-2-phenyl-2H-pyrazol-3-y]-3-[4-(2-iorphoI in-4-yI ethoxy)naphthalen-1 -yi]-urea; 10 I -[5-tert-butyl-2-methyl-2 H-pyrazot-3-yI]-3-j[4-(2-morphol in-4-y-ethoxy)naphthalen-1 yI]-urea; I -[5-tert-butyi-2-(4-chloropheny)-2H-pyrazoI-3-yl-3-4-(2-morphoil- 4 -yi 15 ethoxy)naphthalen-1 -yI]-urea; I .[5-tert-butyI-2-butyl-2H-pyrazo-3-yI-3-[4-(2-morphoi n-4-yI-ethoxy)naphthalen-I -yi] urea; 20 1 -[5-tert-buty-2-(4-methyI-3-carbamylpheny)-2H-pyrazoI-3-yI]-3-[ 4

-(

2 -morpholifl 4 -yi ethoxy)naphthalen-1 -yi]-urea; I -[5-tert-butyI-2-(4-methyI-3-(morpholin-4-yI)methylphel)-2 H-pyrazol-3-yII-3-[4-(2 morpholin-4-yI-ethoxy)naphthalel-1 -yi]-urea; 25 I -[5-tert-butyl-2-(4-methyl-3-d imethylaminomethyl phenyl)-2 H-pyrazol-3-yI]-3-[4-(2 morpholin-4-yI-ethoxy)naphthalel-1 -yI]-urea; I -[5-tert-butyl-2-(3-dimethylamiflomethylphelyl)-2 H-pyrazol-3-yl]-3-[4-(2-morpholin-4 30 yi-ethoxy)naphthalen-1-yi]-urea; I -[5-tert-butyl-2-(2-chloropyrid in-5-yI )-2 H-pyrazol-3-yI]-3-[4-(2-morphoin-4-yl ethoxy)naphthalen-1 -yI]-urea; 35 1 -[5-tert-butyl-2-(2-methyl pyridin-5-yI )-2H-pyrazol-3-yi]-3-[4-(2-morphol in-4-yI ethoxy)naphthalen-1 -yi]-urea; I -[5-tert-butyl-2-(2-methoxypyrid i n-5-yI)-2H-pyrazol-3-yI]-3-[4-(2-morpholin-4-yI ethoxy)naphthalen-1 -yII-urea; WO 03/084503 PCT/EPO3/03434 31 1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl ethoxy)naphthalen-1 -yl]-urea; 5 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6 dimethylmorpholin-4-yl)ethoxy)naphthalen-l1-yl]-urea; 10 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morholin-4-yl-propyn 1-yl)naphthalen-1 -yl]-urea. Particularly preferred compounds of the formula 4 are: 15 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yi]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1 yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1 -oxothiomorpholin-4 20 yl)ethoxy)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl ethoxy)naphthalen-1 -yl]-urea; 25 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morholin-4-yl ethoxy)naphthalen-1-yl]-urea or 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1 yl]-urea. 30 In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 35 W Ar~ -N N Ar-X-Y-Z H H 5 WO 03/084503 PCT/EPO3/03434 32 wherein: Ar 1 is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and 5 thiophene; wherein Ar may be substituted by one or more R 1 , R 2 or R 3 ; Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, 10 tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three

R

2 groups; X is: 15 a) a Cs- 8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C 1

,

4 branched or unbranched alkyl, C 14 alkoxy or C.4 alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, 20 piperazine or pyrazine each being optionally independently substituted with 0-3 C14 branched or unbranched alkyl, C 14 alkoxy, hydroxy, nitrile, mono- or di-(C,. alkyl)amino, C,.

6 alkyl-S(O)m, or halogen; Y is: 25 a bond or a C 14 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(0), S(0) 2 or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C 14 branched or unbranched alkyl which may be substituted by one or more 30 halogen atoms; Z is: a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups consisting 35 of halogen, C 1

.

6 alkyl, C, alkoxy, hydroxy, mono- or di-(C 1

..

3 alkyl)amino, Cl_ 6 alkyl-S(O)m, COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C 1

.

6 alkyl and C 1

-

6 alkoxy; ' WO 03/084503 PCT/EPO3/03434 33 b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4 dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, 5 pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C1., alkyl, C-6 alkoxy, hydroxy, mono- or di-(C 1

,

3 alkyl)amino-C 1

-

3 alkyl, phenylamino-C 1 3 alkyl and C1.3 alkoxy-Cl.

3 alkyl; 10 c) C, alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C-_3 alkyl, C , alkoxyalkyl, pyridinyl-C.

3 alkyl, imidazolyl-C,-., 3 alkyl, tetrahydrofuranyl-C,. 3 alkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C, alkoxy, hydroxy or 15 mono- or di-(C- 3 alkyl)amino, C,_, alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, Cj-e alkoxy, hydroxy or mono- or di-(Cl 1 3 alkyl)amino; R, is : 20 a) C3-10 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or 25 heterocycle selected from the group hereinabove described in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, C_, branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8, cycloalkyl, C, cycloalkenyl, hydroxy, nitrile, C 1

-

3 alkyloxy which is optionally partially or fully 30 halogenated, NH 2 C(O) and di(C.

3 )alkylaminocarbonyl; b) C3.-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be partially or fully halogenated and optionally substituted with one to three Cl, alkyl 35 groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >C=0, >C=S and NH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1.5 branched or unbranched alkyl, WO 03/084503 PCT/EPO3/03434 34 phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or 5 heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1.6, branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C.3 alkoxy which is 10 optionally partially or fully halogenated, NH 2 C(O) and mono- or di(C 1

-

3 )alkylaminocarbonyl; d) a C5.7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is 15 optionally substituted with one to three C, alkyl groups; e) nitrile; or f) C 1

.

6 branched or unbranched alkoxycarbonyl, Cjr branched or unbranched alkylaminocarbonyl, C., branched or unbranched alkylcarbonylamino-Cl.3 alkyl; 20

R

2 is: a C.6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C, branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl; 25

R

3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, 30 isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group 35 consisting of phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C,.alkyl, naphthyl C- alkyl, halogen, WO 03/084503 PCT/EPO3/03434 35 hydroxy, nitrile, C,_ alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1

-

3 )alkylamino, phenylamino, 5 naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph,

NH

2 C(O), a mono- or di-(C 1 3)alkyl aminocarbonyl, C,-5 alkyl-C(O)-C, 1

-

4 alkyl, amino-C,_s alkyl, mono- or di-(C 1

.

3 )alkylamino-Cj. alkyl, amino-S(O) 2 , di

(C,_

3 )alkylamino-S(O) 2 , R 4 -C_ alkyl, Re-C-,5 alkoxy, R 6

-C(O)-C,.

5 alkyl and 10 R 7 -Cj_, alkyl(R,)N, carboxy-mono- or di-(C,-,)-alkyl-amino; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, 15 cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, 20 cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the 25 group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C 1 .6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C 13 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the 30 heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1

_

3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph,

NH

2 C(O), a mono- or di-(Cl 3 )alkyl aminocarbonyl, C, 4 alkyl-OC(O), C, 35 alkyl-C(O)-C 14 branched or unbranched alkyl, an amino-C, 6 alkyl, mono or di-(C 1

.

3 )alkylamino-C,. alkyl, R 9 -C. alkyl, Rio 0 -C,.alkoxy, Rjj-C(O)-C.

5 alkyl, and R, 2 -Cl5alky(R 3 )N; c) cycloalkyl selected froimn the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the WO 03/084503 PCT/EPO3/03434 36 cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C 1 3 alkyl groups; d) C.

7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 5 bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C 1 ,alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C 1 6 branched or unbranched alkyl optionally partially or fully halogenated; 10 or R 1 and R 2 taken together may optionally form a fused phenyl or pyridinyl ring; each R, and R 13 is independently selected from the group consisting of: hydrogen and C,_4 branched or unbranched alkyl optionally be partially or fully halogenated; 15 each R 4 , R 5 , R 6 , R, R 9 , RIO, R 11 and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; mis 0, 1 or 2; 20 W is O or S and pharmaceutically acceptable derivatives thereof. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 25 selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and Wis O. 30 In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: 35 Ar is selected from thiophene and pyrazole; X is. Cs.

7 cycloalkyl or C 57 cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C_4 branched or unbranched alkyl, C, alkoxy or C14 alkylamino; or X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene each being optionally independently substituted with 0-3 C-.4 branched or WO 03/084503 PCT/EPO3/03434 37 unbranched alkyl, C 14 alkoxy, hydroxy, nitrile, mono- or di-(Cl_ 3 alkyl)amino, Cl alkyl-S(O)m or halogen;

R

1 is C 14 alkyl branched or unbranched, cyclopropyl or cyclohexyl optionally partially or fully halogenated and optionally substituted with one to three Cs.3 5 alkyl groups;

R

3 is C 1

_

4 alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl or pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect. 10 In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 15 wherein: Ar is pyrazole; X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C 1

_

4 branched or unbranched alkyl, C,4alkoxy or Cl-4alkylamino; or X is phenyl, pyridine, furan or thiophene each being 20 optionally independently substituted with 0-3 C 1

-

4 branched or unbranched alkyl, C 1

_

4 alkoxy, hydroxy, nitrile, mono- or di-(C, 3 alkyl)amino, C-6 alkyl-S(O)m or halogen. In yet still another preferred embodiment the invention relates to the use of p38 25 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: Y is -CH2-, -CH2CH2-, -CH2NH-, -CH2CH2NH- or a bond; 30 and Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, pyridine, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C13 alkyl and C 1 , alkoxyalkyl, 35 phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C.6 alkoxy, hydroxy or mono- or di-(C 1

-

3 alkyl)amino, C 1 . alkyI-S(O), and pheny-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C., alkoxy, hydroxy or mono- or di-(C 1

-

3 alkyl)amino.

WO 03/084503 PCT/EPO3/03434 38 In a further embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: 5 Ar, is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by R,;

R

3 is C 14 alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally 10 substituted as described hereinabove in the broadest generic aspect. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 15 selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein X is pyridinyl. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the 20 treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein the pyridinyl is attached to Ar, via the 3-pyridinyl position. In another preferred embodiment the invention relates to the use of p38 kinase 25 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 that are mentioned below: 1-[5-tert-butyl-2-p-toly-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthalen-1 30 yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl methyl)phenyl)naphthalen-1 -yl]urea; 35 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4 yl)ethyl)phenyl)naphthalen-1 -yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalen-1 yl]urea; WO 03/084503 PCT/EP03/03434 39 I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(3-(morphoI in-4-yI )phenyl)na phthalen-1 yl]urea; I -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-y]-3-[4-(3-(morphoI in-4-yI 5 methyl)phenyl)naphthalen-1 -yl]urea; I .45-tert-butyI-2-p-tolyi-2H-pyrazoI-3-yi]-3-[4-(6-morphoI in-4-yI methyl-pyrid in-3 yI)naphthalen-1 -yI]urea; 10 1 -[5-tert-butyI-2-p-tolyl-2H-pyrazoI-3-yi]-3-[4-(5-rrphoI i n-4-yI methyl-pyridi n-2 yl)naphthalen-1 -yI]urea; I -[5-tert-butyI-2-p-toly-2H-pyrazoI-3-yIII-3-[4-(5-morphoI in-4-yI methyl-fur-2 yI)naphthalen-1 -yI]urea; 15 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(6-morphol in-4-yI methyl pyridin-3-yl)naphthalen-1 -yI]urea; I -[5-tert-butyl-2-methyl-2H-pyrazoI-3-yI]-3-[4-(6-morphoil- 4 -yI methyl-pyrid in-3 20 yI)naphthalen-1 -yIjurea; I 5tt-uyl2pey-Hpyao--l-3[-4pprin-I -yI methyl phenyl)naphthalen-1 -yllurea; 25 1 -[5-tet-butyI-2-phenyl-2H-pyrazol-3-yl-3-I4-(4-(4-methyI piperazin- 1 yl)methylphenyl)naphthalefl-1 -yl]urea; I -[5-tert-butyl-2-p-tolyt-2 H-pyrazol-3-yI]-3-[4-(3 ,4-d i(morphol in-4-yl methyl)phenyl)naphthalen-1 -yl]urea; 30 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yl)-2 H-pyrazol-3-yI]-3-[4-(6-pyrid in-4-yI methyl pyridin-3-yl)naphthalen-I -yI]urea; I -[5-tert-butyl-2-(6-mlethyl-pyrid in-3-yl)-2 H-pyrazol-3-yl]-3-[4-( 6 -( I -oxo-thiomorpholi n 35 4-ylmethyl)pyridifl-3-yI)flaphthalefl-I-yl]urea;_ I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yll-3-[4-(6-( I -oxo-th iomorp hol in-4 ylmethyl)pyridin-3-y)flaphthalefl-I -yl]urea; WO 03/084503 PCT/EPO3/03434 40 I -15-tert-buty-2-(6-methyl-pyrid i n-3-yI)-2 H-pyrazol-3-yl]-3-[4-(6-tetrahyd ropyran-4 ylmethyl-pyridin-3-yI)naphthalen-1 -yl]urea; I -[5-tert-butyl-2-(6-methyi-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(6-( I -oxo 5 tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)flaphthalefl-I -yI]urea; I -[5-tert-butyl-2-(6-methyl-pyridifl-3-yl)-2 H-pyrazol-3-ylII-3-14-(6-(imidazol-

I

ylmethyl)pyridin-3-yI)naphthalefl-1 -yIlu rea; 10 1 -[2-(3-d imethylami nomethyl phenyl)-5-(1 -methyl-cyclohexyl)-2 H-pyrazol-3-yl]-3-[4-(6 morpholin-4-ylmethyl-pyridifl-3-yI)flaphthalel-1 -yI]urea; 1 -[2-(5-(l -methyl-cyclohexyl )-2-(6-methyl-pyrid in-3-yI)-2H-pyrazoI-3-yl]-3-[4-(6 morpholin-4-ylmethyl-pyridin-3-yI)flaphthalel-1 -yllurea; 15 I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-y]-3-14-(2-morphol in-4-yI methyl-pyrimidi n-5 yl)naphthalen-1 -yl]urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yl)-2H-pyrazoI-3-yl]-3-[4-(3-methoxy-5-(2 20 morpholin-4-yl-ethoxy)phenylnaphthalel-I -yI~u rea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(3-(2-morpholifl-4-yl ethoxy)phenyl)naphthalen-1 -yI]urea; 25 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yl)-2H-pyrazol-3-yl]-3-[4-3 (dimethylamino)phenyl)naphthalel-1 -yllurea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yi]-3-14-3 (methyisulfonyl)phenyl)flaPhthalel-1 -yI]u rea; 30 5-etbtl3f-4(-opoi--ymty-yii--lnptae- ylllureidolthiophene-2-carboxylic acid methyl ester; 5-tert-butyl-3-{3-14-(6-mlorphol in-4-yimethyl-pyridi n-3-yl )naphthalen- I 35 ylljureidolthiophene-2-carboxylic acid methylamide; 5-tert-butyl-I -methyl-3-{3-[4-(6-morpholifl-4-ylmethyI-pyridifl-3yI)flaphthalel-1 yl]u reido}-1 H-pyrrole-2-carboxyI ic acid methyl ester; WO 03/084503 PCT/EP03/03434 41 5-tert-butyl-1 -methyl-3-{3-[4-(6-morphol in-4-ylmethyl-pyrid in-3-yI )naphthalen- 1 yI]ureido}-1 H-pyrrole-2-carboxylic acid methylamide; 2-acetylamino N-(5-tert-butyl-3-{3-[4-(6-morphoIiin-4-yI methyl-pyrid in-3-yi )naphthalen 5 1 -yI]u reidolthiophen-2-ylmethyl)acetamide; 1 -[-etbtl2ptll2Hprzl3y]3[-3mr o i n-4-yI-cyclo hex- 1 e'nyl)naphthalen-1 -yi]urea; 10 1 [-etbtl2ptoy-Hprzl3yl -4(-opoi n-4-yI-cylohept-1 enyl)naphthalen-1 -yllurea; I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(3-(2-morphoI in-4-yI ethylamino)cyclohex-1 -enyl)naphthalen-1 -yI]urea; 15 I 5ti-uy--ptll2-yao-3y]3[-3mrpoi- lccoept- 1 enyl)naphthalen-1 -yI]urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-y]-3-14-(3-(pyrid in-4-yI 20 methylamino)cyclohex-I -enyl)naphthalen-1 -yl]urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(3 (dimethylaminoethylamino)cycIohex- I -enyl)naphthalen-1 -yl]urea; 25 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yII-3-[4-(3-(pyrid in-3-yI-7 methylamino)cyclohex-1 -enyl)naphthalen-1 -yllurea; I -15-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2 H-pyrazol-3-yI]-3-[4-(3-(phenyl methylamino)cyclohex-1 -enyl)naphthalen-1 -yI]urea: 30 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yIJ-3-[4-(3-(2 phenylethylamino)cyclohex-I -enyl)naphthalen-1 -yllurea; I -[5-tert-butyl-2-(6-methyl-pyridijn-3-yI)-2 H-pyrazol-3-yIJ-3-[4-(3-(fu ran-2-yI 35 methylamino)cyclohex-1 -enyl)naphthalen-1 -yIjurea; I -[5-tert-butyl-2-(6-methyl-pyridi n-3-yI)-2 H-pyrazo-3-yI]-3-[4-(3-(2-pyrid in-2-yi ethylamino)cyolohex-1 -enyl)naphthalen-1 -yi]urea; WO 03/084503 PCT/EP03/03434 42 I -[5-tert-butyI-2-(6-methyI-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(3-(2-piperdil- I -yl ethylamino)cyclohex-1 -enyl)naphthalen-1 -yI]urea; I -[5-tert-butyl-2-(6-methyl-pyrid i n-3-yI )-2H-pyrazoI-3-yII-3-[4-(3-(2-i mid azol-4-yI 5 ethylamino)cyclohex-1 -el)faphthalel-I -YI]urea; 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yI]-3-[4-(3-(pyridi n-2-yl methylamino)cyclohex-1 -enyl)naphthalen-1 -yllurea; 10 1 -[5-tert-butyl-2-(6-methyl-pyrid ir-3-yi)-2 H-pyrazol-3-yI]-3-[4-(3-(2-(4 methoxyphenyl)ethylamio)cycIohex-1 -enyl)naphthalen-1 -yI]urea; I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol1-3-yI]-3-[4-(4-morpho i n-4-yl methyl-3-oxo-cyclo hex I -enyl)naphthalen-1 -yI]urea; 15 I -15-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(4-( I -oxo-tetra hyd rothiophen-3 ylmethyl)-3-oxo-cyclohex-1 -enyl)naphthalen-1 -yI]urea; I -[5-tert-butyl-2-p-tolyl-2H-pyrazoI-3-yi]-3-[ 4

-(

4 -(l -oxo-th lomorpholi n-4-ylmethyl )-3 20 oxo-cyclohex-1 -enyl)naphthalen-1 -yI]urea; I -[5-tert-buty-2-p-tolyl-2H-pyrazol-3-yI]-3-[4-(4-methyI piperazin-I -yI methyl)-3-oxo cyclohex-1 -enyl)naphthalen-1 -yl]urea; 25 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-ylj-3-[4-{6-oxo-I -(tetrahyd ro pyran-4-ylmethyl)-l ,2 ,3,6-tetrahydro-pyridin-4-yI}flaphthalefl-I -yI]urea; I -[5-ted-buty-2-(6-methYl-pyrid in-3-yI )-2H-pyrazol-3-yl-3-[4-(2-oxo-I -pyrid in-4 ylmethyl-piperdin-4-yI)flaphthalel-1 -yI]urea; 30 I -[5-tert-butyl-2-p-tolyI-2 H-pyrazol-3-yiII-3-[4-(6-oxo- I -pyridin-4-yI- 1,2 ,3,6-tetrahyd ro pyridin-4-yI)naphthalefl-1 -yI]urea; I -[5-tert-butyl-2-(6-mlethYl-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(6-oxo-1 -pyridi n-4-yI 35 1,2,3 ,6-tetrahydrO-pyrid in-4-yI)naphthaien-1 -yI]urea; 5-tert-butyl-3-{3-[ 4

-(

6 0oxol -pyrid in-4-yI-1 ,2,3 ,6-tetrahyd ro-pyrid in-4-yI)na phthalen- 1 yIju reidolthiophele-2-carboxyic 'acid methyl ester; WO 03/084503 PCT/EPO3/03434 43 5-tert-butyl-1 -methyl-3-{3-[4-(6-oxo-1 -pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4 yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester; 5-tert-butyl- 1 -methyl-3-{3-[4-(6-oxo-1 -pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4 5 yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl amide; 5-tert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-l -enyl)naphthalen-1 yl]ureido}thiophene-2-carboxylic acid methyl ester; 10 5-tert-butyl-1 -methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-l -enyl)naphthalen-1 yl]ureido}pyrrole-2-carboxylic acid methyl ester; and 5-tert-butyl-1 -methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1 -enyl)naphthalen-1 yl]ureido}pyrrole-2-carboxylic acid methyl amide and 15 the pharmaceutically acceptable derivatives thereof. Preferably the invention relates to the use of p38 kinase inhibitors for the preparation 20 of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5: 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl 25 methyl)phenyl)naphthalen-1 -yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4 yl)ethyl)phenyl)naphthalen-l1-yl]urea; 30 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl methyl)phenyl)naphthalen-1 -yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)naphthalen-I -yl]urea; 35 1-[5-tert-butyl-2-p-tlyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2 yl)naphthalen-1 -yl]urea; WO 03/084503 PCT/EPO3/03434 44 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2 yl)naphthalen-1 -yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl 5 pyridin-3-yl)naphthalen-1 -yl]urea; 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yi]-3-[4-(6-morpholin-4-yl methyl-pyridin-3 yl)naphthalen-1-yl]urea and 10 the pharmaceutically acceptable derivatives thereof. In another embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from 15 the compounds of formula 5a as disclosed in WO 00/55139 W Ar>N JN Ar -X-Y-Z I 1 H H 5a wherein: 20 Ar 1 is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar, is optionally substituted by one or more R 1 , R 2 or R.; 25 Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three 30 R 2 groups; X is: a C5, cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C-4alkyl, C14 alkoxy or C,14 alkylamino chains each 35 being branched or unbranched; WO 03/084503 PCT/EPO3/03434 45 phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently 5 substituted with one to three C_4 alkyl, C 14 alkoxy, hydroxy, nitrile, amino, mono- or di-(C, 3 alkyl)amino, mono- or di-(C 1 -3 alkylamino)carbonyl, NH 2 C(O), Cl_6 alkyl-S(O)m or halogen; Y is: 10 a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C.4 alkyl optionally substituted by one or more halogen atoms; 15 Z is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, 20 cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, 25 thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, Cl- alkyl, Cl-e alkoxy, C.3 alkoxy-Cl. alkyl, C 1 _s alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC,-.acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C 1 ,acyl, oxo, hydroxy, pyridinyl 30 C1.3 alkyl, imidazolyl-C-, alkyl, tetrahydrofuranyl-C, _ alkyl, nitrile-C 1

-

3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, Cl_ alkoxy, hydroxy or mono- or di-(C,_ 3 alkyl)amino, amino-S(0)m, C6 alkyl-S(0)m or phenyl-S(0)m wherein the phenyl ring is optionally substituted with one to two halogen, Ce alkoxy, hydroxy, halogen or 35 mono- or di-(C, 1

-

3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-Cl_3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC.

6 alkyl, C1- 3 alkyl, arylC 0 o- 3 alkyl, C.- alkoxyC 1

.

3 alkyl, C1, alkoxy, aroyl,

C

13 acyl, C,,alkyl-S(0)m- or arylCo- 3 alkyl-S(0)m- each of the aforementioned WO 03/084503 PCT/EPO3/03434 46 alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C 1

.

6 alkyl, C.6 alkoxy, hydroxy or mono- or di-(C 1

.

3 alkyl)amino; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted 5 by halogen, C16 alkyl or C-6 alkoxy; or Z is hydroxy, hydroxyC 1

-

3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by Cj_,alkyl, aminoC 16 alkyl, arylCo-alkyl, C1.,alkoxyC 1 , alkyl, C,. alkoxy, aroyl, C, 3 acyl, C 1

.

3 alkyl-S(O)m-, arylCo- 0 alkyl-S(O)m-, nitrileC_ 4 alkyl or C_ 3 alkoxyC 1

,

3 alkyl, each of the 10 aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C, alkyl, Cl, alkoxy, hydroxy or mono- or di-(C 1

.

3 alkyl)amino, C,, alkoxyheteroarylC 0 -3alkyl, heteroarylCo 3 alkyl or heterocycyleC.- 3 alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph, 15 or Z is C 1

.

6 alkyl branched or unbranched, Cl.ealkoxy, C 1 oacylamino, nitrileC,-4alkyl, C 1

.

