MXPA04009605A - Method of treating mucus hypersecretion. - Google Patents

Method of treating mucus hypersecretion.

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Publication number
MXPA04009605A
MXPA04009605A MXPA04009605A MXPA04009605A MXPA04009605A MX PA04009605 A MXPA04009605 A MX PA04009605A MX PA04009605 A MXPA04009605 A MX PA04009605A MX PA04009605 A MXPA04009605 A MX PA04009605A MX PA04009605 A MXPA04009605 A MX PA04009605A
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Mexico
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alkyl
optionally
phenyl
amino
groups
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MXPA04009605A
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Spanish (es)
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Jung Birgit
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Boehringer Ingelheim Pharma
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Publication of MXPA04009605A publication Critical patent/MXPA04009605A/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61P11/12—Mucolytics
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Abstract

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 hypersecretion. Furthermore the invention is directed to pharmaceutical compositions suitable for inhalation comprising p38 kinase inhibitors and to methods for the preparation thereof.

Description

The invention relates to the use of p38 kinase inhibitors for the preparation of a pharmaceutical composition suitable for inhalation, intended for the treatment of mucus hypersecretion. In addition, the invention relates to pharmaceutical compositions suitable for inhalation, comprising p38 kinase inhibitor agents and methods for their preparation. BACKGROUND OF THE INVENTION Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPKs, from Mitogen-Activated Protein Kinases) has been discovered. Members of this family are Ser / Thr kinases, which activate their substrates by phosphorylation [B. Stein and collaborators, Ann. Rep. Med. Chem., 31, pages 289-98 (1996)]. MAPKs are activated on their own by a variety of signals, including those of growth factors, cytokines, UV (ultraviolet) radiation, and stress-inducing agents. A particularly interesting MAPK is p38. P38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP of Cytokine Suppressive Anti-inflammatory Drug Binding Protein) and as RK, Ref .: 158323 and induced with an LPS. Since then, p38 has been isolated and sequenced, as has been the cDNA that encodes it in humans and mice. The activation of p38 has been observed in cells stimulated by stresses, such as a treatment of lipopolysaccharides (LPS), UV, anisomycin, or by osmotic shock, and by cytokines, such as IL-1 and TNF. Based on this finding, it is believed that p38, together with other MAPKs, have a role in mediating the cellular response to inflammatory stimuli, such as accumulation of leukocytes, activation of macrophages / monocytes, tissue resorption, fever, responses to acute phases and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, platelet aggregation induced by thrombin, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. The p38 inhibitory agents have also been implicated in the area of pain administration and treatment by inhibiting the induction of prostaglandin endoperoxides synthase-2. In the conductive airways of the respiratory system, the mucociliary system serves as the main defense mechanism to move particles or digestive tracts, which have been inhaled, out of the airways into the lungs. present in fluids present in the airways serve to limit the toxicity of the particles and deactivate the infectious agents.The physical mechanism of coughing serves to expel mucus from the passages of airways (see, for example, "Foundation of Respiratory Care, "Pierson and Kacmarek, editing coordinators (1992) Churchill Livingstone Inc. New York, New York," Harrison's Principles of Internal Medicine ", Fauci and collaborators, editing coordinators (1997) 14th Edition, McGraw Hill, New York , New York) The mucociliary system consists of ciliated epithelial cells, epithelial goblet cells, and serous and mucosal cells located in submucosal glands The cilia are surrounded by an aqueous layer (periciliar fluid) secreted within the lumen of an airway passage by the active transport of chloride and by the passive movement of water through the epithelium. The cilia make contact with the mucus that floats on this aqueous layer, and through a unidirectional propulsive movement they provide a movement of the mucus towards the glottis (see the quote by Pierson and Kacmarek). The mucus is produced by epithelial goblet cells and submucosal gland cells and is secreted within the lumen of the airway after degranulation. "While mucus generally facilitates the clearance of inhaled particles or infectious agents, a hypersecretion of mucus in the airways can cause a progressive obstruction of these airways. In peripheral airways, cough is ineffective in clearing secretions. In addition, because of their small dimensions, small airways that contain many goblet cells are particularly vulnerable in the obstruction of the airways by mucus. A hypersecretion of the airways affects a substantial number of individuals. Hypersecretion has been implicated, for example, in cystic fibrosis, which is one of the most common fatal genetic diseases in the world. Cystic fibrosis is an autosomal recessive disease that results in the mucosal cell of an airway becoming incapable of responding to activation by a cyclic AMP-dependent protein kinase of the chloride ion channels of the membranes (Pierson et al. Kacmarek). The subsequent electrolyte imbalance reduces the level of hydration of mucus from the airways, thereby resulting in a very viscous mucus in the lungs of an individual afflicted with cystic fibrosis. A hypersecretion obstructs the air passages of individuals with cystic fibrosis, further compromising the function of__the__pjlmon-e-s --- | -CoTño a result of high levels of mucus in the lungs of patients with hypersecretory lung diseases; Mucus clearance is reduced. Pathological agents such as bacteria, eg Pseudomonas aeruginosa, frequently establish colonies within the mucus, resulting in frequent infection of the lungs. Classical methods of treating afflicted individuals with hypersecretion of the airways include antibiotic therapy, bronchodilators (eg, methylxanthines, sympathomimetic agents with strong S2 adrenergic stimulatory properties, anticholinergic agents), use of systemic or inhaled corticosteroids , liquefaction of the mucus by oral administration of expectorants, and supply in the form of aerosols of "mucolytic" agents, P-ex. water, hypertonic saline solution (see Harrison's citation, supra). A newer therapy for cystic fibrosis is the administration of DNAse to target mucus or sputum with richness in DA N (Shak et al. (1990) Proc. Nati. Acad. (USA) 87: 9188-9192; Hubbard, RC et al (1991) N. Engl. J. Med. 326: 812). In addition, a physical therapy of the thorax, consisting of percussion, vibration and drainage, is also used to facilitate the clearance of viscous mucus. A lung transplant may be a final option for the treatment of severe mucosal secretions. Specifically, there is a need for a specific modality that reduces the formation of mucus secretions in the airways. DETAILED DESCRIPTION OF THE INVENTION Surprisingly, it has been found that certain p38 kinase inhibitors, administered by the inhalation route, are suitable for the reduction of a mucus hypersecretion. Accordingly, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, in particular cystic fibrosis. P38 kinase inhibitor agents, applicable within the scope of day invention, are known in the art. Suitable compounds are described, for example, in U.S. Pat. US 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 Patent 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 97/35856, 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 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 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 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 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 disclosures are all incorporated by reference in their entirety. Of particular interest for the use according to the invention are the p38 inhibitory agents which are described 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 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. 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 mucosal hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of Formula 1 as disclosed in WO 99/01131 is a 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 a substituent additional independent selected from alkyl Ca-, halogen, hydroxy, alkoxy Ci-4, alkyl Cx- -thio, alkyl Ci-4-sulfinyl, CH2ORi2, amino, amino substituted with mono- and di-alkyl Ci-6, a heterocyclyl ring with N, whose ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or Ri5, or is N (Ri0) C (O) Rb or NHRa; it is oxygen or sulfur; is phenyl, naphth-l-yl or naphth-yl, or a heteroaryl, which is optionally substituted with one or two substituents, each of which is independently selected, and which, for a 4-phenyl substituent, 4-naphth- l -yl, 5-naphth-2-yl or 6-naphth-2-yl, is halogen, cyano, nitro, C (Z) NR7R17, C (Z) OR16, (CR10R2o) vCOR12, SR5, SOR5, OR12, C1-4alkyl substituted with halo, C1-4alkyl, ZC (Z) R12, NR10C (Z) R16, or (CR10R20) vNR10R2o and that, for other substitution positions, is halogen, cyano, C (Z) NR13Ri4, C (Z) OR3, (CR10R20) m "COR3, S (0) R3, 0R3, C1-alkyl substituted with halo, C1-alkyl is oxygen or sulfur; integer that has a value of 1 to 10, is 0, or an integer 1 or 2, is an integer that has a value of 1 or 2, is 0, or an integer that has a value of 1 to 5; is 0, or an integer having a value of 1 to 2, is -C (H) (A) (R22) is an optionally substituted aryl, heterocyclyl or heteroaryl ring, or A is a substituted Ci-10 alkyl is an optionally substituted Ci-10 alkyl, is aryl, arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, heteroaryl, heteroaryl-C1.6alkyl, wherein each of these moieties may be optionally substituted; is hydrogen, Ci_6 alkyl, C3-7 cycloalkyl, ar ilo, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-6 alkyl, heterocyclyl, or heterocyclyl-C 1-4 alkyl, wherein each of these residues may be optionally substituted; is heterocyclyl, heterocyclyl-Ci-i0 alkyl or R8; is hydrogen, C 1-4 alkyl, C 2- t alkenyl, C 2-4 alkynyl R 6 is hydrogen, a pharmaceutically acceptable cation, C 1-4 alkyl, C 3-7 cycloalkyl, aryl, aryl-C 1-4 alkyl / heteroaryl, heteroaryl-alkyl Ci_, heterocyclyl, aryl, or Ci-i0 alkanoyl; 7 and R17 are each independently selected from hydrogen or Ci-4 alkyl, or R7 and Ri7, together with the nitrogen to which they are attached, form a 5- to 7-membered heterocyclic ring, which ring optionally contains an additional selected heteroatom between oxygen, sulfur or NR15; R8 is C1-10 alkyl, Ci_i0 alkyl substituted with halo, C2-io alkenyl, C2-io alkynyl, C3 cycloalkyl, C5 cycloalkenyl, aryl, aryl-Ci-i0 alkyl, heteroaryl, heteroaryl-Ci-i0 alkyl, ( CR10R20) nORn, (CR10R20) nHS (O) 2RIB, (CR10R20) nRi3 i4; wherein the aryl, arylalkyl, heteroaryl or heteroaryl-alkyl may be optionally substituted; R9 is hydrogen, C (Z) R7 or optionally substituted Ci_i0 alkyl, S (0) 2Ri8 / optionally substituted aryl or optionally substituted aryl-alkyl; Rio and R20 are each independently selected from hydrogen or Ci-4 alkyl; -Ri is hydrogen, Ci_i0 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylC1_10 alkyl, aryl, arylC1-yl, heteroaryl or heteroaryl-C1-10 alkyl, wherein these moieties may be optionally substituted; R12 is hydrogen or Ri6; Ri3 and Ri are each independently selected from hydrogen or optionally substituted Ci-4 alkyl, optionally substituted aryl or optionally substituted arylCi-4alkyl, or together with the nitrogen to which they are attached, form a heterocyclic ring of 5 to 7 members, whose ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; R15 is R10 or C (Z) -C1-4alkyl; R 16 is C 1-4 alkyl, C 1-4 alkyl substituted with halo, or C 3-7 cycloalkyl; R18 is Ci-i0 alkyl, C3_7 cycloalkyl, heterocyclyl, aryl, arylCi -ioalkyl, heterocyclyl, heterocyclylCi-10alkyl / heteroaryl or heteroaryl-Ci-iOalkyl or a pharmaceutically acceptable salt thereof.
Methylene carbon in this chain is a tertiary carbon, and that this will contain a hydrogen residue. This ethylene group has two additional substituents, a residue R22 and a residue A, -C (H) (A) (R22) · Ni A or R22 can be a C1-10 alkyl radical. In a preferred embodiment, R2 is a residue -C (AAi) (A), in which AAi is the residue R22, but is specifically the side chain residue (R) of an amino acid, as described hereinafter. Suitably, A is a C3-7 cycloalkyl ring, aryl, heteroaryl or optionally substituted heterocyclyl, or A is a substituted C1-10 alkyl moiety. When A is an aryl, heteroaryl and heterocyclyl ring, the ring may be independently substituted one or more times, preferably 1 to 3 times, with C1-10 alkyl; halogen; C1-10 alkyl substituted with halo such as CF3; (CR10R2o) tORn; (CR10R2o) tNR12Ri4, especially amino or mono- or di-alkyl Ci-4-amino; (CRi0R20) tS (0) m Ris, where m is 0, 1 or 2; SH; NR10C (Z) R3 (such as NHCO (C1-10 alkyl)); or NR10S (O) raR8 (such as NHS02 (Ci-io alkyl)) Appropriately, t is 0, or an integer from 1 to 4.
When A is an optionally cycloalkyl -s s-t-it "U" rdo7 then it is taT as defined below with the R22 substitution. When A is an optionally substituted heterocyclyl ring, the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or piperidinyl ring. When A is an optionally substituted aryl moiety, it is preferably a phenyl ring. When A is an optionally substituted heteroaryl ring, it is as defined below in the definitions section. When A is a substituted Ci-i0 alkyl moiety, the alkyl chain may be linear or branched. The chain is independently substituted 1 or more times, preferably 1 to 3 times, with a halogen, such as fluorine, chlorine, bromine or iodine; C1-i0 alkyl substituted with halo, such as CF3; C 3-7 cycloalkyl, C 1-6 alkoxy, such as methoxy or ethoxy; Ci-io alkoxy substituted with hydroxy; C1-i0 alkoxy substituted with halo, such as OCF2CF2H; ORn; S (0) mR18 (where m is 0, 1 or 2); NR13R14; C (Z) NR13R14; S (0) m'NRi3 i4; NR23C (Z) Rli; NHS (0) 2R18; C (Z) Rn; OC (Z) Rli; C (Z) ORlx; C (Z) NRlxOR9; N (OR6) C (Z) NR13R14; N (OR6) C (Z) ii; C (= NOR6) Rli; NR23C (= NR19) NR13R14; OC (Z) NR13R14; NR23C (Z) NR13Ri4; or NR23C (Z) ORi0. Preferably A is a C3-7 cycloalkyl, or a Ci-6 alkyl, more preferably a Ci-2 alkyl, ie a methylene or ethylene moiety, more preferably a res-to-nfietii'eñó-que-e 'sfaT replaced with one of the groups indicated above. Preferably, when A is an alkyl Ci_i0, it is substituted with ORn, wherein Rn is preferably hydrogen, aryl or arylalkyl; R13R14; OC (Z) Rn; C (Z) ORn. More preferably, A is substituted with ORn in that Rn is hydrogen. Suitably, R22 is an Ci-io alkyl chain, which chain can be linear or branched and can be optionally substituted independently, one or more times, preferably 1 to 3 times, with a halogen, such as fluorine, chlorine or iodine; a C1-10 alkyl substituted with halo; a Ci-io alkoxy, such as methoxy or ethoxy; an alkoxy < -? 0 substituted with hydroxy; a C1-i0 alkoxy substituted with halo, such as OCF2CF2H; ORn; S (0) raR18; NR13Ri4; C (Z) NR13Ri4; S (0) n, .NR13R14; NR23C (Z) Rli; NHS (0) 2Ri8; C (Z) Rli; OC (Z) ORxl; C (Z) ORn; C (Z) NRiiORg; N (0R6) C (Z) NR13R14; N (0R6) C (Z) R1X; C (= NOR6) Rn; NR23C (= NR19) NR13R14; OC (Z) NR13R14; NR23C (Z) NR13R14; NR23C (Z) OR10; an optionally substituted C3-7 cycloalkyl; an optionally substituted aryl, such as phenyl; an optionally substituted heteroaryl; or an optionally substituted heterocyclyl. Optional substituents on these cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are as defined herein below. they contain a carbon as the first connecting group, that is C (Z) ORn; C (Z) RuOR9, C (Z) Ru, C (Z) NR13R14 and C (= NOR6) Rn, this may be the only carbon in the alkyl chain. Therefore, the R22 group can be, for example, a carboxy, an aldehyde, or an amide, as well as a substituent of a methylene unit, such as carbamoylmethyl, or acetamidomethyl. Preferably R22 is an unsubstituted or substituted C1-6 alkyl group, such as a Ci-3 alkylene moiety such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted with one of the above-mentioned moieties, or as noted above , substituent groups containing a carbon can be substituents for the first methylene unit of the alkyl chain, such as carboxy, C (0) ORn; C (0) NRi3Ri4, or R22 is an optionally substituted aryl group, such as a benzyl or phenethyl group. In other words, R22 may be an optionally substituted alkyl group, or R22 may be C (Z) ORn; C (Z) NRnOR9, C (Z) Rn, C (Z) NR13R14 or C (= NOR6) Rn. Preferably, R22 is an unsubstituted or substituted C1-6 alkyl group, more preferably an alkylene chain Ci_2, such as a methylene or ethylene moiety, most preferably methylene. Preferably, the alkyl chain is substituted with ORn, where Ra is preferably hydrogen, aryl or phenethyl. More preferably, R22 is phenyl, benzyl, CH2OH or CH2-0-aryl. Preferably, one or both of A and R22 contain hydroxy moieties, such as in C 1-6 alkyl-OR n, wherein R 1 X is hydrogen, ie CH 2 CH 2 OH. Suitably, when AAi is the side chain residue (R) of an amino acid, then it is a Ci- 6 alkyl group, which may be linear or branched. This means the R group of the core amino acid of the structure R-C (H) (COOH) (NH2). The residue term R is, for example, CH3- for alanine, (CH3) 2CH- for valine, (CH3) 2CH-CH2- for leucine, phenyl-CH2- for phenylalanine, CH3-S-CH2-CH2- for methionine , etc. All the generally recognized amino acids are included in these groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other amino acids present in nature, not found in proteins, such as β-alanine, α-amino-butyric acid, homocysteine, homoserin, citrulline, ornithine, canavanine, djenkolic acid and β-cyano-alanine, or other amino acids _ that ___ no_-sen - of Preferably, AA ^ is the residue of phenylalanine, or alanine. Preferably, A is a C 1-10 alkyl substituted with hydroxy and R is a C 1-10 alkyl or a C 1-10 alkyl substituted with hydroxy. 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 document O 99/01131: 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; (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -imidazole; In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of a pharmaceutical composition inhalale-d sfri-nada to the treatment of mucosal hypersecretion, characterized in that the p38 kinase inhibitor is selects among the compounds of formula 2_ as disclosed in US 6,277,989 and its pharmaceutically acceptable salts, wherein it is H (1-6C) alkyl or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR2, SR , -OOCR, -NROCR, RCO, -COOR, -CO R2 / -S02NR2, CN, CF3 and N02, in which each of the R is independently H or lower alkyl (of 1-4 C); R2 is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR2, S02NR2, CN, CF3 or N02, wherein each of the R is independently H or lower alkyl ( of 1-4 C), each of the 1, 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 _juno___de el-O-ally-substituted with alkyl, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, optionally substituted, halo, OR, NR2, SR, -OOCR, -NROCR, RCO, -COOR, - C0NR2, S02NR2, CN, CF3 or N02, in which each R is independently H or alkyl (1-4C); 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 compounds of formula 2 as they are disclosed in US 6,277,989, in which R1 is H; R2 is halo, m is O, 1 or 2, and l is 1 or 2; Ar is 4-pyridyl. In a particularly 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 US 6,277,989: 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; 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 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) -S - (3-methoxybenzylamino) quinazoline; 2- (2-fluorophenyl) -4- (4-pyridylamino) -6- (4-methoxybenzylamino) | quinazole ina; 2- (2-fluorophenyl) -4- (4-pyridylamino) -6- (2-isobutylamino) -quinazoline; and 2- (2-fluorophenyl) -4- (4-pyridylamino) -6- (4-methylmercaptobenzylamino) -quinazoline; and their pharmaceutically acceptable salts.