6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C, alkoxy, hydroxy or mono or di-(Cl, alkyl)amino; 20 R, is : a) C-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, 25 furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle, selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C-.6 branched or unbranched alkyl which is optionally partially or fully halogenated, Cs cycloalkyl, Cs,8 cycloalkenyl, hydroxy, nitrile, C1-3 30 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0) and di(C,-3)alkylaminocarbonyl; b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or fully halogenated and 35 optionally substituted with one to three C, alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >C=O, >C=S and NH; WO 03/084503 PCT/EPO3/03434 47 c) C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C,_ branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, 5 pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1.6, branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, 10 cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1.3 alkoxy which is optionally partially or fully halogenated, NH 2 C(O) and mono- or di(C,.)alkylaminocarbonyl; d) a C57 cycloalkenyl selected from the group consisting of cyclopentenyl, 15 cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1, alkyl groups; e) nitrile; or f) C., branched or unbranched alkoxycarbonyl, C-.6 branched or unbranched 20 alkylaminocarbonyl, C1.6 branched or unbranched alkylcarbonylamino-C 1 .3-. alkyl;

R

2 is: a C,01.6 branched or unbranched alkyl optionally partially or fully halogenated 25 and optionally substituted with nitrile, or R 2 is acetyl, aroyl, C, branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;

R

3 is: 30 a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, 35 phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl; naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1.6, branched or unbranched WO 03/084503 PCT/EPO3/03434 48 alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C.alkyl, naphthyl C,alkyl, halogen, hydroxy, oxo, nitrile, C 1

,

3 alkoxy optionally partially or fully halogenated, 5 C 1

.

3 alkoxyC,_,alkyl, CI.

3 thioalkyl, C 1 lthioalkylC 1 ..-alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C,- 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove 10 described in this paragraph, NH 2 C(O), a mono- or di-(C 1

-

3 )alkyl aminocarbonyl, C15 alkyl-C(O)-C 1 4 alkyl, amino-C- alkyl, mono- or di-(C,-_ 3 )alkylamino-Cl-, alkyl, amino-S(O) 2 , di-(C,_ 3 )alkylamino-S(O) 2 ,

R

4

-C

1

,

5 alkyl, Re-Ci-.alkoxy, R.-C(O)-C,.

5 alkyl and R 7

-C

1

.

5 alkyl(R,)N, carboxy-mono- or di-(C,. )-alkyl-amino; 15 b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, 20 cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, 25 cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, 30 imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C., branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C 1

-

3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, 35 nitro, amino, mono- or di-(C,-)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C 1

.

3 )alkyl aminocarbonyl, C1-4 alkyl-OC(O), C- 5 alkyl-C(O)-C 1 -4 branched or unbranched alkyl, an amino-C.

5 alkyl, mono- or di-(C, 1

-

3 )alkylamino-C 1

-

WO 03/084503 PCT/EPO3/03434 49 alkyl, R,-C 1 salkyl, R 0 o-C 1

-

5 alkoxy, R 1 ,-C(O)-Cl_ alkyl and R 12

-C

1 -5 alkyl(R 13 )N; c) cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and 5 bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C, alkyl groups; d) C-.

7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is 10 optionally substituted with one to three C 1-3 alkyl groups; e) acetyl, aroyl, C 1 6 alkoxycarbonylC.

6 alkyl or phenylsulfonyl; or f) C-.6 branched or unbranched alkyl optionally partially or fully halogenated; or R 1 and R 2 taken together optionally form a fused phenyl or pyridinyl ring; 15 each R. and R, 3 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated; 20 each R 4 , R 5 , R 6 , R R, Ro, R 1 and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; mis 0, 1 or2; WisOorS; 25 wherein X is directly attached to one or two -Y-Z, and pharmaceutically acceptable derivatives thereof. In another embodiment the invention relates to the use of p38 kinase inhibitors for 30 the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O. 35 In another embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: WO 03/084503 PCT/EPO3/03434 50 Arl is thiophene or pyrazole each substituted independently by one to three R 1 , R 2 or R 3 ; X is: a Cs57 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo 5 groups or one to three C,-4 alkyl, C14 alkoxy or 0C.4 alkylamino chains each being branched or unbranched; phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazole or 10 piperazinyl; each being optionally independently substituted with one to three

C

14 alkyl, C 1

-

4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C1- 3 alkyl)amino, mono- or di-(C_ 3 alkylamino)carbonyl, NH 2 C(O), C_6 alkyl-S(O)m or halogen; Y is: 15 a bond or a C 1

-

4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by 0 or N, and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C14 alkyl optionally substituted by one or more halogen atoms; 20 Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, 25 tetrahydrofuranyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1.6, alkyl, C,6 alkoxy, C13 alkoxy-C, 1 alkyl, C,6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C 1 3 acyl, oxo, hydroxy, pyridinyl-C,- 3 alkyl, imidazolyl-Cl- alkyl, tetrahydrofuranyl-Cl 3 alkyl, nitrile-C 1 3 alkyl, nitrile, carboxy, 30 phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,6 alkoxy, hydroxy or mono- or di-(C.

3 alkyl)amino, amino-S(O)m, C16 alkyl-S(0)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C., alkoxy, hydroxy, halogen or mono- or di-(Cl 3 alkyl)amino; 35 or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C,3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC l 6 alkyl, Cl.alkyl, arylC 0 o-alkyl, CI5 alkoxyCj_ alkyl, C,5 alkoxy, aroyl,

C

1

.

3 acyl, C 13 alkyl-S(O)m- or arylCo- 3 alkyl-S(O)m- each of the aforementioned WO 03/084503 PCT/EPO3/03434 51 alkyl and aryl attached to the amino group are optionally substituted with one to two halogen, C., alkyl or C1.6 alkoxy; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted 5 by halogen, C 1

.

6 , alkyl or C1.

j , alkoxy; or Z is hydroxy, hydroxyC 1

.-

3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by aroyl, Cl.

3 acyl, Cs.

6 alkyl, C1. alkoxyC. alkyl, pyridinylC 1

.

3 alkyl, tetrahydrafuranylC 1

.

3 alkyl, nitrileC_4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two 10 halogen, Cj, alkoxy, hydroxy or mono- or di-(C 1

.

3 alkyl)amino, or Z is Cl.

6 alkyl branched or unbranched, C, salkoxy or nitrileC,4alkyl;

R

1 is: C.4 branched or unbranched alkyl optionally partially or fully halogenated; 15 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C,1.3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the 20 group consisting of O, S and NH; C0310 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C branched or unbranched alkyl; 25 cyclopentenyl and cyclohexenyl optionally substituted with one to three Cj.3 alkyl groups;

R

2 is: a Cl, branched or unbranched alkyl optionally partially or fully halogenated 30 and optionally substituted with nitrile;

R

3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or 35 heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C _ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, WO 03/084503 PCT/EPO3/03434 52 phenyl C 1 5 -alkyl, naphthyl C,_salkyl, halogen, hydroxy, oxo, nitrile, C,. alkoxy optionally be partially or fully halogenated, C 1 . alkoxyC 1 .,alkyl, C 1

.

3 thioalkyl, C,. 3 thioalkylC,.salkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this 5 paragraph, nitro, amino, mono- or di-(C,.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 4)alkyl aminocarbonyl, C.5 alkyl-C(O)-C_ 4 alkyl, amino-C_ 5 alkyl, mono or di-(C 1

-

3 )alkylamino-Cs., alkyl, amino-S(O) 2 , di-(C.

3 )alkylamino-S(O) 2 , 10 R 4

-C

5 alkyl, R 5 -Cl.5 alkoxy, R 6 -C(O)-Cl.

5 alkyl and R 7 -01C

_

5 alkyl(R,)N, carboxy-mono- or di-(Cl-s)-alkyl-amino; a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl 15 selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C16 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, Cl, alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the 20 heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C,.

3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(Cl 3 )alkyl aminocarbonyl, C 14 alkyl-OC(O), C .5 alkyl-C(O)-C 14 branched or 25 unbranched alkyl,,an amino-C., alkyl, mono- or di-(C1.

3 )alkylamino-C.

5 alkyl,

R

9

-C

16 alkyl, Ro 10 -C, alkoxy, Rl -C(O)-C.

5 aikyl and R 1 2 -C.5 alkyl(R, 3 )N; cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally 30 partially or fully halogenated and optionally substituted with one to three C1.3 alkyl groups; Cj, 1 alkoxycarbonylCealkyl; 35 or R, and R 2 taken together optionally form a fused phenyl or pyridinyl ring; each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C014 branched or Unbranched alkyl optionally partially or fully halogenated; WO 03/084503 PCT/EPO3/03434 53 and each R 4 , R, R 6 , R7, R, RIO, R 11 and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; 5 wherein X is directly attached to one -Y-Z. In another embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from o10 the compounds of formula 5a wherein: Ar, is pyrazole; X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three C.4 alkyl, C 1 -4 alkoxy or C1-4 alkylamino chains each 15 being branched or unbranched; phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C 1

-

2 alkyl, C 1 . 2 alkoxy, hydroxy or halogen; 20 Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, 25 tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 16 alkyl, C., alkoxy, C 1

,

3 alkoxy-C.3 alkyl, C., alkoxycarbonyl, aroyl, morpholinocarbonyl, C.

3 acyl, oxo, hydroxy, pyridinyl-C.

3 alkyl, 30 imidazolyl-C, 1 alkyl, tetrahydrofuranyl-C 1 -3alkyl, nitrile-C 1 - alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C 16 alkoxy, hydroxy or mono- or di-(C, 3 alkyl)amino, amino-S(O), Cj 6 alkyl-S(O)m, or phenyI-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C 16 alkoxy, hydroxy, halogen or mono- or 35 di-(C 1

-

3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C 1 -3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC 1 .alkyl, C,_ 3 alkyl, arylC 0 o- 3 alkyl, C. ,alkoxyC, 3 alkyl, C. alkoxy, aroyl,

C.

3 acyl, C.

3 alkyl-S(O)m-, pyridinylCo.

3 alkyl, tetrahydrafuranylC.3alkyl, or arylCo.

WO 03/084503 PCT/EPO3/03434 54 3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1.j, alkyl or C1.6 alkoxy; or Z is hydroxy, hydroxyC 1 4.,alkyl, halogen, nitrile, amino wherein the N atom is 5 optionally independently mono- or di-substituted by Cl.

6 alkyl, pyridinylC 0 3 alkyl, tetrahydrafuranylCo 3 alkyl, Cl-, alkoxyC,_ 3 alkyl, C0.,acyl, nitrileC 1 4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1. alkoxy, hydroxy or mono- or di-(Cl.

3 alkyl)amino, or Z is C.

6 alkyl branched or unbranched, Cl_,alkoxy or nitrileC 1

-

4 alkyl; 10 R, is: C14 branched or unbranched alkyl optionally partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl 15 optionally partially or fully halogenated and optionally substituted with one to three C1.3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH; 20 0C.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C.3 branched or unbranched alkyl; cyclopentenyl and cyclohexenyl optionally substituted with one to three C1.3 alkyl groups; 25

R

2 is: a C1.6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile; 30 R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove 35 described in this paragraph, C16 branched or unbranched alkyl which is optionally partially or fully halogenated, phenyl Cl. alkyl, halogen, hydroxy, oxo, nitrile, C1.3 alkoxy optionally partially or fully halogenated, Cl_ 3 thioalkyl, C_ 3 thioalkylC1.-alkyl, amino, mono- or di-(C1 3 )alkylamino, NH 2 C(O) or a mono- or di-(C, 1

.

3 )alkyl aminocarbonyl, WO 03/084503 PCT/EPO3/03434 55

C,.

6 alkoxycarbonylC_alkyl; or R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C 1 , alkyl groups 5 or R 1 and R 2 taken together optionally form a fused phenyl or pyridinyl ring. In another embodiment the invention relates to the use of p38 kinase inhibitors for 10 the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Y is -CH 2 -, -O-(CH 2

)

0 3 -, -CH 2

CH

2 -, -CH 2 NH-, -CH 2

CH

2 -NH-, NH-CH 2

CH

2 -,

-CH

2

-NH-CH

2 -, -NH-, -NH-C(O)-, -C(O)-, -CH(OH)-, -CH 2

(CH

2

CH

3 )- or a bond; 15 X is: cyclohexenyl optionally substituted with an oxo group or one to three C14 alkyl,

C

14 alkoxy or C 14 alkylamino chains each being branched or unbranched; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally 20 independently substituted with one to three C 1 -2alkyl, C1- 2 alkoxy, hydroxy or halogen; Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle 25 selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three 30 halogen, C-e alkyl, C-6 alkoxy, C,3 alkoxy-Cl.3 alkyl, C 1

.

6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C, 3 acyl, oxo, hydroxy, pyridinyl-C 1

-

3 alkyl, imidazolyl-C.

3 alkyl, tetrahydrofuranyl-C, 3 alkyl, nitrile-C_ 3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, Cz. alkoxy, hydroxy or mono- or di-(Cl,.

3 alkyl)amino, amino-S(O)m, 35 C 1

-

6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C-6 alkoxy, hydroxy, halogen or mono- or di-(C 1

-

3 alkyl)amino; or Z is optionally substituted With one to three amino or aminocarbonyl wherein the N atom is optionally independently mono- or di-substituted by aminoC 1

.

6 alkyl, WO 03/084503 PCT/EPO3/03434 56

C,

1

.

3 alkyl, arylCo,-alkyl, C.l alkoxyC.

3 alkyl, C,_5 alkoxy, aroyl, C1-3acyl, C 1

.

3 alkyl S(O)m- or arylC 0 o- 3 alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C-.6 alkyl or C- alkoxy; 5 or Z is hydroxy, hydroxyC,_ 3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C 1

.

3 alkyl, pyridinylC 1

.-

2 alkyl, tetrahydrafuranylCo.

2 alkyl, C.

3 alkoxyC.

3 alkyl, C.3acyl, nitrileC, 4 alkyl, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C 1

.

6 alkoxy, hydroxy or mono- or di-(C1.

3 alkyl)amino, 10 or Z is C, 6 alkyl branched or unbranched, C 1 .alkoxy or nitrileC 14 alkyl; R, is: C,4 branched or unbranched alkyl optionally partially or fully halogenated; 15 R 2 is: a C,.3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;

R

3 is: 20 phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of C1- branched or unbranched alkyl which is optionally partially or fully halogenated, C,.3 alkoxy which optionally partially or fully halogenated, C,. 25 3 thioalkyl, C 1 .thioalkylC 1 .alkyl, amino or NH 2 C(O); C_3alkoxycarbonyl; or R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated 30 and optionally substituted with one to three C1_3 alkyl groups. In a further embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of 35 mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Ar is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring is substituted independently by one to two R 2 or R 3 ; X is: WO 03/084503 PCT/EPO3/03434 57 cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with C 1

_

2 alkoxy or hydroxy; 5 Z is: phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, morpholino, thiomorpholino and piperidinyl, 10 each of the aforementioned Z are optionally substituted with one to three C 1 , alkyl, Cj_3 alkoxy, oxo, hydroxy or NH 2 C(O)-; or Z is hydroxyC 1

.

3 alkyl, amino wherein the N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl,

C

1 3 alkoxyC 1

-

3 alkyl, C.,acyl or nitrileC, 4 alkyl, 15 or Z is nitrileC 14 alkyl;

R

3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is 20 optionally substituted with one to two groups selected from the group consisting of C1-2 alkyl which is optionally partially or fully halogenated, C1-2 alkoxy which optionally partially or fully halogenated, C 1

-

2 thioalkyl, C_ 2 thioalkylC 1

-

3 alkyl, amino or NH 2 C(O); 25 C 1 -3alkoxycarbonyl; or R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three Cj.

3 alkyl groups. 30 In a still further embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein X is pyridinyl. 35 In a yet still further embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is WO 03/084503 PCT/EPO3/03434 58 selected from the compounds of formula 5a wherein the pyridinyl is attached to Ar 1 via the 3-pyridinyl position. Preferably the invention relates to the use of p38 kinase inhibitors for the preparation 5 of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a: 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methylphenyl) O10 naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylphenyl) naphthalen-l1-yl]-urea; 15 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylfuran-2-yl) naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl) naphthalen-I -yl]-urea; 20 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yi]-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) 25 naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl

)

naphthalen-1 -yl]-urea; 30 1-[5-tert-butyl-2-p-tolyl-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-(6-(morpholin-4-yl methyl)pyridin-3-yl)-naphthalen-I -yl]-urea; 35 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yi]-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-yi]-3-[4-(3-(2-(morphol in-4- WO 03/084503 PCT/EP03/03434 59 yI)ethylamino)cyclohexeflyl)-flaPhthalefl-l -yi]-urea; I -[5-tert-butyl-2-p-tolyl-2 H-pyrazo-3-yI]-3-II4-(3 ,4-(morpholin-4-yI-methyl)pheflyl) naphthalen-1 -yIl-urea; 5 I -[5-tert-butyI-2-p-tolyi-2H-pyrazoi-3-yi]-3-[4-(4-methyI piperzin-1 -yI-methyl )phenyl) naphthalen-I -yi]-urea; I -[5-tert-butyI-2-p-toly-2H-pyrazo-3-yI1-3-[4-(pi perd in-I -yi-methyI)phenyl) 10 naphthalen-I -yfl-urea; I -[5-tert-butyl-2-(6-methyf -pyridin3y 2-yao--ll3[-3(-prdn2 yI)ethylamino)cyclohexenyl)-naphthalefl-I -yI]-u rea; 15 1 -[5-tert-butyI-2-p-toi-2H-pyrazoI-3-yI1-3-[4-(4-(2-(pyrid in-4 yI)ethylaminomethyl)phenyl)naphthalel-I -yl]-urea; I 5tr-utl2ptly-Hprzo--i--[-4(yiin-3-yI methylaminomethyl)phenyl)naphthalefl-I -yI]-urea; 20 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi)-2H-pyrazol-3-yII-3-14-(4-(3, 4 d imethoxyphenyl methyl)-3-hyd roxyphenyl)naphthalen- I -yi]-u rea; I -[5-tert-butyl-2-p-tolyI-2H-pyrazo-3-yi]-3-4-( 6 -oxo-I ,6-dihyd ro-pyridin-3 25 yI)naphthalen-I -y[]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi)-2 H-pyrazol-3-yI]-3-[4-(4-(morpholi n-4-yl methyl)phenyl)naphthalen-1 -yI]-urea; 30 1 -[5-tert-butyl-2-(6-mlethyl-pyrid in-3-yl)-2H-pyrazol-3-yi]-3-4-(4-(morphoil-4-yl methyl)imidazol-l -yI)naphthalen- I -yi]-urea; I -[5-tert-butyl-2-p-tolyI- 2 H-pyrazoI-3-yi]-3-[4-(4-(morphoil-4-yI-methy)imidazok1I yI)naphthalefl-I -yI]-urea; 35 I -[5-tert-butyI-2-(6-methyl-pyridi n-3-yI)-2 H-pyrazo-'3-yIj-3-[4-(4-(fu ran-3-yi-methyl)-3 hydroxyphenYl)flaphthalefl-l -yi]-urea; I -[5-tert-buty-2-(6-methyI-pyridifl-3-yI)-2H-pyrazoI-3-yi]-3- 4

(

6

-(

4 WO 03/084503 PCT/EP03/03434 60 hyd roxybutylamino)pyrid in-3-y!)-naphthaien-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yII-3-[4-(4-(pyrid in-3-yI-methyl ) 3-hydroxyphenyl)naphthalen-1 -yl]-u rea; 5 1 -[5-tert-butyl-2-(4-methyl-3-carbamylphenyl )-2 H-pyrazo!-3-yi]-3-[4-(6-(morpholin-4 yi-methyl)pyridin-3-yI)naphthalen-I -yI]-urea; I -[5-tert-butyi-2-(6-methyl-pyrid in-3-yI )-2 H-pyrazol-3-yI]-3-[4-(4-(imidazol-2-yI-methyl) 10 3-hydroxyphenyl)naphthalen-1 -yi]-urea; 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazoi-3-yI]-3-[4-(4-(3-hyd roxymorphol in 4-yi-methyl)phenyl)naphthalen-1 -yI]-u rea; 15 1 -[5..tert-butyl-2-(6-m ethyl -pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(4-(N-2- methoxyethy-N methyla minomethyl)phenyl)naphthalen-1 -yl]-u rea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yl)-2 H-pyrazol-3-yi]-3-[4-(4-(4-hydroxymorp hol in 4-yi-methyl)phenyl)naphthalen-1 -yI]-urea; 20 I -[5-tert-butyl-2-(6-methyl-pyridin-3-y)-2 H-pyrazof -3-yl]-3-[4-(3-(morphol in-4-yI methyl)cyclohexenyl)-naphthaien-I -yI]-urea; 1 -[5-tert-butyl-2-(6-methyl-pyrid i n-3-yI)-2 H-pyrazol-3-yI] -3-[4-(4-(tetra hydrofu ran -3-y 25 methyl)-3-hydroxyphenyl)naphthalen-1 -yl]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi)-2 H-pyrazol-3-yIJ-3-[4-(4-(NN-d i-(2 methoxyethyl)aminomethyl)phenyl)naphthalen-I -yI]-urea; 30 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(6-(3 cyanopropoxy)pyridin-3-yI)naphthalen- 1 -yi]-u rea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yll-3-[4-(4-morpholin-4-yI methyl-piperdinyl)naphthalen-1 -yIJ-u rea; 35 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yJ]-3-[4-(4-(N ,N-d i-(2 cyanoethyl)aminomethyl)phenyl)naphthalen-1 -yI]-urea; I -[5-tert-buty[-2-p-tolyl-2H-pyrazol-3-y]-3-[4-( 1 -morphol in-4-yI-inda n-5-yi )- WO 03/084503 PCT/EP03/03434 61 naphthalen-1 -yi]-urea; 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2 H-pyrazol-3-yII-3-[4-(4-(fu ran-2-yi-methyl )-3 hydroxyphenyl)naphthalen-1 -yI]-urea; 5 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yI]-3-[4-(4-(th lomorphol in-4-yI methyl)phenyl)naphthalen-I -yi]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yt]-3-[4-(4-(3 10 carboxamidomorpholin-4-yl-methyl)phenyl)naphthalen-1 -yI]-u rea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yI]-3-[4-(4-(2-methyl-3-oxo piperzin-1 -yi-methyl)phenyl)naphthalen-1 -yII-urea; 15 1 -[5-tert-butyl-2-(2-methylpyrim id in-5-yI )-2 H-pyrazol-3-yI]-3-[4-(6-(morpholi n-4-yI methyl)pyridin-3-yI)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(6-methy-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(6-(4 hyd roxybutyloxy)pyrid in-3-yi)-n aphth ale n- 1 -yl]-urea; 20 I -[3-tert-butyl- I'H-[1 ,4']bipyrazol-5-yI]-3-[4-(6-(morpho in-4-yI-methyl )pyrid in-3 yI)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-y]-3-[4-(4-(fu ran-2-yI-methyl)-3 25 methoxyphenyl)naphthalen-1 -yII-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yJ)-2H-pyrazol-3-yi]-3-[4-(5-(morpholin 4carbonyl)pyrazin-2-yl)-naphthalen-1 -yf]-urea; 30 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yi]-3-[4-(6-(tetrahyd roth lopyra n 4-yI-amino)pyridin-3-yI)-naphthalen-1 -yl]-urea; I -[5-tert-butyl-2-(2-cyanoethyl )-2H-pyrazol-3-yi]-3-[4-(6-(morphol in-4-yI methyl)pyridin-3-yI)-naphthalen-1 -yI]-urea; 35 I -[5-tert-butyl-2-(6-methyl-pyridi n-3-yI )-2H-pyrazol-3-yi]-3-[4-(6-(2 ,6 dimethylmorpholin-4-yl-methyl)pyridin-3-yI)-naphthalen-1 -yI]-urea; I -[5-tert-butyt-2-(2-methoxypyrid in-5-yI )-2 H-pyrazol-3-yI]-3-[4-(6-(morpholin-4-yi- WO 03/084503 PCT/EP03/03434 62 methyl)pyridin-3-yI)-naphthalen-1 -yiI-urea; 1 45-tert-butyl-2-(2-aminoypyrid in-5-yI)-2H-pyrazol-3-yI]-3-[4-(6-(morphol in-4-yI methyl)pyridin-3-yi)-naphthalen-I -yfl-u rea; 5 1 -[5-tert-butyl-2.-(6-oxo-1I,6-dihyd ropyrid in-3-yI )-2H-pyrazol-3-yi]-3-[4-(6-(morphol in-4 yI-methyl)pyrid in-3-yl)-naphthaien-I -yi]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yI]-3-[4-(6-(morphol in-4-yI-4 10 carbonyl)pyridin-3-yI)-naphthalen-I -yJ]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yi]-3-[4-(6-(2-oxa-5-aza bicyclo[2.2. 1 ]hept-5-yI-methyl)pyridin-3-yi)-naphthalen-1 -yl]-u rea; 15 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yI-3-[4-(4-(3-carbamylphenyl)naphthalen-I -yI] urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(4-(N-(2-cya noethyl)-N (pyrid in-3-yI-methyl)aminomethyi)phenyl)-naphthalen-I -yi]-urea; 20 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(4-(N-(2-cya noethyl)-N (pyridin-2-y-methyl)aminomethyl)phenyl)-naphthalen-1 -yi]-urea; I -[5-tert-butyl-2-(6-methy-pyridin-3-yl)-2H-pyrazol-3-yi]-3-[4-(4-(N-(2-cyanoethyl )-N 25 (tetra hyd rofu ra n-2-yI-methyi)a mino methyl)p he nyl)-na phth al en- 1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yl)-2 H-pyrazol-3-yl]-3-[4-(6-(morphol in-4-yI methyl)-4-methoxypyridin-3-yI)-naphthalen-1 -yi]-urea; 30 1 -[5-tert-butyl-2-(6-methyl-pyridin-3-yI)-2 H-pyrazol-3-yi]-3-[4-(6-( I -morpholin-4-yI propyl)pyridin-3-yI)-naphthalen-I -yl]-urea; I -[5-tert-butyI-2-(6-methy-pyridin-3-yI)-2 H-pyrazol-3-yi]-3-[4-(6-(N-(3 methoxypropyl)amino)pyridin-3-yI)-naphthalen-1 -yl]-u rea; 35 I -[5-tert-butyl-2-(6-methyl-pyridin-3-y)-2 H-pyrazo-3-yI]-3-II4-(6-(N-(3-methoxyp ropyl ) N-methylamino)pyridin-3-yI)-naphthalen-1 -yi]-u rea; I -[3-tert-butyl-1 '-methyl-I 'H-[I ,4'Ilbipyrazol-5-yq]-3-[4-(6-(morpholin-4-yl- WO 03/084503 PCT/EP03/03434 63 methyl)pyridin-3-yI)naphthalen-1 -yI]-u rea; I -[5-tert-butyl-2-benzyl-2H-pyrazol-3-yI]-3-[4-(6-(morpholin-4-y-methyl )pyridi n-3-yI) naphthalen-I -yI]-urea; I1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2 H-pyrazol-3-yI]-3-[4-(4-(N-N-di-(2 cyanoethyl)aminomethyl)phenyl)-naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yi]-3-[4-(4-(4-carbamylphenyI)naphthalen-1 -yI] 10 urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-y )-2H-pyrazol-3-yfl-3-[4-(6-( I -oxo tetra hyd roth iopyra n-4y1-a mi no)pyrid in -3-yi)- nap hth alen-I1 -yi]-urea; 15 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2H-pyrazoi-3-yI]-3-[4-(6-(tetrahyd ropyran-4yl amino)pyridin-3-yI)-naphthalen-l -yl]-urea; I -[3-tert-butyl-I '-(3-cyanopropyl)-I 'H-[I ,4']bipyrazol-5-yI]-3-r4-(6-(morphoin-4-y methyl)pyridin-3-yI)naphthalen-I -yi]-urea; 20 1 -[5-te rt-b utyl-2-p-toiyl-2 H-pyrazol-3-y]-3-[4-(3-m eth an esu Ifi nyl phe nyl)na phth ale n- yI]-u rea; I -[5-tert-butyi-2-p-tolyl-2H-pyrazol-3-yI]-3-[4-(3-metha nesu Ifonyl phenyl)na phthalen-I 25 yI]-urea; I -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yI-3-[4-(3-sulfonamidophenyl)naphthalen-I -yi] urea; 30 1 -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yi]-3-[4-(3-(morphol in-4 yl)carbonylphenyl)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2 H-pyrazol-3-yI]-3-[4-(5-(tetrahyd roth jopyran 4yl-amino)pyrazin-2-yI)-naphthalen-I -yI]-urea; 35 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yi]-3-[4-(6 (rnethylcarbonylamino)pyridin-3-yl)-naphthalen-I -yI]-urea; I -[5-tert-butyl-2-p-toiyl-2H-pyrazol-3-yI]-3-[4-(6-(morpholin-4-yl-4-carbonyl )phenyl )- WO 03/084503 PCT/EP03/03434 64 naphthalen-1 -yI]-urea; I -[3-tert-butyl-1 '-(3-methylsulfanylpropyl)-I 'H-[1 ,4']bipyrazol-5-yi]-3-[4-(6-(morpholin 4-yI-methyl)pyridin-3-yI)naphthalen-I -yI]-u rea; 5 I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(5-(morpholin-4-yI-carbonyl )pyrid in-3-yI) naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyridin-3-y)-2H-pyrazol-3-y]-3-[4(5(morpholin-4yl 10 methyl)pyrazin-2-yI)-naphthalen-I -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yI j-3-[4-(6-a minopyrid in-3 yI)naphthalen-1 -yi]-urea; 15 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2H-pyrazol-3-yi]-3-[4-(6-( I -methylpiperd in-4 yI-amino)pyrid in-3-yl)naphthalen- I -yI]-u rea; I -[5-te rt-butyl-2-(2-methyl pyri mid in-5-yi)-2 H-pyrazol-3-yJ]-3-[4-(6-(2-methyl-3-oxo piperzin- I -yI-methyl)pyridin-3-yI)naphthalen-1 -yI]-urea; 20 I -[5-tert-butyl-2-(2-methyl pyrimidin-5-yI)-2 H-pyrazol-3-yi]-3-[4-(6-(morphol in-4-yI carbonyl)pyridin-3-yI)naphthalen-I -yI]-urea; I -[5-tert-butyl-2-(2-methylpyrimidin-5-yI)-2 H-pyrazol-3-yI]-3-[4-(6-(N ,N-d i-(2 25 methoxyethyl)aminomethyl)pyridin-3-y)naphthalen-1 -yI]-u rea; I -[5-tert-butyl-2-(2-methylpyrimid in-5-yI)-2H-pyrazol-3-yl]-3-[4-(6-( 1 -oxo th iomo rphoin-4-yI-methyl)pyrid in-3-yI)na phth ale n- 1 -yl]-u rea; 30 I -[5-tert-butyl-2-(2-methylpyrimid in-5-yI)-2 H-pyrazol-3-yI]-3-[4-(6-(tetrahydropyran-4 yl-amino)pyridin-3-yI)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(2-methylpyrimid in-5-yI )-2H-pyrazol-3-yI]-3-[4-(5-(morpho i n-4-yl methyl)pyrazin-2-yI)naphthalen-1 -ylj-urea; 35 1 -[5-te rt-b utyl-2- (2-methylth io pyri mid!in-5-yi)-2 H-pyrazol-3-yI]-3-[4- (6-(mo rp hol in-4-yl methyl)pyrid in-3-yl)naphthalen-1 -yI]-urea; 1 -[5-tert-butYi- 2 -p-toyf-2H-pyrazo-3-yI-3-4(6(2methy3oxo-piperzin-1 -yI- WO 03/084503 PCT/EPO3/03434 65 methyl)pyridin-3-y!)naphthalen-l -yIJ-urea; I -[5-tert-butyl-2-p-tolyi-2H-pyrazol-3-yi]-3-[4-(6-(pyrid in-3-yI-oxy)pyrid in-3 yI)naphthalen-l -yI]-urea 5 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-y]-3-[4-(6(pyridin3yl-amino)pyrid in-3 yI)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(2-methoxypyrimid in-5-yi)-2H-pyrazol-3-yI]-3-[4-(6-(morpho in-4-yI 10 methyl)pyridin-3-yl)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(5-carbamyl pyrid in-3-y)naphthalen- I -yI] urea; 15 1 -[5-tert-butyl-2-(2-a minopyrimid in-5-yI)-2 H-pyrazol-3-yl]-3-[4-(6-(morphoi in-4-yI methyl)pyridin-3-yI)naphthalen-I -yI]-u rea; I -[5-tert-butyl-2-(2-methyi pyrimid in-5-yI )-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yi methyl)phenyl)naphthalen-1 -yI]-urea; 20 I -[3-tert-butyl-1 '-methyl-I 'H-fl ,4']bipyrazol-5-yiI-3-[4-(6-(morpholin-4-yI methyl)phenyl)naphthalen-1 -yI]-urea; I -15-tert-butyl-2-(2-oyclopropylpyrimid in-5-yI)-2H-pyrazol-3-yI]-3-[4-(6-(morphol in-4-yI 25 methyl)pyridin-3-yI)naphthalen-1 -yI]-urea; 1 -[5-tert-butyl-2-p-tolyi-2H-pyrazol-3-yI]-3-[4-(2-(pyridi n-3-yl-amino)pyrimid ir-5 yI)naphthalen-1 -yl]-urea; 30 1 -[5-tert-butyl-2-p-toiyl-2 H-pyrazol-3-yq]-3-[4-(6-( 1 -oxo-tetrahyd rothiopyra n-4-yi amino)pyrid in-3-yI)naphthalen-1 -yl]-urea; I -f5-te rt-butyf-2-p-to lyi-2 H -pyrazol-3-yI]-3- [4-(6-(th iomorph ol in-4-yI-m ethyl) )pyrid i n-3 y!)naphthalen-1 -yI]-urea; 35 I -[5-tert-butyl-2-p-tolyl-2 H-pyrazol-3-yI]-3-[4-(3-benzyl-3H-imidazo[4 ,5-b]pyrid in-6 yI)naphthalen-1 -yi]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-y].3-[4-(6-(pyrid in-3-yI- WO 03/084503 PCT/EPO3/03434 66 methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5 yl)naphthalen-1 -yl]-urea; 5 1-[ 5 -tert-butyl-2-p-tolyl-2H-pyrazol3yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5 yl)naphthalen-1 -yl]-urea; 1-[ 5 -tert-butyl- 2 -p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl)naphthalen o10 1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo-thiomorpholin-4-yl methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 15 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3 yl)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl-methyl)pyridin-3 yl)naphthalen-1 -yl]-urea; 20 1 -[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morphoiin-4-yl methyl)pyrimidin-5-yl)naphthalen-1l-yl]-urea; and the pharmaceutically acceptable derivatives thereof. 25 In another embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 5a: 30 1-[ 5 -tert-butyl-2-p-tolyl-2H-pyrazol-3-ylp]-3-[4-(5-(morphlin-4-yl-methyl)pyridin-2-yl

)

naphthalen-1 -yl]-urea; 1-[ 5 -tert-butyl- 2 -p-tolyl- 2 H-pyrazol3-ylj-3-[4-(6-(morpholin-4-y-methyl)pyridin-3-yl) naphthalen-1 -yl]-urea; 35 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yi)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2 yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl- WO 03/084503 PCT/EP03/03434 67 methylaminomethyl)phenyl)naphthalel-1 -yi]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazoI-3-yII-3-[4-(4-(morpho in-4-yI methyl)phenyl)naphthalen-1 -yi]-u rea; 5 4 -[5-ter-butyl-2-(6-methyl-pyridil-3-yi)-2H-pyrazoI-3-yi]-3-[ 4

-(

6

-(

4 hydroxybutylamino)pyrid in-3-yI)-naphthalen-1 -yi]-u rea; I -[5-tert-butyl-2-(4-methyl-3-carbamyl phenyl )-2H-pyrazol-3-yI]-3-14-(6-(morphoI in-4 10 yI-methyi)pyridin-3-yI)naphthalefl-1 -yI]-u rea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2 H-pyrazol-3-y]-3-114-(4-(3-hyd roxypiperidi n-I yI-methyl)phenyl)naphthalen-1 -yI]-urea; 15 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yll-3-[4-(4-(4-hyd roxymorpholin 4-yl-methyl)phenyl)naphthalel- I -yII-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2 H-pyrazol-3-yl-3-[4-(3-(morpholifl-4-y methyl)cyciohexenyl)-naphthalefl-I -yI]-urea; 20 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2 H-pyrazol-3-y]-3-114-(4-(tetrahydrofural-3-yi methyl)-3-hydroxyphenyl)flaphthalefl-I -yi]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2H-pyrazol-3-yI]-3-[4-(4-(NN-d i-(2 25 methoxyethyl)aminomethyl)phenyI)naphthalefl-I -yI]-u rea; I -[5-tert-butyi-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yl]-3-[4-(6-(3 cyanopropoxy)pyrid in-3-y)naphthalen-l -yI]-urea; 30 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi )-2 H-pyrazol-3-yII-3-[4-(4-morpholin-4-y methyl-piperdinyl)naphthalefl-1 -yI]-urea; 1 -[5-tert-butyl-2-(6-methyl-pyrid in-3-yi)-2 H-pyrazol-3-yi]-3-[4-(4-(N ,N-d i-(2 cyanoethyl)aminomethyl)Phel)flaphthalefl-l -yI]-urea; 35 I .{5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(4-(furan-2-yi-methyl)-3 hydroxyphenyl)naphthalefl-1 -yI]-urea; I -[5-tert-butyl-2-(6-mlethyl-pyrid in-3-yI)-2 H-pyrazol-3-yII-3-[4-(4-(thiomorpholin-4-yI- WO 03/084503 PCT/EP03/03434 68 methyl)phenyl)naphthalen-1 -yl]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yl]-3-[4-(4-(3 carboxamidopiperidin-l -yi-methyl)phenyl)naphthalen-I -ylI-u rea; 5 I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-y]-3-[4-(4-(2-methyl-3-oxo piperzin-1 -yi-methyl)phenyl)naphthalefl-I -yI]-urea; I -[5-tert-buty-2-(2-methyl pyri mid in-5-yI)-2H-pyrazol-3-yI]-3-[4-(6-(molrphoI in-4-yI 10 methyl)pyridin-3-yI)naphthalefl-I -yI]-urea; I 5tr-btl2(-mty-yrdn3y)-2H-pyrazol-3-yl]-3-[4-(6-(4 hydroxybutyloxy)pyridin-3-yI)-flaphthalefl-I -yll-urea; 15 I -[3-tert-butyl-I 'H-[I ,4'] bipyrazol-5-yI]-3-[4-(6-(morpholin-4-y-methyl )pyrid in-3 yI)naphthalen-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI)-2H-pyrazol-3-yI]-3-[4-(6-(tetrahyd rothiopyran 4-yI-amino)pyrid in-3-y)-naphthalen-I -yi]-u rea; 20 I -[5-tert-butyl-2-(2-cyanoethyl )-2H-pyrazol-3-yIl-3-[4-(6-(morphoI in-4-yI methyipyridin-3-yI)-naphthalefl-1 -yI]-urea; I -[5-tert-butyl-2-(6-methyl-pyrid in-3-yI )-2 H-pyrazol-3-y]-3-14-(6-( 2 ,6 25 dimethylmorpholin-4-yi-methyl)pyrid in-3-yl)-naphthalen-1 -yI]-urea; I -[5-tert-buty-2-(2-methoxypyridil-5-yI )-2 H-pyrazol-3-yI]-3-[4-(6-(morphol in-4-yI methyl)pyridin-3-yl)-naphthalefl-I -yIl-urea; 30 1 -[5-tert-butyl-2-(2-am inoypyrid in-5-yI )-2H-pyrazol-3-yI]-3-[4-(6-(mO rphol in-4-yI methyl)pyridin-3-yI)-naphthalel-1 -yl]-urea; I -[5-tert-butyl-2-(6-methyi-pyrid in-3-yI)-2H-pyrazol-3-y]-3-[4-(6-(morpholifl-4-yI-4 carbonyl)pyridin-3-y)-naphthalefll -yI]-urea; 35 I -[5-tert-butyI-2-(6-methy-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(6-(2-oxa-5-aza bicyclo[2.2. 1 ]hept-5-yi-methyl )pyrid in-3-yi)-naphthalen-I -yI]-u rea; I -[5-tert-butyl-2-(6-methyI-pyrid in-3-yI)-2 H-pyrazol-3-yI]-3-[4-(4-(N-(2-cya noethyl )-N- WO 03/084503 PCT/EPO3/03434 69 (pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-I -yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N (tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1 -yl]-urea; 5 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl methyl)-4-methoxypyridin-3-yl)-naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1 -morpholin-4-yl 10 propyl)pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-[3-tert-butyl-l'-methyl-l'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 15 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl amino)pyridin-3-yl)-naphthalen-1 -yl]-urea; 20 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothlopyran 4yl-amino)pyrazin-2-yl)-naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6 25 (methylcarbonylamino)pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-[3-tert-butyl-1 '-(3-methylsulfanylpropyl)-1 'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin 4-yl-methyl)pyridin-3-yl)naphthalen-I -yl]-urea; 30 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 1 -[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahyd ropyran-4 yl-amino)pyridin-3-yl)naphthalen-1 -yl]-urea; 35 1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-y methyl)pyridin-3-yl)naphthalen-I -yl]-urea; 1-[5-tert-butyl-2-(2-aminopyrimidin-5-yi)-2H-pyrazol-3-yi]-3-[4-(6-(morphoin-4-yl- WO 03/084503 PCT/EPO3/03434 70 methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 1-[3-tert-butyl-l1'-methyl-I1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl methyl)phenyl)naphthalen-1 -yl]-urea; 5 1.-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo-tetrahydrothiopyran-4-yl amino)pyridin-3-yl)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yi]-3-[4-(6-(thiomorpholin-4-y-methyl)pyridin-3 10 yl)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5 yl)naphthalen-1 -yl]-urea; 15 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5 yl)naphthalen-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl methyl)pyridin-3-yl)naphthalen-1 -yl]-urea; 20 1 -[5-tert-butyl-2-(2-methylpyrimid in-5-yl)-2 H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl methyl)pyrimidin-5-yl)naphthalen-1 -yl]-u rea and the pharmaceutically acceptable derivatives thereof. 25 In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 as disclosed in WO 00/55139 30 w G'N ' N -Ar-X-Y-Z I I H H 6 wherein: G is: 35 an aromatic C-10o carbocycle or a nonaromatic C 3

.

10 carbocycle saturated or unsaturated; WO 03/084503 PCT/EPO3/03434 71 a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; 5 or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; wherein G is substituted by one or more R 1 , R 2 or R 3 ; 10 Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R,; 15 X is: a C5.8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C14alkyl, C.4 alkoxy or C,1.

4 alkylamino chains; 20 phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; Y is: 25 a bond or a C-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(0)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C014 alkyl optionally substituted by one or more halogen atoms; 30 Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl each being optionally substituted with one to three halogen, C1_6 alkyl, C16 alkoxy, hydroxy, amino, mono- or di 35 (C.3 alkyl)amino, C, alkyl-S(0)m, CN, CONH 2 , COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, Cj6 alkyl or C-.6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, WO 03/084503 PCT/EPO3/03434 72 thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being 5 optionally substituted with one to three nitrile, C,., alkyl, C 1

.

6 alkoxy, hydroxy, amino, mono- or di-(Cls alkyl)amino-C_ 3 alkyl, CONH 2 , phenylamino-C.

3 alkyl or C 1

.

3 alkoxy-C.

3 alkyl; halogen, C1-4 alkyl, nitrile, amino, hydroxy, C 1 , alkoxy, NH 2 C(O), mono- or di(C, 1

-

3 alkyl) aminocarbonyl, mono- or di(C 1

_

6 alkyl)amino, secondary or tertiary 10 amine wherein the amino nitrogen is covalently bonded to C 3 alkyl or C., alkoxyalkyl, pyridinyl-C, 3 alkyl, imidazolyl-C,- 3 alkyl, tetrahydrofuranyl-C 1 3 alkyl, nitrile-C .,alkyl, carboxamide-C 1 -3alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C 16 alkoxy, hydroxy or mono or di-(C 1 -3 alkyl)amino, C-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl 15 ring is optionally substituted with one to two halogen, C1.6 alkoxy, hydroxy, halogen or mono- or di-(C 1

-

3 alkyl)amino; C,-, alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C.6 alkoxy, hydroxy or mono- or di-(C,_3 alkyl)amino; 20 each R 1 is independently: Cl-,0 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C3-10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, 25 isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1.6, alkyl which is optionally partially or fully halogenated, C3.5 cycloalkanyl, C 5 ., cycloalkenyl, hydroxy, nitrile, C 1

-

3 alkoxy which is optionally partially or fully halogenated or

NH

2 C(0), mono- or di(Cs.

3 alkyl)amino, and mono- or 30 di(Cl_ 3 alkyl)aminocarbonyl; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C13 alkyl groups optionally partially or 35 fully halogenated, CN, hydroxyC 1

-

3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=0, >C=S or NH; WO 03/084503 PCT/EPO3/03434 73 phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C,.3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC,alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently 5 replaced by N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1.3 10 alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1

.

3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=0, >C=S or NH; 15 C,-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three C, branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five 20 halogen, C-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or di(C 1 .,alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being 25 optionally interrupted by one or more heteroatoms chosen from O, N and S(0)m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such 30 cycloalkenyl group is optionally substituted with one to three C1.3 alkyl groups; nitrile, halogen; methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; 35 silyl containing three C1 alkyl groups optionally partially or fully halogenated; C3.6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced WO 03/084503 PCT/EPO3/03434 74 by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrrolidinyl, pyrrolyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or 5 di(C 1 3alkyl)amino optionally substituted by one or more halogen atoms; each R 2 , R 4 , and R 5 is a C-, branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C14 branched or unbranched alkoxy, each being optionally 10 partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C 1

,

3 alkyl S(O)m optionally partially or fully halogenated, or phenylsulfonyl;

C.

6 alkoxy, hydroxy, amino, or mono- or di-(Cl.

4 alkyl)amino, nitrile, halogen; 15 OR 6 ; nitro; or mono- or di-(C,.

4 alkyl)amino-S(O) 2 optionally partially or fully halogenated, or 20 H 2

NSO

2 ; each R 3 is independently: phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, 25 tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, 30 naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, Cl., branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1, alkyl, naphthyl C, 1 _alkyl, halogen, hydroxy, oxo, nitrile, C 1

_

3 alkyloxy optionally 35 partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C_ 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this WO 03/084503 PCT/EP03/03434 75 paragraph, NH 2 C(O), a mono- or di-(Cl.

3 alkyl) aminocarbonyl, C 1

_

5 alkyl-C(O) C1-4 alkyl, amino-C.

5 alkyl, mono- or di-(C 1

.

3 alkyl)amino-Cl, alkyl, amino-S(O) 2 , di-(C,-4alkyl)amino-S(O) 2 , R 7 -C1- 5 alkyl, R.-C 15 -salkoxy, R 9 -C(O)-Cl, alkyl, R 10

-C

1 . alkyl(Rjj)N, carboxy-mono- or di-(Cl.,alkyl)-amino; 5 a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, 10 cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, 15 cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C,, alkyl which is optionally 20 partially or fully halogenated, halogen, nitrile, C,- 3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C. 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino 25 wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(0), mono- or di-(C 1

-.

3 alkyl)aminocarbonyl, C,4 alkyl OC(0), Cr alkyl-C(0)-C 1 4 alkyl, amino-C_ 5 alkyl, mono- or di-(C 1

.

3 )alkylamino Cl. alkyl, R 1 2

-C

1 -5 alkyl, R 13

-C

1 - alkoxy, R 1 4 -C(0)-C 1

-

5 alkyl or R 15

-C

1

-

5 alkyl(R 6 )N; 30 cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three Cl,. alkyl groups, or an analog of such cycloalkyl group wherein one to three ring 35 methylene groups are independently replaced by O, S, CHOH, >C=0, >C=S or NH; WO 03/084503 PCT/EPO3/03434 76 cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1 3 , alkyl groups; 5 C14 alkyl-phenyl-C(O)-C,.4 alkyl-, C.4 alkyl-C(O)-Cl 4 alkyl- or C1-4 alkyl-phenyl S(O)m-CI 4 alkyl-; C-.6 alkyl or C1.6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R, 7 ; 10

OR

18 or C1-6 alkyl optionally substituted with OR 8 ,,; amino or mono- or di-(Cl.,alkyl)amino optionally substituted with R 19 ; 15 R 20

C(O)N(R

2 1 )-, R 22 0- or R 23

R

2 4 NC(O)-; R 2 e(CH 2 )mC(O)N(R 2 1)- or

R

26

C(O)(CH

2 )mN(R 2 1)-;

C

2 -Balkenyl substituted by R 23

R

2 4 NC(O)-; 20 C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C1-4 25 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C 14 alkyl)amino optionally substituted by one or more halogen atoms; or aroyl; 30

R

6 is a:

C,

4 alkyl optionally partially or fully halogenated and optionally substituted with R26; 35 each R 7 , R e , R 9 , R 1 o, R 12 , R 1 3, R 14 , R 15 , R 17 , R 19 , R 2 , and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C 1

-

4 alkyl)amino optionally partially or fully halogenated; WO 03/084503 PCT/EPO3/03434 77 each R, 11 and R 1 6 is independently: hydrogen or C 1 -4 alkyl optionally partially or fully halogenated;

R

1 , is independently: 5 hydrogen or a C14 alkyl optionally independently substituted with oxo or R 25 ;

R

20 is independently: C01I.-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; 10 R 21 is independently: hydrogen or C-3 alkyl optionally partially or fully halogenated; each R22, R 23 and R 24 is independently: hydrogen, C,.s alkyl optionally partially or fully halogenated, said C16 alkyl is 15 optionally interrupted by one or more O, N or S, said C.