In yet another preferred embodiment, the invention is the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the inhibitory agent of p38 kinase is selected from the compounds of formula 3a, 3b, 3c or 3d as disclosed in US 6,340,685 and their pharmaceutically acceptable salts, wherein each of the Z1 and Z2 is independently CR4 or N; wherein each of them is independently selected from H and alkyl (from 1-6C); wherein said alkyl optionally includes one or more heteroatoms selected from O, S, and N, and wherein said alkyl is optionally substituted with one or more substituents selected from halo, OR, SR, NR2_, RCO-γ-? T? ?, CONR2, OOCR, NROCR, CN, = 0, a carbocyclic ring or a 5- or 6-membered heterocyclic ring containing 1-2 N heteroatoms, and an aromatic ring optionally containing 1-2 N heteroatoms, in which R in the optional substituent precedents is H or alkyl (from 1-6C); is where X1 is CO, SO, CHOH or S02; m is 1; Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is 0, 1 or 2; Z3 is N; X2 is CH or CH2; and Ar consists of one or two phenyl moieties directly coupled with X2, said one or two phenyl moieties being optionally substituted with a substituent selected from halo, nitro, (1-6C) alkyl, (1-6C) alkenyl, CN, CF3, CO, COOR, CONR2, NR2 ,, QR-, SR -, - OOCR "; ÑROCR, (in which R in the foregoing is H or alkyl of 1-6C), and phenyl, for its part optionally substituted with the preceding substituents; R2 is selected from H, and alkyl ( 1-6C), wherein said alkyl optionally includes one or more heteroatoms which are selected from 0, S, and N, and wherein said alkyl is optionally substituted with one or more substituents selected from halo, 0R, SR, NR2, RCO , COOR, C0NR2, OOCR, NROCR, (in which R, in the foregoing, is H or alkyl of 1-6C), CN, = 0, a saturated carbocyclic ring of 5 or 6 members or a heterocyclic ring containing 1-2 heteroatoms N, and a 6-membered aromatic ring optionally containing 1-2 heteroatoms N; R3 is H, halo, N02, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR2, RCO, COOR, C0NR2, OOCR, or NROCR in which R is H or alkyl (from 1-6C.) In a particularly preferred embodiment, the invention relates to the use of kinase inhibiting agents. p38 for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the following compounds disclosed in US 6,340,685: carboxamide; 4- (2,3-difluorobenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (3, 5-difluorobenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (3-chlorobenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-carboxymethylbenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-methoxy-benzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-trifluoromethoxybenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-methylbenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (2,4-dichlorobenzoyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (3,4-dichlorobenzoyl) -piperazinyl-benzimidazole-5-ca boxamide; 4- [trans-3- (trifluoromethyl) -cinmoyl] -piperazinyl-benzimidazole-5-carboxamide; 4- (4-chlorobenzoyl) -piperazinyl-benzimidazole-5-carboxamide; 4-benzomethylbenzoyl-piperazinyl-benzimidazole-5-carboxamide; 4- (2-trifluoromethylbenzoyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-methoxybenzoyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (3,4-dichlorophenyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-chlorobenzhydryl) -piperazinyl-benzimidazole-5-carboxamide; 4-trans-1-cinnamylpiperazinyl-benzimidazole-5-carboxamide; 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; 4-benzylpiperazinyl-benzimidazole-5-carboxamide; 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; 4- (biphenylmethyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-phenoxybenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4 - . 4- (4-quinolinylmethyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (4-chlorobenzyl) -piperazinyl-1 - (2-propyl) -indole-5-carboxamide; 4- (3-chlorobenzyl) -piperazinyl-benzimidazole-5-carboxamide; 4- (3-chlorobenzyl) -piperazinyl-N- (2-propyl) -benzimidazole-5-carboxamide; 4- (3-chlorobenzyl) -piperazinyl-N- (2-propyl) -benzimidazole-6-carboxamide; 4- (3-Chlorobenzyl) -piperazinyl-N-methyl-benzimidazole-5-carboxynamine; 4- (3-chlorobenzyl) -piperazinyl-N-methyl-benzimidazole-6-carboxamide; 4- (3-chlorobenzyl) -piperazinyl -N-ethyl-benzimidazole-5-carboxamide and 4- (3-chlorobenzyl) -piperazinyl-N-ethyl-benzimidazole-6-carboxamide In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalablé pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the compounds of formula 4 as disclosed in document 00 00333384 wherein it is a heterocyclyl group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene and in which Ari may be substituted with one or more i, R2 or R3; is phenyl, naphyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinolone, tetrahydroisoquinoline, benzimidazole benzofuran, indanyl, indenyl or indole, each of which being optionally substituted with one to three groups R2; a linker group, is a carbon chain of Ci_i0, saturated or unsaturated, branched or unbranched; wherein one or more methylene groups are optionally independently replaced by O, N or S; and wherein said linker group is optionally substituted with 0-2 oxo groups and with one or more branched or unbranched Ci-4 alkyl groups, which may be substituted with one or more halogen atoms; it is selected from the group consisting of: a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo [, 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, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, mono- or di- (Ci_3 alkyl) amino, Ci_6 alkyl-S ( 0) my phenylamino in which the phenyl ring is optionally substituted with one to two groups consisting of halogen, C 1 -C 6 alkyl and C 1 -C alkoxy; - Tetrahydrophenyl tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, sulfur pentamethylene, pentamethylene sulphoxide, pentamethylene sulfone, tetramethylene sulfide, tetraraethyloxy sulfoxide and tetramethylene sulfone, which are optionally substituted with one to three groups selected from the group consisting of Ci-6alkoxy Ci-6 alkoxy, hydroxy, mono- or di- (Ci_3 alkyl) amino-Ci-3-alkyl, phenylamino-Ci-3-alkyl and Ci-3-alkoxy-C 3 -alkyl; Ci-6 alkoxy, a secondary or tertiary amine in which the amino nitrogen is covalently linked to groups selected from the group consisting of Ci_3 alkyl and Ci-5 alkoxyalkyl and phenyl in which the phenyl ring is optionally substituted with one to two groups consisting of halogen, Ci-6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, C1.6-S (0) r # phenyl-S (0) t, in which the ring of phenyl is optionally substituted with one to two groups consisting of halogen, Ci-6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino; is selected from the group consisting of: "(_a") a branched or unbranched C3-i0 alkyl, which may optionally be partially or fully halogenated, and optionally may be substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, each of said phenyl, naphthyl or heterocyclyl groups being selected from the group described hereinabove, being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci_6 alkyl, which is optionally partially or fully halogenated, C3-8 cycloalkyl, cycloalkenyl Cs-s, hydroxy, cyano, Ci_3-oxy alkyl which is optionally partial or Fully halogenated, NH2C (0) and dialkyl (Ci-3) aminocarbonyl; (b) a 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 optionally substituted with one to three groups Ci-3 alkyl, or an analogous group -a-d ± cho "~ cycloalkyl group, in which one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, > C = 0, > C = S and NH;) a branched C3-10 alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three branched or unbranched Ci-5 alkyl groups, phenyl, naphthyl or heterocyclyl , each of said heterocyclyl groups being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, fu ryl, isoxazolyl and isothiazolyl, and each of said phenyl, naphthyl or heterocyclyl groups being substituted with 0 to 5 groups selected from halogen, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl , cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, Ci_3-oxy alkyl which is optionally partially or fully halogenated, NH2C (0), mono- or di-alkyl (Ci- 3) -amino-carbonyl; D) a C5-7 cycloalkenyl selected from -een-j-ano-consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group may optionally be substituted with one to three Ci-3 alkyl groups; (e) cyano and, (f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; it is selected from the group consisting of: branched or unbranched Ci-6 alkyl, which may optionally be partially or fully halogenated, acetyl, aroyl, branched or unbranched C1-4 alkoxy, which may optionally be partially or fully halogenated, halogen , methoxycarbonyl and phenylsulfonyl; is selected from the group consisting of: a) a phenyl, naphthyl or heterocyclyl 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, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naftipyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein said phenyl group, -n¾- £ t "±±" or ~ no ~ heterocyclyl is optionally substituted with one to five groups selected from the group consisting of a branched or unbranched Ci-alkyl, phenyl, naphthyl, heterocyclyl selected from the group described herein above , a branched or unbranched Ci_6 alkyl optionally partially or wholly halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5 alkyl, naphthyl Ci_5 alkyl, halo, hydroxy, cyano, alkyl Ci-3-oxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy in which the heterocyclic moiety is selected from the group described hereinabove, nitro, amino, mono- or di-alkyl (Ci-3) - amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove, H2C (0), a mono- or di-alkyl (Ci-3) -aminocarbo nyl, Ci-5-alkyl (0) -Ci-4 alkyl, amino-Ci-5-alkyl, mono- or dialkyl (Ci-3) -amino-Ci-s alkyl, amino-S (0) 2, dialkyl (Ci-3) -amino-S (O) 2, R 4-Ci-5 alkyl, R 5 -alkoxy Ci 6 R 6 -C (O) -Cl 5 alkyl and R 7 -Ci 5 -alkyl (R 8) N; a condensed aryl selected from the set -consta of benzocyclobutanyl, indanyl, indenyl, di idronaftilo, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, ciclohexanopirazina, ciclopentanopiridazina, ciclohexanopiridazina, ciclopentanoquinolina, ciclohexanoquinolina, ciclopentanoisoquinolina , cyclohexaneisoquinoline, cyclopentanoindole, cyclohexaneindole, cyclopentanebenzimidazole, cyclohexanebenzimidazole, cyclopentanebenzoxazole, cyclohexanebenzoxazole, cyclopentanoirnidazole, cyclohexaneimidazole, cyclopentanethiophene 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, branched or unbranched Ci_6 alkyl which is optionally partially or fully halogenated, halo, cyano, Ci-3 -oxi alkyl which is optionally partially or fully halogenated, -inylphosphoryloxy, heterocyclyloxy in which the heterocyclic moiety it is selected from the group described hereinabove, nitro, amino, mono- or di-alkyl (Ci-3) -amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove, NH2C (0) , a mono- or di (C1-3) alkyl-aminocarbonyl, alkyl Ci- -OC (0), Ci-5-C (0) alkyl-Ci-4 alkyl branched or unbranched, a C 1-5 -alkyl, mono- or di-alkyl (Ci-3) -amino-Ci-5-alkyl, R 9-Ci-5-alkyl, Ri-alkoxy Rii-C (O) -C1-5 alkyl and R12-Ci-5 alkyl (Ri3) N; a cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl may optionally be partially or fully halogenated and may optionally be substituted with one to three Ci-3 alkyl groups; a C5-7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group may optionally be supersaturated with three alkyl groups Ci - 3; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; f) a branched or unbranched Ct-6 alkyl, which may optionally be partially or fully halogenated; or Ri and R2 taken together, can optionally form a fused phenyl or pyridinyl ring, and wherein each of R8, R13 is independently selected from the group consisting of: hydrogen and branched or unbranched C1-4 alkyl, which it may optionally be partially or totally halogenated; each of the R4 / 5 / s »7 9 # io R11 and R12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; m = 0, 1, 2; r = 0, 1, 2; t = 0, 1, 2; X = O or S, and their acids and physiologically acceptable salts. In a preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition for the prevention of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selects among the compounds of formula 4 as disclosed in WO 00/43384, wherein Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl. A more preferred subgeneric day invention comprises the use of compounds of formula 4 wherein Ar2 is naphthyl. A yet more preferred subgeneric day invention comprises the use of compounds of formula 4, as described in the immediately preceding paragraph, wherein: Ari is thiophene or pyrazole; Ar2 is 1-naphthyl; L is a saturated or unsaturated, branched or unbranched Ci-6 carbon chain in which one or more methylene groups are optionally independently replaced by 0, N or S; and wherein said linker group is optionally substituted with 0-2 oxo groups and one or more branched or unbranched Ci-4 alkyl groups, which may be substituted with one or more halogen atoms; Ri is selected from the group consisting of branched or unbranched Ci-alkyl, cyclopropyl and cyclohexyl which may optionally be partially or fully halogenated and which may optionally be substituted with one to three Ci_3 alkyl groups; R3 is selected from the group consisting of alkyl d. 4 branched or unbranched, cyclopropyl, phenyl, pyridinyl, each of which being optionally substituted as described above, alkoxycarbonylalkyl; C 1-6 alkyl branched or unbranched; cyclopropyl or cyclopentyl optionally substituted as described above. A still more preferred subgeneric day invention comprises the use of compounds of formula 4, as described in the immediately preceding paragraph, wherein Ari is pyrazole. A still further more preferred subgeneric aspect of day invention comprises the use of compounds of formula 4, as described in the immediately preceding paragraph, wherein L is a saturated carbon chain of Ci-5, in which one or more methylene groups they are optionally independently replaced by O, N or S; and wherein said linker group is optionally substituted with 0-2 oxo groups and one or more branched or unbranched Ci-4 alkyl groups, which may be substituted with one or more halogen atoms; - R-eai-i-zaeirone ~ s particularly preferred of L are propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino, each of which being optionally substituted as described herein. A more particularly preferred embodiment of L is optionally substituted ethoxy. The following compounds are representative of the compounds of formula 4 and have a particular interest according to the invention: 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -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- (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; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (2- (methoxymethyl) morpholin-4-yl) ethoxy) -naphthalen-1-yl] -urea; 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-methylethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl) -1-methylethoxy) naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-tl mo3? í © ^^ - 4 - di-e 'ox ^ "iTaT" e ^ "in - i TT] -urea; 1- [5-tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (l-oxothiomorpholin-4-yl) ethoxy] ) naphthalene-1-yl] -urea; 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholine 4-yl-ethoxy) -3-methylnaphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-piperidin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (l-acetylpiperidin-4-yl) ethoxy) naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-thiazolidin-3-yl-ethoxy) naphthalen-1-yl] -urea; . 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl-carbonyloxo) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p-tolyl -2H-pyrazol-3-yl] -3- [4- (2- (tetrahydropyran-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (N-methyl) 2 - . 2-methoxyethylamino) ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (1-oxo-tetrahydrothiophen-3-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-propyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (morpholin-4-ylmethyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-thiazolidin-3-yl-propyl) naphthalen-1-yl] -urea; & e-e ^ -t-rl-¾- ^ p-Ccrril ^ H ^ irazol-3-i1] -3- [4 - (3 - (tetrahydropyran-2-yl-oxy) propyl) naphthalene- 1 -yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (tetrahydropyran-2-yl-oxy) propin-1-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (methoxymethyloxy) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl) -3-methyl-propin-1-yl) -naphthalene-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl) -3,3-dimethylpropin-1-yl) -naphthalene-1-yl ] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (tetrahydropyran-2-yl-oxy) butin-l-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (furan-2-ylcarbonyloxy) ropin-1-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (piperidin-1-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (2-methoxymethylmorpholin-4-yl) propin-1-yl) -naphthalene-1-yl] - urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-4-yl-methoxy] -na-phthaien-d- ^ il-urea- "1- [ 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [ 5-tere.-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3- [4- (3-pyridin-4-yl-propoxy) naph alen-1-yl] -urea; [5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-imidazol-1-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [ 5-tert.-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-benzimidazol-1-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [ 5-tert.-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (3,4-dimethoxyphenyl) -ethoxy) naphthalen-1-yl] -urea; - [5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-4-yl-methyl-amino) -naphthalen-1-yl] -urea; 1- [ 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-4-yl-carbonylamino) naphthalen-1-yl] -urea; 1- [5- tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (morpholin-4-yl-acetamido) naphthalen-1-yl] -urea, -1- [5-tert. -butyl -2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-3-yl-methylamino) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-3-yl-carbonylamino) naphthalen-1-yl] -urea; 1- [5-iso-propyl-2-phenyl-2 H -pyrazol-3-yl] -3- [4- (2-raorpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5- (tetrahydropyran-3-yl) -2-phenyl-2 H -pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1 ^ -5 ^ ciGl-oh-exHL-1 --- 2 - ie ^^ -3- [4- (2-morphol-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5- (2,2,2-trifluoroethyl) -2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morphol-4-yl-ethoxy) naphthalen-1-yl ] -urea; 1- [5- (1-methylcycloprop-1-yl) -2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene-1-yl] -urea; 1- [5-ethoxycarbonyl-2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5- (1-Methylcyclohex-l-yl) -2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene-l-yl] -urea; 1- [5-tert. -butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1 - [5- tere. -butyl -2-benzyl -2H-pyrazol-3-yl] -3 - [4 - (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4-chlorophenyl) -2H-pyrazol-3-yl] -3- [4- (2-morphol-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. butyl-2-butyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naph alen-1-yl] -urea; 1 - [5-tert. -butyl-2 - (ethoxycarbonylmethyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4-methyl-3- (2-ethoxycarbonylvinyl) phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene-1-yl ] -urea; l ^ [- 5 ^ - &, - buti ÷ - ^ - H ^ - ^ etl ^^ ~ (niórToIin-4 ^ il) methylphenyl) -2H-pyrazol-3-yl] -3- [4- ( 2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5- ere. -butil -2 -. { 4-methyl-3-dimethylaminomyl-phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl -2- (3- (2-morpholin-4-yl-ethyl) phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (3- (tetrahydropyran-4-ylamino) phenyl) -2H-pyrazol-3 -yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] - urea; 1- [5-tert. -butyl-2- (3-dimethylaminomethylphenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4- (tetrahydropyran-4-ylamino) phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morphol-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4- (3-benzylureido) phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-chloropyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; l ^ tS ^ t -rG - ^ - bu-fe-il-2 - (- pi-rG? ±? ^ 3 ^? G) ^ 2? ^? t3 ?? 1 - 3 - i 1] - 3 - [4 - (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methyl-pyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethoxy) -naph-alen-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) naphthalene- 1 - il] -urea; 1- [5-tert. -butyl-2- (2-methyl-pyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-propin-1-yl) -naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (2-dimethylaminomethyl-morpholin-4-yl) -ethoxy) -naph-alen-1-yl] -urea; 1- [5-tert. -butyl-2-iso-propyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-cyclopropyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (thiophen-3-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-cyclopentyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-iso-propyl-2H-pyrazol-3-yl] -3- [4- (tetrahydropyran-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-cyclopropyl-2H-pyrazol-3-yl] -3- [4- (1-oxo-tetrahydrothiophen-3-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (thiophen-3-yl) -2H-pyrazol-3-yl] -3- [4- (2-pyridinyl-4-yl-ethoxy) naphthalen-1-yl] -urea; 1 ^ -5 ^ -fce-re -.-- bu-t ÷ -yl-2-crciropent ~ i ~ l ~ 2H-irazoT-3-yl] -3 - [4- (pyridin-4-yl- methoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (pyridin-4-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (2-methylaminopyridin-4-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p-tolyl -2H-pyrazol-3-yl] -3- [4- (3- (1-oxo-tetrahydrothiophen-3-yl) propin-1-yl) naphthalene-1-yl] - urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (t-azolidin-3-yl) propin-1-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (tetrahydropyran-4-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-methylaminopyrimidin-4-yl-methoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (2-methylaminopyrimidin-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (4-methoxybenzimidazol-1-yl) ethoxy) -naph alen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (4-methylaminobenzimidazol-1-yl) ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (2-imidazo [4, 5-b] pyridin-1-yl) ethoxy) -naphthalene-l- il] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- [1/8] naphthyridin-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4 - (2- (3,4-dihÍJdr-o ^ 2¾ - pi-ra-ne - [- 2-3- - ±) pi-r d ± n ^ 5 ^ i'r) ^ t ^) "ña talen- -urea; 1- [5-tert-butyl-2-pyridin-3-yl-2H-pyrazole-3 -yl] -3- [4- (2-methylaminopyrimidin-4-yl-methoxy) -naphthalen-1-yl] -urea; 1- [5-tert-butyl-2- (2-methylpyridin-5-yl) ) -2H-pyrazol-3-yl] -3- [4- (2- (2-methylaminopyrimidin-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert-butyl-2] - (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (4-methoxybenzimidazol-1-yl) ethoxy) naphthalen-1-yl] -urea; [5-tert -butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (4-methylaminobenzimidazol-1-yl) ethoxy) naphthalene- l-yl] -urea; 1- [5-tert-butyl-2- (2-methylpyridin-5-yl) -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- (2-methylpyridin-5-yl) -2H-pyrazole -3 -yl] - 3- [4- (2- [1,8] naphthyridin-4-yl) ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert-butyl-2- ( 2-methylpyridin-5-yl) -2H-pyrazole ol-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-methoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-cyclopropyl-2H-pyrazol-3-yl] -3- [4- (2- (2-methylaminopyrimidin-4-yl) ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-cyclopropyl-2H-pyrazol-3-yl] -3- [4- (2- (4-methoxybenzimidazol-1-yl) ethoxy) -naphthalen-1-yl] -urea; l ^ [- 5 ^ tero -. ^ - b t - il --- 2 - ^ "(4-methylaminobenzimidazol-1-yl) -ethoxy) naphthalen-1-yl] -urea; 1- [5 - tere.-butyl-2-methyl -2H-pyrazol -3 -yl] -3- [4- (2- (2-imidazo [4, 5-b] iridin-1-yl) ethoxy) naphthalen-1-yl ] -urea; 1- [5-tere., butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2- [1,8] naphthyridin-4-yl) ethoxy) naphthalene 1-yl] -urea; 1- [5-tere. -butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2- (3,4-dihydro-2H-pyran [ 2,3-b] pyridin-5-yl) -ethoxy) naphthalen-1-yl] -urea and its physiologically acceptable acids or salts In a particularly preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the following compounds of formula 4 as disclosed in WO 00/43384: 1- [5 -tere -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naph alen-1-yl] -urea; 1- [5- ere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (cis-2,6-dimethylmorpholin-4-yl) ethoxy) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl -2-p-tolyl-2H-pyrazol-3-yl] -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; l ^ -t5 ^ -t.er-G -.- = - bu-ti-l-, 2 - p - tel - il --- 2 # -pi-r zoi ^ 3 ^ il ^ 3 ^ [ -4 ^ 2 ^ (morpholin-4-yl) -2-oxoethoxy) naphthalen-1-yl] -urea; 1- [5- tere. butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl) -2-methylethoxy) naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl) -1-methylethoxy) naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-thiomorpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p-tolyl -2H-pyrazol-3 -yl] -3- [4- (2- (1-oxothiomorpholin-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -methylnaphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p-tolyl -2H-pyrazol-3 -yl] -3- [4- (2- (morpholin-4-yl-carbonyloxo) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (tetrahydropyran-4-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (1-oxo-tetrahydrothiophen-3-yl) ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-propyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (morpholin-4-yl-methyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethyl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl -2-p-tolyl-2H-pyrazol-3 -yl] -3- [4- (3 - (. moxfo-lin ^ -4 ^ il -) - p-popi-n- ^ l --- il -) - na-f-ta -end --- il -] - urea-; - 1- [5- tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (tetrahydropyran-2-yl-oxy) propin-1-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl -2-p- tol i 1 -2H-pyrazol-3-yl] -3- [4- (3- (tetrahydropyran-2-yl-oxy) butin-l-yl) -naphthalene-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (piperidin-1-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (2-methoxymethylmorpholin-4-yl) propin-1-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (pyridin-4-yl-methoxy) naphthalen-1-yl] -urea; 1- [5-tert. butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-pyridin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-pyridin-4-yl-propoxy) naphthalen-1-yl] -urea; 1- [5-tert. butyl -2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-imidazol-1-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (3,4-dimethoxyphenyl) -ethoxy) naphthalen-1-yl] -urea; 1- [5 -terc -butyl -2-p-olyl-2H-pyrazol-3 -yl] -3- [4- (pyridin-4-yl-methylamino) naphthalen-1-yl] -urea; 1- [5- iso-propyl-2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-cyclohexyl-2 phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; morpholin-4-yl-ethoxy) naphthalene-1-yl ] -urea; 1- [5- (1-methylcycloprop-1-yl) -2-phenyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene- l -yl] -urea; 1- [5- (1-Methylcyclohex-l-yl) -2-phenyl-2 H -pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] - urea; 1- [5-tert. -butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naph alen-1-yl] -urea; 1- [5 -tere. -butyl-2- (4-chlorophenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. butyl-2-butyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2 - (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (4-methyl-3- (morpholin-4-yl) methyl phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalene- 1-yl] - urea; 1 - [5-tert. -butyl-2 - (4-methyl-3-dimethylaminomethyl-phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (3-dimethylaminomethyl-phenyl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-chloropyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [_4 ^ (- 2 ^ mor -f-Ql-in --- 4 --- il-- eto d4-naft-a-en ^ ~ i ^] iirea 1- [5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4 - (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -urea, -1- [5-tere. -butyl-2- (pyridin-3-yl) -2H-pyrazol-3-yl ] - 3- [4- (2-morpholin-4-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) naph alen-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-1-yl] -urea; 1- [ 5-tert-Butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-propin-1-yl) -naphthalene- 1-yl] -urea Particularly preferred compounds of formula 4 are: 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholine -4-yl-ethoxy) naphthalen-1-yl] -urea; 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- ( l-oxothiomorpholin-4-yl) ethoxy) naphthalene-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; 1- [5-tert. -butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-l-yl] -urea or 1- [5-tert. butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea.