6 alkyl also being independently optionally substituted by mono- or di-(C 1 ~

-

3 alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(Cl4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono or di-(Cl_ 3 alkyl)amino; 20 or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 or2; WisOorS and pharmaceutically acceptable derivatives thereof. 25 In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein 30 G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl; 35 pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydroberizofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2- WO 03/084503 PCT/EPO3/03434 78 onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, 5 tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R 1 , R 2 or R 3 ; 10 In a further preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein 15 G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R, 20 R 2 or R 3 ; Ar is: naphthyl,,quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally 25 substituted by one or more R 4 or R 5 groups; X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, 30 piperazinyl, pyridazinyl or pyrazinyl Y is: a bond or a C_4 saturated or unsaturated carbon chain wherein one of the carbon atoms 35 is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C,4 alkyl optionally substituted by one or more halogen atoms; Z is: WO 03/084503 PCT/EPO3/03434 79 phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C,., alkyl, C.3 alkoxy, amino, mono- or di-(C, 1

-

3 alkyl)amino, CONH 2 or OH; 5 tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, 10 tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C1.3 alkyl, C1.3 alkoxy, amino, mono- or di

(C_

3 alkyl)amino, CONH 2 , or OH; nitrile, C 1

.

6 alkyl-S(O), halogen, hydroxy, C1-4 alkoxy, amino, mono- or di-(C 16 alkyl)amino, mono- or di-(C, 1

-

3 alkyl)aminocarbonyl or NH 2 C(O); 15 each R, is independently: C3- alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3

-

6 cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three 20 groups selected from halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C 1

-

3 alkoxy which is optionally partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or 25 bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1.3alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1 -3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH; or 30 silyl containing three C 1-4 alkyl groups optionally partially or fully halogenated;

R

2 is independently: halogen, C,_ alkoxy, C1.3 alkyl-S(O)m optionally partially or fully halogenated, 35 phenylsulfonyl or nitrile;

R

3 is independently: phenyl, morpholino, pyridirlyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substituted with one to three WO 03/084503 PCT/EPO3/03434 80 phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C 1

.

6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,~ alkyl, naphthyl C 1 , 5 alkyl, halogen, oxo, hydroxy, nitrile, C,-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(Cl.

3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or 10 heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(Cl.

3 alkyl)aminocarbonyl, C,1., alkyl-C(O)-C 1

-

4 alkyl, mono- or di-(Cl 3 alkyl)amino, mono- or di-(C,.)alkylamino-C 1 ., alkyl, mono- or di-(C, 3 alkyl)amino-S(O) 2 , R-C.- alkyl, R 8 -C alkoxy, R,-C(O)-C.

5 alkyl, RI 0 -Cl-.

5 alkyl(R 1 )N, carboxy-mono- or di-(C 1

-

5 )-alkyl-amino; 15 C 1-3 alkyl or C,4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R, 7 ;

OR

18 or C1.6 alkyl optionally substituted with OR,, 8 ; 20 amino or mono- or di- (C1-5 alkyl)amino optionally substituted with R 1 ,;

R

20

C(O)N(R

21 )-, R 22 0-; R 23

R

2 4 NC(O)-; R 26

CH

2

C(O)N(R

21 )- or

R

26

C(O)CH

2

N(R

2 1 )-; 25 C 2 -4alkenyl substituted by R 2 3

R

24 NC(O)-; or C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, 30 phenyl, pyridinyl, tetrazolyl or one or more C,_4alkyl optionally substituted by one or more halogen atoms; and

R

2 3 and R 24 taken together optionally form imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl ring. 35 In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the WO 03/084503 PCT/EPO3/03434 81 treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein: G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 5 benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ; Ar is naphthyl; 10 Xis phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C,. 4 alkyl, C 1

-

4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C, 1 3 alkyl)amino, mono or di-(C 1 , alkylamino)carbonyl, NH 2 C(O), C6, alkyl-S(O)m or halogen; 15 Y is: a bond or a C14 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted 20 with an oxo group; Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl which are 25 optionally substituted with one to two C_ 2 alkyl or C 1

-

2 alkoxy; tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl which are optionally substituted with one to two C1-2 alkyl or C12 alkoxy; or 30 Cl., alkoxy; each R, is independently: C3.5 alkyl optionally partially or fully halogenated, and optionally substituted 35 with phenyl substituted with zero to three halogen, Cj3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C_ 3 alkoxy which is optionally partially or fully halogenated; WO 03/084503 PCT/EPO3/03434 82 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1.3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC.

3 alkyl or phenyl; and an analog of 5 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and silyl containing three C 1

.

2 independently alkyl groups optionally partially or fully halogenated; 10 each R 2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile; each R 3 is independently: 15 phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to three Cj_ 3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C-.3 alkyloxy optionally partially or fully halogenated; 20 C1.3 alkyl or C, alkoxy each being optionally partially or fully halogenated or optionally substituted with R 17 ;

OR

18 or C,.3 alkyl optionally substituted with OR,, 8 ; 25 amino or mono- or di-(C 1

-

3 alkyl)amino optionally substituted with R 19 ;

R

20

C(O)N(R

21 )-, R 22 0-; R 23

R

24 NC(O)-; R 26

CH

2

C(O)N(R

2 1 )- or

R

26

C(O)CH

2

N(R

21 )-; 30 C 2

.

4 alkenyl substituted by R 23

R

24 NC(O)-; or C2.4 alkynyl substituted with pyrroldinyl or pyrrolyl; and

R

23 and R 2 4 taken together optionally form morpholino. 35 In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the WO 03/084503 PCT/EPO3/03434 83 treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, 5 dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ; Ar is 1-naphthyl; 10 X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; Y is: 15 a bond or

-CH

2 -, -CH 2

CH

2 -, -C(0)-, -0-, -S-, -NH-CH 2

CH

2

CH

2 -, -N(CH,)-, or -NH-; each R 1 is independently: C3.-, alkyl optionally partially or fully halogenated, and optionally substituted 20 with phenyl; cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, CN, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted 25 by methyl; or trimethyl silyl; each R 3 is independently: phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, 30 imidazolyl or pyrazolyl, wherein any of the aforementioned is optionally substituted with C12 alkyl which is optionally partially or fully halogenated; C,13 alkyl or C13 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino; 35

OR

18 or C1.3 alkyl optionally substituted with OR,,; amino or mono- or di-(C 1

.

3 alkyl)amino optionally substituted with R 1 9

;

WO 03/084503 PCT/EPO3/03434 84

CH

3 C(O)NH-, R 22 0-; R 2 3

R

24 NC(O)-; R 26

CH

2

C(O)N(R

2 1 )- or R 2 6

C(O)CH

2

N(R

21 )-;

C

2 4alkenyl substituted by R 2

,R

2 4 NC(O)-; or 5 C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;

R

23 and R 24 are H or R 2 3 and R 2 4 taken together optionally form morpholino; and

R

26 is morpholino. o10 In a further preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 G is 15 phenyl, pyridinyl or naphthyl wherein G is substituted by one or more R 1 , R 2 or R3; X is: imidazolyl or pyridinyl; 20 Y is:

-CH

2 -, -NH-CH 2

CH

2

CH

2 - or -NH-; Z is morpholino; 25 each R 1 is independently: tert-butyl, sec-butyl, tert-amyl or phenyl;

R

2 is chloro; 30

R

3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino or morpholinocarbonyl. 35 In yet a further preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein X is pyridinyl.

WO 03/084503 PCT/EPO3/03434 85 In yet a still further preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein the pyridinyl is attached to Ar 5 via the 3-pyridinyl position. Preferably the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the O10 following compounds of formula 6 1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea 1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-I -yl]-urea 15 1-(4-Chloro-2-trifl uoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl ) naphthalen-1 -yl]-urea 1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl

)

20 naphthalen-1 -yl]-urea 1-(3 ,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1 -yl] urea 25 1-(3- odo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-3-m-tolyl-urea 1-(4-Methylsulfanyi-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1 30 yl]-urea 1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen 1-yl]-urea 35 1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 yl]-urea 1-(2,5-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl] urea WO 03/084503 PCT/EP03/03434 86 1 -[4-(6-Morpholin-4-ylmethyi-pyrid in-3-yI)-naphthalen-1 -yi]-3-naphthalen-2-yI-urea I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yi)-naphthalel-1 -yi]-3-phenyl-urea 5 I -(3-Chloro-phenyI)-3-[4-(6-morphoin-4-ylmethy-pyridil-3-yI)-flaphthalel-1 -yI]-urea I -(4-Chloro-3-trifluoromethy-pheny)-3-I4-(6-morphoil-4-ylmethy-pyridil-3-yI) naphthalen-I -yI]-urea 10 I -[4-(6-Morphoin-4-ymethyI-pyridin-3-y)-flaphthalel-1 -yI]-3-(2,4,6-trichloro-phenyl) urea I -(2-Methyl-3nitro-phenyI)-3-[4-(6-morpholin-4-ylmethy-pyridifl-3-yi)-flaphthaIefl-I 15 yI]-urea I -(4-MethyI-2-nitro-phenyI)-3-[4-(6-morphoin-4-yflmethyl-pyridifl-3-yI)-flaphthalefl-1 yl-u rea 20 1 (,-ihoopey)3[-6mrhln--lehlprdn3y)nptae- -yI] urea I -(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholil-4-y methyl-pyrid in-3-yI)-naphthalen I -yl]-urea 25 I -(2-Chloro-6-methy-pheny)-3-[4-(6-morphoil-4-yflmethy-pyridifl-3-yI)-flaphthalel I -yI]-urea 1 -(2 ,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethy-pyrid in-3-yI )-naphthalen-1 -yI] 30 urea 1 -(4-Methy-3-nitro-phenyI)-3-[4-(6-morpholifl-4-ylmethyI-pyridifl-3-yI)-flaphthalel-1 yI]-u rea 35 1 -(2,4-DimethyI-pheny)-3-[4-(6-morphoin-4-ylmethyI-pyridil-3-yi)-flaphthalel-I -yI] u rea I -(2,3-DimethyI-phenyI)-3-[4-(6-norphoil-4-ylmethyI-pyridifl-3-yl)-flaphthalefl -yi] u rea WO 03/084503 PCT/EP03/03434 87 I -(4-Cyano-phenyl)-3-[4-(6-morpholin-4-yflethy-pyridil-3-yI)-flaPhthalel-1 -yI]-urea 1 -[4-(6-Morphol in-4-yl methyl-pyridi1n-3-yI)-n a phth alen- 1 -yI]-3-(3,4,5-trimethoxy 5 phenyl)-urea I -Biphenylk4-yI-3-I[4-(6-morpholin-4-ylmethyI-pyrid in-3-yI)-naphthalen-1 -yI]-urea 1 -(2 ,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-y methyl-pyrid in-3-yI)-naphthalen-1 -yi] 10 urea I -(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethy-pyridil-3-yI)-flaphthalel I -yi]-urea 15 1 -(2-Fluoro-3-trifl uoromethyl-phenyl)-3-[4-(6-morphol in-4-yI methyl-pyrid in-3-yI ) naphthalen-I -yi]-urea I -(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-yflmethy-pyridifl-3-yI)-flaphthalel- 1 -yI] urea 20 I -(2-Methylsulfanyl-phenyl)-3-[4-(6-morphoI in-4-ylmethyl-pyridin-3-yI)-naphthalen-I yI]-urea I -(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholil-4-ylmethy-pyrid in-3-yI) 25 naphthalen-I -yI]-u rea I -(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholi-4-ylethyI-pyridil-3-yi) naphthalen-I -yI]-urea 30 1 -[4-(6-Morpholin-4-ylmethyI-pyridin-3-yi)-naphthalel-1 -yI]-3-(2 ,4,5-trimethyi-phenyl) urea 1 -[4-(6-Morpholin-4-ylmethyI-pyridifl-3-yI)-flaphthalefl-1 -yI]-3-(4-trifluoromethyi phenyl)-urea 35 I -(3-MethylsulfanyI-phefl-3-[4-(6-morpholifl-4-ylmethyI-pyridifl-3-yl)-flaphthalefl4 yI]-u rea WO 03/084503 PCT/EP03/03434 88 I-2Mtoypey)3[-6mrhln4y mehlprdn3y)nptae- -yI] urea I -(2-Fluoro-5-trifluoromethyI-pheny)-3-4-(6-morphil-4-ylmethyI-pyridifl-yi) 5 naphthalen-1 -yi]-urea I 4Mtoy2mty-pey)3[-6mrhoi--lehlprdi--i-ahhln 1 -yl]-u rea 10 1 -(2-Fluoro-5-nitro-pheny)-3-I4-(6-rphil-4-yI methyl-pyrid in-3-yl)-naphthalen-1 yI]-u rea I 4Ehx-hnl--4(6mrhln4ymty-yrdn3y)nptae- -yI]-urea 15 1 (,-iehx-hnl--[-6mrhln4ymty-prdn3y)nptae- -yI] urea 1 -(4, 5-DimethyI-2-nitro-pheny)-3-[4-(6-morphoil-4-yI methyl-pyrid in-3-yI )-naphthalen 1 -yI]-urea 20 I 5C lr-- eh lp e y)--4(- op oi--l ehy-yii--l-a hh ln I -yl]-urea 1 -(2-1Isop ro pyl-6-methy-ph eny)-3-[4-(6-mrp ho i-4-yfl methyI-pyrid i n-3-yI) 25 naphthaien-1 -yI]-urea I 2Dfurmtoypey)--4(-opoi--lehy-yii--l-ahhin I -yi]-urea 30 1 (-spoy-hnl--4-6mrhln4ymty-prdn3y)nptae- -yI] u rea I -(4-M ethoxy-ph eny)-3-[4-(6-morph oil-4-yfl methyI-pyrid if- 3 -yI)-n ap hthalIen- 1 -yi] urea 35 I 3Ehlpey)--4(-opoi-4ymty-yii-3y)nptae- -yI]-urea 1 -(2- Eth oxy-phe nyl)-3-[4-(6-morp h oil-4-yfl methy-pyrid i n-3-yI)- nap hth alen-1I -yIJ-urea WO 03/084503 PCT/EPO3/03434 89 1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea 4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid ethyl ester 5 1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1 yl]-urea 1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 10 naphthalen-I -yl]-urea 1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1 -yl] urea 15 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-I -yl]-3-(4 trifluoromethylsulfanyl-phenyl)-urea 5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-isophthalic acid dimethyl ester 20 1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-I -yl]-urea 3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-I -yl]-ureido}-benzoic acid 25 ethyl ester 1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea 30 1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea 1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-1 -yl]-urea 35 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-y]-3-(4-pentyloxy-biphenyl-3 yl)-urea WO 03/084503 PCT/EPO3/03434 90 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-ureido} benzoic acid methyl ester 1-(2 ,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl] 5 urea 1 -Benzothiazol-6-yl-3-[4-(6-morpholin-4-yl methyl-pyridin-3-yl)-naphthalen-1 -yl]-urea N-(2,5-Diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl] 10 ureido}-phenyl)-benzamide 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1-yl]-3-(3-phenoxy-phenyl) urea 15 1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morphoin-4-ylmethyl-pyridin-3-yl) naphthalen-l1-yl]-urea 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-N phenyl-benzamide 20 1-(2-Methyl-1,3-dioxo-2,3-dihydro-1 H-isoindol-5-yl)-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morphoiin-4-ylmethyl-pyridin-3-yl)-naphthalen 25 1-yl]-urea N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl] ureido}-benzenesulfonamide 30 1-[3-(2-Methyl-[1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea 1-(3-Methoxy-5-trifl uoromethyl-phenyl)-3-[4-(6-morpho in-4-ylmethyl-pyridin-3-yl) naphthalen-I -yl]-urea 35 1-(2 , 4 -Dimethoxy-phenyl)-3-[4-(6-morphoIin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl] urea WO 03/084503 PCT/EP03/03434 91 I -(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethy-pyridin-3-yI)-naphthalen yI]-urea I -(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen- 1 5 yII-urea 1 -(4-Chloro-2-nitro-phenyl)-3-[4-(6-morphoin-4-ymethyl-pyrid in-3-yI)-naphthalen-1 yI]-u rea 10 1 -(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid in-3-yI)-naphthalen I -yi]-urea 1 -(3,5- D imeth oxy-ph enyl)-3-[4-(6-morp ho Iin-4-yl methyl-pyrid i n-3-yI)-n a phth ale n- 1 -yI] urea 15 I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen-1 -yI]-3-(4-trifluoromethoxy phenyl )-u rea I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yi]-3-(3 20 trifluoromethylsulfanyl-phenyl)-urea I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yI)-naphthaen-1 -yl-3-(2-phenoxy-phenyl) urea 25 1 -(2-Methoxy-5-n itro-phenyl)-3-[4-(6-morphol in-4-yl methyi-pyrid in-3-yI)-naphthalen- 1 yI]-urea I -(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y) naphthalen-1 -yI]-urea 30 I -(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y) naphthalen-1 -yII-urea I -(2-tert-Butyl-5-methyl-pyrid in-4-yI)-3-[4-(6-morphoiin-4-y methyl-pyrid in-3-yI ) 35 naphthalen-1 -yI]-urea I -(3-Methyl-naphthalen-2-y)-3-[4-(6-morpholin-4-ylmethy-pyridin-3-yl)-naphthalen-1 yl]-urea WO 03/084503 PCT/EP03/03434 92 I -( 3 -tert-ButyI-phenyI)-3-[4-(6-morphoin4ymethypyridin3ylI-naphthalen1l -yI] urea 1 -(4-M ethyl- biph enyl-3-y)-3-[4-(6-mo rphol in-4-y methy-pyrid in3ylIna phthale n- -yI] 5 urea 1 -( 4 -tert-Butyl-biphenyl-2-yI)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1 yl]-urea lo 1 -(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ymethyl-pyridin3-yl) naphtha len-I -yl]-urea I -(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3yl) naphthalen-I -yI]-urea 15 I -(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3yi) naphthalen-I -yl]-urea I -(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholi n-4-ylmethy!-pyrid in-3-yI) 20 naphthalen-I -yIJ-urea I -(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethylpyridin-3yl) naphthalen-I -yl]-urea 25 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3yl) naphthalen-1 -yI]-urea. I -(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl )-methyl-amino]-pyrid in-3 yI-naphthalen-1 -yl)-urea 30 1 -(5-te rt-B utyl-2-methyl-p heny)-3-[4-(4-mo rph oli n4yl methyl-imid azoll -yI) naphthalen-1 -yI]-urea I -(5-tert-ButyI-2-methy-pheny)3[4-(6-morphoin4ymethy-pyridin-3ylI> 35 naphthalen-1 -yI]-urea I -(5-tert-Butyl-2-methyl-phenyl )-3-{ 4

-[

6

-(

3 -methoxy-propyla mino)-pyridin-3-y] naphthalen-1 -yl}-urea WO 03/084503 PCT/EPO3/03434 93 1 -(5-tert-B utyl-2-methyl-pyrid i n-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea 1-(5-tert-Butyl-2-morpholin-4-yl-phenyl )-3-[4-(6-morpholin-4-yl methyl-pyridin-3-yl) 5 naphthalen-I -yl]-urea 1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-mlOrpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-1 -yl]-urea o10 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl phenyl)-urea I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-I -yl]-3-(4-trifluoromethoxy phenyl)-urea 15 1-[5-(1,1-Dimethyl-pro pyl)-2-methoxy-phenyl]-3-[4-(6-morphlin-4-yl methyl-pyridin-3 yl)-naphthalen-1 -yl]-urea 1-[5-tert-Butyl-2-(1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 20 naphthalen-1 -yl]-urea 1 -[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morphoI in-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea 25 1-[5-tert-Butyl-2-(3-hydroxy-propyl )-phenyl]-3-[4-(6-morpholin-4-yl methyl-pyridin-3-yl) naphthalen-1 -yl]-urea 1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4 ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea 30 1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 35 yl]-ureido}-phenyl)-acetamide and the pharmaceutically acceptable derivatives thereof.

WO 03/084503 PCT/EP03/03434 94 I -(2-tert-Butyl-5-methyl-pyridi n-4-yI)-3-[4-(6-morpholin-4-yI methyl-pyrid in-3-yl) naphthalen-1 -yI]-urea; 1 -(- ty-n hha n2y)3[-6m p l -- lmty-yi -- l-aphhaen 5 yI]-u rea; I 3tr-uy-hnl-3[-4mrhln4ymthlpey)nptae- -yI]-urea; I -(3-tert-Butyl-phenyl)-3-[4-(6-morphoil- 4 -YI methyl-pyridin-3-yI)-naphthalel-1 -yI] 10 urea; I 4Mty-ihnl--l--4(-opoln4ymty-yiin3y)nptae- -yI] urea; 1'5 1 (-etBtlbpey--i)3[-6mrhln4ymtylprdn3y)nptae- yi]-urea; I -(5-Chloro-2 ,4-d imethoxy-phenyl)-3-[4-(6-morphoI in-4-yI methyl-pyrid ir-3-yI ) naphthalen-1 -yi]-urea; 20 1 -(5-1 sop ro pyl-2-methyl- ph enyl)-3-4-(6-morphoI i n-4-yI methyl-pyrid i n-3-yI) naphthalen-I -yI]-urea; I -(5-sec-Buty-2-methoxy-phenyI)-3-I4-(6-morphoI in-4-yI methyl-pyrid in-3-yI ) 25 naphthalen-I -yI]-urea; I -(5-tert-B utyl-2-methoxy-3-propy-PhelI)-3-[4-(6-morphol in-4-yI methyl-pyrid in-3-yi) naphthalen-1 -yI]-urea; 36 1 (-etBtl2mtoyehlpey)3[4(-opoi--lehlprdn3y) naphthalen-1 -yI]-urea; I 5tr-uy--ehx-pey)3[-2mrhln4-lehlprmdn5y) naphthalen-I -yI]-urea; 35 I 5tr-uy--ehx-pey)3[-4timrhoi--lehlpey) naphthalen-I -yi]-urea; WO 03/084503 PCT/EP03/03434 95 I -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morphoin-4-yflmethy-pyrid in-3-yI) naphthalen-1 -yI]-urea; I -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethy-phel)-flaphthael-1 5 yI]-urea; I -(5-tert-Butyl-2-methoxy-phenyl )-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl] naphthalen-1 -yI}-urea; 10I 1-(5-tert-Butyi-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazif- 1 -ylmethyl)-pyridin-3 yI]-naphthalen-1 -yi}-urea; I -(5-tedt-B utyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-p ropyl)-methyl-amino]-pyrid in-3 yI-naphthalen-1 -yI)-urea; 15 I -(5-ted-B utyl-2-methyl-phenyl )-3-[4-(4-morpholi n-4-yI methyl-imidazol-1 -yI) naphthalen-1 -yI]-urea; I -(5-tert-ButyI-2methy-phenyl)-3-[4-(4-morpholin-4-ylmethyI-phefl)-flaphthalefl-I 20 yI]-urea; I -(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morphol in-4-yI methyl-pyrid in-3-yI) naphthalen-1 -yI:-urea; 25 1 -(5-tert-Butyl-2-methyl-phenyl )-3-{4-[6-(3-methoxy-propylami no)-pyrid in-3-yI] naphthalen-1 -yI}-urea; I -(5-tert-Butyl-2-methyl-pyridin-3-yI)-3-[4-(6-morphol in-4-ylmethyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 30 I -(5-tert-Butyl-2-morpholin-4-yI-phenyl)-3-[4-(6-morphoi in-4-ylmethyl-pyridin-3-yI) naphthalen-I -yII-urea; I -(6-tert-Butyl-2-chloro-3-methyl-pyrid in-4-yi)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 35 yi)-naphthalen-1 -yI]-urea; I -(6-tert-Butyl-2-chloro-3-methy-pyrid in-4-yI )-3-[4-(6-th iomorpholin-4-ylmethyl pyridin-3-yI)-naphthalen-1 -yI]-urea; WO 03/084503 PCT/EP03/03434 96 I -[2-Methoxy-5-( I -methyl-cyclopropyl)-phenyl-3-[4-(2-morpholil-4-YI methyl pyrimidin-5-yI)-naphthalen-1 -yl]-urea; I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalel-1 -yI]-3-(3-tritluoromethyl 5 phenyl)-urea; I -[4-(6-Morphol in-4-yl methyl-pyrid in-3-yI )-naphthalen- I -yi]-3-(4-trifluoromethoxy phenyl)-urea; 10 1 -[5-( 1,1 -0imethyl-propyl)-2-methoxy-phenyl]-3-14-(4-th lomorphol in-4-yI methyl phenyl)-naphthalen-I -yl]-urea; 1 -[5-(1,1 I Dimethyl-propyI)-2-methoxy-phenyl-3-[4-(6-morphoi-4-yImfethyl-pyrid in-3 yl)-naphthalen-1 -yl]-urea; 15 1 -[5-(l -Cyano-cyclopropyl )-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethYl pyrimidin-5-yl)-naphthalen-1 -yl]-u rea; I -[5-tert-Butyl-2-( I H-pyrazol-4-yl)-phenyll-3-[4-(6-morphol in-4-yI methyl-pyridin-3-yI) 20 naphthalen-1 -yl]-urea; I -[5-tert-Butyl-2-(2-methyl-pyri mid in-5-yl)-phenyll-3-[4-(5-pyrid in-4-yi methyl-pyrid in-2 yi)-naphthalen-1 -yI]-urea; 25 1 -[5-tert-Butyl-2-(2-methyl-pyrimid in-5-yI )-phenyl]-3-[4-(6-morphol in-4-yl methyl pyridin-3-yl)-naphthalen-1 -yl]-u rea; I -[5-tert-Butyl-2-(3-hyd roxy-propyl)-phenyl]-3-[4-(6-morpholin-4-yl methyl-pyridi n-3-yl) naphthalen-I -yl]-urea; 30 I -[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morphol in-4 ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-u rea; I -[5-tert-Butyl-2-(morphol ine-4-ca rbonyl )-phenyl]-3-[4-(6-morpholin-4-ylmethyl 35 pyridin-3-yl)-naphthalen-1 -yl]-urea; 2-[4-tert-B utyl-2-(3-{4-16-(2 ,6-d imethyl-mo rpholI in-4-yI methyl)-pyrid i n-3-yl] -n a phth ale n 1 -yl-ureido)-phenoxy]-acetamide; WO 03/084503 PCT/EPO3/03434 97 3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1 -yl}-benzamide; 4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1 -yl] ureido}-benzamide; 5 and the pharmaceutically acceptable derivatives thereof. More preferably the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus 10 hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 6 1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 15 1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl] urea; 1-(4-Methyl-biphenyl-3-yi)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl] 20 urea; 1-(4-tert-Butyl-biphenyl-2-ylI)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 yl]-urea; 25 1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 30 1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 35 naphthalen-1-yl]-urea; 1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl )-methyl-amino]-pyridin-3 yl}-naphthalen-1 -yl)-urea; WO 03/084503 PCT/EPO3/03434 98 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 5 naphthalen-1-yl]-urea; 1-[5-(1,1 -Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-I -yl]-urea; 10 1-[5-tert-Butyl-2-(1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl]-urea; 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea; 15 1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-yl methyl-pyridin-3-y ) naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl 20 pyridin-3-yl)-naphthalen-1 -yl]-urea; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 yl]-ureido}-phenyl)-acetamide 25 and the pharmaceutically acceptable derivatives thereof. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 30 selected from the compounds of formula 7 as disclosed in WO 00/55139 W G'\EJ-N Ar-X-Y-Z I H 7 7 wherein: 35 E is carbon or a heteroatom group chosen from -0-, -NH- and -S-; WO 03/084503 PCT/EPO3/03434 99 G is: an aromatic C6-10 carbocycle or a nonaromatic C 3

.