In another preferred embodiment, the invention relates to The preparation of an inhalable pharmaceutical composition intended for the treatment of a mucosal hypersecretion, characterized in that the inhibitory agent of the mucosal hypersecretion of the mucosal hypersecretion p38 kinase is selected from the compounds of formula 5 as disclosed in WO 00/55139 in which : Ari is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; in which Ari can be substituted with one or more Ri, R2 or R3; Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each of which being optionally substituted with zero to three groups R2; a) a C5-8 cycloalkenyl or cycloalkenyl optionally unsubstituted with-0-2-T-T-T-γ3-aden-ss-groups of "C1-4alkyl, Ci-4alkoxy or Cinylamine alkyl branched or unbranched, b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperidine, piperazine or pyrazine, each of which being optionally independently substituted with 0-3 groups branched or unbranched Ci-4 alkyl, C 1-4 alkoxy, hydroxy, nitrile, mono- or di- (C 1-3 alkyl) amino, Ci-6-S (0) m alkyl, or halogen, is: a bond or a saturated or unsaturated, branched or unbranched Ci-4 carbon chain, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by 0, H, S (O), S (0) 2 or S , and in which Y is optionally independently substituted with 0-2 oxo groups and one or more branched or unbranched Ci-4 alkyl groups, which may be ar substituted with one or more halogen atoms; is: a) phenyl, pyridine, pyrimidine, pyridazine, imidazole. furan, thiophene, pyrano, which are optionally s_us_ti_t_ui_do-S with one-a-res-groups-consisting-of-halogen, Ci_6 alkyl, Ci-6 alkoxy, hydroxy, mono- or di- (C1-3 alkyl) amino, alkyl Ci-6-S (0) m, COOH and phenylamino in which the phenyl ring is optionally substituted with one to two groups consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; 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 , pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, Ci-6alkyl, Ci-6alkoxy, hydroxy, mono- or di- (C1-alkyl) 3) amino-Ci-3 alkyl, phenylamino-Ci_3 alkyl and Ci-3-alkoxy Ci_3 alkyl; Ci-6 alkoxy, a secondary or tertiary amine in which the amino nitrogen is covalently linked to groups selected from the group consisting of Ci-3 alkyl, Ci_5i alkoxy-pyridinyl-Ci_3 alkyl, imidazolyl-Ci_3 alkyl, tetrahydrofuranyl-alkyl Ci-3, phenylamino, in which the phenyl ring is optionally substituted with one to two halogen groups -, - aLcoxy_C-i-6-, -hydroxy-G-mono-o-di - (- aiq-ui-1) -TG- 3) amino, alkyl Ci-6-S (0) m, and phenyl-S (O) m, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_s alkoxy, hydroxy or mono - or di- (alkyl Ci-3) aniino; is: a) a branched or unbranched C3-i0 alkyl, optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl , pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each of said phenyl, naphthyl or heterocyclyl being selected from the group described hereinabove in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, nitrile, Ci-3-oxy alkyl, which is optionally partially or fully halogenated, NH2C (0) and dialkyl (Ci-3) aminocarbonyl; b) a C3_7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopene-n-tan-yl-, eie-l-ehe-xaiiii-4-yi-eiOheptanriO, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, each one of them optionally partially or wholly halogenated and optionally substituted with one to three Ci-3 alkyl groups, or a group analogous to said cycloalkyl group in which one to three ring methylene groups are replaced by groups independently selected from the group consists of 0, S, CHOH, > C = 0, > C = S and MH; a branched C3-i0 alkenyl, optionally partially or wholly halogenated and optionally substituted with one to three branched or unbranched Ci-5 alkyl groups, phenyl, naphthyl or heterocyclyl, each of said heterocyclyl groups being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of said phenyl, naphthyl or heterocyclyl groups being substituted with 0 to 5 groups selected from the group consisting of halogen, alkyl Branched or unbranched Ci-6, which optionally is partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bj._c.i_c.l_ahexan lcL, hi_ci_al_Qhep_t.ani.lo., Hidr_oxi_, ni_t.r_il. or_,. C1-3 alkoxy which is optionally partially or fully halogenated, ¾C (0). and mono- or dialkyl (Ci- 3) aminocarbonyl; d) a CS-i cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three C 1-3 alkyl groups; e) nitrile; or f) branched or unbranched Ci-6-carbonyl alkoxy, branched or unbranched Ci-6-aminocarbonyl alkyl, Ci-s-carbonylamino-Ci_3 alkyl branched or unbranched; is: a branched or unbranched Ci-6 alkyl, optionally partially or wholly halogenated, acetyl, aroyl, branched or unbranched C1-4 alkoxy, optionally partially or wholly halogenated, halogen, methoxycarbonyl or phenylsulfonyl; is: a) a phenyl, naphthyl or heterocyclyl group selected from the group consisting of pyridinyl. pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imi_da.z_o_l_i.l_o_, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naphypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein said phenyl, naphthyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of phenyl, naphthyl, heterocyclyl selected from the group described hereinbefore in this paragraph, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl-Ci_5 alkyl, naphthyl Ci_5 alkyl, halogen, hydroxy, nitrile, alkyl Ci-3-oxy that can optionally be partial or halogenated, phenyloxy, naphthyloxy, heteroaryloxy wherein the heterocyclic moiety is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl (Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino. that the heterocyclic moiety is selected from the group described hereinabove in this paragraph, NH2C (0), a mono- or di-alkyl (Ci-3) -aminocarbonyl, alkyl d-5-C (0) - Ci_4 alkyl, Ci_5 alkyl amino, mono- or di-alkyl (Ci_ 3) amino-Ci_5 alkyl, amino-S (O) 2, di-alkyl (Ci-3) amino-S (0) 2, R4-Ci_5 alkyl, R5-C1-5 alkoxy (R6-C (0) - C1-5 alkyl and R7-C1-5 alkyl- (RB) N, carboxy-mono- or di (C1-5) alkyl-amino; b) a fused aryl selected from the group consisting of benzocyclobutannyl, indanyl, indenyl dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cic1ohexanopirazina, ciclopentanopiridazina, ciclohexanopiridazina, ciclopentanoquinolina, cic1ohexanoquino1 ina, ciclopentanoisoquinolina, ciclohexanoisoquinolina, ciclopentanoindol, cyclohexanoindole, cyclopentanobenzimidazole , cyclohexanebenzimidazole, cyclopentanebenzoxazole, cyclohexanebenzoxazole, cyclopentane imidazole, cyclohexaneimidazole, cyclopentanethiophene 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, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, branched or unbranched Ci-6 alkyl optionally partially or fully halogenated, halogen, nitrile, Ci-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy in which the The heterocyclic moiety is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl (Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, NH2C (0), a mono- or di-alkyl (Ci- 3) aminocarbonyl, alkyl Ci_-0C (0), alkyl C 5 - C (O) - branched or unbranched Ci_4 alkyl, an amino-Ci- 5 alkyl, mono- or di-alkyl (Ci-3) amino-Ci_5 alkyl, R3-Ci_5 alkyl, Rio-C13 alkoxy, Rn -C (0) -C1-5 alkyl, and R12-C1-5 alkyl- (Ri3) N; a cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, in which the cycloalkyl is optionally partially or wholly halogenated and optionally substituted with one to three C 1-3 alkyl groups; . . d) a C 5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three C 1-3 alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) a branched or unbranched Ci- 6 alkyl, optionally partially or wholly halogenated; or Ri and R2 taken together, can optionally form a fused phenyl or pyridinyl ring; each of the e and R13 is independently selected from the group consisting of: hydrogen and C1-4 alkyl branched or unbranched, optionally partially or fully halogenated; each of the R4 / 5 Re R7 R9 / Rio, R11 and R12 is independently selected from the set consisting of m is 0, 1 or 2; W is O or S and its pharmaceutically acceptable derivatives. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucosal hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 in which: Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is 0. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor agent is selected from the compounds of formula 5 as disclosed in WO 00/55139 in which: Ari is selected from thiophene and pyrazole; X is C5-7 cycloalkyl or C5-7 cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 Ci-4 alkyl groups, Ci-4 alkoxy or Ci-4-amino branched alkyl or without X is phenyl,. pyridine, tetrahydropyridine, pyrimidine, furan or thiophene. each being optionally independently substituted with 0-3 Ci_4 alkyl, Ci-4 alkoxy, hydroxy, nitrile, mono- or di- (Ci_3 alkyl) amino, Ci_6-S (0) m alkyl or halogen; Ri is branched or unbranched Ci-4 alkyl, cyclopropyl or cyclohexyl optionally halogenated partially or wholly and optionally substituted with one to three Ci_3 alkyl groups; R3 is branched or unbranched Ci-4 alkyl, phenyl, pyrimidinyl, pyrazolyl or pyridinyl, each of which being optionally substituted as described hereinbefore in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described earlier in this specification in the broader generic aspect. In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended 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 Ari is pyrazole; X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 Ci-4 alkyl, C 1-4 alkoxy or C 1-4 amino-branched or unbranched alkyl groups; or X is phenyl, pyridine, furan or thiophene, each of which is optionally independently substituted with 0-3 Ci-4 alkyl, Ci_4 alkoxy, hydroxy, nitrile, mono- or di- (Ci-3 alkyl) amino groups , Ci-6-S (0) m alkyl, branched or unbranched, or halogen. In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the compounds of formula 5 as disclosed in WO 00/55139 in which: Y is -CH2-, -CH2CH2-, -CH2NH-, -CH2CH2NH- or a bond; and Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, pyridine, a secondary amine or iodine in which the amino oxygen is covalently linked to selected groups from the set consisting of Ci-3 alkyl and C 1-5 alkoxy-alkyl, phenylamino in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, Ci_6-S (0) alkyl and phenyl-S (0) m wherein the phenyl ring is optionally substituted with one to two halogen groups, C_6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino. In a further embodiment the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula £ >; as disclosed in WO 00/55139, in which: Arx is 5-tert. -butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted with R3; R3 is branched or unbranched Ci_4 alkyl, phenyl, pyrimidinyl, pyrazolyl, pyridinyl, each of which being optionally substituted as described hereinbefore in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or optionally substituted cyclopentyl, descriptive in broader generic aspect. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of Formula 5 as disclosed in document 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 intended 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, in which the pyridinyl is linked to Arx through the 3-position of pyridinyl. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula í > as disclosed 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl) phenyl) -naphthalen-1-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; 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 -tere. -butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3- [4- (4-dimethylaminophenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl) phenyl) -naphthalen-1-yl] -urea; 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-1-yl] -urea; 1- [5-tert. -but il-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethyl-pyridin-2-yl) -naphthalen-1-yl] -urea; 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-methyl-pyridin-3-yl) -naphthalene-1-yl] urea; 1- [5-tert. -butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-phenyl-2H-pyrazol-3-yl] -3- [4- (4-piperidin-1-ylmethyl-phenyl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butil ^ 2 ^ f-eiii-l --- 2fl- i-ra-zo-l-3 ^ "G] ^ 3 ^" [4- (4- (4-me ilpiperazin-l-yl) methylphenyl) naphthalen-1-yl] urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3,4-di (morpholin-4-yl-methyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6-pyridin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6- (l-oxo-thiomorpholin-4-ylmethyl) pyridin-3-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-thiomorpholin-4-ylmethyl) pyridin-3-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-tetrahydropyran-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl ] urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6- (l-oxo-tetrahydrothiophen-3-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6- (imidazol-1-ylmethyl) pyridin-3-yl) -naphthalene-l- il] urea; 1 - [2 - (3-dimethyl-ylaminomethyl-phenyl) -5- (1-methyl-cyclohexyl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl ) naphthalene-1-yl] urea; 1- [2- (5- (1-methyl-cyclohexyl) -2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4 -ylmethyl-pyridin-3-yl) naphthalen-1-yl] urea; 4-ylmethyl-pyrimidin-5-yl) naphthalen-1-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3-methoxy-5- (2-morpholin-4-yl-ethoxy) phenyl) naphthalene-1-ylurea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (2-morpholin-4-yl-ethoxy) phenyl) -naphthalene-1 -yl] urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4-3- (dimethylamino) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4-3- (methylsulfonyl) phenyl) naphthalen-1-yl] -urea; methyl ester of 5- tere acid. -butil-3 -. { 3 - [- (6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl] ureido} thiophene-2-carboxylic acid; 5-tert. methyl acid amide. -butil-3-. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} thiophene-2-carboxylic acid; methyl ester of 5-tert. -butyl-methyl-3 -. { 3 - [4 - (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} - 1H- pyrrole-2-carboxylic acid; 5-methyl acid amide. -butyl-l-methyl-3 -. { 3 - [4 - (6 Morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] ureido} -1H- pyrrole-2-carboxylic acid; 2-Acetylamino-N- (5-tert -butyl-3-. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido}. -thiophen-2-ylme) acetamide; 1-. [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-cyclohex-1-enyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-p-razol-3 -yl] -3- [4- (3-morpholin-4-yl-cyclohepty-l-enyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (2-morpholin-4-yl-ethylamino) cyclohex-l-enyl) -naphthalene-l-yl] urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-yl-cycloheptyl-enyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (pyridin-4-yl-methylamino) -cyclohex-l-enyl) naphthalene -l-il] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (dimethylaminoethylamino) -cyclohex-l-enyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (pyridin-3-yl-methylamino) -cyclohex-l-enyl) naphthalene -l-il] urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (phenyl-methylamino) -cyclohex-l-enyl) -naphthalene-l-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-phenylethylamino) -cyclohex-l-enyl) -naphthalene-1-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (furan-2-yl-methylamino) -cyclohex-l-enyl) naphthalene -1-illurea; 1 - . 1 - [5-erc ^ buijLl ^ - (- 6-me-tá-1- ± r di "ñ ^ 3 ^ Tl) -2H-pyrazol-3-yl] - 3 [4- (3- (2 - pyridin-2-yl-ethylamino) -cyclohex-1-enyl) naphthalene-1-ylurea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (2-piperidin-1-yl-ethylamino) -cyclohex-1-enyl) ) naphthalen-1-yl] urea; 1- [5-tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [3- (3 - (2-imidazol-4-yl-ethylamino) -cyclohex-1-enyl] ) naphthalene-1-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (3- (pyridin-2-yl-methylamino) -cyclohex-1-enyl) naphthalene -1-yl] urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3 -i 1] -3 [4 - (3 - (2 - (4-methyl-oxyphenyl) ethylamino) -cyclohex- 1- enyl) naphthalen-1-yl] urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethyl-3-oxo-cyclohex-1-enyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (1-oxo-tetrahydrothiophen-3-methylmethyl) -3 -oxo-cyclohex-1-enyl) naphthalene- 1 il] urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (1-oxo-thiomorpholin-4-ylmethyl) -3 -oxo-cyclohex-1-enyl) naphthalene- l-il] urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-methyl-piperazin-l-ylmethyl) -3-oxo-cyclohex-l-enyl) -naphthalene-1-yl] -urea; 1- . { 5 -tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4-. { 6-oxo-l- (tetrahydro-pyrano-4-ylmethyl) -1,2,3,6-tetrahydro pyridin-4-yl} naphthalen-1-yl] urea; 1- [5 -tere. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (2-oxo-1-pyridin-4-ylme-il-piperidin-4-yl) naphthalen-1 -yl] urea; 1- [5-tert. -but il -2 -p- tol il-2H-pyrazol-3-yl] -3- [4- (6-oxo-l-pyridin-4-yl-1, 2,3,6-tetrahydro-pyridin- 4 -yl) naphthalen-1 -yl] urea; 1- [5-tert. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6-oxo-l-pyridin-4-yl-l, 2,3,6 -tetrahydro-pyridin-4-yl) naphthalen-1-yl] urea; methyl ester of 5-tert. -butil -3 -. { 3- [4- (6-Oxo-l-pyridin-4-yl-1, 2,3,6-tetrahydro-pyridin-4-yl) -naphthalen-1-yl] -ureido} thiophene-2-carboxylic acid; methyl ester of 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-5-tere-acid amide. -butyl-l-methyl -3 -. { 3- [4 - (6-oxo-l pyridin-4-yl-l, 2,3,6-tetrahydro-pyridin-4-yl) naphthalen-1-yl] ureido} pyrrole-2-carboxylic acid; methyl ester of 5-tert. -butil-3-. { 3- [4- (3-morpholin-4-yl-cyclohex-1-enyl) naphthalen-1-yl] -ureido} thiophene-2-carboxylic acid; morpholin-4-yl-cyclohex-1-enyl) -naphthalen-1-yl] ureido} pyrrole-2-carboxylic acid; and 5-tere acid methyl amide. -butyl -1-methyl -3 -. { 3- [4- (3-morpholin-4-yl-cyclohex-l-enyl) -naphthalen-1-yl] ureido} pyrrole-2-carboxylic acid and its pharmaceutically acceptable derivatives. 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 compounds of formula 5: 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl-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-1-yl] -urea; 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-1-yl] -urea; 1- [5-tert. -but i 1-2 -p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethyl-pyridin-2-yl) naphthalen-1-yl] -urea; 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- l - [5-tert. -butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea and its pharmaceutically acceptable derivatives. 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 kinase inhibitor p38 is selected from the compounds of formula 5a as disclosed in document O 00/55139 5a in that: Arx is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ari is optionally substituted with one or more Ri, R2 or R3; Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinol ina, tetrahydroisoquinoline, benzimidazole, benzofuran, indi nJLloy__indeni.l.o-e-i-ndol -; - each of them being optionally substituted with zero to three groups R2; is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three C1-4alkyl chains, Ci-4alkoxy or Ci-4alkylamino (each branched or unbranched) phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4, 5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three alkyl groups (¾-4, C1-4 alkoxy, hydroxy, nitrile, amino, mono- or di- (Ci-3 alkyl) amino, mono- or di- (C1-3 alkyl-amino) carbonyl, NH2C (0), Ci-6-S (0) alkyl or halogen, is: a saturated or unsaturated, branched or unbranched Ci-4 carbon chain or bond, optionally partially or totally halogenated, in which one or more C atoms are optionally replaced by O, N or S (0) m and that Y is optionally independently substituted with one to two oxo, nitrile, phenyl, hydroxy or one or more C1-4 alkyl groups optionally substituted with one or more halogen atoms; is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocyclyl selected from piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or -thia-5-aza-bicyclo [2.2.1] heptanyl, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z groups is optionally substituted with one to three halogen groups, Ci-6 alkyl, Ci-S alkoxy, Ci-3 alkoxy Ci-3 alkyl, Ci-6 Ci-6 alkoxycarbonyl, aroyl, heteroaroyl, C 1-3 heterocyclyl-acyl wherein the heteroaryl and heterocyclyl are as defined hereinbefore in this paragraph, acyl Ci-3, oxo, hydroxy, pyridinyl-C 1-3 alkyl, imidazolyl-C 1-3 alkyl, tetrahydrofuranyl-Ci- 3, nitrJJ. al.quil.o-C-i ^ 3-¡-n-i-trrl r; ca.oxoxy, phenyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-S alkoxy, hydroxy or mono- or di- (C 1-3 alkyl) amino, amino-S (O) ra, alkyl Ci-SS (0) mo phenyl-S (0) m in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy, halogen or mono- or di- (Ci-alkyl) 3) amino; Z is optionally substituted with one to three amino, aminocarbonyl or amino-Ci-3 alkyl groups in which the N atom is optionally mono- or di-substituted independently with amino-Ci-6 alkyl, Ci alkyl -3, aryl-C0-3 alkyl, Ci-5 alkoxy-C1-3 alkyl, C1-5 alkoxy, aroyl, Ci-3 acyl / Ci-3-S (0) alkyl- or aryl-alkyl CQ-3 -S (0) m-, in which each of the aforementioned alkyl and aryl, attached to the amino group, is optionally substituted with one to two halogen groups, Cn-6 alkyl, Ci-6 alkoxy, hydroxy or mono- or di- (alkyl Ci-3) amino Z is optionally substituted with one to three aryl groups, heterocyclyl or heteroaryl as described above in this paragraph, each of which in turn is optionally substituted with halogen, Ci-6alkyl or Ci-6alkoxy Z is hydroxy, hydroxy-C 1-3alkyl, halogen, nitrile, Amink__in ___ N-N-N-atom is optionally mono- or di-substituted independently with Ci_6 alkyl, Ci_6-amino-aryl, ar-C3-alkyl, Ci-5-alkoxy-C1-3 alkyl , Ci-5 alkoxy, aroyl, C1-3 acyl < alkyl Ci_3-S (0) m-, aryl-alkyl C0-3-S (0) m-, nitrile-C1-4alkyl or C1-3alkoxy-Ci -3alkyl, each of the alkyl and aryl groups attached to the amino group, mentioned above, is optionally substituted with one to two halogen groups, Ci-6 alkyl, Ci-6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) -amino, Ci_6-heteroaryl-C0- 3, heteroaryl-C0-3 alkyl or heterocyclyl-Co-3 alkyl, wherein the heteroaryl and heterocyclyl are described above in this paragraph, Z is branched or unbranched Ci-6 alkyl, Ci-6 alkoxy, Ci_3-amino acyl, nitrile-Ci-4 alkyl, Ci-6-S (0) m alkyl, and phenyl-S (0) m / in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (C 1-3 alkyl) amino; is: a) a branched or unbranched Ci-io alkyl, optionally partially or wholly halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, t-ie-nyl-, trif'l-5-isoxazolyl and isothiazolyl; each of said phenyl, naphthyl or heterocyclyl being selected from the group described hereinabove, and being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci-6 alkyl, which optionally is partially or totally halogenated, C3-8 cycloalkyl, C5-B cycloalkenyl, hydroxy, nitrile, Ci-3-oxy alkyl, which is optionally partially or fully halogenated, NH2C (0) and dialkyl (Ci-3) aminocarbonyl; a C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or wholly halogenated and optionally substituted with one to three Ci_3 alkyl groups, or a group analogous to said cycloalkyl group, wherein from 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; a branched C3-i0 alkenyl, optionally partially or fully halogenated and optionally substituted with one to three branched C1-5 alkyl groups - if r-ami-fi-car7 phenyl, naphthyl or heterocyclyl, each of said heterocyclyl groups being independently selected from the group set consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of said phenyl, naphthyl or heterocyclyl groups being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci_6 alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, Ci-3 alkoxy which is optionally partially or fully halogenated, NH2C (0) and mono- or di-alkyl (Ci- 3) aminocarbonyl; d) a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three Ci-3 alkyl groups; e) nitrile; of) branched or unbranched Ci-s-carbonyl alkoxy, Ci-6 ^ alkyi-car-bo-nile-branched-branched alkyl, branched alkyl Ci-e-carbonylamino-Ci-3 alkyl or unbranched, it is a branched or unbranched C1-6 alkyl, optionally partially or fully halogenated and optionally substituted with nitrile, or R2 is acetyl, aroyl, branched or unbranched Ci_4 alkoxy, optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl is: a) a phenyl, naphthyl or heterocyclyl 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, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naftipyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein said group enyl, naphthyl or heterocyclyl is optionally substituted with one to five groups selected from the group consisting of a "phenyl", heterocyclyl selected from the group described hereinbefore in this paragraph, branched or unbranched Ci-6 alkyl , which optionally is partially or wholly halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl-C 1 -C 5 alkyl / naphthyl C 1 -C 5 alkyl, halogen, hydroxy, oxo, nitrile, C 1 -C 6 alkoxy 3 optionally partially or wholly halogenated, Ci-3-alkyloxy Ci-5-alkyl (thio-Ci-3-alkyl (thio-Ci_3-alkyl Ci_5-alkyl, phenyloxy, naphthyloxy, heteroaryloxy in which the heterocyclic moiety is selected from the group described hereinbefore in this paragraph, nitro, amino, mono- or di-alkyl (Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described herein above. in this paragraph, NH2C (0), a mono- or di (C1-3) alkyl-aminocarbonyl, C1-5-alkyl (0) -C1-4 alkyl, amino-C1-5 alkyl / mono- or di-alkyl (Ci-3) amino-Ci-5 alkyl, amino-S (0) 2 / di- (Ci_3) alkylamino-S (0) 2, R4-C1-5 alkyl, R5-Ci_5 alkoxy, R6- C (O) -Ci-5 alkyl and R7-Ci-5- alkyl (8) N, carboxy-mono- or di-alkyl (Ci-5) - a fused aryl selected from the group consisting of benzocyclobutannyl, indanyl, indenyl yl, dihidronaf, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cic1ohexanopiridina, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cic1ohexanopirazina, ciclopentanopiridazina, ciclohexanopiridazina, ciclopentanoquinolina, ciclohexanoquinolina, ciclopentanoisoquinolina, ciclohexanoisoquinolina, ciclopentanoindol, cyclohexanoindole, Cyclopentanebenzimidazole, Cyclohexanebenzimidazole, Cyclopentanebenzoxazole , cyclohexanebenzoxazole, cyclopentaneimidazole, cyclohexaneimidazole, cyclopentanethiophene 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, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolinium, C 1 -C 6 -alkyl, unsubstantial-or-unsubstantiated, optionally partially or fully halogenated, halogen, nitrile, Ci-3 alkoxy optionally partial or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy in which the heterocyclic moiety is selected from the group described hereinabove, nitro, amino, mono- or di (C1-3) alkyl amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described herein above, NH2C (0), a mono- or di-alkyl (Ci-3) -aminocarbonyl, alkyl Ci-4-OC (0), Ci-5-C (0) alkyl-branched or unbranched Ci_4 alkyl, a amino-Ci_5 alkyl, mono- or di-alkyl (C! _3) amino-Ci-5 alkyl, R9-Ci-5 alkyl, Ri0-Ci-5 alkoxy, Ru-C (O) -C1-5 alkyl and Ri2 -alkyl C1-5- (¾3) N; a cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and is optionally substituted with one to three C 1-3 alkyl groups; a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl-x-f-cyclohepfenadiene, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three Ci- 3; e) acetyl, aroyl, C6-carbonyl alkyloxyC ^ g alkyl or phenylsulfonyl; or f) a branched or unbranched Ci-alkyl, optionally partially or wholly halogenated; or Ri and R? taken together, they optionally form a fused phenyl or pyridinyl ring; each of R8 and R13 is independently selected from the group consisting of: hydrogen and branched or unbranched Ci-4 alkyl, optionally partially or wholly halogenated; each of R4 / R5, R6, R7, R9, Rio, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; m is 0, 1 or 2; W is O or S; wherein X is directly linked to one or two -Y-Z, and their pharmaceutically acceptable derivatives. In another embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucosal hypersecretion.-Face-G-ter-iz-ado because the inhibitory agent of the p38 kinase is selected from the compounds of formula 5a in which: Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl, and is O. In another embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of a composition inhalable pharmaceutical intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor agent is selected from the compounds of formula 5a in which: Ari is thiophene or pyrazole, each independently substituted with one to three Ri, R2 or R3; X is: a C5_7 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three C1_alkyl chains, C1_4alkoxy or C1_4alkylamino chains, each being branched or unbranched; phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, piperidinyl, benzimidazole or piperazinyl; each of which is optionally independently substituted with one to three C1-Ci groups. , C 1 -hydroxy alkoxy, nixylyl, -amino-, -mene- or di- (C 1 -3) amino, mono- or di- (C 1 -3-amino) carbonyl, NH 2 C (0) alkoxy, Ci-6-S (0) alkyl or halogen; Y is: a bond or a carbon chain of saturated or unsaturated, branched or unbranched, optionally halogenated partially or wholly, in which one or more C atoms are optionally replaced by O or N, and in which Y is optionally substituted independently with one to two oxo, nitrile, phenyl, hydroxy groups or with one or more C 4 alkyl groups optionally substituted with one or more halogen atoms; Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocyclyl selected from piperazinyl, 2-oxa-5-azabicyclo [2.2.1] -heptanyl, pentamethylene sulfuryl, pentametisole sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z is optionally substituted with one to three halogen groups, Ci- 6 alkyl, Ci- 6 alkoxy, C 1-3 alkoxy-Ci_3 alkyl, Ci-6 alkoxy carbonyl, aroyl , morpholinocarbonyl, Ci-3 acyl, oxo, hydroxy, pyridinyl-Ci- 3 alkyl, imidazoli-1-C 1 -3 alkyl, __-1 -hydroxy-n-alyl-nitrile-Ci-3 alkyl, nitrile, carboxy, phenyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, amino-S (O) m, Ci_6-S alkyl (0) mo phenyl-S (0) m wherein the phenyl ring is optionally substituted with one to two halogen groups, alc Ci_6 oxy, hydroxy, halogen or mono- or di- (C1-3 alkyl) amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-Ci-3 alkyl groups in which the N atom is optionally mono- or di-substituted independently with amino-Ci- 6 alkyl, Ci-3 alkyl, aryl-C0-3 alkyl, Ci-5 alkoxy-Ci- 3 alkyl, Ci-5 alkoxy, aroyl, Ci_3 acyl, C1-3-S-alkyl (0) m- or aryl-C0-3-S (0) alkyl m-, each of the aforementioned alkyl and aryl groups attached to the amino group is optionally substituted with one to two halogen groups, Cx-S alkyl or C 1-6 alkoxy; or Z is optionally substituted with one to three aryl, heterocyclyl or heteroaryl groups as described above in this paragraph, each of which in turn is optionally substituted with halogen, Ci-6 alkyl or Ci-alkoxy; or Z is hydroxy, hydroxy-C1-3 alkyl / halogen, nitrile, amino in which the N atom is optionally mono- or di-substituted independently with aroyl, C1-3 acyl, Ci-6 alkyl, Ci alkoxy -5-Ci_3 alkyl, pyridinyl-d-3 alkyl, tetrahydrofuranyl-C 1-3 alkyl, nitrile-Ci- or alkyl, in which the phenyl ring is optionally substituted with one to two halogen groups, C 1-6 alkoxy, hydroxy or mono- or di- (C 1-3 alkyl) amino, Z is branched or unbranched C 1-6 alkyl, C 1-6 alkoxy or nitrile-C 1 -alkyl; is: a branched or unbranched C1-4 alkyl, optionally partially or wholly halogenated; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three Ci_3 alkyl groups, or a group analogous to said cycloalkyl group, wherein one to three ring methylene groups are replaced by independently selected groups between the set consisting of 0, S and NH; a C3-i0 branched alkenyl, optionally partially or wholly halogenated and optionally substituted with one to three branched or unbranched alkyl groups 01-5; cyclopentenyl and cyclohexenyl optionally substituted with one to three Ci_3 alkyl groups; a branched or non-branched Ci-6 alkyl or N-alkyl-r-opo-i-en-a-1-methogenated partially or wholly and optionally substituted with nitrile; is: a phenyl or heterocyclyl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein said phenyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of a phenyl group, heterocyclyl selected from the group described hereinbefore in this paragraph, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl-C1- alkyl 5, naphthyl-Ci-5 alkyl, halogen, hydroxy, oxo, nitrile, Ci-3 alkoxy optionally partially or fully halogenated, C1-3 alkoxy-Ci-5 alkyl, thio-C1-3alkyl, thio-C1-3alkyl - Ci-5 alkyl, phenyloxy, naphthyloxy, heteroaryloxy in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl ( Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, H2C (0), a mono- or di-alkyl (¾_3) aminocarnil, alkyl Ci_s-C (O) -C 1-4 alkyl < amino-Ci_5 alkyl; mono- or di-alkyl (Ci-3) amino-Ci_5 alkyl, amino-S (0) 2, di (C 1-3) alkylamino-S (O) 2, R 4-Ci-5 alkyl / R 5 -alkoxy C1-5, Rs-C (O) -alkyl Ci-5 and R7-alkyl Ci-S- (R8) N, carboxy-tnono- or di-(C1-5) alkyl-amino; a condensed aryl selected from the group consisting of benzocyclobutannyl, indanyl and indenyl; wherein the condensed aryl 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, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, halogen, nitrile, Ci-3 alkoxy optionally being partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy in which the heterocyclic moiety is selected from the assembly described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl (Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, NH2C ( 0), a mono- or di-alkyl (C! _3) -aminocarbonyl, alkyl Ci-4-0C (0), Ci-5-C (O) alkyl-Ci-4 alkyl branched or unbranched icar, an amino-Ci-5 -alkyl, mono- or dialkyl (1-3C) amino-C1-5alkyl, Rg-Ci-5alkyl / Ri0-alkoxy Ci-s, Rii-C (0) alkyl-Ci- s and R12-C1-5 alkyl (Ri3) N cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, in which the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1 alkyl groups -3; C6-C6-alkoxy-Ci-6alkyl; or Ri and R2 taken together optionally form a fused phenyl or pyridinyl ring; each of R8 and R13 is independently selected from -the group consisting of: hydrogen and C1-4 alkyl branched or unbranched, optionally partially or fully halogenated; and each of the R4, R5, R6, R7 / 9 Rio, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; where X is directly linked to a -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 kinase inhibitor p38 is selected from the compounds of formula 5a in which: Ari is pyrazole; X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or with one to three C 1-4 alkyl chains, C 1-4 alkoxy or C 1-4 alkylamino, each being branched or unbranched; phenyl, furanyl, thienyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which being optionally independently substituted with one to three Ci-2 alkyl, Ci-2 alkoxy, hydroxy or halogen groups; Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocyclyl selected from 2-oxa-5-aza-bicyclo [2.2.1] heptanil, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen groups, Ci- 6 alkyl / Ci-6 alkoxy, Ci-3 alkoxy-Ci- 3 alkyl; alkoxy Ci_g-carbonyl, aroyl, morpholinocarbonyl, Ci- 3 acyl, oxo, hydroxy, pyridinyl-Ci-3 alkyl, imidazolyl-C 1-3 alkyl, tetrahydrofuranyl-Ci-3 alkyl, nitrile-Ci_3 alkyl, nitrile, carboxy, phenyl in that the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy (hydroxy or mono- or di- (Ci_3 alkyl) amino, amino-S (O) m, Ci_6-S alkyl (0) m , or phenyl-S (0) m wherein the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy, halogen or mono- or di- (Ci_3 alkyl) amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-Ci-3 alkyl groups in which the N atom is optionally mono- or di-substituted independently with amino-Ci-6 alkyl, Ci-3 alkyl, aryl-alkyl C0-3, alkoxy Cx-s-C1-3alkyl, C1-5alkoxy, aroyl, acyl Ci-3, alkyl C1-3-S (0) m-, pyridinyl-C0-3alkyl, tetrahydrofuranyl -alkylC0- 3, or aryl-alkyl C0-3-S (O) m-, each of the alkyl and aryl groups attached to the amino group, mentioned above, is optionally substituted with one to two halogen groups, 0 to 6 alkyl or 6 to 6 alkoxy; or Z is hydroxy, hydroxy-Ci-3 alkyl, halogen, nitrile, amino wherein the N atom is optionally mono- or di-substituted independently with Ci-6 alkyl, pyridinyl-C0_3 alkyl, tetrahydrofuranyl-C0- alkyl 3, Ci-5-alkoxy Ci-3 alkyl, Cx-3 acyl, nitrile-Ci- or phenyl alkyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, Z is branched or unbranched Ci_6 alkyl, Ci- 6 alkoxy or trilo-Ci-4 alkyl; is: a branched or unbranched Ci-4 alkyl, optionally partially or wholly halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three Ci-3 alkyl groups, or a group analogous to said cycloalkyl group, wherein one to three ring methylene groups are replaced by groups independently selected from the set consisting of O, S and NH; an optionally halogenated branched C3_10 alkenyl partially or wholly and optionally substituted with one to three branched or unbranched C1-3 alkyl groups; cyclopentenyl and cyclohexenyl optionally substituted with one to three C1-3 alkyl groups; is: a branched or unbranched Ci- 6 alkyl group, optionally partially or wholly halogenated and optionally substituted with nitrile; R3 is: a phenyl or heterocyclyl group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein said phenyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of a phenyl or heterocyclyl selected among the group described hereinabove in this paragraph, a branched or unbranched C1-6alkyl, which is optionally partially or fully halogenated, phenyl-Ci_5alkyl / halogen, hydroxy, oxo, nitrile, Ci-3alkoxy optionally partially or fully halogenated , thioalkyl Ci-3, thioalkyl Ci-3-C1-5alkyl, amino, mono- or di-C1-3alkylamino, H2C (0) or a mono- or di-alkyl (Ci_3) ) aminocarbonyl, Ci_6-carbonyl alkyloxy Ci_s or R3 is cyclopropyl or cyclopentyl, each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or Ri and R2 taken together form optional a phenyl ring or fused pyridinyl. 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 _5_a in which: Y is -CH2-, -O- (CH2) 0-3-, -CH2CH2-, -CH2NH-, -CH2CH2-NH-, NH- -CH2-NH-CH2-, -NH-, - HC (O) -, -C (O) -, -CH (OH) -, CH2 (CH2CH3) - or a bond; X is: cyclohexenyl optionally substituted with an oxo group or with one to three Ci-4 alkyl chains, Ci-4 alkoxy or Ci_4-amino alkyl, each branched or unbranched; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which being optionally independently substituted with one to three C1_2 alkyl, C1-2 alkoxy, hydroxy or halogen groups; Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocyclyl selected from 2 -oxa-5-aza-bicyclo [2.2.1] heptanil, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl and piperidinyl, each of the aforementioned Z is optionally substituted with one to three halogen groups, Ci-6 alkyl, Ci-s alkoxy, Ci-3-alkyloxy-3alkyl, Ci_6-carbonyl alkoxy , aroyl, morpholinocarbonyl, acyl Ci_3, oxo, hydroxy, pyridinyl-C1-3alkyl, imidazolyl-C1_3alkyl, tetrahydrofuranyl-Ci_3alkyl, nitrile-Ci_3alkyl (nitrile, carboxy, phenyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, amino-S (O) m, Ci_6-S (0) m alkyl, or phenyl- S (0) ra in which the phenyl ring is optionally substituted with one to two groups of halogen, Ci-6 alkoxy, hydroxy, halogen or mono- or di- (Ci_3 alkyl) amino; Z is optionally substituted with one to three amino or aminocarbonyl groups in which the N atom is optionally mono- or di-substituted independently with amino-C 1-6 alkyl / Ci-3 alkyl, aryl-C 3-3 alkyl, alkoxy Ci-5-Ci-3-alkyl, Ci-5-alkoxy, aroyl, acyl Ci-3i-alkyl-C1-3-S (0) m- or aryl-alkylC0-3-S (O) m-, each of the alkyl and aryl groups attached to the amino group, mentioned above, is optionally substituted with one to two halogen groups, Ci_6 alkyl or Ci_6 alkoxy; Z is hydroxy, hydroxyCi-3alkyl / halogen, nitrile, amino wherein the N atom is optionally mono- or di-substituted independently with Ci-3-alkyl pyridinyl-C1-2alkyl, tetrahydrofuranyl-alkylCyi 2, Ci-3-alkoxy Ci-3 alkyl, Ci-3 acyl, nitrile-C 1-4 alkyl, phenyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono - or di- (alkyl Ci-3) amino, or Z is branched or unbranched Ci_6 alkyl, Ci-6 alkoxy or nitrilo-Ci-4 alkyl; a branched or unbranched C1-4 alkyl, optionally partially or wholly halogenated; R2 is: a branched or unbranched C1-3 alkyl, optionally partially or wholly halogenated and optionally substituted with nitrile; R3 is a phenyl group or selected heterocyclyl from the group consisting of pyridinyl, pyrimidinyl and pyrazolyl, wherein said phenyl or heterocyclyl is optionally substituted with one to five groups selected from the group consisting of alkyl CX- 3 branched or branching, which is optionally partially or fully halogenated, Ci-3 alkoxy optionally partially or wholly halogenated, thio-Ci-3 alkyl, thioalkyl Ci_3-Ci-5 alkyl, amino or H2C (O); Ci-3-carbonyl alkoxy; or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three Ci-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 intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a in which: Ari is 5-tert. -butyl-pyrazol-3-yl; wherein the pyrazole ring is independently substituted by one to two R2 or R3; X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which being optionally independently substituted with Ci_2 alkoxy or hydroxy; Z is: phenyl, heteroaryl selected from pyridinyl and furanyl, heterocyclyl selected from 2-oxa-5-aza- bicyclo [2.2.1] heptanyl, pentamethylene sulfuryl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z is optionally substituted with one to three Ci-3 alkyl, Ci- 3 alkoxy, oxo, hydroxy or NH 2 C (0) - groups; or Z is hydroxy C 1-3 alkyl, amino wherein the N atom is optionally mono- or di-substituted independently I with pyridinylmethyl, tetrahydrofuranylmethyl, alkoxy Ci - 3 alkyl Ci- acyl C1 - 3 alkyl or nitrilo Ci- 4, or Z is nitrile-Ci- 4 alkyl; R3 is a phenyl group or selected heterocyclyl from the group consisting of pyridinyl, pyrimidinyl and pyrazolyl, wherein said phenyl or heterocyclyl is optionally substituted with one to two groups selected from the group consisting of alkyl Ci - 2, optionally is partially or fully halogenated, Ci-2 alkoxy, which is optionally partially or fully halogenated, thio-Ci-2 alkyl / thio-Ci- 2 alkyl, Ci- 3 alkyl, amino or NH 2 C (0); C3-carbonyl alkoxy; or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups. In still a further embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a in which X is pyridinyl.
In yet 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 among the compounds of formula 5a in which the pyridinyl is attached to Arx through the 3-position of pyridinyl. Preferably the invention relates to the use of inhibitors of p38 kinase for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, wherein the kinase inhibitor p38 agent is selected from the compounds of formula 5a: 1 - [5-tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-yl-methylphenyl) -naph alen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [3- (4-morpholin-4-yl-methylphenyl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-yl-methyl-furan-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-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (4-morpholin-4-yl) ethylphenyl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-dimethylaminomethylphenyl) -naph alen-1-yl] -urea; 1- [5 -tere. -but il-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-yl-methyl) pyridin-2-yl) -naphthalen-1-yl] - urea; 1- [5 -tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2 - (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) iridin-3-yl) - naphthalene-1-yl] -urea; 1- 15-tere. -butyl-2-methyl-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- (3- (2- (morpholin-4-yl) ethylamino) -cyclohexenyl) - naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3,4- (norpholin-4-yl-methyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-methylpiperazin-1-yl-methyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (piperidin-1-yl-methyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (pyridin-2-yl) ethylamino) -cyclohexenyl) - naphthalene-1-yl] -urea 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (2- (pyridin-4-yl) ethylaminomethyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-yl-ritylaminomethyl) phenyl) -naphthalen-1-yl] -urea; l- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3,4-dimethoxyphenyl-ethyl) -3 -hydroxyphenyl) naphthalen-1-yl] -urea; 1- [5-tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-oxo-l, 6-dihydro-pyridin-3-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (rrDrfolin-4-yl-methyl) phenyl) -naphthalene-l- il] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tnorpholin-4-yl-methyl) imidazol-1-yl) naphthalen-1-yl] -urea; 1- [5-tere. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl-methyl) imidazol-1-yl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furane-3-yl-methyl) -3-hydroxyphenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutylamino) pyridin-3- il) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-yl-methyl) -3-hydroxyphenyl) naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) -naphthalene-1 -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (imidazol-2-yl-methyl) -3-hydroxyphenyl) naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-hydroxymorpholin-4-yl-butyl) phenyl) naphthalene-1 -yl] -urea; 1- [5-tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (? -2-methoxyethyl-N-methylaminomethyl) phenyl) naphthalen-1 -yl] -urea; 1--. { 5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (4-hydroxymorpholin-4-yl-tnethyl) phenyl) -naphthalen-1- il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl-methyl) -cyclohexenyl) -naphthalene-1- il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tetrahydrofuran-3-yl-methyl) -3-hydroxyphenyl) naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (?,? - di- (2-methoxyethyl) aminomethyl) phenyl) naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (3-cyanopropoxy) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tere, -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-yl-methyl-piperidinyl ) naphthalene-1-yl] -urea; l- [-tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N; 'N-di- (2-cyanoethyl) aminomethyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (l-morpholin-4-yl-indan-5-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-2-yl-methyl) -3-hydroxyphenyl) naphthalene- 1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (thiomorpholin-4-yl-methyl) phenyl) -naphthalene-l- il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-carboxamidomorpholin-4-yl-methyl) phenyl) naphthalene-l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (2 · methyl-3-oxo-piperazin-1-yl-methyl) ) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1 -yl] -urea; 1- [5-tert. -butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutyloxy) pyridin-3-yl) -naphthalene-l-yl] -urea; 1- [3-tert-butyl-l'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene -l-il] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furane-2-yl-methyl) -3-methoxyphenyl) naphthalene-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (TTiorpholin-4-carbonyl) pyrazine- 2-yl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydrothiopyrano-4-yl-amino) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-cyanoethyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalene-1-yl] - urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2,6-diT-triethyl) -TDrpholin-4-yl-methyl) pyridin-3 -yl) -naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (2-aminopyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (mDrpholin-4-yl-methyl) pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-oxo-l, 6-dihydropyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6- (rtDrfolin-4-yl-tT! ethyl) pyridine- 3-yl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2- (6-methyl-1-pyridin-3-yl) -2H-pyrazol-3-yl] -3 [4- (6- (morpholin-4-yl-4-carbonyl) -pyridin-3-yl) ) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4 - (6- (2-oxa-5-aza-bicyclo [2.2.1] - hept -5-yl-met il) iridin-3-yl) -naphthalen-l-yl] -urea; -1 -. [- 5 ^ te_rc_. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (3-carbamylphenyl) naphthalen-1-yl] -urea; 1- [5-tere. -butyl- 2- (6-Methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- (pyridin-3-yl-methyl) ) aminomethyl) phenyl) -naphthalene-l-yl] -urea; 1- [5-tere. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- (pyridin-2-ylmethyl) aminomethyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tere. -butyl- 2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- (tetrahydrofuran-2-ylmethyl) ) aminomethyl) phenyl) -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) -4-methoxypyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tere, -butyl-2- (6-methyl -pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-morpholin-4-yl-propyl) -pyridin-3-yl) -naphthalene-1-yl] -urea; 1- [5-tere, -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N- (3- methoxypropyl) amino) -pyridin-3-yl) -naft alen-l-il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N- (3-methoxypropyl) -N-amylamino) pyridine- 3-yl) -naphthalen-1-yl] -urea; 1- [3 -tere. -butyl-1'-methyl-1? - [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2-benzyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) -naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N - -N-di- (2-ciancethyl) -aminomethyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4-74- (- ~~ carbamylphenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-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-4-yl-amino) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [3-tert-butyl-l '- (3-cyanopropyl) -1? - [1,4] bipyrazol-5-yl] -3- [4- (6 (morpholin-4-yl-methyl) pyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-methanesulfinyl-phenyl) -naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-ethanesulfonylphenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-sulfonamidophenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (mDrpholin-4-yl) carbonylphenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (tetra (± rotiopyran-4-yl) -amino) pyrazin-2-yl) -naphthalen-1-yl] -urea; 1- [5-tert-butyl-2- (6-rrethyl-pyridin-3-yl) -2H-pyrazol-3-yl) ] -3- [4- (6- (R-ethylcarbonylamino) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert-butyl-2-p-tolyl-2H-pyrazole-3] -yl] -3- [4- (6- (morpholin-4-yl-4-carbonyl) phenyl) -naphthalen-1-yl] -urea; 1- [3-tere. -butyl-1 '- (3 -methylsulfanylpropyl) -1? - [1,4 '] bipyrazol-5-yl] 3- [4- (6- (trorpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] -urea; - [5-ter = .-- butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (tnorpholin-4-yl-carbonyl) pyridin-3-yl) -naphthalene-1-yl] -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5 - (morpholin-4-yl-methyl) pyrazin-2-yl) -naphthalen-1-yl] -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) - 2H-pyrazol-3-yl] -3- [4- (6-aminopyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tert -butyl-2- (6-methyl-pyridine -3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-methylpiperidin-4- il-artiino) pyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tere. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-methyl-3-oxo-piperazin-1-yl-methyl) pyridine -3-yl) naphthalene-l-yl] -urea 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-carbonyl) -pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N, N-di- (2-methoxyethyl) -aminomethyl) pyridin-3 -yl) naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (l-oxo-thiomorpholin-4-yl-methyl) pyridin-3-yl ) naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-yl-amino) pyridin-3-yl) -naphthalene-1 -yl] -urea; 1- [5-tert. -butyl-2- (2-me-ilpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (5- (niorpholin-4-yl-tnethyl) pyrazin-2-yl) -naphthalene- 1-yl] -urea; 1- [5-tert. -butyl-2- (2-rtethylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (rrorfolin-4-yl-riiethyl) -pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (2-methyl-3-oxo-piperazin-1-yl-methyl) pyridin-3-yl) -naphthalene -1-yl] -urea; 1- [5-tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-yl-oxy) pyridin-3-yl) naphthalene- l -yl] -urea 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-yl-amino) pyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methoxypyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1 -yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-carbamylpyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-aminopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (NiDrpholin-4-yl-itiethyl) -pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyriraidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl-butyl) -phenyl) naphthalene-l-yl] -urea; 1- [3-tert-butyl-l '-methyl-1H- [1,4'] bipyrazol-5-yl] -3- [4- (6- (rfolfolin 4-yl-methyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-cyclopropyl-pyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) -pyridin-3-yl) -naphthalene-1 -yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (pyridin-3-yl-arnino) pyritinidin-5-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyrano-4-yl-amino) -pyridin-3-yl) -naphthalene-l- il] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (tiorrorfolin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-benzyl-3H-imidazo [4,5-b] pyridin-6-yl) -naphthalene-1-yl ] -urea; l- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-methyl-pyridin-3-yl) -naphthalene -1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl-carbonyl) pyrimidin-5-yl) -naphthalene-l-yl] -urea; 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- (3-amino-4-carbamylphenyl) 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) -naphthalene-l- il] -urea; 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) -naphthalene-l-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl) naphthalen-1 -yl] -urea; and its pharmaceutically acceptable derivatives. 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 the invention. Formula 5a: 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-yl-methyl) pyridin-2-yl) -naphthalen-l-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalene-l-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2 (pyridin-2-yl) ethylamino) -cyclohexenyl) -naphthalene -l-il] -urea; 1- [5-tert.-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-yl-methyladenomethyl) phenyl) -naphthalene-l-yl ] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (irorpholin-4-yl-methyl) phenyl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutylamino) pyridin-3-yl) -naphthalene-1-yl ] -urea; 1- [5-tert. -butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (6 (morpholin-4-yl-methyl) -pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-hydroxy-piperidin-1-yl-methyl) ) phenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (4-hydroxyorpholin-4-yl-methyl) ) phenyl) naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-Tnethyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (tnorpholin-4-yl-methyl) -cyclohexenyl) -naphthalen-1-yl] -urea; 1- [5-tert.-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tetrahydrofuran-3-yl-methyl) -3-hydroxyphenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di- (2-methoxyethyl) -aminomethyl) phenyl ) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (3-cyanopropoxy) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-yl-methyl-piperidinyl) naphthalen-1-yl] -urea; 1- . { 5-tere, -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di- (2-cyanoethyl)) -aminomethyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tere, -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furane-2-yl-methyl) -3-hydroxyphenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (thiomorpholin-4-yl-methyl) phenyl) naphthalene-l-yl ] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-carboxamidopiperidin-1-yl-methyl) phenyl) -naphthalene-l- il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (2-methyl-3-oxo-piperazin-1-yl-methyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1 -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutyloxy) pyridin-3-yl) -naphthalene-1-yl ] -urea; 1- [3-tert-butyl-1H- [1,41] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydrothiopyrano-4-yl-amino) pyridin-3-yl) - naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-cyanoethyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalene-1-yl] - urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3) -yl) -naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (2-aminopyridin-5-yl) -2H-pyrazolo-3-yl] -3 -_ [4 ^ j6r (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-4-carbonyl) -pyridin-3-) il) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-oxa-5-aza-bicyclo [2.2.1] hept -5-yl-methyl) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (G-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- (pyridin-3- il-methyl) aminomethyl) phenyl) -naphthalen-1-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; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-methyl) -4-methoxypyridin-3- il) -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-propyl) pyridin-3-yl ) -naphthalene-1-yl] -urea; 1- [3-tert. -butyl-1 '-methyl-l'H- [1, 4'] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-yl-methyl) pyridin-3-yl) naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyrano-4-yl-amino) pyridin-3-yl ) -naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (S-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-yl-amino) pyridin-3-yl) -naphthalene- l -yl] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (tetra-idrothiopyran-4-yl-amino) -pyrazin-2-yl) -naphthalene -l-il] -urea; 1- [5-tert. -butyl-2- (6-methyl-pyridyl ^^] J ^ 2IL ^ irazol ^ - (iretilca bonylamino) pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [3-tere, -butyl-1 '- (3-methylsulfanylpropyl) -l'H- [1,41] bipyrazol-5-yl] 3- [4- (6- (morpholin-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- (l-oxo-thiomorpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-yl-amino) pyridin-3-yl) -naphthalene-1 -yl] -urea; 1- [5-tert. -butyl-2- (2-methylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) aftalen-l -yl] -urea; 1- [5-tert. -butyl-2- (2-airdnopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1 -i1] -urea; 1- [3-tert. -butyl-11 -mstil-l'H- [1,41] bipyrazol-5-yl] -3- [4- (6- (morpholine 4-yl-methyl) phenyl) naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyrano-4-yl-amino) pyridin-3-yl) naphthalene-l-yl ] -urea; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (thiomorpholin-4-ylmethyl) 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; 1- [5-tert. -butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (irorpholin-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-1-pyridin-3-yl) naphthalene-1-yl ] -urea; 1- [5-tert. -butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl-methyl) pyrimidin-5-yl) naphthalen-1 -ilI ^ ure_a_y_ its pharmaceutically acceptable derivatives. 