1 0 carbocycle saturated or unsaturated; 5 a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 6-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; 10 or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; wherein G is optionally substituted by one or more R,, R 2 or R 3 ; 15 Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or Rs; 20 X is: a C.-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C,14alkyl, C, alkoxy or C 1

-

4 alkylamino chains each being branched or unbranched; 25 aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C14 alkyl, 30 C 1

,

4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C, 1

-

3 alkyl)amino, mono- or di (C, alkylamino)carbonyl,

NH

2 C(0), Cj., alkyl-S(O)m or halogen; Y is: a bond or a C,4 saturated or unsaturated branched or unbranched carbon 35 chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(0)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C4 alkyl optionally substituted by one or more halogen atoms; WO 03/084503 PCT/EPO3/03434 100 Z is: aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, 5 cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, 10 thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 1 , alkyl, C 1

,

6 alkoxy, C1-3 alkoxy-Cj. alkyl, Cj.6 alkoxycarbonyl, aroyl, C 1 acyl, oxo, hydroxy, pyridinyl-C, 3 alkyl, imidazolyl-C,.,alkyl, tetrahydrofuranyl-C 1 -3alkyl, nitrile-Cl- 3 alkyl, nitrile, carboxy, phenyl wherein the 15 phenyl ring is optionally substituted with one to two halogen, C., alkoxy, hydroxy or mono- or di-(Cl, alkyl)amino, C, alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C16 alkoxy, hydroxy, halogen or mono- or di-(C,.

3 alkyl)amino; or Z is optionally substituted with one to three amino or amino-C., alkyl wherein 20 the N atom is optionally independently mono- or di-substituted by aminoC, 6 alkyl, C 1 oalkyl, arylC 0

-

3 alkyl, C15 alkoxyC. alkyl, Cl alkoxy, aroyl, C 1 oacyl, C. 3 alkyl-S(O)m- or arylCo- 3 alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C., alkyl or C.6 alkoxy; 25 or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, Cl.6 alkyl or C, alkoxy; or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-.

3 acyl, C1- 6 alkyl or 30 C 1

.

3 alkoxyC 1 .alkyl, C 1

.

6 alkyl branched or unbranched, C 1 6 alkoxy,

C

13 acylamino, nitrileC,-4alkyl, C-.6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C, alkoxy, hydroxy or mono- or di-(Cl 3 alkyl)amino; 35 each R, is independently: C1.10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(0)m, and wherein said C01-10 alkyl is optionally substituted with one to three C3.10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, WO 03/084503 PCT/EPO3/03434 101 pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1.6, alkyl which is optionally partially or fully halogenated, C,- cycloalkanyl, C5.8 cycloalkenyl, 5 hydroxy, nitrile, C1.3 alkoxy which is optionally partially or fully halogenated or

NH

2 C(0), mono- or di(C.

3 alkyl)amino, and mono- or di(C..alkyl)aminocarbonyl; or R 1 is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or 10 cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C 1 . alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC,_ 3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=O, >C=S or NH; 15 phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1. alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC, 3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently 20 replaced by N; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three Cj_, alkyl optionally 25 partially or fully halogenated, nitrile, hydroxyC 1

.

3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=0, >C=S or NH; C3-10 branched or unbranced alkenyl each being optionally partially or fully 30 halogenated, and optionally substituted with one to three C,, branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with one to five halogen, C 1

.

6 e alkyl which is optionally partially or fully halogenated, 35 cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1.3, alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or di(C,.

3 alkyl)aminocarbonyl; the C3.-10 branched or unbranced alkenyl being WO 03/084503 PCT/EPO3/03434 102 optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, 5 cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1.

3 alkyl groups; oxo, nitrile, halogen; 10 silyl containing three C 1

,

4 alkyl groups optionally partially or fully halogenated; or C36 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced 15 by O, NH or S(0)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C 1 -3alkyl)amino optionally substituted by 20 one or more halogen atoms; each R 2 , R 4 , and R. is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated,

C

1

.

6 acyl, aroyl, C 1

,

4 branched or unbranched alkoxy, each being optionally 25 partially or fully halogenated, halogen, methoxycarbonyl, C_3 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;

OR

6 , C 1 -e alkoxy, hydroxy, nitrile, nitro, halogen; 30 or amino-S(O)m- wherein the N atom is optionally independently mono- or di substituted by C, 6 alkyl or arylCo- 3 alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C 1 3 alkyl, arylC 0 oalkyl, C_ 6 acyl, Cl 6 alkyl-S(O),- or arylC 0 o 3 alkyl-S(O),-, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and 35 optionally substituted with one to two C1,6 alkyl or C_ 6 alkoxy; each R 3 is independently: phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, WO 03/084503 PCT/EPO3/03434 103 triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, 5 each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C.

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C 1 , 10 alkyl, naphthyl C 1 -alkyl, halogen, hydroxy, oxo, nitrile, C1 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(Cl_ 3 alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino 15 wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 3 alkyl) aminocarbonyl, C, alkyl-C(O)

C

1 , alkyl, amino-C.

5 alkyl, mono- or di-(C,_.alkyl)amino, mono- or di-(C 1 , 3 alkyl)amino-Cs.

5 alkyl, amino-S(O) 2 , di-(C 3 alkyl)amino-S(O) 2 , R 7

-C

1 -. alkyl, R, C alkoxy, R,-C(O)-Cl 5 alkyl, RI 0 -C,_s alkyl(R,4)N, carboxy-mono- or di-(C, 20 5 alkyl)-amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from 25 cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, 30 cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, 35 pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C,., alkyl which is optionally partially or fully halogenated, halogen, nitrile, C, alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C_ WO 03/084503 PCT/EPO3/03434 104 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), mono- or di-(C 13 alkyl)aminocarbonyl, C1- 4 alkyl OC(O), C,-, alkyl-C(O)-C 14 alkyl, amino-C.

5 alkyl, mono- or di-(C_ 5 3 )alkylamino-C,_ alkyl, R 12

-C

1 alkyl, R 13 -Cl., alkoxy, R 14

-C(O)-C_

5 alkyl or R 15 Cs, alkyl(R,, 16 )N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be 10 partially or fully halogenated and optionally substituted with one to three C- 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=0, >C=S or NH; 15 cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1

.

3 alkyl groups; C14 alkyl-phenyl-C(O)-Cl.4 alkyl-, C1.-4 alkyl-C(O)-C, 4 alkyl- or C_4 alkyl-phenyl 20 S(O)m-CI-4 alkyl-; Cj-_ alkyl or C,, branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R 1 7 ; 25 OR, 8 or C1, alkyl optionally substituted with OR, 8 ; amino or mono- or di-(C 1

.

5 alkyl)amino optionally substituted with Ri9;

R

2 0

C(O)N(R

2 1 )-, R 2 2 0-or R 23

R

2 4 NC(O)-; R 2 6(CH 2 )mC(O)N(R21)-, R 2 3

R

24 NC(O)-C. 30 3 alkoxy or R 2 6C(O)(CH 2 )mN(R 21 )-;

C

2

-

6 alkenyl substituted by R 23

R

24 NC(O)-; C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully 35 halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, WO 03/084503 PCT/EPO3/03434 105 piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms;

C

1

.

6 acyl or aroyl; 5

R

6 is a: C1-4 alkyl optionally partially or fully halogenated and optionally substituted with R26; , 10 each R 7 , R,, R 9 , R 10 , R 12 , R 13 a, R 14 , R 1 5, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(Ci- 4 alkyl)amino optionally partially or fully halogenated; 15 each R 1 , and R 16 is independently: hydrogen or C-4 alkyl optionally partially or fully halogenated;

R,,

8 is independently: hydrogen or a C.4 alkyl optionally independently substituted with oxo or R 25 ; 20

R

20 is independently:

C

1 -3 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;

R

21 is independently: 25 hydrogen or C,_ 3 alkyl optionally partially or fully halogenated; each R2, R 2 3 and R 24 is independently: hydrogen, C 1 ., alkyl optionally partially or fully halogenated, said C1.6 alkyl is optionally interrupted by one or more O, N or S, said C, alkyl also being 30 independently optionally substituted by mono- or di-(C 1 3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C,.4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono or di-(C,.

3 alkyl)amino; or R 23 and R 2 4 taken together optionally form a heterocyclic or heteroaryl ring; 35 m = 0, 1 or 2; Wis 0 or S and pharmaceutically acceptable derivatives thereof.

WO 03/084503 PCT/EPO3/03434 106 In a preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein: 5 E is -CH 2 -, -NH- or -0-; Wis O; and G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, 10 benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl; pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, 15 benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2 onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1 H indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, 20 piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, 25 heptacanyl, thioxanyl or dithianyl; wherein G is optionally substituted by one or more R 1 , R 2 or R 3 . In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the 30 treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein: E is -NH-; G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, 35 benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-IH-indolyl or indolinonyl, wherein G is optionally substituted by one or more R 1 , R 2 or R 3

;

WO 03/084503 PCT/EP03/03434 107 Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R 5 groups; 5 X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently 10 substituted with one to three C,4 alkyl, C1- 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.

3 alkyl)amino, mono- or di-(Cl.

3 alkylamino)carbonyl,

NH

2 C(O), Cj.6 alkyl-S(O)m or halogen; Y is: 15 a bond or a C 0 1-4 saturated or unsaturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1.4alkyl optionally substituted by one or more halogen atoms; 20 Z is: phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from 2 oxa-5-aza-bicyclo[2.2.1]heptanyl, tetrahydropyrimidonyl, pentamethylene 25 sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyrrolidinyl and dioxolanyl which 30 are optionally substituted with one to three nitrile, C,., alkyl, C 1

.

3 alkoxy, amino, mono- or di-(C.

3 alkyl)amino, CONH 2 or OH; or Z is optionally substituted by phenyl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen,

C

1

-

3 alkyl or C.3 alkoxy; 35 or Z is nitrile, nitrileC 1

.

3 alkyl, C-6. alkyl-S(O)m, halogen, hydroxy, C1.3 alkyl, C,1.3 acylamino, C1-4 alkoxy, amino, mono- or di-(C 1

-

3 alkyl)aminocarbonyl, or amino mono or di-substituted by aminoC 1

.

6 alkyl or C 1

.

3 alkoxyC,- 3 alkyl; each R, is independently: WO 03/084503 PCT/EPO3/03434 108 C,., alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(0)m, and wherein said Cs, alkyl is optionally substituted with one to three

C

3 .6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl, isoxazolyl or 5 isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C.3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C 13 alkoxy which is optionally partially or fully halogenated; 10 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C 1

.

3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC,.

3 alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are 15 independently replaced by O, S, CHOH, >C=0, >C=S or NH; oxo; C3.6 alkynyl branched or unbranched carbon chain optionally partially or fully 20 halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C14 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, 25 tetrazolyl, or mono- or di(C 1

.

3 alkyl)amino optionally substituted by one or more halogen atoms; or silyl containing three C4 alkyl groups optionally partially or fully halogenated; 30

R

2 is independently: a C-., branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1.-2 alkyl-S(0)m 35 optionally partially or fully halogenated, or phenyl-S(0)m; C , alkoxy, hydroxy, nitrile, nitro, halogen; WO 03/084503 PCT/EPO3/03434 109 or amino-S(O)m- wherein the N atom is optionally independently mono- or di substituted by C 1

.

3 alkyl or arylC 0 salkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C.I 3 alkyl, arylC 0 o 3 alkyl, Cj. 3 acyl, C 1

-

4 alkyl-S(O)m- or arylCo- 3 alkyl-S(O)m-, each of the aforementioned alkyl 5 and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C, alkyl or C,., alkoxy;

R

3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, 10 imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C 1 , alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1- alkyl, naphthyl C, 15 5 alkyl, halogen, oxo, hydroxy, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1 .3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or 20 heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 13 alkyl)aminocarbonyl, C,., alkyl-C(O)-C 14 alkyl, mono- or di-(C. 3 alkyl)amino, mono- or di-(C 1

.

3 )alkylamino-C,_s alkyl, mono- or di-(C, 3 alkyl)amino-S(O) 2 , R 7

-C,-_

5 alkyl, R 8

-C.

5 alkoxy, R,-C(O)-Ci- alkyl, R 1 0 -C.5 alkyl(R, 1 )N, carboxy-mono- or di-(C1.5)-alkyl-amino; 25 C13 alkyl or C1-4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R 1 7;

OR

18 or C,-6 alkyl optionally substituted with OR,,; 30 amino or mono- or di- (C- alkyl)amino optionally substituted with R 1 ,,;

R

20

C(O)N(R

21 )-, R 22 0-; R 23

R

24 NC(O)-; R 26

CH

2

C(O)N(R

21 )-,

R

23

R

24

NC(O)-C

1

.

2 alkoxy or R 2 6

C(O)CH

2

N(R

2 1 )-; 35

C

2

.

4 alkenyl substituted by R 23

R

2 4 NC(O)-; or C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated wherein one of the methylene groups is optionally replaced by O, WO 03/084503 PCT/EPO3/03434 110 and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C 1

_

4 alkyl optionally substituted by one or more halogen atoms; 5 C,0 3 acyl; and

R

23 and R 24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring. 10 In yet another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 15 selected from the compounds of formula 7 wherein: G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4 dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or 20 indolinonyl, wherein G is optionally substituted by one or more R 1 , R 2 or R 3 ; Ar is naphthyl; X is 25 phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C1-4 alkyl, C 1

_

4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C- 3 alkyl)amino, mono- or di-(C1- 3 alkylamino)carbonyl, NH 2 C(O), C , alkyl-S(O)m or halogen; 30 Y is: a bond or a C014 saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo; 35 Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-aza- WO 03/084503 PCT/EPO3/03434 111 bicyclo[2.2.1]heptanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl each of which are optionally substituted with one to two C1.2 alkyl or C1.2 alkoxy; or Z is hydroxy, C1, alkyl, C,-, alkoxy, C1.3 acylamino, C,3 alkylsulfonyl, nitrile C1, 5 alkyl or amino mono or di-substituted by Cl alkoxyC 1 -3alkyl; each R 1 is independently: Cj, alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or 10 S(0)m, and wherein said Cj- alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl each optionally substituted with one to three halogen, C.s alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C, 3 alkoxy which is optionally partially or fully halogenated; 15 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1.3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC 1 -3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl 20 wherein one ring methylene group is replaced by O; oxo; C2-4 alkynyl optionally partially or fully halogenated wherein one or more 25 methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(Clalkyl)amino optionally substituted by one or more halogen 30 atoms; or silyl containing three C-.2 alkyl groups optionally partially or fully halogenated; 35 each R 2 is independently: a C1-4 alkyl optionally partially or fully halogenated, C.4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O)m, ethyl-S(0)m each optionally partially or fully halogenated or phenyl-S(0)m; WO 03/084503 PCT/EPO3/03434 112 or R 2 is mono- or di-Clacylamino, amino-S(O)m or S(O)mamino wherein the N atom is mono- or di-substituted by C 1 -3alkyl or phenyl, nitrile, nitro or amino; each R 3 is independently: 5 phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each of the aforementioned is optionally substituted with one to three C,- 3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C,13 alkoxy optionally partially or fully halogenated; 10 C.3 alkyl or C1-3 alkoxy optionally partially or fully halogenated or optionally substituted with R, 7 ;

OR,

8 or Cj, alkyl optionally substituted with OR, 8 ; 15 amino or mono- or di-(C,- 3 alkyl)amino optionally substituted with R 19 ;

R

20

C(O)N(R

21 )-, R 22 0-; R 23

R

2 4 NC(O)-; R 2 6

CH

2

C(O)N(R

2 1 )-, NH 2 C(O)methoxy or

R

26

C(O)CH

2

N(R

21 )-; 20 C2-4 alkenyl substituted by R 23

R

2 4 NC(O)-; or C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;

C,_

3 acyl and 25

R

23 and R 2 4 taken together optionally form morpholino. In another preferred embodiment the invention relates to the use of p38 kinase 30 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein: G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, 35 dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin 8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1lH-indol-5 yl, indolinyl, indolonyl, or indolinonyl , wherein G is optionally substituted by one or more R 1 , R 2 or R 3

;

WO 03/084503 PCT/EPO3/03434 113 Ar is 1-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or 5 pyrazinyl; Y is: a bond or

-CH

2 -, -CH 2

CH

2 -, -C(0)-, -0-, -S-, -NH-CH2CH 2 CH2-, -N(CH3)-, 10 CH 2

(CN)CH

2

-NH-CH

2 or -NH-; Z is morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza bicyclo[2.2.1]heptanyl, Cl-3alkoxyphenylpiperazinyl, hydroxy, C 1

_

3 alkyl, 15 N,N-diC_ 3 alkoxyC 1 -3alkylamino, C.

3 acylamino, C 1

.

3 alkylsulfonyl or nitrileCzalkyl; each R, is independently: C1-5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by O or N, and wherein said Cj-, alkyl is 20 optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted by C,3alkoxy; cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully 25 halogenated, nitrile, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or trimethyl silyl; propynyl substituted hydroxy or tetrahydropyran-2-yloxy; 30

R

2 is is mono- or di-C 13 acylamino, amino-S(0)m or S(O)m amino wherein the N atom is mono- or di-substituted by C,.

3 alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, _methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl; 35 each R 3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol or pyrazolyl, each is optionally substituted with C12 alkyl which is optionally partially or fully halogenated; , WO 03/084503 PCT/EPO3/03434 114 C1-3 alkyl or C13 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino; 5 OR 18 or C1,3 alkyl optionally substituted with OR 18 ; amino or mono- or di-(C 1

.

3 alkyl)amino optionally substituted with R 1 9 ; CH3C(O)NH-,

R

22 0-; R 2 3

R

2 4 NC(O)-; R 28

CH

2

C(O)N(R

2 1 )-, NH 2 C(O)methoxy or 10 R 2 6

C(O)CH

2

N(R

21 )-;

C

2 4 alkenyl substituted by R 23

R

24 NC(O)-; or C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl; 15 C1.

2 acyl; and

R

2 3 and R 24 are H or R 2 3 and R 24 taken together optionally form morpholino; and 20 R 26 is morpholino. In another preferred embodiment the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is 25 selected from the compounds of formula 7 wherein: G is phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1lH-indol-5-yl or 2 30 naphthyl wherein G is optionally substituted by one or more R 1 , R 2 or R 3 ; X is: imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; 35 Y is: a bond, CH 2

(CN)CH

2

-NH-CH

2 , -CH 2 -, -NH-CH 2

CH

2

CH

2 - or -NH-; WO 03/084503 PCT/EPO3/03434 115 Z is morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl, hydroxy, methyl, N,N dimethoxyethylamino, acetylamino, methylsulfonyl or cyanoethyl; 5 each R, is independently: tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl;

R

2 is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, 10 phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or trihalomethylsulfonyl;

R

3 is independently: methyl, C 1

.

3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, C 1 _ 15 4 alkylamino, NH 2 C(O)methoxy, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl. In yet another preferred embodiment the invention relates to the use of p38 kinase 20 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein X is pyridinyl. In still another preferred embodiment the invention relates to the use of p38 kinase 25 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein the pyridinyl is attached to Ar via the 3-pyridinyl position. 30 Preferably the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 7 : 35 1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1-yl] urea; 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin1 -yl) naphthalen-1 -yl]-urea; WO 03/084503 PCT/EPO3/03434 116 1 -(6-Chloro-4-trifluoromethyl-pyrid in- 2 -y)- 3 -[4-(6-morpholin-4-ylmethyl-pyridin3y) naphthaien-I -yi]-urea; 5 1 -( 4 -Difluoromethoxy-phenyi)-3-[4-(6-morphoin4ylmethyl-pyrid in-3-yl)-naphthalen I -yI]-urea; 1 (- ty- phhaen2y)3[-6 opho -- lmty-yi -- l- ptaln yl]-urea; 10 I -[2-Methoxy-5-(I -methyl-I -phenyI-ethyl)-phenyl]-3-[4-(6-morpholin-4ylmethyl pyridin-3-yl)-naphthalen-1 -yI]-urea; (5-tert-Butyl-2-methyl-.phenyl)carba mic acid 3 -(6-{4-[3-(5-tert-butyl-2-methyl-phenyl) 15 ureido]-naphthalen-1 -yI}-pyridin-2-ylamino)-propyI ester; I -(6-tert-Butyl-benzo[I

,

3 Idioxo-5-yl)-3-[4-(6-morpholin-4-ylmethyI..pyridin-3yl) naphthalen-1 -yl]-urea; 20 N-(5-tert-B utyl-2-methoxy-3-{3-[4-(6-morpholin-4-ymethyl-pyrid in-3-yI)-naphthaf en-I yl]-ureido}-phenyl)-acetamide; I ,3-B is-r4-(6-morphol in-4-yl methyl-pyrid in-3-yI)-naphtha len-I -yl]-u rea; 25 1 -[5-tert-Butyl-3-(2 ,2-d imethyl-[1 ,3]d loxola n-4-yl methyl)-2-hyd roxy-phenyl]-3-[4-(6 morpholin-4-ylmethyl-pyridin-3-y)-naphthalen-1 -ylI-urea; I -[5-tert-Butyl-2-(2-pyrrolidin-I -yI-ethoxy)-phenyl]-3-[4-(6-morpholin4ymethy pyridin-3-yI)-naphthalen-I -ylJ-urea; 30 I -[5-tert-Butyl-3-(2 ,3-d ihyd roxy-propyl)-2-hydroxy-phenyi]-3-4(6-morpholin-4 ylmethyl-pyridin-3-yl)-naphthalen-I -yI]-urea; I -(2,3-Dimethyi-l H-indo- 5 -y)- 3

-[

4

-(

6 -morphoin4ymethypyridin3y)naphthalen 35 1-yl]-urea; I -[ 4

-(

6 -Morphoiin-4-yimethyl-pyridin-3-yly-naphtha en-I -yI]-3-(2-p-tolyioxy-5 trifluoromethyl-phenyl)-u rea; WO 03/084503 PCT/EPO3/03434 117 l-[ 2

-(

2 -Methoxy-phenoxy)-5-trinluoromethy..ph enyl]-3-[4-(6-morphol in-4-ylmethyl pyridin-3-yi)-naphthalen-I -yI]-urea; I -[ 4 -(6-Morpholin-4-ylmethyl-pyrid in-3-y)-naphthalen- I -yi]-3-naphthalen-1 -yI-u rea; 5 I -{ 5 -tert-ButyI-2-methyi-3-[3.(tetrahyd ro-pyran-2-yloxy)-prop- I -ynyil]-phenyl}-3-[4-(6 morpholin-4-ylmethyl-pyrid in-3-yI)-naphthalen- I -yi]-u rea; I -{5-tert-Butyl-2-[3-(tetrahyd ro-pyran-2-yloxy)-prop-1I-ynyl]-pheny}-3-[4-(6-mo rphol in 10 4-ylmethyl-pyrid in-3-y!)-naphthalen-1 -yI]-urea;

I-(

5 -Hydroxymethy-2methyIpheny)3[4(6morphoin4-ymethyl-pyridin 3 -yI) naphthalen-1 -yI]-urea; 15 l-( 2 -Methoxy-dibenzofuran3yI)-3[4(6morpholin-4-ymethyl-pyridin- 3 -y) naphthalen-1 -yl]-urea; l-( 2