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 mucosal hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula S_ as disclosed in document O 00/55139 wherein: G is: a C6-io aromatic carbocycle or a saturated or unsaturated C3-i0 non-aromatic carbocycle; a 6-10 member heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 5-8 membered monocyclic heterocyclyl containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocyclyl, which contains one or more heteroatoms chosen from O, N and S; where G is substituted_ - ^ oi_j-inL_o_more_R1_í-R2-e-R3-; is: phenyl, naphthyl, quinolini soquinolini tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl indolyl, each of which being optionally substituted with one or more R4 or R5; is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three C1-4alkyl chains, C1-4alkoxy or C1-4alkylamino; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4, 5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; is: a bond or a chain of saturated or unsaturated, branched or unbranched Ci-4 carbons, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by O, or S (0) m and Y is optionally substituted independently with one ^ _d s_grupoa_ oxo-, - phenyl-lo-or-one-or more C-4 alkyl groups optionally substituted with one or more halogen atoms; is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each of which being optionally substituted with one to three halogen groups, alkyl Ci_ s, Ci_6 alkoxy, hydroxy, amino, mono- or di- (Ci -3 alkyl) amino, Ci-e-S (0) m alkyl, CN, CONH2, COOH or phenylamino in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkyl or Ci-6 alkoxy, tetrahydropyranyl, tetrahydrofuranyl, 1/3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl , piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, each of which being optionally substituted with one to three nitrile groups, alkyl CL-6, C 1-6 alkoxy, hydroxy, amino, mono- or di- (Ci-3 alkyl) amino-C 1-3 alkyl, CONH 2, phenylamino-Ci-3 alkyl or Ci-3-alkoxy Ci-3 alkyl; halogen, Ci_4 alkyl, nitrile, araino, hydroxy, Ci-6 alkoxy, NH2C (0), mono- or di (Ci_3 alkyl) aminocarbonyl, mono- or di (Ci_6 alkyl) amino, a secondary or tertiary amine wherein the amino nitrogen is covalently linked to 0 to 3 -alkyl or Ci-5alkoxyalkyl, pyridinyl-Ci_3alkyl, imidazolyl-Ci-3alkyl, tetrahydrofuranyl-Ci-3alkyl, nitrile-Ci-3alkyl, carboxamido-C1alkyl -3, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino, Ci_6 alkyl-S (0) mo phenyl-S (0) m, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy, halogen or mono- or di- (C 1-3 alkyl) amino; C 1-6 alkyl-S (0) m, and phenyl-S (0) m, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- ( C1-3 alkyl) amino; each of Ri is independently: a C1-10 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-i0 cycloalkanyl groups, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or iso iazo loj_est_ando s sti-tui-do-eada-one "of the groups mentioned above optionally with one to five groups selected from halogen, alkyl Ci-6 which is optionally partially or fully halogenated, cycloalkanyl C3-8, C5_8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C (O), mono- or di (C1_3 alkyl) amino, and mono- or di (Ci_3 alkyl) aminocarbonyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, each of which being optionally halogenated partially or wholly and optionally substituted with one to three optionally halogenated C1-3 alkyl groups partially or completely, CN, hydroxy-C1-3 alkyl or aryl; or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by 0, S (0) me CHOH, > C = 0, > C = S O NH; phenyloxy or benzyloxy, each of which being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or completely halogenated, CN, hydroxyC1-3 alkyl or aryl; or a group analogous to said cycloaryl group, in which one to two methine ring groups are independently replaced by N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cyclohexylphenyl, cyclohexyl, cyclohexanyl or bicycloheptanyl, each optionally being partially or fully halogenated and optionally substituted with one to three optionally partially halogenated C, _3 alkyl groups or totally, CN, hydroxy-C1-3 alkyl or aryl; or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by O, S (0) m, CHOH, > C = 0, > C = S or NH; a branched or unbranched C3-i0 alkenyl, each being optionally partially or fully halogenated, and optionally being substituted with one to three branched or unbranched C1-5 alkyl groups, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned groups being substituted with zero to five halogen groups, a C 1-6 alkyl optionally being partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl , cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, Ci-3-oxy alkyl which is optionally partially or fully halogenated, NH2C (0), mono- or di (alkyl d-3) aminocarbonyl; C3-10 alkenyl being branched or unbranched, optionally ^^^ oj ^ x -um -do ^ e3fL- ^ nx3-no ~ m heteroatoms chosen from 0, N and S (0) m; cyclopentenyl, cyclohexenyl, cyclohexadiene, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein said cycloalkene group is optionally substituted with one to three C3-3 alkyl groups; nor rilo, halogen; methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; silyl containing three C 1-4 alkyl groups optionally partially or wholly halogenated, a branched or unbranched C 3-6 alkynyl carbon chain, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by 0, NH or S (0) m and wherein said alkynyl group is optionally substituted independently with one to two oxo, pyrrolidinyl, pyrrolyl groups, one or more d-4 alkyl groups optionally substituted with one or more halogen atoms, nitrile, orfolin, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di- (Ci-3 alkyl) amino optionally substituted by one or more halogen atoms; one of R2, R4 and R5 is a branched or unbranched Ci-6 alkyl, optionally partially or wholly halogenated, acetyl, aroyl, branched or unbranched Ci-4 alkoxy, e-ada-a-e being optionally halogenated partially or completely, halogen, nitrile, methoxycarbonyl, optionally partially or fully halogenated C1-3-S (0) m alkyl, of enylsulfonyl; Ci-6 alkoxy (hydroxy, amino, or mono- or di- (alkyl Ci-) amino, nitrile, halogen; OR6; nitrile; or mono- or di- (C 1-4 alkyl) amino-S (O) 2 optionally partially or fully halogenated, or H2NS02, each of R3 is independently: phenyl, naphthyl, orpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl , tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naf tipiridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned groups is optionally substituted with one to three phenyl, naphthyl, heterocyclyl or heteroaryl groups as previously described in this paragraph, branched or unbranched Ci-6 alkyl, which is optionally partial or halogenated, cyclopropani-loT-ei-elobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5 alkyl, naphtyl-Ci-5 alkyl, halogen, hydroxy, oxo, nitrile, Ci-3 alkyl optionally halogenated partially or wholly, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyl-oxy in which the heterocyclyl or heteroaryl moiety is as previously described in this paragraph, nitro, amino, mono- or di- (Ci-3 alkyl) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH2C (0), a mono- or di- (Ci-3 alkyl) aminocarbonyl, Ci-5- alkyl C (O) -Ci-4alkyl, Ci_5alkylamino, mono- or di- (Ci-3alkylamino) Ci-5alkyloxy, amino-S (0) 2 / di- (Ci-3alkylamino) -S (0) 2, R7-C1-5 alkyl, R8-Ci-5 alkoxy, R9-C (0) -Ci-5 alkyl, Rio-Ci-5 alkyl (Rn) N, carboxy-mono- or di - (alkyl Cx_s) -amino; a condensed aryl selected from benzocyclobutyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexaneopyrazinyl, cyclopentane-nepi-rda ^ zxyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanequinolinyl, cyclopentanoisoquinolinyl, cyclohexaneisoquinolinyl, cyclopentaneindolyl, cyclohexaneindolyl, cyclopentanebenzimidazolyl, cyclohexanebenzimidazolyl, cyclopentanebenzoxazolyl, cyclohexanebenzoxazolyl, cyclopentanoimidazolyl, cyclohexaneimidazolyl, 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, Ci-6 alkyl groups optionally is partially or fully halogenated, halogen, nitrile, Ci_3-oxy alkyl which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, nitro, amino, mono or di- (alkyl Ci-3) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH2C (0), mono- or di- (alkyl) Ci-3) aminocarbonyl, alkyl Ci-4-OC (0), alkyl Ci-5-C (O) -alkyl Ci_4i amino-alkyl Ci-5í mono- or dd ^ a jguil -¾ ^^ - aTO;o - ¾d ^ u ± io Ci-5, R12-Ci-5 alkyl / R13-alkoxy 0? , R14-C (O) -alkyl Ci_s or Ris-alkyl C1-5- (Rie) N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which optionally being partially or wholly halogenated and optionally substituted with one to three C1-3alkyl groups or a group analogous to said cycloalkyl group, in which one to three methylene ring groups are independently replaced by 0, S, CHOH, > C = 0, > C = S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups; alkyl Ci-4-phenyl-C (O) -C1- alkyl-, Ci_4-C (0) alkyl-Ci-4- alkyl or Ci_4 alkyl-phenyl-S (0) ra-Ci_4 alkyl; Ci-e alkyl or Ci-branched or unbranched alkoxy, each of which is optionally partially or fully halogenated or optionally substituted with R17; 0Ri8 or Ci-6 alkyl optionally substituted with 0Ri8; amino or mono- or di- (Ci-5 alkyl) amino optionally substituted with R19; R20C (O) N (R21) -, R220- or R23R24NC (0) -; R26 (CH2) mC (0) N (R21) - or C2-6 alkenyl substituted with R23R2 NC (O) -; a C3-6 alkynyl carbon chain (branched or unbranched, optionally partially or fully halogenated, in which one or more methylene groups are optionally replaced by O, NH, S (0) m and wherein said alkynyl group is optionally substituted independently with one to two oxo, pyrrolidinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, one or more C 1 alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (Ci- 4 alkyl) amino optionally substituted with one or more halogen atoms, or aroyl, an: Ci_4 alkyl optionally partially or fully halogenated and optionally substituted with R26; each of the R R8, R9 Ri0, Ri2 # R13, R15, i7 # R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, py idinyl, tetrazolyl, amino or mono- or di- (alkyl Ci-4) amino optionally halogenated partially or wholly; "Each of the Rn and R16 is independently: hydrogen or an optionally halogenated Ci-4 alkyl partially or wholly; e is independently: hydrogen or a Ci-4 alkyl optionally substituted independently with oxo or R2s; R20 is independently: a C1-10 alkyl optionally partially or wholly halogenated, phenyl, or pyridinyl, R21 is independently: hydrogen or a C1-3 alkyl optionally partially or fully halogenated, each of R22 R23 and R24 is independently: hydrogen, an alkyl Ci -6 optionally partially or fully halogenated, said Ci-6 alkyl is optionally interrupted by one or more O, N or S, said Ci-6 alkyl being also optionally substituted independently with mono- or di- (Ci-3 alkyl) aminocarbonyl, phenyl, pyridinyl, amino or mono- or di- (Ci-4 alkyl) amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di- (alkyl) C1-3) amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 O 2; W is O or S and its pharmaceutically acceptable derivatives. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of Formula 6 in which G is: phenyl, naphthyl, benzocyclobutanyl, dihydronafatyl, tetrahydronafatyl, benzocycloheptyl, benzocycloheptenyl, indanyl, indenyl; pyridinyl, pyridinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolyl, isoquinolinyl, tetrahydroisoquinoline, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiofenyl, benzooxazolonyl, benzo [1,4] oxazin-3-onyl , benzodioxolyl, benzo [1,3] dioxol-2-onyl, benzofurano-3-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, fimimidyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl. tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihidroxazinilo, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianil; wherein G is substituted with one or more Rif R2 or R3; In a further preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of the formula in which G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, in which G is substituted with one or more Rx, R2 or R3; Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl, each of which being optionally substituted with one or more groups R4 or R5; X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, - Y is: a bond or a carbon chain of Ci-4 saturated or unsaturated, wherein one of the carbon atoms is optionally replaced by O, N or S (0) m, and wherein Y is optionally substituted independently with one to two oxo, phenyl or one or more alkyl groups Ci-4 optionally substituted with one or more halogen atoms; Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl, which are optionally substituted with one to three nitrile groups, Ci-3 alkyl, C 1-3 alkoxy, amino, mono- or di- (Ci-3 alkyl) amino, CONH2 or OH; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxydyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulphuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, which are optionally substituted with one to three nitrile groups, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di- (Ci-3 alkyl) amino, CONH2 or OH; nitrile, Ci-6-S (0) m alkyl, halogen, hydroxy, Ci-4 alkoxy, amino, mono- or di- (Ci_6 alkyl) amino, mono- or di- (Ci_3 alkyl) aminocarbonyl or NH2C (0) ); one of Ri is independently: C3-6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-6 cycloalkyl groups, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned groups being optionally substituted with one to three groups selected from halogen, Ci-3 alkyl optionally being partially or fully halogenated, hydroxy, nitrile or Ci-3 alkoxy optionally being partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, CN, hydroxy-C1-3alkyl or phenyl; or a group analogous to said cycloalkyl group, wherein one to three ring methylene groups are independently replaced by O, S, CHOH, > C = 0, > C = S or NH; or silyl containing three Ci-4 alkyl groups optionally partially or fully halogenated; R 2 is independently: halogen, Ci-3 alkoxy, Ci-3-S (0) m alkyl optionally partially or wholly halogenated, phenylsulfonyl or nitrile; R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, each of which being optionally substituted with one to three phenyl, naphthyl, heterocyclyl or heteroaryl groups as previously described in this paragraph, Ci-6 alkyl optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5 alkyl, naphthyl Ci-5 alkyl, halogen, oxo, hydroxy, nitrile, optionally partially or fully halogenated Ci_3-oxy alkyl, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, nitro, amino, mono- or di- (Ci-3 alkyl) -amino , phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, N H2C (O), mono- or di- (alkyl d-3) aminocarbonyl, C 1-5 alkylC (0) -C 1-4 alkyl, mono- or di- (C 1 -C 3) amino, mono- or di- (C1-3 alkyl) -amino-C1-5 alkyl, mono- or di- (C1_3 alkyl) amino-S (O) 2, R7-C1_5 alkyl R8- C1-5 alkoxy, R9-C (O) -alkyl d-5, Rio-alkyl Ci-5 (Rn) N, carboxy-mono- or di (C 1-5) alkyl amino; C 1-3 alkyl or C 1-4 alkoxy each optionally being partially or completely halogenated, or optionally substituted with Ri 7; ORis or Ci-6 alkyl optionally substituted with 0Ri8; amino or mono- or di- (C 1-5 alkyl) amino optionally substituted with R 19; R20C (0) N (R21) -, R22O-; R23R24NC (0) -; R26CH2C (O) N (R21) - O C2- alkenyl substituted with R23R24NC (0) -; or a C2-4 alkynyl carbon chain, branched or unbranched, optionally partially or wholly halogenated, and optionally independently substituted with one to two oxo, pyrrolidinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl groups , tetrazolyl or one or more Ci_4 alkyl groups optionally substituted with one or more halogen atoms; and R23 and R2 taken together optionally form an imidazolyl, piperidinyl, morpholinyl, piperazinyl or pyridinyl ring. In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition - intended for the treatment of mucosal hypersecretion, characterized in that the p38 kinase inhibitor is; selected from the compounds of formula 6 in which: G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted with one or more R1 # R2 or R3; Ar is naphthyl; X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, each of which being optionally independently substituted with one to three alkyl groups Ci-4j C 1-4 alkoxy, hydroxy, nitrile, amino, mono- or di- (Ci-3 alkyl) amino, mono- or di- (C 1-3 -alkylamino) carbonyl, NH 2 C (0), alkyl d-6-S (0) or halogen; Y is: a bond or in which one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group; Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl, which are optionally substituted with one to two Ci-2 alkyl or Ci_2 alkoxy groups; tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl, which are optionally substituted with one to two alkyl groups Ci-2 or Ci-2 alkoxy; or Ci-3 alkoxy; each of Ri is independently: a C3-5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen groups, C1-3 alkyl optionally being partially or fully halogenated, hydroxy, nitrile or alkoxy Ci-3 which is optionally partially or totally halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or completely halogenated, CN, hydroxy-C1-3alkyl or phenyl; and a group analogous to cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, in which a ring methylene group is replaced by O; and silyl independently containing three C1-2 alkyl groups optionally partially or wholly halogenated; each of R is independently: bromine, chlorine, fluoro, methoxy, methylsulfonyl or nitrile; each of R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned groups is optionally substituted with one to three 0-3 alkyl groups which are optionally partially or wholly halogenated, halogen, oxo, hydroxy, nitrile and optionally partially or fully halogenated alkyl (3-oxy): Ci_3 alkyl or C1-3 alkoxy, each of which optionally being partially or wholly halogenated or optionally substituted with R17; ORis or C3-alkyl optionally substituted with ORi8; amino or mono- or di- (Ci-3 alkyl) amino optionally substituted with Ri9; R20C (O) N (R21) -, R22O-; R23R24NC (0) - R26CH2C (O) N (R21) - or C2_4 alkenyl substituted with R23R24NC (O) -, or C2-4 alkynyl substituted with pyrrolidinyl or pyrrolyl, and R23 and R2 taken together optionally form a morpholino In still another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents 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 in which G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more Rl7 R2 or R3; Ar is l-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl; Y is: a bond or -CH2-, -CH2CH2-, -C (0) -, -0-, -S-, -NH-CH2CH2CH2-, N (CH3) - or -NH-; each of Ri is independently: C3_5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl; cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl, optionally substituted with one to three methyl groups optionally partially or wholly halogenated, CN, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted with methyl; or trimethyl silyl; each of the R3 is independently: phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the aforementioned groups is optionally substituted with C1-2alkyl which is optionally partial or totally halogenated; Ci-3 alkyl or Ci-3 alkoxy, each of which optionally being partially or wholly halogenated or optionally substituted with diethylamino; 0Ri8 or C1-3 alkyl optionally substituted with ORi8; amino or mono- or di- (C 1-3 alkyl) amino optionally substituted with R 19; CH3C (0) NH-, R22O-; R23R24NC (0) -; R26CH2C (0) N (R21) - or R26C (0) CH2N (R21) -; C2-4 alkenyl substituted with R23R24NC (O) -; or C2-4 alkynyl substituted with pyrrolidinyl or pyrrolyl; R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and R26 is morpholino. In a further preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of the formula in which G is phenyl, pyridinyl or naphthyl in which G is substituted with one or more RX / R2 or R3; X is: imidazolyl or pyridinyl; Y is: ~ ZCH2-, -NH-CH2CH2CH2- or -NH-; Z is morpholino; each of the Ri is independently: tere. -builo, sec-butyl, tere. -amily or phenyl; R2 is chlorine; R3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino or morpholinocarbonyl. In yet a further preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected among the compounds of formula _6 wherein X is pyridinyl. In still a further preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from among the compounds of formula (5) in which the pyridinyl is attached to Ar through the 3-position of pyridinyl.
Preferably, the invention relates to the use of p38 kinase O2 bing agents for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the group consisting of: following compounds of formula (5- 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-1-yl] -urea 1- (4-chloro-2-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-chloro-5-trifluoromethyl-phenyl) -3- [4- (6-morpholine -4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3,4-dimethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3- il) -naphthalen-1-yl] -urea 1- (3-iodo-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-methylsulfanyl-phenyl) -3- [4 - (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3-chloro-4-methyl-phenyl) -3- [4- (6-morpholin-4 -ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-chloro-3-nitro-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3- il) -naphthalen-1-yl] -urea 1- (2, 5-dichloro-phenyl) -3- [4- (6-norpholin-4-ylmethyl-pyridin-3-yl) -naftalen -? ^? ] -urea 1- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3-naphthalen-2-yl-urea 1- [4- (6-morpholine- 4-ylmethyl-pyridin-3-yl) -naphthalen-l-yl] -3-phenyl-urea 1- (3-chloro-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3 -yl) -naphthalen-1-yl] -urea 1- (4-chloro-3-trifluoromethyl-phenyl) -3- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl ] -urea 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (2,4,6-trichloro-phenyl) -urea 1- (2 -methyl-3-nitro-phenyl) -3- [4- (6-niorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-methyl-2-nitro- phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2,3-dichloro-phenyl) -3- [4- ( 6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-methoxy-5-methyl-phenyl) -3- [4- (6-mDrpholin-4-ylmethyl) -pyridin-3-yl) -naphthalen-l-yl] -urea 1- (2-chloro-6-tetiethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea 1- (2,4-dichloro-phenyl) -3- [4- (6-rtiDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -u rea 1- (4-methyl-3-nitro-phenyl) -3- [4- (6-morpholin-4-ylmstyl-pyridin-3-yl) -naphthale-1-yl] -urea 1- (2,4 -diTrethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthal¾i ^ l ~ iX] ^ urea 1- (2,3-dimethyl-phenyl) -3- [ 4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-cyano-phenyl) -3- [4- (6-ttorpholin-4-ylmethyl- pyridin-3-yl) -naphthalen-1-yl] -urea 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (3,4,5 -trimethoxy-phenyl) -urea l-biphenyl-4-yl-3- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-l-yl] -urea 1- (2, 5 -difluoro-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (3-chloro-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (2-fluoro-3-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4- benzyloxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-methylsulfanyl-phenyl) -3- [4- ( 6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-fluoro-6-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl) -pyridin-3-yl) -naphthalen-l-yl] -urea 1- (4-fluoro-3-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -3- (2, 4,5-trimethyl-phenyl) -urea 'l-; [4 C6-mDrfólTñ- ^ -naftalen-l-il] -3- (4- trifluoromethyl-phenyl) -urea 1- (3-methylsulfanyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl -pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-methoxy-phenyl) -3- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -yl] -urea 1- (2-fluoro-5-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-methoxy-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-fluoro-5-) nitro-phenyl) -3- [4- (6-itiorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-ethoxy-phenyl) -3- [4- ( 6-morpholin-4-yl-ethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2,5-dimethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridine -3-yl) -naphthalen-1-yl] -urea 1- (4,5-dimethyl-2-nitro-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (5-chloro-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (2-isopropyl-6-methyl-phenyl) -3- [4- (6-morpholin-4-yl-ethyl-pyridin-3-yl) -na phthalen-1-yl] -urea 1- (2-difluoromethoxy-phenyl) -3- [4- (6-rtiorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- ( 4-isopropyl-phenyl) -3- [4- (6-morpholin-4-yl-ethyl-pyridin-3-yl) - "naft" aléñ = ~ il] -urea "1- (4-methoxy-phenyl) -3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3-ethyl-phenyl) -3- [4- (6-morpholin-4- ilmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-ethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -urea 1- (4-butoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea ethyl ester of 4 -. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -benzoic acid 1- (4-butyl-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2, 6-dibromo-4-isopropyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3-methoxy-phenyl) - 3- [4- (6-inorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- [4- (6-irorpholin-4-ylmethyl-pyridin-3-yl) - Naphthalen-1-yl] -3- (4-trifluoromethylsulfanyl-phenyl) -urea 5-dimethyl ester. { 3- [4- (6-N-norpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -isophthalic 1- (3-cyclopentyloxy-4-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 3-ethyl ester -. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -benzoic 1 ^ - ^ - üerc ~ bui ^ ^ hrdrox ^ phenyl) - ^ [¾ ^ C6-morphoryl 4-yl 3-yl) -naphthalen-l-yl] -urea 1- (2-hydroxymethyl- 4-phenyl-cyclohexyl) -3- [4- (6-rnorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-rt-ethylsulfanyl-5-trifluoromethyl-phenyl) - 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) - Naphthalene-1-yl] -3- (4-pentyloxy-biphenyl-3-yl) -urea 4-methoxy-3-methyl ester. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -benzoic 1- (2,5-diethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea l-benzothiazol-6-yl -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea N- (2,5-diethoxy-4- { 3- [4- ( 6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido.} - phenyl) -benzamide 1- [4- (6-morpholin-4-yl-ethyl-pyridin-3-yl ) -naphthalene-1-yl] -3- (3-phenoxy-phenyl) -urea 1- (5-ethanesulfonyl-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridine- 3-yl) -naphthalen-l-yl] -urea 4-methoxy-3-. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -N-enyl-benzamide 1- (2-methyl-l, 3-dioxo-2,3-dihydro-lH-isoindol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridine- 3-yl) -naphthalen-l-yl] -urea 1- (2,3-dimethyl-lH-indol-5-yl) -3- [4- (6-morpholin-4-yl-yryl-pyridin-3-i ) -naphthalene-1-yl] -urea N-butyl-4-methoxy-3-. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -benzenesulfonamide 1- [3- (2-methyl- [1,3] dioxolan-2-yl) -phenyl] -3- [4- (6-rrDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -urea 1- (3-methoxy-5-trifluoromethyl-phenyl) -3- [4- (6-rnorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1 - (2,4-Dimethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-methyl-4-nitro) phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-methoxy-4-nitro-phenyl) -3- [ 4- (6-tnorfolin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-chloro-2-nitro-phenyl) -3- [4- (6-morpholine- 4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-chloro-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3 -yl) -naphthalene-1-yl] -urea 1- (3, 5-dirnetoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- [4- (6-morpholin-4-yl-triethyl) -pyridin-3-yl) -naphthalen-1-yl] -3- (4-trifluoromethoxy-phenyl) -urea 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1 -yl] -3- (3-trifluororaethylsulfanyl-phenyl) -urea 1- [4- (6-mDrpholin-4-yl-ethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (2-phenoxy) phenyl) -urea l ^ 2-rtethoxy ^ 5 ^ il or: phenyl-3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5 -chloro-2,4-dimethoxy-phenyl) -3- [4- (6-rrDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3,5-bis- trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (2-tert-butyl-5-methyl-pyridine- 4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3-methyl-naphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (3-tert-butyl-phenyl) -3- [4- (6-Trorpholin- 4-ylmethyl-pyridin-3-yl) -naphthalen-l-yl] -urea 1- (4-ethyl-biphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (4-tert. -butyl-biphenyl-2-yl) -3- [4- (6-Trorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-chloro-2,4- dimethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-isopropyl-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-sec-butyl-2-ethoxy-phenyl) -3- [4- (6 -Thorfolin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-tert-butyl-2-methoxy-3-propyl-phenyl) -3- [4- (6 -morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-tert-butyl-2-methoxymethyl-phenyl) -3- [4- (6-morpholin-4 -ylmethyl-p-irldιTI ^ 3 ~ iT) -naphthalen-l-iT] -urea 1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl) -pyridin-3-yl) -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 1- (5-tert-butyl-2-methyl-phenyl) -3- [4- (4-morpholine 4-butyl-imidazol-1-yl) -naphthalene-1-yl] -urea 1- (5-tert-butyl-2-thylene-phenyl) -3- [4- (6-morpholin-4 -ylmethyl -pyridin-3-yl) -naphthalen-1-yl] -urea 1- (5-tert. -butyl-2-methyl-phenyl) -3-. { 4- [6- (3-methoxy-propylartan) -pyridin-3-yl] -naphthalene-1-yl} -urea 1- (5-tert-butyl-2-methyl-pyridin-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (5-tert-butyl-2-morpholin-4-yl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea 1- (6-tert-butyl-2-chloro-3-methyl-pyridin-4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -urea 1- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (3-trifluoromethyl-phenyl) -urea 1- [4- (6-rrorfolin-4-ylmethyl-pyridin-3-yl) -naphthalen-l-yl] -3- (4-trifluoromethoxy-phenyl) -urea 1- [5- (1,1-dimethyl-propyl) -2 -raetoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- [5-tert. -butyl-2- (lH-pyrazol-4-yl) -phenyl] -3- [4- (6-N-arfolin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea l ~ fS ^ terc ^ uTn.T 2 ^ T2-me-il-pyrimidin-5-yl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea 1- [5-tert. -butyl-2- (3-hydroxy-propyl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea 1- [5- tert -butyl-2- (3-morpholin-4-yl-3-oxo-propyl) -phenyl] -3- [4- (6-raorpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl ] -urea 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-rtethoxy-3- { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido.} - phenyl) - acetamide and its pharmaceutically acceptable derivatives. 1- (2-tert-Butyl-5-methyl-pyridin-4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (3-methyl-naphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (3-tert-Butyl-phenyl) -3- [4- (4-morpholin-4-ylmethyl-phenyl) -naphthalen-1-yl] -urea; 1- (3-tert-Butyl-phenyl) -3- [4- (6-nnorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (4-Methyl-biphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (4-tert-Butyl-biphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-chloro-2,4-dimethoxy-phenyl) -3- [4- (6-raorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; (5-phenyl-2-pyridinyl) -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; -tert -butyl-2-methoxy-3-propyl-phenyl) -3- [4- (6-rtorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 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-tethoxy-phenyl) -3- [4- (2-morpholin-4-ylmethyl-pyriraidin-5-yl) -naphthalene-1-yl] -urea; 1- (5-tert.-butyl- 2-methoxy-phenyl) -3- [4- (4-thiomorpholin-4-ylmethyl-phenyl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-tnetoxy-phenyl) -3- [4- (6-morpholin-4-yl-phenyl-phenyl) -naphthalene-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. {4- [4- (tetrahydro -pirano-4-ylamino) -phenyl] -naphthalene-l-yl.}. -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. {4- [6- ( 4- methyl-piperazin-1-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-Butyl-2-methyl-phenyl) -3- (4-. {6 - [(3-methoxy-propyl) -methyl-amino] -pyridin-3-yl}. naphthalene-1-yl) -urea; 1- (5-tert-Butyl-2-methyl-phenyl) -3- [4- (4-morpholin-4-ylmethyl-imidazol-1-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-methyl-phenyl) -3- [4- (4-morpholin-4-ylmethyl-phenyl) -naphthatene ^ 1 ^ 1 ^ areaT 1- (5-tert. -butyl-2-m-butyl-phenyl) -3- [4- (6-N-arfolin-4-yl-ethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methyl-phenyl) -3-. { 4- [6- (3-methoxy-propylamino) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tert-Butyl-2-methyl-pyridin-3-yl) -3- [4- (6-rahorpholin-4-yl-ethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-morpholin-4-yl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l- il] -urea; 1- (6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl) -3- [4- (6-thiomorpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l- il] -urea; 1- [2-methoxy-5- (1-methyl-cyclopropyl) -phenyl] -3- [4- (2-morpholin-4-ylmethyl-pyrimidin-5-yl) -naphthalen-1-yl] -urea; 1- [4- (6-morpholin-4-yl-ethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (3-trifluoromethyl-phenyl) -urea; 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (4-trifluorothiethoxy-phenyl) -urea; 1- [5- (1, 1-dimethyl-propyl) -2-rnetoxy-phenyl] -3- [4- (4-thiomorpholin-4-ylmethyl-phenyl) -naphthalen-1-yl] -urea; 1- [5- (1, 1-diitiethyl-propyl) -2-rafthoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] - urea; 1- [5- (1-cyano-cyclopropyl) -2-methoxy-phenyl] -3- [4- (2-morpholin-4-ylmethyl-pyrimidin-5-yl) -naphthalen-1-yl] -urea; ilmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (2-methyl-pyrimidin-5-yl) -phenyl] -3- [4- (5-pyridin-4-ylmethyl-pyridin-2-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; 1- [5-tert. -butyl-2- (3-hydroxy-propyl) -phenyl] -3- [4- (6-morpholin-4-yl-ethyl-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; 1- [5-tert. -butyl-2- (morpholine-4-carbonyl) -phenyl] -3- [4- (6-morpholin-4-ylmstyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 2- [4-tere. -butyl-2- (3- { 4- [6- (2,6-dimethyl-nx3-trinin-4-yl-ethyl) -pyridin-3-yl] -naphthalen-1-yl}. -ureido) -phenoxy ] -acetamide; 3- . { 4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl} - benzamide; 4-tert. -butil-2-. { 3- [4- (2-Chloro-4-morpholin-4-ylmethyl-phenyl) -naphthalen-1-yl] -ureido} -benzamide; and its pharmaceutically acceptable derivatives. More preferably, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of the formula 6-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (3-tere. -butyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (4-Methyl-biphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (4-tert-Butyl-biphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 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; 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) -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; 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) -naphthalen-1-yl] -urea; 1- [5- (1, 1-dimethyl-propyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- [5-tert. -butyl-2- (1H-pyrazol-4-yl) -phenyl] -3- [4- (6-morpholin-4-yl-me-1-yl-pi-rd-di-1- [5 -terc -butyl-2- (2-methyl-pyrimidin-5-yl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea; 1- [5-tert-butyl-2- (3-hydroxy-propyl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1 -yl] -urea; 1- [5-tert-butyl-2- (morpholine-4-carbonyl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) - naphthalene-1-yl] -urea; N- (5-tert-butyl-2-methoxy-3. {3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -l-il] -ureido.}.-phenyl) -acetamide and its pharmaceutically acceptable derivatives In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for treatment of mucosal hypersecretion, characterized in that the p38 kinase inhibitor agent is selected from the compounds of formula 7 as disclosed in the document. nto WO 00/55139 7 in that: E is a carbon or a group with heteroatom chosen from -O-, -NH- and -S-; G- ^ is -: - ^ an aromatic carbocycle Cg-io or non-aromatic carbocycle? 3-10, saturated or unsaturated; a 6-14 membered heterocyclic, monocyclic, bicyclic or tricyclic, containing 1 or more heteroatoms chosen from 0, N and S; a 6-8 membered monocyclic heterocyclyl, which contains one or more heteroatoms chosen from 0, N and S; or an 8-11 membered bicyclic heterocyclyl, which contains one or more heteroatoms chosen from O, N and S; wherein G is optionally substituted with one or more Ri, R2 or R3; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl, each of which being optionally substituted with one or more R4 or R5; X is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three Ci_4 alkyl chains, Ci_4 alkoxy or Ci_4 alkylamino, being-e-ad-a-una de-el ^ -as- ami-íH.-cada-o-sl-n- ami-fi-car-; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4, 5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4 alkoxy, hydroxy, nitrile, amino, mono- or di- (Ci_3) amino, mono- or di- (alkyl) groups Ci-3-amino) carbonyl, NH2C (0), Ci-6-S (0) alkyl or halogen; a saturated or unsaturated, branched or unbranched Ci-4 carbon chain or chain, optionally partially or wholly halogenated, in which one or more C atoms are optionally replaced by 0, N or S (0) ra and wherein Y is optionally substituted independently with one to two oxo, nitrile, phenyl groups or one or more Ci_4 alkyl optionally substituted with one or more halogen atoms; aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, fu-mannyl-, -thieni or -pi-r-anyl-, -heterocyclicheyl ", prated between tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo [2.2.1] heptanil, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z being optionally substituted with one to three halogen groups, Ci-6-alkyl, Cx-6-alkoxy, C-3-alkoxy-Ci_3 alkyl, Ci_6-carbonyl alkoxy, aroyl, Ci-3 acyl, oxo, hydroxy, pyridinyl-Cx_3 alkyl, imidazolyl-0-3alkyl, tetrahydrofuranyl-Cx-3alkyl, nitrile-Ci-3alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino, Ci_6-S (0) m alkyl, or phenyl-S (0) ) m in which the phenyl ring is optionally substituted by one to two halogen groups, Ci_6 alkoxy, hydroxy, halogen or mono- or di- (Ci-3 alkyl) amino; or Z is optionally substituted with one to three groups "anu.no or amino-alkTTi" or "-i-3-e'n-I'os-a'-o" N-"" this is optionally mono- or di- independently substituted with amino-Ci-5 alkyl, Ci-3 alkyl / arylC0-3 alkyl, Ci_5 alkoxy C1-3 alkyl, Ci_5 alkoxy, aroyl, C1-3 acyl Ci_3-S alkyl (0) m- or arylC0-3-S (O) m-, each of the aforementioned alkyl and aryl groups attached to the amino group is optionally substituted with one to two halogen groups, Ci-6 alkyl or Ci-6 alkoxy or Z is optionally substituted with one to three aryl, heterocyclyl or heteroaryl groups as previously described in this paragraph, each of which in turn is optionally substituted with halogen, Ci-6 alkyl or Ci-6 alkoxy, or Z is hydroxy, halogen, nitrile, amino in which the N atom is optionally mono- or di-substituted independently with acyl Ci-3, alkyl Ci-6 or alkoxy Ci-3alkyl Ci_3, alkyl Ci-6 branched or without ram ificar, Ci-6 alkoxy, Ci-3-amino acyl, nitrile-alkyl Ci-4, Ci-6-S (0) alkyl and phenyl-S (0) m, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy / hydroxy or mono- or di- - (Ci-3 alkyl) amino; each of the Ri is independently: "un-6r-io ~ ad-qu lo -rami-f ± cado ~ o-s ± n-rami-f-rcar -; - opri &na na ment - partially or totally halogenated , wherein one or more C atoms are optionally independently replaced by O, N or S (0) m, and wherein said Ci-io alkyl is optionally substituted with one to three C3_i0 cycloalkyl groups, hydroxy, oxo ^ _ phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl, each of the aforementioned groups being optionally substituted with one to five - groups selected from halogen , Ci-6 alkyl optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C3-alkoxy optionally partially or fully halogenated or NH2C (O), mono- or di (alkyl) Ci-3) -amino, and mono- or di- (C 1-3 alkyl) -aminocarbonyl; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy-Ci-3 alkyl or aryl or a group analogous to said cycloalkyl group, in which from one to three groups -me -i-leno__de-anillo_es_tán_r_ee.rap-l_ozado.s independently by O, S (0) m, CHOH, > C = 0, > C = S or NH; phenyloxy or benzyloxy, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxyC1-3 alkyl or aryl; or a group analogous to said cycloaryl group, in which one to two methine ring groups are independently replaced by N; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy-C1alkyl -3 or aryl; or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by O, S (0) m, CHOH, > C = 0, > C = S or NH; branched or unbranched C3-i0 alkenyl, each optionally being partially or fully halogenated, and optionally substituted with one to three branched or unbranched C1-5 alkyl groups, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -? -? - G-? T ?? -? -? -? T i-mida-z-el-i-1-? T pi-razol-ile-í ti-en-ile fu-ri-lo- isoxazolyl or isothiazolyl, each of the aforementioned groups being substituted by one to five halogen groups, Ci_6 alkyl optionally being partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile , alkyl Ci-3-oxy which is optionally partially or fully halogenated, NH2C (0), mono- or di (alkyl Ci-3) aminocarbonyl; the C3-i0 alkenyl being branched or unbranched, optionally interrupted by one or more heteroatoms chosen from O, N and S (0) m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three alkyl groups oxo, nitrile, halogen; silyl containing three C, alkyl groups optionally partially or wholly halogenated; or a C3-S / branched or unbranched alkynyl carbon chain, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by O, H or S (0) m and wherein said alkynyl group is optionally substituted de-ma-ne-ra-i-ndepend-i-en-te-eon ~ -üíie-a-dos-gr-upos-exe-¡-hydr-ox-i -; - pyrrolidinyl, pyrrolyl, tetrahydropyranyl, one or more groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (Ci-3 alkyl) amino optionally substituted with one or more halogen atoms; each of R2, R and R5 is a branched or unbranched C1-6 alkyl, optionally partially or fully halogenated, C1-6 acyl, aroyl, branched or unbranched C1-4 alkoxy, each being optionally partially or completely halogenated, halogen, methoxycarbonyl, Ci_3-S (0) m alkyl. optionally partially or fully halogenated, or phenyl-S (0) m; 0R6, Ci-6 alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S (0) m- in which the N atom is optionally mono- or di-substituted independently with Ci-6 alkyl or arylC0-3 alkyl, or amino in which the N atom is optionally mono - or di-substituted independently with C1-3 alkyl, aryl-Co-3 alkyl, Ci-6 acyl, Ci-6-S (0) m- or aryl-C0-3-S (0) alkyl - each of the aforementioned alkyl and aryl groups in this subparagraph is optionally partially or fully halogenated and optionally substituted with one to two -g-tu os-aiguüo-Ci-6-o-alkoxy-Ci-6-; each of the R3 is independently: phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, [1, 3, 4] oxadiazole, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naftipyridinyl, quinoxalinyl , quinazolinyl, purinyl or indazolyl, each of the aforementioned groups is optionally substituted with one to three phenyl, naphthyl, heterocyclyl or heteroaryl, as previously described in this paragraph, branched or unbranched Ci-6 alkyl, which optionally is partial or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-C 1-5 alkyl, naphthyl-C 1-5 alkyl, halogen, hydroxy, oxo, nitrile, Ci_3 alkoxy optionally partially or wholly halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heterocyclyl or hetero oaril is as before it was de-ser-ibe-en-est-para, - ni-tr, -amino, -mono- or di ^ - ~ (Ci-3 alkyl) -amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH2C (0), a mono- or di- (C1- alkyl) 3) -aminocarbonyl, C 1-5 alkylC (O) -C 1-4 alkyl, aminoC 1-5 alkyl, mono- or di- (Ci_5 alkyl) amino, mono- or di- (Ci-3 alkyl) amino -Ci-5 alkyl, amino-S (0) 2 / di- (C 1-3 alkyl) amino-S (0) 2 > R7-Ci-5 alkyl, Rs-Ci-5 alkoxy < Rg-C (0) -Ci-5 alkyl, Ri0-Ci_5- (R11) N, carboxy-mono- or di- (Ci-5 alkyl) -amino; an aryl condensate selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, ciclohexanopiridinilo, ciclopentanopirimidinilo, ciclohexanopirimidinilo, ciclopentanopirazinilo, ciclohexanopirazinilo, ciclopentanopiridazinilo, ciclohexanopiridazinilo, ciclopentanoquinolinilo, ciclohexanoquinolinilo, ciclopentanoisoquinolinilo, ciclohexanoisoquinolinilo, ciclopentanoindolilo , cyclohexaneindole, cyclopentanobenzimidazolyl, cyclohexanebenzimidazolyl, cyclopentanebenzoxazolyl, cyhexanzbenzoxazyl, cyclo-1-opentanoimidazole-Lo -, - cyclohexaneimidazolyl, 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 1-6 alkyl groups optionally is partially or fully halogenated, halogen, nitrile, Ci-3-oxy alkyl which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, nitro, amino , mono- or di- (C 1-3 alkyl) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH 2 C (0), mono- or di- (C 1 -C 3 alkyl) -aminocarbonyl, C 1 -C 0 alkyl (0), C 1 -C 5 alkyl (0) -Ci 4 alkyl, C 1-5 aminoalkyl, mono- or di-alkyl (C ^ -3) amino-Ci-5 alkyl, Ri2-Ci_5 alkyl, Ri3-Ci-5 alkoxy, R14-C (0) -a C1-5 alkyl or R15-C1-5 alkyl - (Ri6) N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of -eil-os © pc-ione-l-mente pa-re-ial-o-tota-l-msnte-ha-l-ogenad © - optionally substituted with one to three C1-3 alkyl groups) or a group analogous to said cycloalkyl group, wherein one to three ring methylene groups are independently replaced by O, S, CHOH, > C = 0 (> C = S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups; Ci-4-phenyl-C alkyl (0) -Ci-4alkyl, Ci-4alkyl (0) -alkyl C; L_- or alkyl Ci_4-phenyl-S (O) m-Ci_4 alkyl-; Ci_6 alkyl or C1- alkoxy 6 branched or unbranched each of which is optionally partially or fully halogenated or optionally substituted with Ri7; ORie or Ci-6 alkyl optionally substituted with 0Ri8 amino or mono- or di- (Ci-5 alkyl) amino optionally substituted with Ri9; R20C (O) N (R2i) -, R22O- or R23R24NC (0) -; R26 (CH2) mC (O) N (R21) -, R23R24NC (0) - alkoxy Cx_3 or R26C (O) (CH2) mN (R21) - C2-6 alkenyl substituted with R23R24NC (0) -, a C2-6 alkynyl carbon chain, branched or unbranched, optionally partially or completely halogenated, in which one or more methylene groups are optionally replaced by 0 , N H, S (0) m and in which said alkynyl group is optionally substituted in the manner - - - - independently - with - one - two - groipos - oxo, - irrolddiniJ ^ morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl , tetrazolyl, one or more C 1 alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (alkyl Ci-) amino optionally substituted with one or more halogen atoms; acyl Ci-6 or aroyl; R6 is: a Ci_4 alkyl optionally halogenated partially or wholly and optionally substituted with R26; each of R7, R8, R < ?, Rio # R12, R13, i R15 »17 R19 R25 Y R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di- (Ci-4 alkyl) amino optionally partially or wholly halogenated; each of Ru and Ri6 is independently: hydrogen or optionally halogenated C1-4 alkyl partially or wholly; R18 is independently: hydrogen or Ci-4 alkyl optionally substituted independently with oxo or R25 R20 is independently: optionally halogenated partial or -tota-l-men-fce-, - f-ei-io-o-ir-idinyl-o-R2i is independently: hydrogen or Ci-3 alkyl optionally partially or fully halogenated; each of R22 / R23 and R24 is independently: hydrogen, Ci-6 alkyl optionally partially or wholly halogenated, said Ci-6 alkyl is optionally interrupted by one or more O, N or S, said Ci-6 alkyl being optionally also independently substituted with mono- or di- (alkyl Ci-3) aminocarbonyl, phenyl, pyridinyl, amino or mono- or di- (Ci_4 alkyl) amino, each of which optionally is partially or fully halogenated and optionally substituted with mono- or di- (Ci_3 alkyl) amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 or 2; W is O or S and its pharmaceutically acceptable derivatives. In a preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that -the.ag.ent.e_i.nhib.idor_de-la- _ci-na.sa__p.3-8 is selected from the compounds of formula 7 in which: E is -CH2-, -NH- O -0-; W is O; and G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl; pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinoline, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, 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-lH-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, thiazolinyl, imidazolinyl, - tetrahydropyridinyl, homopiperidinyl , pyrrolinyl, tetrahydropyrimidinyl, decahydrcquinolinyl, decahydroisoquinolinyl, thiotonolpholino, thiazolidinyl, dihydroxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanil or dithianyl; where G is optionally substituted with one or you will go Rlf R2 or R3.
In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 in which: E is -NH-; G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-lH-indolyl or indolinonyl, wherein G is optionally substituted with one or more Ri, R2 or R3; Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl, each of them being-optional-l-triente-sustritui-do-TT? -uo-o-má-s-gru -pos-R¾-o-R5-; X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4 alkoxy, hydroxy, nitrile, amino, mono- or di- (alkyl) groups C1-3) amino (mono- or di- (alkyl Ci-3 amino) carbonyl, NH2C (0), Ci-6-S (0) alkyl or halogen; Y is: a carbon chain or a C1- chain saturated or unsaturated, in which one or more of the C atoms is optionally replaced by 0, N or S (0) ra and wherein Y is optionally substituted independently with one to two oxo, nitrile, phenyl or one or more C1-4 alkyl groups optionally substituted with one or more halogen atoms: Z is: phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocyclyl selected from ^ 2 ^ oxa- ^ -a-za- -GÍGl ^ - [2-r2 ^ -] - he fea il-o- tetrahydropirimidonil, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl, tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomo rfolino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyrrolidinyl and dioxolanyl, which are optionally substituted with one to three nitrile groups, Ci-3 alkyl, Ci-3 alkoxy, amino, mono- or di- (Ci-3 alkyl) amino, CONH2 or OH; or Z is optionally substituted with phenyl, heterocyclyl or heteroaryl as previously described in this paragraph, each of which in turn is optionally substituted with halogen, Ci-3 alkyl or Ci-3 alkoxy > - or Z is nitrile, nitrile-Ci_3 alkyl, Ci_6-S (0) m alkyl, halogen, hydroxy, Ci-3 alkyl, Ci-3-amino acyl, Ci-4 alkoxy, amino, mono- or di- (alkyl) Ci-3) aminocarbonyl, or amino mono or di-substituted with amino-Ci-6 alkyl or C 1-3 alkoxy-Ci-3 alkyl; each of Ri is independently: branched or unbranched Ci-6 alkyl, optionally partially or wholly halogenated, in which one or more C atoms are optionally independently replaced by Q_, N or. S (0) m, and wherein said alkyl Q is optionally substituted with one to three C3-6 cycloalkyl groups, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned groups being optionally substituted with one to three groups selected from halogen, Ci-3 alkyl optionally being partially or fully halogenated, hydroxy, nitrile and C 1-3 alkoxy optionally being partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy- or C1-3alkyl or phenyl, or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by 0, S, CHOH, >; C = 0, > C = S or H; OXO; a C3-6 alkynyl / branched or unbranched, optionally halogenated chain, partially or wholly, in which one or more methylene groups are optionally replaced by O, NH or S (0) m and wherein said alkynyl group is optionally substituted independently with one to two groups oxo, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, alkyl ¾_.4 optionally substituted with one or more halogen atoms, nitrile, tnorfolino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (Ci-3 alkyl) amino optionally substituted with one or more halogen atoms; or silyl containing three Ci_4 alkyl groups optionally partially or wholly halogenated; independently: a branched or unbranched Ci_5 alkyl, optionally partially or fully halogenated, acetyl, aroyl, branched or unbranched C1-4 alkoxy, each of which optionally being partially or wholly halogenated, halogen, methoxycarbonyl, Ci-2-S alkyl (0) m optionally partially or fully halogenated, or phenyl-S (0) m; Ci-3 alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S (0) m- in which the N atom is optionally mono- or di-substituted independently with C1-3 alkyl or arylC0-3 alkyl, or amino in which the N atom is optionally mono - or di-substituted independently with Ci-3 alkyl, arylC0-3 alkyl, acyl Ci-3, alkyl C1-4-S (0) m- or aryl-alkylC0-3-S (0) m -, each of the aforementioned alkyl and aryl groups in this subparagraph is optionally partially halogenated or -totally and- optionally substituted with one to two C1-3 alkyl or C1-3 alkoxy groups; s independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, [1, 3, 4] oxadiazole, pyrazolyl, each of which is optionally substituted with one to three phenyl, naphthyl, heterocyclyl or heteroaryl groups as previously described in this paragraph, alkyl ¾_6 which is optionally partially or fully halogenated, cyclopropanyl, cyclobutaneyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5 alkyl, naphthyl Ci-5 alkyl, halogen, oxo , hydroxy, nitrile, C1-3 alkoxy optionally partially or wholly halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, nitro, amino, mono- or di- (C1-alkyl) -3) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this patent Paragraph, NH2C (0), a mono- or di- (alkyl). 3) aminocarbonyl, Ci-5-C (O) alkyl-C 1-4 alkyl, mono- or di- (C 1-3 alkyl) amino, mono- or di (C 1-3) alkylaminoalkyl C, mono - or di- (alkyl Ci-3) amino-S (O) 2, R 7 -alkyl Ci-5, R 8 -alkoxy Ci-Sl R 9 -C (0) -alkyl Ci-5í R 10- - alkyl-Ct = s4R .t) *, - Ga- ^ boxi ^ mono ^ o -di-alkyl- ((?? - ^ -) - am-i-ne-; Ci-3 alkyl or Ci-4 alkoxy, each being of them optionally partially or wholly halogenated or optionally substituted with R 17; 0R 18 or C 1-6 alkyl optionally substituted with 0Ri8; amino or mono- or di- (Ci- 5 alkyl) amino optionally substituted with R 19; R 20 C (O) N (R 21) ) R22O-; R23R24NC (0) -; R26CH2C (O) N (R21) -, R23R24NC (O) -alkoxy C1-2 or R26C (0) CH2N (R21) -; C2-4 alkenyl substituted with R23R24NC (O) - or a branched or unbranched C2- alkynyl carbon chain, optionally partially or completely halogenated, in which one of the methylene groups is optionally replaced by 0, and optionally substituted independently with one to two oxo, pyrrolidinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C 1-4 alkyl groups optionally substituted with one or more halogen atoms; Ci-3 acyl; and R23 and R2 taken together optionally form an imidazolyl, piperidinyl, morpholino, piperazinyl or pyridinyl ring. In still another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the repair of a composition-fa-rma-c-eut-isa-inhaiatel-e-intended for the treatment of a mucus hypersecretion, characterized in that the p38 kinase inhibitor agent is selected from the compounds of formula 1 in which: 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 indolinonyl, wherein G is optionally substituted with one or more Ri, R2 or R3, - Ar it is naphthyl; X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, each of which being optionally independently substituted with one to three alkyl groups Ci-4, alkoxy C1-, hydroxy, nitrile, amino, mono- or di- (C 1-3 alkyl) amino, mono- or di- (C 1-3 -alkylamino) carbonyl, NH 2 C (0), Ci-6-S (0) alkyl or halogen; Y is: a bond or a saturated Ci-4 carbon chain, in which one or more of the C atoms is optionally replaced by O, N or S and in which Y is optionally substituted in an ind "-pend- fe-e- GOB-niferiio- o-oxo; is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-azabicyclo [2.2.1] heptanil, morpholine, thiomorph olino, thioitiorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl, each of which is optionally substituted with one to two Ci-2 alkyl or Ci-2 alkoxy groups; or Z is hydroxy, Ci-3alkyl, C1-3alkoxy, Ci-3-amino acyl, Ci-3-sulfyl onyl, nitrile-Ci-3alkyl, or mono-amino or di-substituted with Ci-3-alkyloxyC1alkyl -3; one of the Rj. is independently: branched or unbranched Ci-5 alkyl, optionally partially or wholly halogenated, in which one or more C atoms are optionally independently replaced by 0, N or S (0) m, and wherein said Ci-alkyl is 5 is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl, each optionally substituted with one to three halogen groups, Ci-3 alkyl optionally being partially or fully halogenated, hydroxy, nitrile and Ci_3 alkoxy optionally partially or totally halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy C1-3alkyl or phenyl; and a group analogous to cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, in which a ring methylene group is replaced by O; oxo; independently substituted with one to two oxo, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, Ci_4 alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (Ci-3 alkyl) amino optionally substituted with one or more halogen atoms; or silyl containing three C1-2 alkyl groups optionally partially or wholly halogenated; Each of R2 is independently: an optionally partially or fully halogenated Ci_4 alkyl, Ci_4 alkoxy optionally partially or wholly halogenated, bromine, chlorine, fluoro, methoxycarbonyl, methyl-S (0) m, ethyl-S (0) m each one of them optionally partially or fully halogenated or phenyl-S (O) m; or R 2 is mono- or di-acyl C 1-3 amino, amino-S (0) m or S (0) amino in which the N atom is mono- or di-substituted with C 1-3 alkyl or phenyl, nitrile, nitro or Not me; Each of R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, fully halogenated, halogen, oxo, hydroxy, nitrile and Ci-3 alkoxy optionally partially or fully halogenated; Ci-3 alkyl or Ci-3 alkoxy optionally halogenated partially or totally or optionally substituted with R17; ORie or Ci-3 alkyl optionally substituted with ORi8; amino or mono- or di- (C: -3 alkyl) amino optionally substituted with R19; R20C (O) N (R21) -, R22O-; R23R24NC (0) -; R26CH2C (O) N (R21) -, NH2C (0) methoxy or R26C (O) CH2N (R2i) -; C2-4 alkenyl substituted with R23R24NC (O) -; or C2-4 alkynyl substituted with pyrrolidinyl or pyrrolyl; - C1-3 acyl and R23 and R2 taken together optionally form a morpholino. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of Formula 1_ in that: dihydro-lH-indol-5-yl, indolinyl, indolonyl, or indolinonyl, wherein G is optionally substituted with one or more Ri, R2 or R3; Ar is l-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl; Y is: a bond or -CH2-, -CH2CH2-, -C (0) -, -O-, -S-, -NH-C¾CH2CH2-, -N (CH3) -, CH2 (CN) CH2-NH- CH2 O -NH-; Z is rahorfolino, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo [2.2.1] heptanyl, Ci-3-phenylpiperazinyl alkoxy, hydroxy, C 1-3 alkyl, N, N-di-alkoxy Ci-3 -alkyl Ci_3-amino, acyl C1-3-amino, alkyl Ci-3-sulfonyl or nitrile-Ci-3 alkyl; each of Ri is independently: Ci-5 alkyl optionally halogenated partially or wholly, in which one or more C atoms are optionally cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or wholly halogenated, nitrile, hydroxymethyl or phenyl; or 2- tetrahydrofuranyl substituted with methyl; or trimethyl silyl; propynyl substituted with hydroxy or tetrahydropyran-2-yloxy; R 2 is mono- or di-acyl Ci-3-amino, amino-S (0) mo or S (0) amino in which the N atom is mono- or di-substituted with C 1-3 alkyl or phenyl, bromine , chlorine, fluoro, nitrile, nitro, amino, methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl; each of R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1, 3,] oxadiazole or pyrazolyl, each of which is optionally substituted with Ci-alkyl. 2 which is optionally partially or totally halogenated; amino or mono- or di- (alkyl Ci-3) amino optionally substituted with R19; CH3C (0) NH-, R22O-; R23R24NC (0) -; R26CH2C (O) N (R21) -, NH2C (O) methoxy or R26C (O) CH2N (R21) -; C2-4 alkenyl substituted with R23R2NC (0) -; or C2-4 alkynyl substituted with pyrrolidinyl or pyrrolyl; C1-2 acyl; and R23 and R2 are H or R23 and R2 taken together optionally form a morpholino; and R26 is morpholino.