,

5 -Di-ter-buty-pheny)3[4(6morphoin4ymethy-pyridin3yi)naphthalenI1 yI]-u rea; 20 1 -[3-(4-Bromo-1 -methyl-I H-pyrazol-3-yI)-phenyl-3-[4(6-morphol in-4-ylmethyl pyridin-3-y)-naphthalen-I -yl]-urea; 1 -(3-Hyd roxy-5,6, 7,8-tetra hyd ro-naphthalen-2-y)-3-[4-(6-morpholin-4-ymethyl 25 pyridin-3-yl)-naphthalen-I -yI]-urea; 1 -(l -Acetyi-2 ,3-dihyd ro- I H-indol- 5 -yi)-3-[4-(6-morpholin.4..ylmethyl-pyrid in-3-yl) naphthalen-1 -yl]-urea; 30 1 -[4-(6-Morphol in-4-ylmethyi-pyrid in-3-yi)-naphthalen- I -yI]- 3 -(3-oxazol-5-yI-phenyl) urea; I -[ 4

-(

6 -Morphoin-4-ymethy-pyridin3y)naphthalenI1 -yl]-3-(3-[I ,3,4]oxadiazoi-2-yI phenyl)-urea; 35 I -(2-Methoxy-5-trifluoromethypheny)3[4-(6-mrpholin-4-ymethyl-pyridin-3-yI) naphthalen-1 -yl]-urea; Fu ran-2-ca rboxylic acid ( 4 -tert-butyl- 2

-

3 -[4-(6morphoin4ylmethyl-pyrd in-3- yI)- WO 03/084503 PCT/EP03/03434 118 naphthalen-1 -yl]-u reido}-phenyl)-amide; I -( 2 -Methoxy-4-phenyamino-pheny)34(6morphoin4ylmethyl-pyridin-3-yl) naphthalen-1 -yI]-urea; 5 I -( 5 -Methoxy-2-methyl-phenyl)34(6-morphoI in-4y methyl-pyrid in-3-yi)-naphthalen 1 -yI]-u rea; 1-( 3 -Hyd roxy-na phthae n2y)3[4(6mo rp hoi n4-ymethypyridi n-3yI)-na phtha le n 10 I1-yI]-u rea; N ,N-Diethy- 4 -methoxy-3{3-[4(6morphoin4ymethypyridin3yl)naphthalen-I -yI] ureido}-benzenesulfonamide; 15 1 -(2,2-Difluoro-benzo[1

,

3 Idioxo-5-y)-3-[4-(6-morphoin-4-ymethy-pyridin-3yl) naphthalen-1 -yl]-urea; I -[5-(1 I -Dimethy-propy)-2-phenoxy-pheny]3[4(6morphoin4-ymethyl-pyridin-3 yl)-naphthalen-1 -yi]-urea; 20 1-5(,- ehlprponl--ehlphny]3[-6mr lin4y ehlprdin 3-yi)-naphthalen-1 -yI]-urea; 2 -Chloro- 5 -{3-[4-(6-morphoin-4-ymethy-pyridin3y)naphthalen-I -yI]-ureido} 25 benzoic acid isopropyl ester; I -( 4 -Amino-3,5-dibromo-phenyl)-3-[4-(6morphoin4ymethy-pyridin-3yi) naphthaien-1 -yl]-urea; 30 1 -[5-tert-B utyl-3-(3-hydroxy-prop- I -yny!)-2-methyl-ph enyl]-3-[4-(6-morphol in-4 ylmethyl-pyridin-3-yI)-naphthalen-1 -yI]-urea; 1 -[5-tert-Butyl-2-(3-hydroxy-prop- I -yny)-phenyl-3-[4-(6-morpholin-4-ylmethyl-pyridin 3-yl)-naphthalen-1 -yI]-urea; 35 I -[5-tert-Butyl-3-(2 ,2-dimethyl-[1 ,3]d joxola n-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6 mo rp hoiin -4-yl methyl-pyrid in-3-y)-na phth ale n- -yI]-urea; I -[5-tert-Butyi-3-(2,3-d ihydroxy-propy)2methoxyphenyp3[4-(6morpho in-4- WO 03/084503 PCT/EP03/03434 119 ylmethyl-pyridin-3-yI)-naphthalen-1 -ylI-urea; 1 -(5-tert-B utoxy-2-methoxy-ph enyl)-3-[4-(6-morphol in-4-yI methyl-pyridin-3-yI) naphthalen-1 -yI]-urea; 5 I -[5-(1 -Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4(6morpholin-4ylmethyl-pyridin 3-yI)-naphthalen-I -yl]-urea; I -[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4(6-morpholin-4 10 ylmethyl-pyridin-3-yl)-naphthaien-1 -yI]-urea; I -(5-te rt-B utyl-2-methoxy-ph en yl)-3-[4-(6- [1 ,3]d ioxola n-2-yI-pyrid in -3-yl)-n a phth ale n I -yl]j-urea; 15 1 -(5-tert-Butyl-2-pyrrolid in-I -yI-phenyl)-3-[4-(6-morphol in-4-yl methyl-pyrid in-3-yl) naphthalen-1 -yi]-urea; I -(5-tert-Butyl-2-dimethylamino-pheny)-3-[4-(6-morpholin4ylmethyl-pyridin-3y) naphthalen-1 -yl]-urea; 20 I -(5-tert-Butyl-2-propoxy-phenyl )-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi) naphthalen-1 -yI]-urea; I -( 5 -tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethylpyridin3yl)naphthalen-1 25 yl]-urea; I -(5-tert-Butyi-2-methoxy-phenyl )-3-{4-[6-(2 ,6-d imethyl-morpholin-4-yl methyl )-pyrid in 3-yl]-naphthalen-I -yI}-urea; 30 2-(5-tert-B utyl-2-methoxy-phenyl )-N-[4-(6-morphoi in-4-ylmethyl-pyrid in-3-yI) naphthalen-1 -yl]-acetamide; I -( 2 -Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin.4ylmethyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 35 I -(3,3-Dimethyl-2-oxo-2 ,3-dihydro-1 H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yi)-naphthalen-1 -yi]-urea; I -( 5 -tert-Butyl-2-cyclopentyloxy-phenyl)-3[4(6morphoin4ylmethyl-pyridin-3-y) WO 03/084503 PCT/EPO3/03434 120 naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1 -ylmethyl)-pyridin 3-yl]-naphthalen-1 -yi}-urea; 5 1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yi]-urea; 1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 10 naphthalen-1 -yl]-urea; 1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-[4-(6-morpholin-4 ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea; 15 1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1 yl]-urea; 20 N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl]-ureido}-phenyl)-acetamide; 1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y)-3-[4-(6 25 morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yi]-urea; 1-[6-tert-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8 yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yi]-urea; 30 1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI) naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y) naphthalen-I -yl]-urea; 35 1-(5-tert-Butyl-2-imidazol-1 -yI-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen-1 - WO 03/084503 PCT/EP03/03434 121 yl]-ureido}-phenyl)-methanesulfonamide; 1 -(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morphoI in-4-ylmethyl-pyrid in 3-yl)-naphthalen-1 -yl]-urea; 5 N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-yl methyl-pyridin-3-yl)-naphthalen-1 yl]-ureido}-phenyl)-bis(methanesulfon)amide; I -[5-tert-Butyl-2-(1 -methyl-I H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl 10 pyrid i n-3-yI)-n ap hth ale n- 1 -yl]-u rea; I -(2-Meth anes u fi nyl-5-trifl u orom ethyl- ph enyl)-3-[4- (6-mo rp hol i n-4-yl methyl-pyrid i n-3 yI)-naphthalen-1 -yl]-urea; 15 1 -(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-1 -yl]-urea; I -[4-(6-{[B is-(2-methoxy-ethyl)-ami no]-methyl}-pyrid in-3-yl)-naphthalen- I -yi]-3-(5-tert butyl-2-methoxy-phenyl)-u rea; 20 I -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-d imethylamino-pyrrolidin-I -yimethyl) pyridin-3-yI]-naphthalen-1 -yl}-urea; N-[1 -(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-I -yI}-pyridin-2 25 ylmethyl)-pyrrolidin-3-yl]-acetamide; I -(I -Acetyl-3,3-dimethyl-2,3-d ihydro-I H-indol-5-yI)-3-14-(6-morpholin-4-ylmethyl pyridin-3-yI)-naphthalen-1 -yIJ-u rea; 30 N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morphol in-4-yf methyl-pyrid in-3-yl)-naphthalen-1 yl]-u reido)-phenyl)-p ropiona mid e; 1 -(5-tert-B utyl-2-methyl-benzooxazol-7-y )-3-[4-(6-morp hotin-4-yI methyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 35 I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl )-naphthalen-1 -yl]-3-(3 trifluoromethanesulfonyl-phenyl)-urea; N-(5-tert-B utyl-2-methoxy-3-{3-[4-(6-morpholi n-4-yI methyl-pyrid in-3-yl)-nap hthalen-1 - WO 03/084503 PCT/EPO3/03434 122 yl]-ureido}-phenyl)-isobutyramide; 2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-ureido) phenoxy)-acetamide; 5 1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-y)-3-[4-(6-morpholin-4-yImethyl pyridin-3-yi)-naphthalen-1 -yl]-urea; 1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yI)-3-[4-(6-morpholin-4-ylmethyl 10 pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yI)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-1 -yl]-urea; 15 1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- 3 -(1,3,3-trimethyl-2,3 dihydro-1 H-indol-5-yl)-urea; 20 1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 25 yl]-ureido}-phenyl)-benzenesulfonamide; Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yl)-naphthalen-I -yl]-ureido}-phenyl)-amide; 30 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1 -yl) naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-( 1-methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4-ylmethyl piperidin-1 -yl)-naphthalen-1 -yl]-urea; 35 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl) naphthalen-I -yl]-urea; 1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-mo'rpholin-4-ylmethyl-pyridin-3-yl)- WO 03/084503 PCT/EP03/03434 123 naphthalen-1 -yI]-urea; I -(5-tert-Butyl-2-methoxy-pyrid in-3-yl )-3-[4-(6-morphol in-4-yI methyl-pyridi n-3-yI) naphthalen-1 -yI]-urea; 2,2 ,2-Trif] uoro-ethanesu Ifon ic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morphol in-4 ylmethyl-pyridin-3-yI)-naphthalen-1 -yI]-ureido)-phenyl)-amide; N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-flaphthalel-I -yI}-pyrazin-2-yI) 10 methanesulfonamide; I -[4-(6-{[Bis-(2-cyano-ethyl )-a minol-methyl}-pyrid in-3-yI )-na phthalen- I -yi]-3-(5-tert butyl-2-methoxy-phenyl)-u rea; 15 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1 -ylmethyl)-pyrid in-3 yl-naphthalen-1 -yI}-urea; I -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorphol in-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yI]-urea; 20 I -(5-tert-B utyl-2-methoxy-ph enyl)-3-4-[6-(2,6-d i methYl-p ipe rid i n-i1 -ylmethyl)-pyridin 3-yI]-naphthalen-1 -yI}-urea; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-( I -oxo-tetrahyd ro-th iopyran-4-ylamino) 25 pyrid in-3-y]-naphthalen- I -yI}-urea; I -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetra hyd ro-pyran-4-ylamino)-pyrid in-3-yI] naphthalen-1 -yl}-urea; 30 1 -(5-tert-B utyl-2-methoxy-ph enyl)-3- [4-(6-{[(2-cya no-ethyl )- (tetra hyd ro-fu ra n-2 ylmethyl)-amino]-methyl}-pyridin-3-yI)-naphthalen-1 -yI]-urea; 1 -(5-tert-Butyl-2-methoxy-pheny)-3-{4-[6-(2-methoxymfethyi-morphoin-4-ylmethyI) pyridin-3-y]-naphthalen-l -yl}-u rea; 35 1 -(5-tert-Butyl-2-methoxy-ph eny)-3-(4-{6-X2-mo rph oi n-4-yl-ethy a min o)-methyIF pyridin-3-yI-naphthalen-1 -yl)-urea; I -(5-tert-ButyI-2-methoxy-phenyl)-3-{4-[6-(2-methyI-3-oxo-piperazin-1 -ylmethyl)- WO 03/084503 PCT/EPO3/03434 124 pyridin-3-yl]-naphthalen-1 -yl}-urea; 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-I -yl}-pyridin-2 ylmethyl)-piperidine-3-carboxylic acid amide; 5 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1 -yl}-pyridin-2 ylmethyl)-piperidine-4-carboxylic acid amide; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo- 14-thiomorpholin-4-ylmethyl) lo pyridin-3-yl]-naphthalen-1 -yl}-urea; 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea; 15 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1 -ylmethyl)-pyridin-3-yl] naphthalen-1 -yl}-urea; 1 -{4-[6-(4-Acetyl-piperazin-1 -ylmethyl)-pyridin-3-yl]-naphthalen-1 -yl}-3-(5-tert-butyl-2 methoxy-phenyl)-urea; 20 4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2 ylmethyl)-piperazine-l-carboxylic acid ethyl ester; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin 25 3-yl}-naphthalen-1 -yl)-urea; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl] pyridin-3-yl}-naphthalen-1-yl)-urea; 30 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amin o] methyl}-pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyi-ethylamino)-methyl] pyridin-3-yl}-naphthalen-1 -yl)-urea; 35 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2. 1]hept-5-ylmethyl) pyridin-3-yl]-naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin- WO 03/084503 PCT/EP03/03434 125 3-yIJ-naphthalen-1 -yI}-urea; I -(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1 -yI-ethylamino)-methyl] pyridin-3-yI}-naphthalen-1 7YI)-urea; 5 I -(5-tert-B utyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yI-piperazin-I -yI methyl) pyrid in-3-yI]-naphthalen-1 -yl}-urea; I -(5-tert-B utyl-2-methoxy-phenyl )-3-{4-[6-(4-pyrid in-2-yI-piperazin-I -yl methyl)-pyrid in 10 3-yI]-naphthalen-1 -yi}-urea; I -(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin- 1 ylmethyl]-pyridin-3-yI}-naphthalen-1 -yI)-urea; 15 1 -(5-tert-Butyl-2-methoxy-phenyl )-3-{4-[6-(morpholi ne-4-carbonyl )-pyrid in-3-yi] naphthalen-1 -yl}-urea; I -(5-tert-B utyl-2-methoxy-phenyl )-3-{4-[6-(2-th ia-5-aza-bicyclo[2 .2. 1 ]hept-5-ylmethyl ) pyridin-3-yi]-naphthalen-1 -yI}-urea; 20 I -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morphol in-4-ylmethyl-pyrazin-2-yI) naphthalen-1 -yI]-urea; I -(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yI)-3-[4-(6-morphoin-4 25 ylmethyl-pyridin-3-yI)-naphthalen-1 -yi]-urea; I -(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morphol in-4-ylmethyl-pyrid in-3-yI) naphthalen-1 -yl]-urea; 30 N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-I -yl}-pyridin-2-yi) acetamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin3yl)-naphthalen-1 yl]-ureido}-phenyi)-N-methyl-acetamide; 35 N-(5-tert-ButyI-2-methoxy-3-{3-[4-(6-morphoin-4-ylmethyl-pyridin-3-yi)-naphthalen-I yl]-u reid o}-ph enyl)-2 ,2 ,2-trifi uo ro-aceta mid e; I -(5-tert-B utyl-2-methoxy-phenyl )-3-{4-f 6-(pyrid in-3-yloxy)-pyrid in-3-yl]-naphthalen-1 - WO 03/084503 PCT/EPO3/03434 126 yl}-urea; S1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-naphthalen 1-yl}-urea; 5 [4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl phenyl ester; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 10 yl]-ureido}-phenyl)-methanesulfonamide and and the pharmaceutically acceptable derivatives thereof. In another preferred embodiment the invention relates to the use of p38 kinase 15 inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 7 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 20 yl]-urea; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 yl]-ureido}-phenyl)-acetamide; 25 1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4 ylmethyl-pyridin-3-yl)-naphthalen-I -yl]-urea; 1-(2,3-Dimethyl-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen 1-yl]-urea; 30 1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1 -ynyl]-phenyl}-3-[4-(6 morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 35 naphthalen-l-yl]-urea; 1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin 3-yl)-naphthalen-1 -yl]-urea; WO 03/084503 PCT/EP03/03434 127 I -[5-tert-Butyl-3-(3-hyd roxy-prop-1 -ynyl)-2-methyl-phenyll-3-[4-(6-morpholifl-4 ylmethyl-pyridin-3-yl)-naphthalefl-1 -yi]-u rea; I -[5-tert-Butyl-2-(3-hyd roxy-prop-1 -ynyl)-p henyl]-3-[4-(6-mo rph o in-4-yl methyl -pyrid in 5 3-yI)-naphthalen-I -yI]-urea; I -[5-tert-Butyl-3-(2,2-d imethyl-Il ,3]dioxolan-4-ylmethyl )-2-methoxy-phenyl]-3-[4-(6 morpholin-4-ylmethyl-pyrid in-3-yi)-naphthalen-1 -yi]-urea; 10 1 -[5-tert-Butyl-3-(2,3-dihyd roxy-propyI)-2-methoxy-phenyIII-3-[4-(6-morpholiflA ylmethyl-pyridin-3-yI)-naphthalefl-1 -yl]-urea; I -(5-tert-B utoxy-2-methoxy-phenyl)-3-14-(6-morphoil-4-YI methyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 15 1 -[5-(l -Cyano-cyclopropy)-2-methoxyphel-3-[4-(6-morpholi-4-yflmethylkpyridil 3-yl)-naphthalen-1 -ylI-urea; I -[5-tert-Butyl-3-(2-d lethylami no-ethyl)-2-methoxy-phenyl-3-[4-(6-morpholi n-4 20 ylmethyl-pyridin-3-yI)-naphthalel-1 -yI]-urea; I -(5-tert-Butyl-2-methoxy-p henyl)-3-[4-(6-[1 ,3]dioxolan-2-yI-pyrid in-3-yI )-naphthalen I -yl]-urea; 25 I -(5-tert-Butyl-2-pyrrolidin-1 -yI-phenyI)-3-[4-(6-morphoi-4-yflmethyI-pyridifl-3-yI> naphthalen-1 -yI]-urea; I -(5-tert-ButyI-2-dimethylamino-phel)-3-4-(6-morphQI in-4-ylmethyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 30 I -(5-tert-Butyl-2-propoxy-pheflyl )-3-[4-(6-morphol in-4-yI methyl-pyridin-3-yl) naphthalen-1 -yl]-urea; I 5tr-utl2mtoy-hnl--[-6hdoymty yiin-3-yl)-naphthalen-1 35 yI]-urea; I -(5-tert-Butyl-2-methoxy-phel)-3-{4-[6-(2 ,6-d imethyl-morphol in-4-yI methyl )-pyridin 3-yI]-naphthalen-I -yI}-urea; WO 03/084503 PCT/EP03/03434 128 I -(5-Cyclohexyl-2-methoxy-phenyl)-3-14-(6-morphol in-4-yl methyl-pyrid in-3-yl) naphthalen-1 -yI]-urea; I -(2,4- D imethoxy-5-trifl u oro meth yl-p hen yl)-3-[4-(6-mo rphol in-4-yl meth yl-pyrid in-3-y) 5 naphthalen-1 -yI]-urea; I -(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morphol in-4-yl methyl-pyrid in-3-yl) naphthalen-1 -yI]-urea; 10 1 -(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthaen-1 ylI-u rea; N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morphol in-4-yl methyl-pyrid in-3-yI) naphthalen-1 -y1j-u re idol- ph enyl)-aceta mid e; 15 I -(6-tert-B utyl-4-methyl-3-oxo-3 ,4-d ihyd ro-2 H-benzo[1 ,4]oxazin-8-y )-3-[4-(6 morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen-I -yI]-urea; I -(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morphol in-4-yI methyl-pyrid in-3-yl ) 20 naphthalen-1 -yI]-urea; I -(5-tert-Butyl-2-isopropoxy-phenyl )-3-[4-(6-morpholi n-4-yl methyl-pyridin-3-yl ) naphthalen-1 -yI]-urea; 25 1 -(5-tert-Butyl-2-imidazol- I -yl-phenyl)-3-[4-(6-morphol in-4-ylmethyl-pyrid in-3-yl) naphthalen-1 -yI]-urea; I -(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin 3-yl)-naphthalen-1 -yl]-urea; 30 N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morphoiin-4-ylmethyl-pyridin-3-yI)-naphthalen-1 yl]-ureido}-phenyl)-bis(methanesulfon)amide; I -[5-tert-B utyl-2-( 1-methyl-I H-pyrazol-4-yI)-phenyl]-3-[4-(6-morphol in-4-yl methyl 35 pyridin-3-yl)-naphthalen-1 -yl]-urea; I -(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 yi)-naphthalen-I -yI]-urea; WO 03/084503 PCT/EP03/03434 129 I -[4-(6-{[B is-(2-methoxy-ethyl )-amino]-methyl}-pyrid in-3-yI)-naphthalen-1 -yI]-3-(5-tert butyl-2-methoxy-phenyl)-u rea; N-[1 -( 5

-{

4 -[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-I -yI}-pyridin-2 5 yI methyl)-pyrrol id in-3-yI]-acetamide; 1 -(1 -Acetyl-3,3-d imethyl-2 ,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yI)-naphthalen-1 -yi]-u rea; 10 N-(5-tert-ButyI-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyrid in-3-yI)-.naphthalen-1 yI]-u reido}-phenyl)-propionamide; I -(5-tert-ButyI-2-methyI-benzooxazol-7-yi)-3-[4-(6-morpho in-4-yI methyl-pyrid in-3-y!) naphthalen-1 -yi]-urea; 15 I -[4-(6-Morpholin-4-ylmethyl-pyridin-3-y)-naphthalen-I -yI]-3-(3 trifluoromethanesulfonyl-phenyl)-u rea; N-(5-te rt- B utyl-2-meth oxy-3-{3-[4-(6-mo rphol in-4-yl meth yl-pyrid in -3-yJ)-na phth alen- 1 20 yl]-u reido}-p henyl)-isobutyra mid e; 2-(4-tert-Butyl-2-{3-[4-(6-morphol in-4-ylmethyI-pyrid in-3-yI)-naphthalen-1 -yi]-ureido} phenoxy)-acetamide; 25 1 -(5-tert-Butyi-2-oxo-2 7 3-d ihydro-benzooxazol-7-yI)-3-[4-(6-morphol in-4-ylmethyl pyridin-3-yI)-naphthalen-1 -yl]-urea; I -(5-tert-Butyl-3-cya no-2-methoxy-phenyl)-3-[4-(6-morphoi in-4-ylmethyl-pyrid in-3-yI) naphthalen-1 -yI]-urea; 30 I -(5-tert-Butyl-benzooxazol-7-y)-3-[4-(6-morpholi n-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yI]-urea; N-(5-tert-B utyl-2-methoxy-3-{3-[4-(6-morpholin-4-y methyl-pyrid in-3-y )-naphth alen-1 35 ylI-ureido-phenyl)-benzenesulfonamide; Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-mo rphoiin-4-ylmethyi-pyrid in-3 yi)-naphthalen-1 -yi]-ureido}-phenyl)-amide; WO 03/084503 PCT/EPO3/03434 130 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yI methyl-pyrimid in-5-yl) naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) 5 naphthalen-1-yl]-urea; 1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; 10 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4 ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-ureido}-phenyl)-amide; N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen- I -yl}-pyrazin-2-yl) methanesulfonamide; 15 1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1 -yl]-3-(5-tert butyl-2-methoxy-phenyl)-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1 -ylmethyl)-pyridin-3 20 yi]-naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl]-urea; 25 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperid in-I -ylmethyl)-pyridin 3-yl]-naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1 -oxo-tetrahydro-thiopyran-4-ylamino) pyridin-3-y]-naphthalen-1 -yl}-urea; 30 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yI] naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2 35 ylmethyl)-amino]-methyl}-pyridin-3-yi)-naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl) pyridin-3-y]-naphthalen-1 -yl}-urea; WO 03/084503 PCT/EPO3/03434 131 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1 -ylmethyl) pyridin-3-yi]-naphthalen-1 -yl}-urea; 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1 -yl}-pyridin-2 5 ylmethyl)-piperidine-3-carboxylic acid amide; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1 -oxo-1 14-thiomorpholin-4-ylmethyl) pyridin-3-yl]-naphthalen-1 -yl}-urea; lo 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1 -ylmethyl)-pyridin-3-yl] naphthalen-1 -yl}-urea; 15 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl] pyridin-3-yl}-naphthalen-1 -yl)-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino] 20 methyl}-pyridin-3-yl)-naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclol2.2.1]hept-5-ylmethyl) pyridin-3-yi]-naphthalen-1 -yl}-urea; 25 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin 3-yi]-naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin- 1 ylmethyl]-pyridin-3-yl}-naphthalen-1 -yl)-urea; 30 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl] naphthalen-1 -yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yI) 35 naphthalen-1 -yl]-urea; 1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yI)-3-[4-(6-morpholin-4 ylmethyl-pyridin-3-yi)-naphthalen-1 -yl]-urea; WO 03/084503 PCT/EPO3/03434 132 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1 -yl]-urea; N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl) 5 acetamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yi)-naphthalen-1 yl]-ureido}-phenyl)-N-methyl-acetamide; 10 N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yI]-naphthalen-1 yl}-urea; 15 [4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl phenyl ester; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 20 yl]-ureido}-phenyl)-methanesulfonamide and and the pharmaceutically acceptable derivatives thereof. Particularily preferred according to the invention is the use of p38 kinase inhibitors 25 for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds: WO 03/084503 PCT/EP03/03434 133 Example 1: N{ o - ° 0 N N ON'^ O HH Example 2: I ON N N N N I I H H 5 , Example 3: -/ N 0 \N N N N I I HH