In another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the kinase inhibitor p38 is selected from the compounds of formula 1 in which: G is phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl, benzooxazolyl, 2,3-dihydrobenzooxazole-7 ilo, 2 -oxo-2, 3-dihydro-lH-indol-5-yl or 2-naphthyl, wherein G is optionally substituted with one or more Ri, R2 X is imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; Y is: a bond, CH2 (CN) CH2-NH-CH2, -CH2-, -NH-CH2CH2CH2- or - H-; Z is morpholin-4-yl, dioxolan-2-yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, methoxyphenylpiperazinyl, hydroxy, methyl, N, N-dimethoxy-ethylamino, acetylamino, methylsulfonyl or cyanoethyl; each of the Ri is independently: tere. -butyl, sec. -butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropyl, hydroxypropyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl; R 2 is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, phenylsulfonylamino, N, N- di (methylsulfonyl) amino, methylsulfonyl or trihalomet ilsulfonyl; R 3 is independently: methyl, C 1-3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, C1-4alkylamino, NH2C (O) methox, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl In yet another preferred embodiment, the invention is compounds of formula 7 in which X is pyridinyl. In yet another preferred embodiment, the invention relates to the use of p38 kinase inhibitor agents for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 in which the pyridinyl is attached to Ar through the 3-position of pyridinyl. Preferably, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula ? _: 1- (4-tert-Butyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5- tere.-Butyl-2-methyl-phenyl) -3- [4- (4-morpholin-4-ylme-il-piperidin-1-yl) -naphthalen-1-yl] -urea; 1- (6-chloro-4-trifluoromethyl-pyridin-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [2-methoxy-5- (1-methyl-1-phenyl-ethyl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl ] -urea; 3- (5- { 4 - [3 - (5-tere-Butyl-2-methyl-phenyl) -ureido] -naphthalen-1-yl.} - pyridin-2-ylamino) -propyl ester of (5- tert -butyl-2-methyl-phenyl) -carbamic acid; 1- (6-tere. -butyl-benzo [1,3] dioxol-5-yl) -3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea; N- (5-tert-Butyl-2-methoxy -3 - { 3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido. .phenyl) -acetamide; 1,3-bis- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tere. -butyl-3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-hydroxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl ) - naphthalene-1-yl] -urea; 1- [5-tert. -butyl-2- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-3 - (2,3-dihydroxy-propyl) -2-hydroxy-phenyl] -3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- (2, 3-dimethyl-lH-indol-5-yl) -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- (2-p-tolyloxy-5-trifluoromethyl-phenyl) -urea; naphthalene-1-yl -urea; l-. { 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-l-yl] -urea; l-. { 5-tert. -butyl-2- [3- (tetrahydro-pyran-2-yloxy) -prop-1-ynyl] -phenyl} -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-hydroxymethyl-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (2-methoxy-dibenzofuran-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (2,5-di-tert-butyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [3- (4-bromo-l-methyl-lH-pyrazol-3-yl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1 -yl] -urea; 1- (3-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl ] -urea; 1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3-oxazol-5-yl-phenyl) -urea; ilmethyl-p rid n-3 - -na ta en-l- -urea; (4-tert-Butyl-2- (3 - [4- (6-morpholin-4-ylme-yl-pyridin-3-yl) -naphthalen-1-yl] -ureido.} - phenyl) -amide furan carboxylic acid: 1- (2-methoxy-4-phenylamino-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; (5-methoxy-2-methyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (3-hydroxy-naph alen-2-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; N, N-diethyl-4-methoxy -3- { 3 - [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido.} - benzenesulfonamide; 1- (2, 2-difluoro-benzo [1,3] dioxol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- [5- (1, 1-dimethyl-propyl) -2-phenoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea; 1- [5- (2, 2-dimethyl-propionyl) -2-metyl-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naph alen-1-yl] -urea; 2-chloro-5-isopropyl ester. { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} -benzoic; 1- (4-amino-3,5-dibromo-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5- tere. -butyl-3 - (2,2-dimethyl- [1, 3] dioxolan-4-ylmethyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl ) - naphthalene-1-yl] -urea; 1- [5-tert. -butyl-3- (2,3-dihydroxy-propyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] - urea; 1- (5-tert -butoxy-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5- (1-cyano-cyclopropyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-3 - (2-diethylamino-ethyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6- [1, 3] dioxolan-2-yl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- (5- tere.-butyl-2-pyrrolidin-1-yl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-dimethylamino-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-propoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6-hydroxymethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; pyridin-3-yl) -naphthalen-1-yl-acetamide; 1- (2-methoxy-5-phenoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-7-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -l-il] -urea; 1- (5-tert-Butyl-2-cyclopentyloxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -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-yl} -urea; 1- (5-cyclohexyl-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (2,4-dimethoxy-5-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1 -. { 6- tere. -butyl-3 -oxo-3, 4-dihydro-2H-benzo [1,4] oxazin-7-yl) 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- l -yl] -urea 1- (5-tert-butyl-2-methoxy-3-nitro-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -urea; 1- (3-amino-5-tere-butyl-2-methoxy-phenyl) -3- [4- (6-methyl-pyridin-3-yl) -naphthalen-1-yl] -urea; N-acetyl-N- (5-tert-butyl-2-methoxy -3 -. {3 - [4 - (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido.}.-phenyl) -acetamide; 2 H -benzo [1,4] oxazin-8-yl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-ethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-isopropoxy-phenyl) -3- [4- (β-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-imidazol-1-yl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea; N- (5-tert-Butyl-2-methoxy-4- (3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido. phenyl) - methanesul fonamide; 1 - . 1- (5- tere.-Butyl-3-ethylamino-2-methoxy-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-yl] -ureido. .phenyl) -bis (methanesulfon) amide; 1- [5-tert. -butyl-2- (1-methyl-1H-pyrazol-4-yl) -phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- (2-methanesulfinyl-5-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (2-ethanesulfonyl-5-trifluoromethyl-phenyl) -3- [4- (6-morpholine- pyrrolidin-1-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; N- [1- (5- { 4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl.} - pyridin-2-ylmethyl) - pyrrolidin-3-yl] -acetamide; 1- (l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -l-il] -urea; N- (5-tert-Butyl-2-methoxy-3-. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} .phenyl) -propionamide; 1- (5-tert-Butyl-2-methyl-benzooxazol-7-yl) -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- (3-trifluoromethanesulfonyl-phenyl) -ure; N- (5- e.-butyl-2-methoxy-3-. {3- [4- (6-rrorfolin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido}. phenyl) -isobutyramide; 2- (4-tert.-Butyl-2- { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido}. -phenoxy) - acetamide; 1- (5-tert-Butyl-2-oxo-2,3-dihydro-benzyxazol-7-yl) -3- [4- (6-morpholin-4-yl-phenyl-pyridin-3-yl) -naphthalene- l -yl] -urea; 1- (6-tert-Butyl-3-cyano-2-tnetoxy-thiethoxy-pyridin-4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1- il] -urea; 1- (6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l- il] -urea; 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-yl] -ureido} .phenyl) -benzenesulfonamide; (5-tert-Butyl-2-methoxy-3. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -ureido} - phenyl) -amide of ethanesulfonic acid; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (4-trorpholin-4-ylmethyl-piperidin-1-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-2- (1-methyl-1H-pyrazol-4-yl) -phenyl] -3- [4- (4-morpholin-4-ylmethyl-piperidin-1-yl) -naphthalene-1-yl] - urea 1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-rnorpholin-4-ylmethyl-pyrirnidin-5-yl) -naphthalen-1-yl] -urea; l- (5-tert-Butyl-2-methylsulfanyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -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; (5-tert-Butyl-2-methoxy-3-. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido} - phenyl) -amide of 2,2,2-trifluoromethanesulfonic acid; N- (5- { 4- [3- (5-tert-Butyl-2-methyl-phenyl) -ureido] -naphthalen-1-yl.} - pyrazin-2-yl) -methanesulfonarnide; 1- [4- (6- { [Bis- (2-cyano-ethyl) -amino] -methyl} - pyridin-3-yl) -naphthalene-l- 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6-thiomorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2,6-dimethyl-piperidin-1-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (1-oxo-tetrahydro-thiopyrano-4-ylamino) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (tetra idro-pyrano-4-ylamino) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6- { [(2-cyano-ethyl) - (tetrahydrofuran-2-ylmethyl) -amino] - methyl.}. pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-methoxymethyl-morpholin-4-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- (4-. {6- [(2-tnorpholin-4-yl-ethylamino) methyl] -pyridin-3-yl}. -naphthalene-1-yl) -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-methyl-3-oxo-piperazin-1-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5- {4- [3- (5-tert-Butyl-2-tethoxy-phenyl) -ureido] -naphthalen-1-yl} -pyridin-2-ylmethyl) -piperidine acid amide -3-carboxylic acid; 1- (5- {4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl} -pyridin-2-ylmethyl) -piperidine acid amide -4-carboxylic acid; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (l-oxo-l, 4-thiomorpholine-4- ilmethyl) -pyridin-3-yl] -naphthalen-1-yl} -urea; l-. { 4- [6- (4-acetyl-piperazin-1-ylmethyl) -pyridin-3-yl] - naphthalene-1-yl} -3- (5-tert-Butyl-2-methoxy-phenyl) -urea; 4 - (5- {4- [3 - (5-tere-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl} -pyridin-2-ylmethyl) ethyl ester - piperazine-1-carboxylic acid; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- (4- (6- [(2-pyridin-3-yl-ethylamino) -methyl] -pyridin-3-yl}. naphthalene-1-yl) -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3- (4-. {6- [3-ylamino] -methyl] -pyridin [tetrahydro-furan] -methyl] -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] -methyl] -pyridin-3-yl) -naphthalen-1-yl] -urea; 1 -. {5-tert-butyl-2-methoxy -phenyl) -3- (4- { 6- [(2-methylsulfanyl-ethylamino) methyl] -pyridin-3-yl.} - naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-oxa-5-azabicyclo [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-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- (4- (6- [(2-piperazin-1-yl-ethylamino) -methyl] -pyridin-3-yl}. Naphthalene-1-yl) -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. {4- [6- (4-pyrimidin-2-yl-piperazine- piperazin-1-ylmethyl] -pyridin-3-yl} -naphthalene-1-yl) -urea; 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- [6- (2-thia-5-azabicyclo [2.2.1] hept-5-lmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (5-morpholin-4-ylmethyl-pyrazin-2-yl) -naphthalen-1-yl] -urea; 1- (6-tert.-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridine -3-yl) -naphthalene-l-yl] -urea; 1- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea; N- (5- { 4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl} - pyridin-2-yl) -acetamide; N- (5-tert-Butyl-2-methoxy-3- (3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido. phenyl) -N-methyl-acetamide; N- (5-tert-butyl-2-methoxy-3-. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene) -l-il] -ureido.}.-phenyl) -2,2,2-trifluoro-acetamide: 1- (5-tert-butyl-2-methoxy-phenyl) -3- { 4- [6 - (pyridin-3-yloxy) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. {4 - [6- (pyridin-3-ylamino) -pyridin-3-yl] -naphthalen-1-yl} -urea; 3-tert-butyl-phenyl ester of [4- (6-morpholine-4]] - and its pharmaceutically acceptable derivatives. In another preferred embodiment, the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 1_ 1- (3-methyl-naphthalen-2-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) -naphthalene-1-yl] -ureido} phenyl) -acetamide; 1 - . 1 - [5 -tere. -butyl -3- (2,3-dihydroxy-propyl) -2-hydroxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (2, 3-dimethyl-lH-indol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1 - . { 5-tere. -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) -naphthalen-1-yl] -urea; 1- [5- (2,2-dimethyl-propionyl) -2-methyl-phenyl] -3 - [4 - (6-morpholine morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5 -tere. -butyl -3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl ) - naphthalene-1 -yl] -urea; 1- [5-tert. -butyl-3- (2,3-dihydroxy-propyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - urea; 1- (5-tert -butoxy-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5- (1-cyano-cyclopropyl) -2-methoxy-phenyl] -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- [5-tert. -butyl-3- (2-diethylamino-yl) -2-methoxy-phenyl] -3- [4 - (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; l- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6- [1,3] dioxolan-2-yl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-pyrrolidin-1-yl-phenyl) -3- [4- (6-rrorfolin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-dimethylamino-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-propoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6-hydroxymethyl-pyridin-3-yl) - il) -naphthalen-1-yl] -urea; 1- (2,4-dimethoxy-5-trifluoromethyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 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; N-acetyl-N- (5-tert-butyl-2-methoxy-3-. {3- [4- (6-rnorpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido.}.-phenyl) -acetamide; 1- (6-tert-butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo [l (4] oxazin-8-yl) -3- [4- (6-morpholin-4 -ylniethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-ethoxy-phenyl) -3- [4- (6-norpholin-4-yl-phenyl-pyridin-3-yl) -naphthalene-1-yl] -urea; 1- (5-tert-Butyl-2-isopropoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-imidazol-1-yl-phenyl) -3- [4- (6-rrorfolin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -urea; 1- (5-tert-Butyl-3-ethylamino-2-methoxy-phenyl) -3- [4- (6-m &g; rfolin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl ] -urea; N- (5-tert-Butyl-2-methoxy-3-. {3- [4- (6-morpholin-4-yl-ethyyl-pyridin-3-yl) -naphthalene-1-yl] -ureido}. phenyl) -bis (methanesulfon) amide; 1- [4- (6- { [Bis- (2-methoxy-ethyl) -amino] -methyl] -pyridin-3-yl) -naphthalen-1-yl] -3- (5-tert. .butyl-2-methoxy-phenyl) -urea; N- [1- (5- { 4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl] -pyridin-2-ylmethyl) -pyrrolidin- 3-yl] -acetamide; 1- (1-acetyl-3 (3-dimethyl-2 (3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -urea; N- (5-tert-butyl-2-methoxy-3. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l- il] -ureido.}.-phenyl) -propionamide; 1- (5-tert-butyl-2-methyl-benzyxazol-7-yl) -3- [4- (6-trDrpholin-4-ylmethyl-pyridin-3 -yl) -naphthalene-1-yl] -urea; 1- [4- (6-mDrpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -3- (3-trifluoromethylanesulfonyl-phenyl) -urea; N - (5-tere. -butyl-2-methoxy-3- { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido.}.-phenyl) -isobutyramide; 2- (4-tert-butyl-2- { 3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -yl] -ureido.}. -phenoxy) -acetamide, 1- (5-tert-butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl) -3- [4- (6- morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-3-cyano-2-azethoxy-phenyl) -3- [4- (6 -morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-benzyxazole-7-yl) -3- 14- (6-rrorfolin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; naphthalene-l-il] -ureido} phenyl) -amide of ethanesulfonic acid; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (2-morpholin-4-ylmethyl-pyrimidin-5-yl) -naphthalen-1-yl] -urea; 1- (5-tert-Butyl-2-methylsulfanyl-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naph-1-yl] -urea; .1- (5-tert-Butyl-2-methoxy-pyridin-3-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naph-alen-1 il] -urea; (5-tert-butyl-2-methoxy -3 - { 3 - [4 - (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] - 2,2, 2-trifluoromethanesulfonic acid ureido.}. phenyl) -amide; N- (5- { 4- [3- (5-tert-Butyl-2-methyl-phenyl) -ureido] -naphthalen-1-yl}. Pyrazin-2-yl) -methane-siilphonamide; 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-Mysteyl-piperazin-1-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6-thiomorpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -urea; (5-tert -butyl-2-methoxy-phenyl) -3-. { 4- [6- (2,6-dimethyl-piperidinylmethyl) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6- { [(2-cyano-ethyl) - (tetrahydrofuran-2-ylmethyl) -araino] - methyl.}. pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-methoxymethyl-morpholin-4-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-methyl-3-oxo-piperazin-1-, ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; 1- (5- {4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl) -pyridin-2-ylmethyl) -piperidine- amide 3-carboxylic; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (l-oxo-ll4-thiomorpholin-4-yl-ethylene) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene -l-il] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (3-oxo-piperazin-1-ylmethyl) pyridin-3-yl] -naphthalene-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; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (6-. {T (2-cyano-ethyl) -pyridin-3-ylmethyl-amino] -methyl}. -pyridin-3-yl) -naphthalen-1-yl] -urea; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) -pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tere, -butyl-2-methoxy-phenyl) -3-. { 4- [6- (2,6-dimethyl-morpholin-4-ylmethyl) -pyridin-3-yl] -naphthalene-1-yl} -urea; pyridin-3-yl] -naphthalen-1-yl} -urea; 1- (5-tert-Butyl-2-methoxy-phenyl) -3- [4- (5-morpholin-4-ylmethyl-pyrazin-2-yl) -naphthalen-1-yl] -urea; 1- (6-tere .butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6- mDrpholin-4-ylmethyl-pyridin -3-yl) -naphthalene-l-yl] -urea; 1- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-l-yl] -urea; N- (5- { 4- [3- (5-tert-Butyl-2-methoxy-phenyl) -ureido] -naphthalen-1-yl} - pyridin-2-yl) -acetamide; N- (5-tert-Butyl-2-methoxy-3. {3- [4- (6-inorpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido}. -phenyl) -N-methyl-acetamide; N- (5-tert-Butyl-2-methoxy-3-. {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido} .-phenyl) -2,2, 2-trifluoroacetamide; 1- (5-tert-butyl-2-methoxy-phenyl) -3-. { 4- [6- (pyridin-3-yloxy) -pyridin-3-yl] -naphthalene-1-yl} -urea; 3-tert. ester - [- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -carbamic acid butyl-phenyl ester; N- (5-tert.-Butyl-2-methoxy-3. {3 - [- (6-morpholin-1-methylmethyl-pyridin-3-yl) -naphthalene-1-yl] -ureido. phenyl) -methanesulfonamide and its pharmaceutically acceptable derivatives. It is particularly preferred according to the invention select from the following compounds: Example 1: Example 2 Example 5: Example 6: 2, 3a, 3b, 3c, 3d, 5, 5a, 6 and 7. A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or to any other compound which, after its administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or a pharmacologically active residue thereof. It should be understood that a pharmacologically active metabolite means any compound day 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, 5a, 6 and 7. The pharmaceutically acceptable salts of the compounds mentioned above in this specification include those derived from pharmaceutically acceptable acids or bases of inorganic and organic character. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2- acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of this invention and their salts by the addition of pharmaceutically acceptable acids. Salts derived from suitable bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (C 1 -C 4) alkyl salts. Within the scope of the present invention, references to the term "physiologically acceptable salts" are to be understood by reference to the term "pharmaceutically acceptable salts".
In another aspect, the present invention relates to appropriate inhalable pharmaceutical formulations containing at least one p38 kinase inhibitor in a therapeutically effective amount to treat mucus hypersecretion. Inhalable formulations according to the invention include inhalable powders, aerosols for dosing containing a propellant agent or inhalable solutions free of a propellant. Inhalable powders according to the invention contain p38 kinase inhibitors, optionally mixed with physiologically excipients "Propellant" also includes concentrates or sterile inhalable solutions ready for use. Formulations that can be used within the scope of the present invention are described in greater detail in the following part of the specification. In inhalable pharmaceutical compositions, the p38 kinase inhibitor agent may be present in an amount such that from a single dose apply from 100 to 10,000 / xg, preferably from 1,000 to 9,000, most preferably from 1,500 to 8,000 μl.; of p38 kinase inhibitor agent. Preferred pharmaceutical compositions within the scope of the invention provide for the administration of from about 2,000 to about 7,000 g, more preferably from 2,500 to 6,000 g of the p38 kinase inhibitor agent by a single dose. Preferably, they are administered from about 3,000 to about 5.5? 0 μ < 3 of a p38 kinase inhibitor agent once or twice a day to the patient who needs it. A) Inhalable powders: Inhalable powders which can be used according to the invention, may contain the p38 kinase inhibitor either alone or in mixture with suitable physiologically acceptable excipients. invention the following physiologically acceptable excipients can be used: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and poly -saccharides (eg dextran), polyalcohols ( eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, the mono- or di -saccharides are used, with the use of lactose or glucose being 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 particularly preferred. Within the scope of the inhalable powders according to the invention, the excipients have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. Sometimes, it may seem appropriate to add finer fractions of excipients with an average particle size of 1 to 9 μ to the aforementioned excipients. These finer excipients are also selected from the aforementioned group of possible excipients. Finally, in order to produce the inhalable powders of of particles from 0.5 to 10 μ ??, more preferably from 1 to 6 μp ?. The processes for producing the inhalable powders according to the invention, by grinding and comminution to micrometer size as well as by final mixing of the ingredients, are known from the prior art. The inhalable powders according to the invention, which contain a physiologically acceptable excipient in addition to the p38 kinase inhibitor agent, can be administered, for example, by means of inhalers which dose a single dose from a delivery charge by means of a measuring chamber, such as is described in U.S. Pat. US 4570630A, or by other means, such as are described in German Patent Application DE 36 25 685 A. Inhalable powders according to the invention, which contain the p38 kinase inhibitor optionally in conjunction with a physiologically acceptable excipient, can be administered for example using the inhaler known by the name Turbuhaler® or using inhalers as disclosed for example in EP 237507A. Preferably, the inhalable powders according to the invention, which in addition to the inhibitory agent International Patent WO 94/28958. A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in capsules is shown in Figure 1. This inhaler (called Handyhaler) is characterized by a housing 1, which contains two windows 2, a cover 3, in which they find holes for the air intake and that is provided with a screen 5 fixed through a sieve housing 4, an inhalable chamber 6 connected with the cover 3, next to which a trigger 9 provided with two sharp needles is provided. 7 and movable against a spring 8, a mouthpiece 12 that is connected to the housing 1, the cover 3 and a cap 11, through a spindle 10 to enable it to be opened or closed by folding and three holes 13 with diameters below 1 mm in the central region around chamber 6 for capsule and below housing 4 for sieve and sieve 5. The main air stream enters between cover 3 and base 1 near the hinge. The roof has a reduced width in this area, which forms the entrance gap The current enters the device between the embouchure and the cover, and then flows between the filter holder and the cover into the mainstream. Due to the production tolerances there is a certain uncertainty in this circulation because of the actual width of the gap between the filter holder and the cover. In the case of new or reworked tools, the resistance to the circulation of the inhaler may therefore be a little outside the desired value. To correct this deviation, the cover has in the central region around the chamber 6 for capsule and below the housing 4 for sieve and the sieve 5 three holes 13 with diameters below 1 mm-, through these holes 13 circulates air from the base inside the main air stream and thereby slightly reduces the circulation resistance of the inhaler. The actual diameter of these holes 13 can be chosen by suitable inserts in the tools, in such a way that the average resistance to the circulation can be made equal to the desired value. If the inhalable powders according to the invention are packaged in capsules (inhalers) for the preferred use described above, the quantities packaged in each capsule should together or separately, the doses of the p38 kinase inhibitor that have been mentioned above for each individual dose. B) aerosols for inhalation driven by a propellant gas: Inhalation aerosols with a propellant gas content, which can be used according to the invention, can contain the p38 kinase inhibitor dissolved in the propellant gas or in dispersed form . Propellant gases, which can be used to prepare aerosols for inhalation, are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as derivatives, preferably fluorinated, of methane, ethane, propane, butane, cyclopropane or cyclobutane. The aforementioned propellant gases can be used in such a case by themselves or in mixtures between them. Particularly preferred propellant gases are fluorinated derivatives of alkanes, selected from TG134a (1, 1, 1, 2-tetrafluoro-ethane), TG227 (1, 1, 2, 3, 3, 3-heptafluoro-propane) and mixtures thereof. among them. The aerosols for inhalation driven by a propellant agent, according to the invention, may contain lubricants as well as agents for adjusting the pH value. All these ingredients are known in the prior art. The aerosols for inhalation driven by a propellant, according to the invention, can contain up to 5% by weight of the p38 kinase inhibitor. The aerosols for inhalation driven by a propellant, which can be used according to the invention, contain, for example, from 0.002 to 5% by weight, from 0.01 to 3% by weight, or from 0.015 to 2% by weight, by weight of p38 kinase inhibitor.