ON/

WO 03/084503 PCT/EP03/03434 134 Example 4: N I 01 H O H H Example 5: N 0 N 0 N NN N I I I H 0 H H 5 Example 6: -~ N 0O N O N N 10 H H 10 Example 7: N H 0 H H and the pharmaceutically acceptable derivatives thereof. 15 The invention includes the use of pharmaceutically acceptable derivatives of the compounds of formula 1, 2, 3a, 3b, 3c, 3d, 4, 5, 5a, 6, and 7. A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a 20 pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of WO 03/084503 PCT/EP03/03434 135 the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formulas 1,2, 3a, 3b, 3c, 3d, 4, 5, Sa, 6, and 7. 5 Pharmaceutically acceptable salts of the compounds mentioned hereinbefore include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, O10 naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., 15 magnesium), ammonium and N-(C 1

-C

4 alkyl) 4 + salts. Within the scope of the present invention references to the term physiologically acceptable salts are to be understood as references to the term pharmaceutically acceptable salts. 20 In another aspect the present invention relates to pharmaceutical preparations suitable for inhalation containing at least one p38 kinase inhibitor in a therapeutically effective amount for treating mucus hypersecretion. Inhalable preparations according to the invention include inhalable powders, 25 propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the p38 kinase inhibitors optionally mixed with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The formulations which may 30 be used within the scope of the present invention are described in more detail in the next part of the specification. In the inhalable pharmaceutical compositions the p38 kinase inhibitor may be present in such an amount that per single dose about 100 to 10000 pg, preferably 1000 to 9000 Pg, more preferably 1500 to 8000pg of the p 38 kinase inhibitor are 35 applied. Preferred pharmaceutical compositions within the scope of the invention provide for the administration of about 2000 to about 7000 pg, more preferably 2500 to 6000 pg of the p38 kinase inhibitor per single dose. Preferably about 3000 to WO 03/084503 PCT/EP03/03434 136 about 5500 pg p38 kinase inhibitor are administered once or twice daily to the patient in need thereof. A) Inhalable powder: 5 The inhalable powders which may be used according to the invention may contain the p38 kinase inhibitor either on its own or in admixture with suitable physiologically acceptable excipients. If the p38 kinase inhibitor is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to 10 prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or 15 glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250pm, preferably between 10 and 20 150pm, most preferably between 15 and 80pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9pm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active the p38 kinase inhibitor, 25 preferably with an average particle size of 0.5 to 10 Om, more preferably from 1 to 6pm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. Inhalable powders according to the invention which contain a physiologically 30 acceptable excipient in addition to the p38 kinase inhibitor may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. The inhalable powders according to the invention which contain the p38 kinase inhibitor optionally in conjunction with a physiologically acceptable 35 excipient may be administered for example using an inhaler known by the name Turbuhaler@ or using inhalers as disclosed for example in EP 237507 A. Preferably, WO 03/084503 PCT/EPO3/03434 137 the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to the p38 kinase inhibitor are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958. 5 A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in capsules is shown in Figure 1. This inhaler (Handyhaler) is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 10 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and three holes 13 with diameters below 1 mm in the central region around the capsule 15 chamber 6 and underneath the screen housing 4 and screen 5. The main air flow enters the inhaler between deck 3 and base 1 near to the hinge. The deck has in this range a reduced width, which forms the entrance slit for the air. Then the flow reverses and enters the capsule chamber 6 through the inlet tube. The flow is then further conducted through the filter and filter holder to the mouthpiece. A 20 small portion of the flow enters the device between mouthpiece and deck and flows then between filterholder and deck into the main stream. Due to production tolerances there is some uncertainty in this flow because of the actual width of the slit between filterholder and deck. In case of new or reworked tools the flow resistance of the inhaler may therefore be a little off the target value. To correct this 25 deviation the deck has in the central region around the capsule chamber 6 and underneath the screen housing 4 and screen 5 three holes 13 with diameters below 1 mm. Through these holes 13 flows air from the base into the main air stream and reduces such slightly the flow resistance of the inhaler. The actual diameter of these holes 13 can be chosen by proper inserts in the tools so that the mean flow 30 resistance can be made equal to the target value. If the inhalable powders according to the invention are packed into capsules (inhalers) for the preferred use described above, the quantities packed into each capsule should be 1 to 50mg, preferably 3 to 45mg, more particularly 5 to 40mg of 35 inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of the p38 kinase inhibitor mentioned hereinbefore for each single dose.

WO 03/084503 PCT/EPO3/03434 138 B) Propellant gas-driven inhalation aerosols: Inhalation aerosols containing propellant gas which may be used according to the invention may contain the p38 kinase inhibitor dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation 5 aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred 10 propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2 tetrafluoroethane), TG227 (1,1,1, 2 ,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-driven inhalation aerosols which may be used according to the invention may also contain other ingredients such as co-solvents, stabilisers, 15 surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art. The propellant-driven inhalation aerosols which may be used according to the invention may contain up to 5 wt.% of the p38 kinase inhibitor. The propellant-driven 20 inhalation aerosols which may be used according to the invention contain, for example, 0.002 to 5 wt.%, 0.01 to 3 wt.%, 0.015 to 2 wt.% of the p38 kinase inhibitor. If the p38 kinase inhibitors are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10m, preferably from 25 0.1 to 5tm, more preferably from 1 to 5pVm. The propellant-driven inhalation aerosols according to the invention which may be used according to the invention may be administered using inhalers known in the art (MDIs = metered dose inhalers). Accordingly, in another aspect, the present 30 invention relates to the use of the p38 kinase inhibitor according to the invention to prepare pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. 35 In addition, the present invention relates to the use of the p38 kinase inhibitors according to the invention to prepare cartridges which when fitted with a suitable valve can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the WO 03/084503 PCT/EPO3/03434 139 inhalable aerosols containing propellant gas according to the invention are known from the prior art. C) Propellant-free inhalable solutions: 5 It is particularly preferred to use the p38 kinase inhibitors according to the invention to prepare propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by 10 volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing the p38 kinase inhibitor are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids 15 include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have 20 already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. 25 According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the 30 present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100mg/100ml, preferably less than 50mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100ml are preferred. 35 Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions which may be used according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols particularly isopropyl alcohol, glycols - particularly propyleneglycol, WO 03/084503 PCT/EP03/03434 140 polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or 5 substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic 10 acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. 15 The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with 20 pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml. 25 Preferred formulations contain, in addition to the solvent water and the p38 kinase inhibitor, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present. 30 The propellant-free inhalable solutions which may be used within the scope of the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of 35 less than 100pL, preferably less than 50pL, more preferably between 10 and 30pL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20pm, preferably less than 10m, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.

WO 03/084503 PCT/EP03/03434 141 An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 5 6a and 6b). The nebulisers (devices) described therein are also known by the name Respimat®. This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the p38 kinase inhibitors. Because of O10 its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient. The nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols. 15 The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterised by - a pump housing which is secured in the upper housing part and which comprises at one end a nozzle body with the nozzle or nozzle arrangement, 20 - a hollow plunger with valve body, - a power takeoff flange in which the hollow plunger is secured and which is located in the upper housing part, - a locking mechanism situated in the upper housing part, - a spring housing with the spring contained therein, which is rotatably 25 mounted on the upper housing part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction. The hollow plunger with valve body corresponds to a device disclosed in 30 WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to Figures 1 to 4, especially Figure 3, and the relevant parts of the description. The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active 35 substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of 10 to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred.

WO 03/084503 PCT/EPO3/03434 142 The valve body is preferably mounted at the end of the hollow plunger facing the valve body. The nozzle in the nozzle body is preferably microstructured, i.e. produced by 5 microtechnology. Microstructured valve bodies are disclosed for example in WO-94/07607; reference is hereby made to the contents of this specification, particularly Figure 1 therein and the associated description. The valve body consists for example of two sheets of glass and/or silicon firmly 10 joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the length is preferably 7 to 9 microns. 15 In the case of a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle openings at the outlet end the directions of spraying may be at an angle of 20 to 1600 to one another, preferably 60 to 1500, most 20 preferably 80 to 1000. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred. The directions of spraying will therefore meet in the vicinity of the nozzle openings. 25 The liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns. The locking mechanism contains a spring, preferably a cylindrical helical 30 compression spring, as a store for the mechanical energy. The spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member. The travel of the power takeoff flange is precisely limited by an upper and lower stop. The spring is preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an external torque which is 35 produced when the upper housing part is rotated counter to the spring housing in the lower housing part. In this case, the upper housing part and the power takeoff flange have a single or multiple V-shaped gear.

WO 03/084503 PCT/EPO3/03434 143 The locking member with engaging locking surfaces is arranged in a ring around the power takeoff flange. It consists, for example, of a ring of plastic or metal which is inherently radially elastically deformable. The ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of 5 the locking member move into the path of the power takeoff flange and prevent the spring from relaxing. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annual o10 plane. Details of the construction of the locking mechanism are given in WO 97/20590. The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid. When the atomiser is actuated the upper housing part is rotated relative to the lower 15 housing part, the lower housing part taking the spring housing with it. The spring is thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is biased, the power takeoff part in the upper housing part is moved along by a given 20 distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle. If desired, a number of exchangeable storage containers which contain the fluid to be atomised may be pushed into the atomiser one after another and used in 25 succession. The storage container contains the aqueous aerosol preparation according to the invention. The atomising process is initiated by pressing gently on the actuating button. As a result, the locking mechanism opens up the path for the power takeoff member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid 30 leaves the nozzle of the atomiser in atomised form. Further details of construction are disclosed in PCT Applications WO 97/12683 and WO 97/20590, to which reference is hereby made.

WO 03/084503 PCT/EPO3/03434 144 The components of the atomiser (nebuliser) are made of a material which is suitable for its purpose. The housing of the atomiser and - if its operation permits - other parts as well are preferably made of plastics, e.g. by injection moulding. For medicinal purposes, physiologically safe materials are used. 5 Figures 2a/b attached to this patent application, which are identical to Figures 6a/b of WO 97/12687, show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention. Figure 2a shows a longitudinal section through the atomiser with the spring biased while Figure 2b shows a longitudinal section through the atomiser with the spring o10 relaxed. The upper housing part (51) contains the pump housing (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At 15 its end the hollow plunger carries the valve body (58). The hollow plunger is sealed off by means of the seal (59). Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed. On the power takeoff flange is the stop (61) on which the power takeoff flange abuts when the spring is biased. After the biasing of the spring the locking member (62) moves between the 20 stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon. The spring housing (67) with compression spring (68) is rotatably mounted on the 25 upper housing part by means of the snap-in lugs (69) and rotary bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the exchangeable storage container (71) for the fluid (72) which is to be atomised. The storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of 30 active substance solution). The spindle (74) for the mechanical counter is mounted in the covering of the spring housing. At the end of the spindle facing the upper housing part is the drive pinion (75). The slider (76) sits on the spindle.

WO 03/084503 PCT/EPO3/03434 145 The nebuliser described above is suitable for nebulising the aerosol preparations which may be used according to the invention to produce an aerosol suitable for inhalation. If the propellant-free inhalable solutions which may be used according to the 5 invention are nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a o10 defined mass on each actuation. However, the propellant-free inhalable solutions which may be used according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or other stationary nebulisers. Accordingly, in a further aspect, the invention relates to the use according to the 15 invention of the p38 kinase inhibitor for preparing a pharmaceutical formulation in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®. Preferably, the invention relates to the use according to the invention of the p38 kinase inhibitors for preparing propellant-free 20 inhalable solutions or suspensions characterised in that they contain the p38 kinase inhibitors in conjunction with the device known by the name Respimat®. In addition, the present invention relates to the use according to the invention of the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to 25 the invention as described hereinbefore. The propellant-free inhalable solutions or suspensions which may be used within the scope of the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may 30 be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.

WO 03/084503 PCT/EPO3/03434 146 Accordingly, in another aspect, the present invention relates to the use according to the invention of the p38 kinase inhibitor in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable 5 for administering these solutions, characterised in that the device is an energy operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods. The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention to the following embodiments by way of O10 example. Examples of Formulations Inhalable powders (filled in capsules): 1) Ingredients pg per capsule Example 1 3500 Lactose 3500 Total 7000 15 2) Ingredients pg per capsule Example 1 3000 Lactose 4000 Total 7000 3) Ingredients pg per capsule Example 1 5000 Lactose 5000 Total 10000 WO 03/084503 PCT/EP03/03434 147 4) Ingredients pg per capsule Example 1 5000 Lactose 2000 Total 7000 5) Ingredients pg per capsule Example 1 5000 Total 5000 5 6) Ingredients pg per capsule Example 2 3500 Lactose 3500 Total 7000 7) Ingredients pg per capsule Example 2 3000 Lactose 4000 Total 7000 8) Ingredients pg per capsule Example 2 5000 Total 5000 10 9) Ingredients pg per capsule Example 3 5000 Lactose 5000 Total 10000 WO 03/084503 PCT/EP03/03434 148 10) Ingredients pg per capsule Example 3 5000 Lactose 2000 Total 7000

Claims (1)

1. 2- L - Q I I H H 4 4 wherein Arl is a heterocyclic group selected from the group consisting of pyrrole, 20 pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein Ar, may be substituted by one or more R 1 ,R 2 or R 3 ; Ar 2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, 25 indanyl, indenyl or indole each being optionally substituted with one to three R 2 groups; L, a linking group, is a C110 saturated or unsaturated branched or unbranched carbon chain; 30 wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C1 4 branched or unbranched alkyl which may be substituted by one or more halogen atoms; 35 Q is selected from the group consisting of: WO 03/084503 PCT/EPO3/03434 155 d) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5 b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with 5 one to three groups selected from the group consisting of halogen, C1.6 alkyl, C1.6 alkoxy, hydroxy, mono- or di-(C 1 .3 alkyl)amino, C1.6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C.6 alkyl and C. , alkoxy; 10 e) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4 dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene 15 sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of C,-6 alkyl, C.6 alkoxy, hydroxy, mono- or di-(Cl 3 alkyl)amino-C 1 - 3 alkyl, phenylamino-C1. 3 alkyl and Cl. alkoxy-C 1 -. 3 alkyl; f) Cj.6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is 20 covalently bonded to groups selected from the group consisting of C 1 -. 3 alkyl and Cl. alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C,. 6 alkoxy, hydroxy or mono- or di-(C 1 - 3 alkyl)amino, C16 alkyl-S(O)r, phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups 25 consisting of halogen, Cj_6 alkoxy, hydroxy or mono- or di-(C 1 -3 alkyl)amino; R, is selected from the group consisting of: (g) C3.10 branched or unbranched alkyl, which may optionally be partially or 30 fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being 35 substituted with 0 to 5 groups selected from the group consisting of halogen, C, branched or unbranched alkyl which is optionally partially or fully halogenated, C3s cycloalkyl, C. cycloalkenyl, hydroxy, cyano, C,.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(O) and di(C 1 -. 3 )alkylaminocarbonyl; WO 03/084503 PCT/EPO3/03434 156 (h) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be substituted with one to 5 three C 1 - 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, >C=O, >C=S and NH; (i) C-3.10 branched alkenyl which may optionally be partially or fully. halogenated, and which is optionally substituted with one to three C., 10 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 15 groups selected from halogen, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C1.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or 20 di(C 1 3)alkylaminocarbonyl; (j) C5.7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C 1 .3 alkyl groups; 25 (k) cyano; and, (I) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R 2 is selected from the group consisting of: a Cj, branched or unbranched alkyl which may optionally be partially or fully 30 halogenated, acetyl, aroyl, C, branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl; 35 R 3 is selected from the group consisting of: g) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, WO 03/084503 PCT/EPO3/03434 157 benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group 5 consisting of a C,-, branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C., branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cl. alkyl, 10 naphthyl Cl_ alkyl, halo, hydroxy, cyano, C1.3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C 1 - 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is 15 selected from the group hereinabove described, NH 2 C(O), a mono- or di (C 1 .- 3 )alkyl aminocarbonyl, C15- alkyl-C(O)-C_ 4 alkyl, amino-C. 5 alkyl, mono or di-(C 1 .- 3 )alkylamino-C 1 .- alkyl, amino-S(O) 2 , di-(Cl 3 )alkylamino-S(O) 2 , R 4 Cl. alkyl, R 5 -C1.5 alkoxy, R 6 -C(O)-Cl_ 5 alkyl and R 7 -C., alkyl(R,)N; h) a fused aryl selected from the group consisting of benzocyclobutanyl, 20 indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, 25 cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene 30 and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which 35 is optionally partially or fully halogenated, halo, cyano, C,.3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C 1 z)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl WO 03/084503 PCT/EPO3/03434 158 moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(Cl. 3 )alkyl aminocarbonyl, C 1 -4 alkyl-OC(O), C,., alkyl-C(O)-C_ 4 branched or unbranched alkyl, an amino-C 1 . 5 alkyl, mono- or di-(C 1 - 3 )alkylamino-C., alkyl, R 9 -C 15 alkyl, Rlo-C 1 5 alkoxy, 5 R 1 1 -C(O)-Cj_ alkyl, and R 1 2-C 1 5 alkyl(R, 3 )N; i) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which the cycloalkyl may optionally be partially or fully halogenated and which may optionally be substituted with one to three o10 C1-3alkyl groups; j) C 5 - 7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C 1 . 3 alkyl groups; and 15 k) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; I) C- 6 branched or unbranched alkyl which may optionally be partially or fully halogenated; or R, and R 2 taken together may optionally form a fused phenyl or pyridinyl ring, 20 and wherein each R, R 13 is independently selected from the group consisting of: hydrogen and C,4 branched or unbranched alkyl which may optionally be partially or fully halogenated; 25 each R 4 , R 5 , R 6 , R 7 , R9, RIo, R 11 and R 12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; m = 0, 1,2; 30 r= 0, 1,2; t= 0, 1,2; X = O or S and physiologically acceptable acids or salts thereof. WO 03/084503 PCT/EPO3/03434 159 9) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 5 W Ar "N J N ArE-X-Y-Z I I H H 5 wherein: 5 Ar, is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Arl may be substituted by one or more R 1 , R 2 or R 3 ; 10 Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three 15 R 2 groups; X is: a) a C.-8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C14 branched or unbranched alkyl, C-4 alkoxy or C14 alkylamino 20 chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 0-3 C 1 4 branched or unbranched alkyl, C, 4 alkoxy, hydroxy, nitrile, 25 mono- or di-(C, 3 alkyl)amino, C1-6 alkyl-S(O)m, or halogen; Y is: a bond or a C,4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene 30 groups are optionally replaced by O, NH, S(0), S(0) 2 or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C,, branched or unbranched alkyl which may be substituted by one or more halogen atoms; 35 Z is: WO 03/084503 PCT/EPO3/03434 160 a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups consisting of halogen, C 1 . 6 alkyl, C1., alkoxy, hydroxy, mono- or di-(C. 3 alkyl)amino, C_6 alkyl-S(O)m, COOH and phenylamino wherein the phenyl ring is 5 optionally substituted with one to two groups consisting of halogen, C1,6 alkyl and C, alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4 dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, 10 cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C-6 alkyl, C16 alkoxy, hydroxy, mono- or di-(C 1 - 3 alkyl)amino-C0 3 alkyl, phenylamino-C 1 - 3 alkyl and Cl.3 alkoxy-Cl. 3 15 alkyl; c) Cl.6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl, C1,5 alkoxyalkyl, pyridinyl-C-. 3 alkyl, imidazolyl-C 1 , alkyl, tetrahydrofuranyl-C l . 3 alkyl, phenylamino, wherein the phenyl ring is 20 optionally substituted with one to two halogen, C.6 alkoxy, hydroxy or mono- or di-(C, 1 - 3 alkyl)amino, C1_6 alkyl-S(O)m,, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C_6 alkoxy, hydroxy or mono- or di-(Cl- 3 alkyl)amino; 25 R, is : a) C3-10 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, 30 furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, Cl., branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8 cycloalkyl, Cs. cycloalkenyl, 35 hydroxy, nitrile, C , alkyloxy which is optionally partially or fully halogenated, NH 2 C(O) and di(C 1 -3)alkylaminocarbonyl; b) C 3 - 7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be partially or WO 03/084503 PCT/EPO3/03434 161 fully halogenated and optionally substituted with one to three C.3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >C=O, >C=S and NH; 5 c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three Cs, branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, 10 furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C,-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, 15 bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1_3 alkoxy which is optionally partially or fully halogenated, NH 2 C(O) and mono- or di(C 1 . 3 )alkylaminocarbonyl; d) a C5.7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 20 bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1.3 alkyl groups; e) nitrile; or f) C 1 .- 6 branched or unbranched alkoxycarbonyl, C-.6 branched or unbranched alkylaminocarbonyl, C-. branched or unbranched alkylcarbonylamino-C 1 - 3 25 alkyl; R 2 is: a Cj, branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C, branched or unbranched alkoxy optionally partially or fully 30 halogenated, halogen, methoxycarbonyl or phenylsulfonyl; R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, 35 pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is WO 03/084503 PCT/EPO3/03434 162 optionally substituted with one to five groups selected from the group consisting of phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1., branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, 5 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C1, alkyl, naphthyl C, alkyl, halogen, hydroxy, nitrile, C1.3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in 10 this paragraph, nitro, amino, mono- or di-(Cl 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C1- 3 )alkyl aminocarbonyl, C1,, alkyl-C(O)-C 1 - 4 alkyl, amino-C 1 . 5 alkyl, mono- or di-(C, 3 )alkylamino-C_ 5 alkyl, amino-S(O) 2 , di 15 (C 1 - 3 )alkylamino-S(O) 2 , R 4 -C, 15 alkyl, R.-C 1 salkoxy, R 6 -C(O)-C,., alkyl and R 7 -C.,- alkyl(R,)N, carboxy-mono- or di-(C, 5 )-alkyl-amino; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group 20 consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, 25 cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the 30 group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1,6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C,-3 alkoxy which is optionally partially or 35 fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C,_ 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, WO 03/084503 PCT/EPO3/03434 163 NH 2 C(O), a mono- or di-(C 1 .z)alkyl aminocarbonyl, C 1 4 alkyl-OC(O), C 1 5 alkyl-C(O)-C 14 branched or unbranched alkyl, an amino-C 1 ., alkyl, mono or di-(C, 13 )alkylamino-C,_s alkyl, R 9 -C.5 alkyl, R 1 0 -C, . 5 alkoxy, R,, -C(O)-Cl- 5 alkyl, and R 12 -C 1 - , alkyl(R, 13 )N; 5 c) cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C 1 3 alkyl groups; d) C5.7 cycloalkenyl selected from the group consisting of cyclopentenyl, 10 cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three CI. 3 alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C 1 - 6 branched or unbranched alkyl optionally partially or fully halogenated; 15 or R 1 and R 2 taken together may optionally form a fused phenyl or pyridinyl ring; each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally be partially or fully 20 halogenated; each R 4 , R 5 , R 6 , R 7 , R 9 , RI 0 , RI, and R 1 2 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; 25 mis 0, 1 or2; W is O or S and pharmaceutically acceptable derivatives thereof. 10) Use according to claim 4, characterized in that the p38 kinase inhibitor is a 30 compound of formula 5a W Ar N N Ar-X-Y-Z I I H H 5a wherein: 35 Ar, is: WO 03/084503 PCT/EPO3/03434 164 pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Arl is optionally substituted by one or more R 1 , R 2 or R 3 ; 5 Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R 2 groups; 10 X is: a C.- 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C 1 4 alkyl, C, alkoxy or C,. 4 alkylamino chains each being branched or unbranched; 15 phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently 20 substituted with one to three C-4 alkyl, C 1 - 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1 , 3 alkyl)amino, mono- or di-(Cl. 3 alkylamino)carbonyl, NH 2 C(O), C 1 6 alkyl-S(O)m or halogen; Y is: 25 a bond or a C 1 4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; 30 Z is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, 35 cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4- WO 03/084503 PCT/EPO3/03434 165 dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 1 . 6 alkyl, C 1 , 6 alkoxy, C1-3 alkoxy-Cl_ 3 alkyl, C 1 6 alkoxycarbonyl, 5 aroyl, heteroaroyl, heterocycleC, 3 acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C,. 3 acyl, oxo, hydroxy, pyridinyl C., alkyl, imidazoly-C 1 3 alkyl, tetrahydrofuranyl-C, 3 alkyl, nitrile-C 1 3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C 1 , 6 alkoxy, hydroxy or mono- or di-(C 1 .3 alkyl)amino, 10 amino-S(O)m, C1. alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, Cl, alkoxy, hydroxy, halogen or mono- or di-(C.. 3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C 1 , 3 alkyl wherein the N atom is optionally independently mono- or di-substituted 15 by aminoC 1 6 alkyl, C 1 . 3 alkyl, arylCo- 3 alkyl, Cs alkoxyC 1 .- 3 alkyl, C 1 salkoxy, aroyl, C 1 3acyl, C 1 -3alkyl-S(O)m- or arylCo- 3 alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C16 alkyl, C,.6 alkoxy, hydroxy or mono- or di-(Cs., alkyl)amino; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as 20 hereinabove described in this paragraph each in turn is optionally substituted by halogen, C 1 ,_o alkyl or C_ 6 alkoxy; or Z is hydroxy, hydroxyC, 3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C 1 . 6 alkyl, aminoC,,alkyl, arylCO- 3 alkyl, C,.,alkoxyC 1 -3alkyl, C 1 ,_salkoxy, aroyl, C,. 3 acyl, C1.3alkyl-S(O)m-, 25 arylCo- 3 alkyl-S(O)m-, nitrileC, 4 alkyl or C 1 - 3 alkoxyC 1 -3alkyl, each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C.6 alkyl, C 1 _ 6 alkoxy, hydroxy or mono- or di-(C 1 - 3 alkyl)amino, Cl., alkoxyheteroaryC 0 . 3 alkyl, heteroarylC 0 o- 3 alkyl or heterocycyleCo. 3 alkyl wherein the heteroaryl and heterocycle is hereinabove 30 described in this paragraph, or Z is C. 6 alkyl branched or unbranched, C,.,alkoxy, C 1 . 3 acylamino, nitrileC,. 4 alkyl, C1 , alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1, alkoxy, hydroxy or mono or di-(Cl- 3 alkyl)amino; 35 R, is: a) C,-,o branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, WO 03/084503 PCT/EP03/03434 166 pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle, selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of 5 halogen, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, C,-3 cycloalkyl, C,-, cycloalkenyl, hydroxy, nitrile, C,.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0) and di(C 1 . 3 )alkylaminocarbonyl; b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, 10 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or fully halogenated and optionally substituted with one to three C1., alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of 15 O, S, CHOH, >C=0, >C=S and NH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three Cj.5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, 20 pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1. branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, 25 cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C.3 alkoxy which is optionally partially or fully halogenated, NH 2 C(0) and mono- or di(Cl_ 3 )alkylaminocarbonyl; d) a C.7 cycloalkenyl selected from the group consisting of cyclopentenyl, 30 cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1.3 alkyl groups; e) nitrile; or f) Cj, branched or unbranched alkoxycarbonyl, C, branched or unbranched 35 alkylaminocarbonyl, C,1. branched or unbranched alkylcarbonylamino-C, 3 alkyl; R 2 is: WO 03/084503 PCT/EPO3/03434 167 a Cl 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R 2 is acetyl, aroyl, C.4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl; 5 R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, 10 isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group 15 consisting of a phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C 1 ., branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C1.alkyl, naphthyl C alkyl, halogen, 20 hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, C1 alkoxyC 1 . 5 alkyl, C 1 . 3 thioalkyl, Cs 3 thioalkylCl. 5 alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C,. 1 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino 25 wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(Cl_ 3 )alkyl aminocarbonyl, C 1 ., alkyl-C(O)-C, 1 alkyl, amino-Cl., alkyl, mono- or di-(C 1 -3)alkylamino-C, 5 alkyl, amino-S(O) 2 , di-(C 1~ -3)alkylamino-S(O) 2 , R 4 -C1-5alkyl, R -C-. 5 alkoxy, R 6 -C(0)-C 1 _ alkyl and R 7 -C, 1 , alkyl(R,)N, 30 carboxy-mono- or di-(C, 5 )-alkyl-amino; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, 35 cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, WO 03/084503 PCT/EPO3/03434 168 cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the 5 group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C 16 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C 1 , 3 alkoxy which is optionally partially or 10 fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C, 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C, 3 )alkyl 15 aminocarbonyl, C 1 4 alkyl-OC(O), C 1 _ 5 alkyl-C(O)-C 1 -4 branched or unbranched alkyl, an amino-C 1 ., alkyl, mono- or di-(C, 3 )alkylamino-C 1 , alkyl, R 9 -CIs alkyl, R 1 0 -C, 5 alkoxy, R 11 -C(O)-C 1 - alkyl and R 12 -C 1 5 alkyl(R 1 3 )N; c) cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, 20 cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C 1 - 3 alkyl groups; d) C 5 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 25 bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C 1 - 3 alkyl groups; e) acetyl, aroyl, C. 6 alkoxycarbonylC 1 -alkyl or phenylsulfonyl; or f) C 1 , branched or unbranched alkyl optionally partially or fully halogenated; 30 or R, and R 2 taken together optionally form a fused phenyl or pyridinyl ring; each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated; 35 each R 4 , R5, R 6 , R 7 , R 9 , Rio, R 1 1 and R 1 2 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; m is 0, 1 or 2; WO 03/084503 PCT/EPO3/03434 169 WisOorS; wherein X is directly attached to one or two -Y-Z, and pharmaceutically acceptable derivatives thereof. 5 11) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 6 W G-N.N -,Ar-X-Y-Z I I H H 6 wherein: 10 G is: an aromatic C 6 . 10 carbocycle or a nonaromatic C 3 - 10 carbocycle saturated or unsaturated; a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S; 15 a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; 20 wherein G is substituted by one or more R 1 , R 2 or R 3 ; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, 25 dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or Rs; X is: a C-., 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo 30 groups or one to three C 1 .4alkyl, C,- 4 alkoxy or C-4 alkylamino chains; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-bjpyridine, piperazinyl, pyridazinyl or pyrazinyl; 35 Y is: WO 03/084503 PCT/EPO3/03434 170 a bond or a C14 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(0)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more 5 C1. 4 alkyl optionally substituted by one or more halogen atoms; Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl each being optionally substituted 10 with one to three halogen, C1.8 alkyl, C.6 alkoxy, hydroxy, amino, mono- or di (Cl-3 alkyl)amino, C., alkyl-S(O)m, CN, CONH 2 , COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C., alkyl or Cl.6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 15 dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being 20 optionally substituted with one to three nitrile, C1.6 alkyl, C, alkoxy, hydroxy, amino, mono- or di-(C 1 - 3 alkyl)amino-C 1 . 3 alkyl, CONH 2 , phenylamino-C. 3 alkyl or C. 3 alkoxy-C1- 3 alkyl; halogen, C14 alkyl, nitrile, amino, hydroxy, C-.6 alkoxy, NH 2 C(0), mono- or di(C 1 alkyl) aminocarbonyl, mono- or di(C 1 . 6 alkyl)amino, secondary or tertiary 25 amine wherein the amino nitrogen is covalently bonded to C1.3 alkyl or C1.-5 alkoxyalkyl, pyridinyl-C , alkyl, imidazolyl-C , 3 alkyl, tetrahydrofuranyl-C, 3 alkyl, nitrile-C 3 alkyl, carboxamide-C , alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C,-6 alkoxy, hydroxy or mono or di-(C ,. alkyl)amino, C,6 alkyl-S(O)m, or phenyl-S(0)m, wherein the phenyl 30 ring is optionally substituted with one to two halogen, C.6 alkoxy, hydroxy, halogen or mono- or di-(C, 3 alkyl)amino; C,. alkyl-S(0)m, and phenyl-S(0)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1.6 alkoxy, hydroxy or mono- or di-(C, 3 alkyl)amino; 35 each R, is independently: C1.10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C 3 1 0 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, WO 03/084503 PCT/EPO3/03434 171 isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C 1 . 6 alkyl which is optionally partially or fully halogenated, C3., 8 cycloalkanyl, C,.8 cycloalkenyl, hydroxy, nitrile, C1.3alkoxy which is optionally partially or fully halogenated or 5 NH 2 C(O), mono- or di(Cl. 3 alkyl)amino, and mono- or di(C 1 . 3 alkyl)aminocarbonyl; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and 10 optionally substituted with one to three C,. 3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1 .- 3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=0, >C=S or NH; 15 phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C.3alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1 3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N; 20 cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C 1 - 3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC,_zalkyl or 25 aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=0, >C=S or NH; C3.10 branched or unbranced alkenyl each being optionally partially or fully 30 halogenated, and optionally be substituted with one to three C 1 ., branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five halogen, C 1 . alkyl which is optionally partially or fully halogenated, 35 cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or di(C 1 -3alkyl)aminocarbonyl; the C,310 branched or unbranced alkenyl being WO 03/084503 PCT/EPO3/03434 172 optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, 5 cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C 13 alkyl groups; nitrile, halogen; 10 methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; silyl containing three C14 alkyl groups optionally partially or fully halogenated; C36 alkynyl branched or unbranched carbon chain optionally partially or fully 15 halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(0)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrrolidinyl, pyrrolyl, one or more C14 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or 20 di(C,-alkyl)amino optionally substituted by one or more halogen atoms; each R 2 , R 4 , and R. is a C 1 , branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C14 branched or unbranched alkoxy, each being optionally 25 partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C 1 , alkyl S(O)m optionally partially or fully halogenated, or phenylsulfonyl; Cl, alkoxy, hydroxy, amino, or mono- or di-(C 1 4 alkyl)amino, nitrile, halogen; 30 OR 6 ; nitro; or mono- or di-(Cl4 alkyl)amino-S(O) 2 optionally partially or fully halogenated, or 35 H 2 NS0 2 ; each R 3 is independently: phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, WO 03/084503 PCT/EPO3/03434 173 tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, 5 each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C,., branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1.5 10' alkyl, naphthyl C. alkyl, halogen, hydroxy, oxo, nitrile, C,, alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1 . 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino 15 wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C,_ 3 alkyl) aminocarbonyl, C.5 alkyl-C(O) C 1 . 4 alkyl, amino-Cl., alkyl, mono- or di-(C,_ 3 alkyl)amino-C_. alkyl, amino-S(O) 2 , di-(C, 1 . 3 alkyl)amino-S(O) 2 , R 7 -C 1 . 5 alkyl, R 8 -C 1 ,. 5 alkoxy, R 9 -C(O)-C 15 alkyl, R, 0 -C, . alkyl(Rj,)N, carboxy-mono- or di-(C,_salkyl)-amino; 20 a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, 25 cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, 30 cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C_, alkyl which is optionally 35 partially or fully halogenated, halogen, nitrile, C1.3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C,. 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino WO 03/084503 PCT/EPO3/03434 174 wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), mono- or di-(C. 3 alkyl)aminocarbonyl, C1-4 alkyl OC(O), C1.5 alkyl-C(O)-Cl. 4 alkyl, amino-C_ 5 alkyl, mono- or di-(C 1 . 3 )alkylamino C j , alkyl, R 1 2 -C 1 -5alkyl, R 13 -C.,alkoxy, R 1 4 -C(O)-C 1 5 alkyl or R 1 6 -C 1 . 5 5 alkyl(R, 16 )N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 10 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, 15 cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C, alkyl groups; C,14 alkyl-phenyl-C(O)-C, 4 alkyl-, C14 alkyl-C(O)-Cl 1 4 alkyl- or C1.4 alkyl-phenyl S(O)m-C,- 4 alkyl-; 20 Cj, alkyl or Cl.6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R 1 7 ; OR,, 18 or C16 alkyl optionally substituted with OR,, 8 ; 25 amino or mono- or di-(Cl_ 5 alkyl)amino optionally substituted with R 19 ; R 2 0 C(O)N(R 21 )-, R 22 0- or R 23 R 2 4 NC(O)-; R 26 (CH 2 )mC(O)N(R 2 1)- or R 26 C(O)(CH 2 )mN(R 2 1)-; 30 C 2 .ealkenyl substituted by R 23 R 24 NC(0)-; C26 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced 35 by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C1-.4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or WO 03/084503 PCT/EPO3/03434 175 di(C_ 4 alkyl)amino optionally substituted by one or more halogen atoms; or aroyl; 5 R 6 , is a: C 4 alkyl optionally partially or fully halogenated and optionally substituted with R26; each R7, R 8 , R 9 , R 1 0 io, R 12 , R 13 , R 14 , R 15 , R 17 , R 19 , R 2 5 and R 26 is independently: 10 nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C 1 - 4 alkyl)amino optionally partially or fully halogenated; each Rj and R 16 is independently: 15 hydrogen or C1-4 alkyl optionally partially or fully halogenated; R 1 8 is independently: hydrogen or a C-4 alkyl optionally independently substituted with oxo or R 2 ,; 20 R 20 is independently: Cl.10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; R 21 is independently: hydrogen or C, 3 alkyl optionally partially or fully halogenated; 25 each R 22 , R 23 and R 24 is independently: hydrogen, C-.6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C-6 alkyl also being independently optionally substituted by mono- or di-(C,_alkyl)aminocarbonyl, 30 phenyl, pyridinyl, amino or mono- or di-(C4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono or di-(C,. 3 alkyl)amino; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring; 35 m = 0, 1 or2; Wis O orS and pharmaceutically acceptable derivatives thereof. WO 03/084503 PCT/EPO3/03434 176 12) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 7 W GE N .Ar-X-Y-Z H 7 wherein: 5 E is carbon or a heteroatom group chosen from -0-, -NH- and -S-; G is : an aromatic C6-10 carbocycle or a nonaromatic C 3 . 10 carbocycle saturated or O10 unsaturated; a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S; 15 a 6-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; 20 wherein G is optionally substituted by one or more R 1 , R 2 or R 3 ; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, 25 dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R,; X is: a C.- cycloalkyl or cycloalkenyl optionally substituted with one to two oxo 30 groups or one to three C1.4alkyl, C1-4 alkoxy or C 1 - 4 alkylamino chains each being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, 35 benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4alkyl, WO 03/084503 PCT/EPO3/03434 177 C, 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1 , 3 alkyl)amino, mono- or di (C1-3 alkylamino)carbonyl, NH 2 C(O), C, alkyl-S(O)m or halogen; Y is: 5 a bond or a C, saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(0)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C,4 alkyl optionally substituted by one or more halogen atoms; 10 Z is: aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, 15 cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4 dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, 20 thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C,6 alkyl, C . alkoxy, C 1 , alkoxy-C. 3 alkyl, C., alkoxycarbonyl, aroyl, C 1 _ 3 acyl, oxo, hydroxy, pyridinyl-C , 3 alkyl, imidazolyl-C 1 -3alkyl, tetrahydrofuranyl-C_ 3 alkyl, nitrile-C. 3 alkyl, nitrile, carboxy, phenyl wherein the 25 phenyl ring is optionally substituted with one to two halogen, C ,6 alkoxy, hydroxy or mono- or di-(C 1 . 3 alkyl)amino, C16 alkyl-S(0)m, or phenyl-S(0)m wherein the phenyl ring is optionally substituted with one to two halogen, C16 alkoxy, hydroxy, halogen or mono- or di-(C., alkyl)amino; or Z is optionally substituted with one to three amino or amino-C 1 - 3 alkyl wherein 30 the N atom is optionally independently mono- or di-substituted by aminoC_ 6 alkyl, C 1 3 alkyl, arylC 0 o- 3 alkyl, Cj_5 alkoxyC 1 _,alkyl, Co.alkoxy, aroyl, C 1 . 3 acyl, C. 3 alkyl-S(O)m- or arylC 0 o 3 alkyl-S(0)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C, alkyl or C1.6 alkoxy; 35 or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C,.6 alkyl or C,.6 alkoxy; or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C ,acyl, C. 6 alkyl or WO 03/084503 PCT/EPO3/03434 178 C,. 3 alkoxyC 1 , 3 alkyl, C 1 - 6 alkyl branched or unbranched, C 1 , 6 alkoxy, C 1 3 acylamino, nitrileC 1 , 4 alkyl, C 1 6 alkyI-S(O)m, and pheny-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,. alkoxy, hydroxy or mono- or di-(C 1 - 3 alkyl)amino; 5 each R, is independently: C 1 0 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(0)m, and wherein said C-10 alkyl is optionally substituted with one to three 10 C3.1 0 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C- 6 alkyl which is optionally partially or fully halogenated, C 38 cycloalkanyl, C., cycloalkenyl, 15 hydroxy, nitrile, C,-3 alkoxy which is optionally partially or fully halogenated or NH 2 C(0), mono- or di(C 1 ,alkyl)amino, and mono- or di(C,- 3 alkyl)aminocarbonyl; or R 1 is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or 20 cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C 1 3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC 1 - 3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH; 25 phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC 1 - 3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently 30 replaced by N; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C 13 alkyl optionally 35 partially or fully halogenated, nitrile, hydroxyC_ 3 alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=O, >C=S or NH; WO 03/084503 PCT/EPO3/03434 179 C310 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C1.5, branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or 5 isothiazolyl, each of the aforementioned being substituted with one to five halogen, C1.6, alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1.3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(O), mono- or 10 di(C 1 3 alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(0)m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, 15 cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1.3 alkyl groups; oxo, nitrile, halogen; 20 silyl containing three C-.4 alkyl groups optionally partially or fully halogenated; or C3. alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced 25 by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C1,4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C,. 3 alkyl)amino optionally substituted by 30 one or more halogen atoms; each R 2 , R 4 , and R 5 is a Cl, branched or unbranched alkyl optionally partially or fully halogenated, C 1 . 6 acyl, aroyl, C14 branched or unbranched alkoxy, each being optionally 35 partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(0)m optionally partially or fully halogenated, or phenyl-S(0)m; OR 6 , C-, alkoxy, hydroxy, nitrile, nitro, halogen; WO 03/084503 PCT/EPO3/03434 180 or amino-S(O)m- wherein the N atom is optionally independently mono- or di substituted by C,_,alkyl or arylC 0 o- 3 alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C_ 3 alkyl, arylC 0 .3alkyl, C, 6 acyl, C, 6 alkyl-S(O)m- or arylC 0 o-3alkyl-S(O)m-, each of the aforementioned alkyl 5 and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C, alkyl or C-. 6 alkoxy; each R 3 is independently: phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 10 pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, 15 each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C, 6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,_5 20 alkyl, naphthyl C.-, alkyl, halogen, hydroxy, oxo, nitrile, C. 3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C, 3 alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino 25 wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 _ 3 alkyl) aminocarbonyl, C,, alkyl-C(O) C 1 - 4 alkyl, amino-C 1 - alkyl, mono- or di-(C,4alkyl)amino, mono- or di-(C,. 3 alkyl)amino-C. 5 alkyl, amino-S(O) 2 , di-(Cl3alkyl)amino-S(O) 2 , R7-CI_ 5 alkyl, R 8 Cl.5 alkoxy, R 9 -C(O)-C.. 5 alkyl, Rlo-Cl-. 5 alkyl(R,4)N, carboxy-mono- or di-(C. 30 5 alkyl)-amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from 35 cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, WO 03/084503 PCT/EPO3/03434 181 cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, 5 naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, Cl., alkyl which is optionally partially or fully halogenated, halogen, nitrile, C13 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as 10 hereinabove described in this paragraph, nitro, amino, mono- or di-(Cl 3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O), mono- or di-(Cl 3 alkyl)aminocarbonyl, C1. alkyl OC(0), C-, alkyl-C(O)-C 1 . 4 alkyl, amino-C 1 5 alkyl, mono- or di-(C_ 15 3 )alkylamino-C- 5 alkyl, R 1 2 -C, 1 , alkyl, R 3 -C 1 -5 alkoxy, R 14 -C(0)-C 1 . 5 alkyl or R 1 , C. alkyl(R, 16 )N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be 20 partially or fully halogenated and optionally substituted with one to three C 1 -3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=0, >C=S or NH; 25 cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1 ,alkyl groups; C_4 alkyl-phenyl-C(0)-C_ 4 alkyl-, C14 alkyl-C(O)-C1- 4 alkyl- or Cl4 alkyl-phenyl 30 S(0)m-C. 4 alkyl-; C1_ alkyl or Cz_ branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R,; 35 OR 18 or Cj-, alkyl optionally substituted with OR, 8 ; amino or mono- or di-(C,alkyl)amino optionally substituted with R19; WO 03/084503 PCT/EPO3/03434 182 R 20 C(O)N(R 21 )-, R 22 0- or R 23 R 2 4 NC(O)-; R 26 (CH 2 )mC(O)N(R21)-, R,,R24NC(O)-Cl 3 alkoxy or R 26 C(O)(CH 2 )mN(R 2 ,)-; C 2 _alkenyl substituted by R 23 R 24 NC(0)-; 5 C26 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, 10 piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C, alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C, 4 alkyl)amino optionally substituted by one or more halogen atoms; 15 C,. 6 acyl or aroyl; R 6 is a: C,_4 alkyl optionally partially or fully halogenated and optionally substituted with R26; 20 each R 7 , Re, R 9 , R 1 0 io, R 1 2 , R 1 3, R 1 4 , R 15 , R 1 7 , R 1 9 , R 25 and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C 1 - 4 alkyl)amino optionally partially or fully halogenated; 25 each R 11 and R 16 is independently: hydrogen or C,4 alkyl optionally partially or fully halogenated; R,, is independently: 30 hydrogen or a C1-4 alkyl optionally independently substituted with oxo or R 25 ; R 20 is independently:. 01.10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; 35 R 21 is independently: hydrogen or C1.3 alkyl optionally partially or fully halogenated; each R 22 , R 23 and R 2 4 is independently: WO 03/084503 PCT/EPO3/03434 183 hydrogen, C1.6 alkyl optionally partially or fully halogenated, said C. alkyl is optionally interrupted by one or more O, N or S, said C. alkyl also being independently optionally substituted by mono- or di-(C 1 . 3 alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C,.4alkyl)amino each of which is 5 optionally partially or fully halogenated and optionally substituted with mono or di-(C,-. 3 alkyl)amino; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 or2; o10 WisOorSand pharmaceutically acceptable derivatives thereof. 13) Pharmaceutical preparations suitable for inhalation containing at least one p38 15 kinase inhibitor in a therapeutically effective amount for treating mucus hypersecretion. 14) Pharmaceutical composition according to claim 13, characterised in that a single administration corresponds to a dose of the p38 kinase inhibitor of 100 to 20 10000pg. 15) Pharmaceutical composition according to claim 13 or 14, characterised in that it is a formulation selected from among inhalable powders, propellant-containing metering aerosols and propellant-free inhalable solutions or suspensions. 25 16) Pharmaceutical composition according to claim 13, 14 or 15, characterised in that it is an inhalable powder which contains the p38 kinase inhibitor in admixture with suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, 30 or mixtures of these excipients with one another. 17) Inhalable powder according to claim 16, characterised in that the excipient has a maximum average particle size of up to 2501-m, preferably between 10 and 150gm. 35 18) Capsules, characterised in that they contain an inhalable powder according to claim 16 or 17. WO 03/084503 PCT/EPO3/03434 184 19) Pharmaceutical composition according to claim 15, characterised in that it is an inhalable powder which contains only the p38 kinase inhibitor as its ingredients. 20) Pharmaceutical composition according to claim 15, characterised in that it is a 5 propellant-free inhalable solution or suspension which contains water, ethanol or a mixture of water and ethanol as solvent. 21) Pharmaceutical composition according to one of claims 13 to 20, characterised in that the p38 kinase inhibitor is selected from the group of compounds 10 disclosed in US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 15 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 20 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 25 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 30 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 35 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and JP 2000 86657. WO 03/084503 PCT/EPO3/03434 185 22) Pharmaceutical composition according to claim 21, characterised in that the p38 kinase inhibitor is selected from the group of compounds disclosed in US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 5 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403. O10 23) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 1 R 1 N N 15 wherein R 1 , R 2 , and R 4 may have the meanings given in claim 5. 24) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 2 R N,-(CH2)nAr 2 wherein R 1 , R 2 , Ar, m, n, and I may have the meanings given in claim 6. 2 20 wherein R 1 , R 2 , Ar, m, n, and I may have the meanings given in claim 6. WO 03/084503 PCT/EPO3/03434 186 25) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 3a, 3b, 3c, or 3d R 3 R -2 R Z R 3-Z2 R R 3a, R 3b, R 3c, or 5 Z2 z R R 3d wherein R 1 , R 2 , R 3 , Z1, and Z 2 , have the meanings given in claim 7. o10 26) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 4 x Ar.. N NAr2- L - Q I I H H 4 wherein Arl, Ar 2 , X, L and Q may have the meanings given in claim 8. 15 27) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 5 W Ar 'N ) N .Ar-X-Y-Z I I H H 5 wherein Ar, Ar 2 , W, X, Y and Z may have the meanings given in claim 9. 20 WO 03/084503 PCT/EPO3/03434 187 28) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 5a W Ar -N N Ar2-X-Y-Z I I H H 5a wherein Ar, Are, W, X, Y and Z may have the meanings given in claim 10. 5 29) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 6 W G'N NJ Ar-X-- Z I I H H 6 wherein Ar, W, G, X, Y and Z may have the meanings given in claim 11. 10 30) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 7 W G'E .NAr-X-Y-Z H 7 7 wherein Ar, W, G, E, X, Y and Z may have the meanings given in claim 12. 15 20 25