If the p38 kinase inhibitor agents are present in a dispersed form, the active substance particles preferably have an average particle size of up to 10 μP, preferably from 0.1 to 5 μP, more preferably 1. at 5 μp ?. The aerosols for inhalation driven by a propellant, according to the invention, which can be used according to the invention, can be administered using inhalers known in the prior art (MDI 's = metered dose inhalators = metered dose inhalers). . Correspondingly, in another aspect, the present invention is driven by a propellant agent, as described herein above, combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to the use of the p38 kinase inhibitor agents according to the invention for preparing cartridges which, when coupled with an appropriate valve, can be used in a suitable inhaler, and which contain one of the above mentioned aerosols for inhalation containing a propellant gas, according to the invention. Appropriate cartridges and methods of loading these cartridges with the inhalable aerosols containing a propellant gas according to the invention are known from the prior art. C) Inhalable solutions free of propellant: It is particularly preferred to use p38 kinase inhibitors according to the invention to prepare inhalable solutions and suspensions free of propellants. The solvent used may be an aqueous or alcoholic solution, preferably an ethanolic solution. The solvent can be water alone or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum value is of 30 percent in volume. The rest of the volume is constituted by water. The solutions and suspensions containing the p38 kinase inhibitor are adjusted to a pH of 2 to 7, preferably 2 to 5, using appropriate acids. The pH can be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric 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 sulfuric acids. It is also possible to use acids that have already formed a salt by adding acid with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the aforementioned acids can also be used, particularly in the case of acids, which have other properties besides their acidifying qualities. ex. as flavoring substances, antioxidants or complexing agents, such as citric acid or ascorbic acid. According to the invention, it is particularly preferred to use the acid the known salts thereof, sodium edetate, as a stabilizer or complexing agent. Other embodiments may contain this compound or these compounds. In a preferred embodiment, the content, based on sodium edetate, is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. In general, inhalable solutions in which the sodium edetate content is from 0 to 10 mg / 100 ml are preferred. Co-solvents and / or other excipients can be added to inhalable solutions free of propellant, which can be used according to the invention. The preferred co-solvents are those containing hydroxyl groups or other polar groups, P-ex. alcohols - in particular isopropyl alcohol -, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol -, glycol ethers, glycerol, poly (oxyethylene) -alcohols and poly (oxyethylene) -esters of fatty acids. The terms "excipients" and "additives" mean in this context any pharmacologically acceptable substance, which is not an active substance, but which can be formulated together with the active substance (s) in the pharmacologically appropriate solvent, to they have no pharmacological effect, or in connection with the desired therapy, they have no appreciable pharmacological effect, or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants, such as soy lecithin, oleic acid, sorbitan esters, such as polysorbates, poly (vinyl pyrrolidone), other stabilizers, complexing agents, antioxidants and / or preservatives, which guarantee or prolong the duration of the use of the finished pharmaceutical formulation, flavoring substances, vitamins and / or other additives known in the prior art. The additives also include pharmacologically acceptable salts, such as sodium chloride, as isotonic agents. Preferred excipients include antioxidants, such as, for example, ascorbic acid, as long as it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and the like vitamins or provitamins that occur in the human body. Preservatives may be used in order to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, particularly cetyl pyridinium chloride, Previous technique. The aforementioned preservatives are preferably present in concentrations of up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml. Preferred formulations contain, in addition to the solvent water and p38 kinase inhibitor, only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is not present. The inhalable solutions free of propellants, which can be used within the scope of the invention day, are administered in particular using inhalers of the class of which are capable of nebulizing a small amount of a liquid formulation in the therapeutic dose over the course of few seconds to produce an appropriate aerosol for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which an amount of less than 100 μ ?, preferably of less than 50 μ ?, more preferably between 10 and 30 μ? of a solution of an active substance, it may be nebulized preferably in a spray action to form an aerosol with an average particle size of less than 20 μ ??, preferably less than 10 μ ??, such that the inhalable aerosol corresponds to the Liquid pharmaceutical for inhalation is described for example in International Patent Application WO 91/14468 as well as in WO 97/12687 (compare in particular Figures 6a and 6b). The nebulizer devices (devices) described therein are also known by the name Respimat®. This nebulizer (Respimat®) can be used advantageously to produce the inhalable aerosols according to the invention, which contain p38 kinase inhibitor agents. Due to its cylindrical shape and its manageable size, less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time. The nebulizer projects a defined volume of a pharmaceutical formulation using high pressures through small nozzles, such that inhalable aerosols are produced. The preferred atomizer consists essentially of a housing upper part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, nozzle arrangement, a hollow plunger with a valve body, a power take-off flange, on which the hollow plunger is fixed, and which is located on the upper part of the housing, a locking mechanism, which is located in the upper part of the housing, a spring housing with the spring contained therein, which is mounted so as to rotate on the upper part of the housing by means of a rotation support, a lower housing part, which is engaged on the housing of the housing. spring in the axial direction. The hollow plunger with a valve body corresponds to a device disclosed in WO 97/12687. It partially penetrates the cylinder of the pump housing and is arranged axially movable in the cylinder. In particular, reference is made to Figures 1 to 4, especially to Figure 3, and to the relevant parts of the specification. The hollow piston with valve body exerts on the fluid on its high pressure side, at the moment when the spring is actuated, a pressure of 5 to 60 MPa (approximately 50 to 600 bar), preferably of. they prefer volumes of 10 to 50 microliters, while volumes of 10 to 20 microliters are particularly preferred and a volume of 15 microliters per spraying stroke is very particularly preferred. The valve body is preferably mounted next to the end of the hollow plunger which faces the valve body. The nozzle in the nozzle body is preferably microstructured, ie produced by a micrometric technology. Disclosed microstructured valve bodies are disclosed, for example, in WO-94/07607; the content of this specification is hereby referred to, particularly to Figure 1 which appears therein and to the associated description. The valve body consists, for example, of two sheets firmly connected to each other on the basis of glass and / or silicon, of which at least one sheet has one or more microstructured channels, which connect the input side in the nozzle with the side of exit from the mouthpiece. On the outlet side from the nozzle is located at least one circular or non-circular hole with a depth of 2 to 10 micrometers and a width of 5 to 15 micrometers, being nozzles, preferably two, the directions of projection of the nozzles in the nozzle body may extend parallel to each other, or they may be inclined with respect to each other in the direction of the nozzle orifice. In a nozzle body with at least two nozzle orifices on the outlet side, the projection directions may be inclined with respect to each other at an angle of 20 to 160 °, preferably 60 to 150 °, in a highly efficient manner. preferable from 80 to 100 °. The nozzle orifices are preferably arranged at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably from 30 to 70 micrometers. Distances of 50 micrometers are highly preferred. The directions of projection will therefore be in the vicinity of the nozzle orifices. The liquid pharmaceutical formulation impinges on the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized through the nozzle orifices to form an inhalable aerosol. The preferred sizes of particles or droplets of Preferably a helical cylindrical compression spring, as a storage for mechanical energy. The spring acts on the PTO flange as a drive member, whose movement is determined by the position of a locking member. The path of the PTO flange is limited precisely by one upper and one lower stop. The spring is tensioned, preferably, by means of a transmission that increases the power, eg a helical displaceable gear, through an external torque, which occurs when the upper part of the housing rotates against the spring housing in the lower part of the housing. In this case, the upper part of the housing and the PTO flange contain a gear in the form of a single V or multiple V. The blocking member with intercalary locking surfaces is arranged in a ring around the intake flange of force. This consists, for example, of a ring itself elastically deformable radially, based on a plastic material or a metal. The ring is arranged in a plane that forms a right angle with the axis of the atomizer. After the spring has been tensioned, the locking surfaces of the locking member move in the path of the PTO flange and prevent the spring from relaxing. the actuating button moves parallel to the annular plane, preferably into the atomizer; this causes the deformable ring to deform in the annular plane. Details of the construction of the locking mechanism are given in WO 97/20590. The lower part of the housing is pushed in the axial direction through the spring housing and covers the frame, the propulsion of the spindle and the storage container for the fluid. When the atomizer is actuated, the upper part of the housing is rotated with respect to the lower part of the housing, with the lower part of the housing carrying the spring housing with it. In this way, the spring is jointly compressed and tensioned by means of the helical displaceable gear, and the locking mechanism automatically latches. The angle of rotation is preferably a fraction of a whole number of 360 degrees, eg 180 degrees. At the same time that the spring is tensioned, the power take-off part located in the upper part of the housing is moved by a given distance, the hollow piston is pushed back inside the cylinder in the pump housing, as a result of which If desired, a number of interchangeable storage containers containing the fluid to be atomized can be pushed into the atomizer one after the other and can be used in succession. The storage container contains the aqueous aerosol composition according to the invention. The atomization process is started by pressing lightly on the drive button. As a result, the locking mechanism leaves clear the path for the PTO member. The tensioned spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomizer in an atomized form. Further constructive details are disclosed in PCT Patent Application Nos. 97/12683 and WO 97/20590, to which reference is made herein. The component parts of the atomizer (nebulizer) are made of a material appropriate for its purpose. The housing of the atomizer, and - whenever its operation permits - also other parts, are preferably made of a plastic material, eg by Figures 2a b attached to this patent application, which are identical to Figures 6a / b of WO 97/12687, show the nebulizer (Respimat®), which can be used advantageously to inhale the aqueous formulations of aerosols according to with the invention Figure 2a shows a longitudinal section through the atomizer when the spring is tensioned, while Figure 2b shows a longitudinal section through the atomizer when the spring is relaxed. The upper part (51) of the housing contains the housing (52) of the pump, next to which end the mount (53) for the nozzle of the atomizer is mounted. In the frame are the nozzle body (54) and a filter (55). The hollow piston (57), fixed on the PTO flange (56) of the locking mechanism, partially penetrates the cylinder of the pump housing. At its end, the hollow plunger supports the valve body (58). The hollow piston is sealed by the sealing gasket (59). Inside the upper part of the housing is located the stop (60), on which the PTO flange rests when the spring is relaxed. Next to the PTO flange is the stop (61), on which the PTO flange rests when the PTO is tensioned.
The upper part of the housing terminates at the mouth (65) and is hermetically sealed by means of the protective cap (66) which is connected to the locking member. can be placed on top of it The spring housing (67), provided with a compression spring (68), is supported so as to be able to rotate in the upper part of the housing by means of the elastic jump appendages (69) and the rotation support. The lower part (70) of the housing is pushed on the spring housing. Inside the spring housing is the storage container (71), interchangeable, for the fluid (72) to be atomized. The storage container is hermetically sealed by the plug (73), through which the hollow plunger penetrates into the storage container and is immersed at its end in the fluid (supply of active substance solution). The spindle (74) for the mechanical counter mechanism is mounted on the cover of the spring housing. Next to the end of the spindle, which is oriented towards the upper part of the housing, is the drive pinion (75). The slide (76) sits on the spindle. appropriate for inhalation. If the inhalable solutions free of propellant, which can be used according to the invention, are nebulized using the method described above (Respimat®), the quantity supplied must correspond to a defined amount with a tolerance of not more than 25%, preferably at 20% of this amount in at least 97%, preferably at least 98%, of all operations of the inhaler (projection performances). Preferably, between 5 and 30 mg of the formulation, most preferably between 5 and 20 mg of the formulation, are supplied as a defined mass in each actuation. However, inhalable solutions free of propellant, which can be used according to the invention, can also be nebulized by means of inhalers other than those described above, eg jet stream inhalers or other stationary nebulizers. Accordingly, in a further aspect, the invention relates to the use according to the invention of the kinase inhibitor p38 for preparing a pharmaceutical formulation in the form of inhalable solutions or suspensions, free of propellant, as before ~ the Réspimat®. Preferably, the invention relates to the use according to the invention of p38 kinase inhibitors to prepare inhalable, propellant-free solutions or suspensions, characterized in that they contain p38 kinase inhibitors in conjunction with the device known per se. the name of Respimat®. In addition, the present invention relates to the use according to the invention of the devices for inhalation, preferably Respimat®, characterized in that they contain the inhalable solutions or suspensions, free of propellant, according to the invention, as described previously in this specification.
The inhalable solutions or suspensions, free of propellant, which can be used within the scope of the invention day, can take the form of concentrates or sterile inhalable solutions or suspensions, ready for use, as well as the aforementioned solutions or suspensions, intended for use. to its use in a Respimat®. Formulations ready for use can be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations, ready for use, can be administered using fixed or portable nebulizers, which are operated with energy, which produce refers to the use according to the invention of the p38 kinase inhibitor agent in the form of inhalable solutions, suspensions, free of propellant, as described above, which take the form of concentrates or sterile formulations, ready for use, combined with an appropriate device for administering these solutions, characterized in that the device is an autonomous or portable nebulizer, which is operated with energy, which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles .
The following Examples serve to illustrate the present invention in more detail by way of example, without restricting the scope of the invention to the following embodiments.
Examples of Formulations Inhalable powders (loaded in capsules): 2) 5) 6) Ingredients pg per capsule Example 2 3,500 Lactose 3,500 Total 7,000 Ingredients] ig per capsule Example 2 3,000 Lactose 4,000 Total 7,000 8) 10) It is made _cxüx & In relation to this date, the best method known by the applicant to carry out said invention is that which is clear from the present description of the invention.

Claims (1)

  1. Claims Having described the invention as above, the content of the following claims is claimed as property: 1. Use of a p38 kinase inhibiting agent for the preparation of an inhalable pharmaceutical composition intended for the treatment of mucus hypersecretion. 2. Use according to claim 1, wherein the hypersecretion of mucus is associated with cystic fibrosis. 3. Use according to claim 1 or 2, wherein the p38 kinase inhibitor agent is selected ^ entee-ei- 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 from PCT Patent 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 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 98/47892, WO 98/47899, WO 98/50356, WO ccT-ei-a84. 00334? 2ß9? < ß1 fi: 55554431 F.2'13 OCT-01-200 15515 DE: ßß33472 &9? 431 fl: 5SS5 431? .3? 3 DE: t3Z33 * 72S9B43í F.10'-3 alguilo '¾. «, heteroaryl, eteroaryl-alkyl in which 8033472698431 OCT-0l-200 15:16 DE: OCT-ei-200 15s 17 DE: 8033472696 W31: 5555 < W31 CCT-01-50B 15:17 OF 0033 *? 2698 < t31 «: S555431 P.13'13 each of them is independently alkyl (from 1-6 C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR2, SO2NR2, CN, CF3 or O2, in which each of the R is independently H or lower alkyl (from 1-4 C); each of the 1, m and n is independently 0, 1 or 2; Y Ar is phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, or benzimidazolyl, each optionally substituted with alkyl, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, optionally substituted, halo, OR, R2, SR, -OOCR, -NROCR, RCO, -COOR, -CONR2, SO2 R2, CN, CF3 or NO2, wherein each R is independently H or (1-4C) alkyl; or their pharmaceutically acceptable salts. 7. Use according to claim 4, wherein the p38 kinase inhibitor is a compound of formula 3a, 3b, 3c or 3d. or and their pharmaceutically acceptable salts, wherein each of Z1 and Z is independently CR4 or N; wherein each of them is independently selected from H and alkyl (from 1-6C); wherein said alkyl optionally includes one or more heteroatoms selected from 0, S and N, and wherein said alkyl is optionally substituted with one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR , CN, = 0, a carbocyclic ring or a 5- or 6-membered heterocyclic ring containing 1-2 N heteroatoms, and an aromatic ring optionally containing 1-2 N heteroatoms, wherein R in the preceding optional substituents is H or alkyl (from 1-6C); R1 is what is CO, SO, CHOH or S02; is 1; is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; is 0, 1 or 2; is N; is CH or CH2; and consists of one or two phenyl moieties directly coupled with, one or two phenyl moieties being optionally substituted with a substituent selected from halo, nitro, (1-6C) alkyl, (1-6C) alkenyl, CN, CF3, RCO, COOR, C0NR2, NR2, OR, 1-6C alkyl), and phenyl, optionally substituted with the preceding substituents; it is selected from H, and alkyl (from 1-6C); wherein said alkyl optionally includes one or more heteroatoms which are selected from 0, S and N, and wherein said alkyl is optionally substituted with one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, C0NR2, OOCR , NROCR, (in which R, in the foregoing, is H or alkyl of 1-6C), CN, = 0, a saturated carbocyclic ring of 5 or 6 members or a heterocyclic ring containing 1-2 heteroatoms N, and a 6-membered aromatic ring that optionally contains 1-2 heteroatoms N; R3 is H, halo, NO2, (1-6C) alkyl, (1-6C) alkenyl, CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR wherein R is H or alkyl ( from 1-6C). 8. Use according to claim 4, wherein the p38 kinase inhibitor is a compound of formula 4 wherein Ari is a heterocyclyl group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and in that Ari may be substituted with one or more Rx, R2 or R3; Ar2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each of which being optionally substituted with one to three groups R2; L, a linker group, is a C1-10 carbon chain, saturated or unsaturated, branched or unbranched; wherein one or more methylene groups are optionally independently replaced by 0, N or S; and wherein said linker group is optionally substituted with 0-2 oxo groups and with one or more branched or unbranched Ci-4 alkyl groups, which may be substituted with one or more halogen atoms; it is selected from the group consisting of: 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 one to three groups selected from the group consisting of halogen, Ci-6 alkyl / Ci-6 alkoxy, hydroxy, mono- or di- (Ci-3 alkyl) amino, Ci_6-S alkyl (0) my phenylamino in which the phenyl ring is optionally substituted with one to two groups consisting of halogen, Ci_6 alkyl and Ci_s alkoxy; e) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulphone, piperidine, piperidinone, tetrahydropyrimidone, 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 Ci-6alkyl, Ci-6alkoxy, hydroxy, mono - or di- (C 1-3 alkyl) amino C 1 -C 3 alkyl, phenylamino C 1 -C 3 alkyl and C 1-3 alkoxy C 1-3 alkyl; Ci-6 alkoxy, a secondary or tertiary amine in which the amino nitrogen is covalently linked to groups selected from the group consisting of Ci_3 alkyl and Ci_5 alkoxyalkyl and phenyl in which the phenyl ring is optionally substituted with one to two groups they consist of halogen, Ci-S alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino, Ci_6-S (O) r "; renyl -S (O) t alkyl, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, Ci-6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino, selects from the group consisting of:) a branched or unbranched C3_i0 alkyl, which may optionally be partial or fully halogenated, and optionally may be substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each of said phenyl, naphthyl or heterocyclyl groups selected from the group described hereinabove, being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci_6 alkyl, which optionally is partially or fully halogenated, C3_8 cycloalkyl C5_8 cycloalkenyl, hydroxy, cyano, C1-3alkyl-oxy that is optionally partially or fully halogenated, N¾C (0) and di-alkyl (Ci-3) aminocarbonyl; h) a C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopenyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and optionally substituted with one to three alkyl groups Ci_3, or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are replaced by groups independently selected from 0, S, CHOH, >; C = 0, > C = S and NH; i) a branched C3-i0 alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three branched or unbranched Ci-5 alkyl groups, phenyl, naphthyl or heterocyclyl, each of said heterocyclyl groups being selected independently between the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of said phenyl, naphthyl or heterocyclyl groups being substituted with 0 to 5 groups selected from halogen C 1-6 branched or unbranched alkyl, optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bi-rheohexamyl and bicycloheptanyl, hydroxy, cyano, Ci-3-oxyalkyl optionally partial or fully halogenated, NH2C (O), mono- or di-alkyl (Ci-3) -aminocarbonyl; a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group may optionally be substituted with one to three C1_3 alkyl groups; cyano; and, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; it is selected from the group consisting of: Ci_s branched or unbranched alkyl, which may optionally be partially or fully halogenated, acetyl, aroyl, C1-branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl; is selected from the group consisting of: g) a phenyl, naphthyl or heterocyclyl 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, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naft ipyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein said phenyl, naphthyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of a branched or unbranched Ci-6 alkyl, phenyl, naphthyl, heterocyclyl selected from the group described hereinbefore, an alkyl C1 -6 branched or unbranched which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5alkyl naphthyl-Ci-5alkyl, halo, hydroxy, cyano, alkyl C! _3-oxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy in which the heterocyclic moiety is selected from the group described hereinabove, nitro, amino, mono- or di (C1-3) alkyl-amino , phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove, NH2C (0), a mono- or di-alkyl (C) i-3) -aminocarbonyl, Ci_5-C (O) -C1-4 alkyl, amino_C1_5alkyl, mono- or di (C1_3alkyl) -amino-Ci-5 alkyl, amino-S (0) 2, dialkyl (C 1-3) -amino-S (O) 2, R 4 -alkyl Ci-5, R 5 -alkoxy d-5, R 6 -C (O) -alkyl Cx.5 and R 7 -alkyl Ci-5- (R8) N; 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, cic1ohexanopirimidina, cyclopentanopyrazine, ciclohexanopirazina, ciclopentanopiridazina, ciclohexanopiridazina cyclopentanoquinoline, cyclohexanequinoline, iclopentanoisoquinoline, cyclohexaneisoquinoline, cyclopentanoindole, cyclohexaneindole, iclopentanobenzimidazole, cyclohexanebenzimidazole, cyclopentanebenzoxazole, cyclohexanebenzoxazole, cyclopentaneimidazole, cyclohexaneimidazole, lopentanothiophene 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, branched or unbranched Ci-6 alkyl which is optionally partially or fully halogenated, halo, cyano, C1-3alkyl oxy that is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy in which the heterocyclic moiety is selected among the group described hereinabove, nitro, amino, mono- or di-alkyl (Ci-3) -amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove, NH2C (0), a mono- or dialkyl (C! _3) -aminocarbonyl, C 1 -C 4 alkyl (0), C 1-5 alkyl C (O) -C 1-4 alkyl branched or unbranched, an amino-alkyl or Ci-5i mono- or di-alkyl (Ci_3) -amino-Ci-5 alkyl, R9-Ci_5 alkyl / R10-Ci_5 alkoxy Rn-C (O) -Ci-5 alkyl and R12-Ci_ alkyl 5 (Ri3) N; i) a cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl may optionally be partially or fully halogenated and may optionally be substituted with one to three C1-3 alkyl groups; - j) a C5_ cycloalkenyl selected from the group Which comprises cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group may optionally be substituted with one to three C 1-3 alkyl groups; and 20 k) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; 1) a branched or unbranched Ci- 6 alkyl, which may optionally be partially or fully halogenated; or Ri and R2 taken together, can optionally form A fused phenyl or pyridinyl ring, and in which each of the R 8, R 3 is independently selected from the group consisting of: hydrokine and branched or unbranched C 1-4 alkyl, which may optionally be partially or fully halogenated; each of the R 4, R 5, R 6, R 7, R 9, Rio, R n and R 12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; m = 0, 1, 2; r = 0, 1, 2; t = 0, 1, 2; X = O or S and its acids and physiologically acceptable salts. 9. Use according to claim 4, wherein the p38 kinase inhibitor is a compound of formula wherein: Ari is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; in which Arx can be substituted with one or more Ri, R2 or is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaffyl, tetrahydroquinol ina, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each of which being optionally substituted with zero to three groups R2; is: a) a C5_8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C1-4 alkyl chains, Ci-4 alkoxy or branched or unbranched Cx-j-amino alkyl; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperidine, piperazine or pyrazine, each of which being optionally independently substituted with 0-3 branched or unsubstituted C 1-4 alkyl groups branching, Ci_4 alkoxy, hydroxy, nitrile, mono- or di- (C 1 -skylamino, Ci_6-S (0) m alkyl, or halogen, is: a bond or a saturated or unsaturated Ci-4 carbon chain , branched or unbranched, optionally partially or completely halogenated, in which one or more methylene groups are optionally replaced by 0, NH, S (O), S (O) 2 or S, and wherein Y is optionally substituted independently with 0-2 oxo groups and one or more branched or unbranched C1-4 alkyl groups, which may be substituted with one or more halogen atoms, is: a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups that they consist of halogen, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, mono- or di- (Ci-3 alkyl) amino, Ci-6-S (0) m, -C0QH_y-phenylamino in which the phenyl ring is optionally substituted with one to two groups consisting of halogen, Ci-6 alkyl and Ci-6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, sulfoxide, pentamethylene, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, Cys alkyl, Ci-6 alkoxy, hydroxy, mono- or di- (alkyl) C1-3) amino-Ci-3 alkyl, phenylamino-Ci_3 alkyl and Ci-3-alkoxy Ci-3 alkyl; Ci-6 alkoxy, a secondary or tertiary amine in which the amino nitrogen is covalently linked to groups selected from the group consisting of Ci-3 alkyl / Ci-5 alkoxy / pyridinyl-C 1-3 alkyl, imidazolyl-Ci_3 alkyl, tetrahydrofuranyl-Ci_3 alkyl, phenylamino, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci-6 alkoxy, hydroxy or mono- or di- (Ci_ 3 alkyl) amino, Ci_6-S alkyl (0) m, and phenyl-S (0) m, wherein the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino; a branched or unbranched C3-10 alkyl, optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl , furyl, isoxazolyl and isothiazolyl; each of said phenyl, naphthyl or heterocyclyl being selected from the group described hereinabove in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci_6 alkyl, which optionally is partial or fully halogenated, C3-8 cycloalkyl, C5_8 cycloalkenyl, hydroxy, nitrile, Ci-3alkyloxy, optionally partially or fully halogenated, NH2C (O) and dialkyl (Ci-3) aminocarbonyl; a C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, each being optionally halogenated pTTcrai or fully and optionally substituted with one to three C1_3 alkyl groups, or a group analogous to said cycloalkyl group in which 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; a branched C3_i0 alkenyl, optionally partially or fully halogenated and optionally substituted with one to three branched or unbranched C1-5 alkyl groups, phenyl, naphthyl or heterocyclyl, each of said heterocyclyl groups being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of said phenyl, naphthyl or heterocyclyl groups being substituted with 0 to 5 groups selected from the group consisting of halogen, Ci- 6 branched or unbranched, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, Ci-3 alkoxy optionally partially or fully halogenated, NH2C (0) and mono- or dialkyl (Ci- 3) dihydrocarbonyl; a C5_7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three C1_3 alkyl groups; nitrile; or branched or unbranched Ci-6-carbonyl alkoxy, branched or unbranched C1-6 alkylaminocarbonyl, Ci-6-carbonylamino-Ci-3 alkyl branched or unbranched; is: a branched or unbranched Ci-6 alkyl, optionally partially or wholly halogenated, acetyl, aroyl, branched or unbranched Ci-4 alkoxy, optionally partially or wholly halogenated, halogen, methoxycarbonyl or phenylsulfonyl; is: a) a phenyl, naphthyl or heterocyclyl 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, benzoisoxazolyl, benzopyrazolyl, benzothiofranyl, cinolinyl, pterinidinyl, phthalazinyl, naphthipyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein said phenyl, naphthyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of of phenyl, naphthyl, heterocyclyl selected from the group described hereinabove in this paragraph, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl-Ci_5alkyl, naphthyl-C1.5alkyl, halogen, hydroxy, nitrile, C C_3-oxy alkyl which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy in which the remainder heterocyclic is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl (Ci-3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, NH2C (0), a mono- or di-alkyl (C! -3) -aminocarbonyl, Ci_5-C (0) alkyl-1-4 alkyl, Ci-5-aminoalkyl, mono- or di-alkyl ( Ci_ 3) amino-C1-5alkyl, amino-S (0) 2, di-alkyl (Ci_3) amino-S (0) 2, R4 -alkyl Ci_5, R5 -alkoxy Ci-5, R6-C (0) -C1-5 alkyl and R7-C1-5 alkyl- (R8) N, carboxy-mono- or di-C1-5 alkyl-amino; a condensed aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexane pyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanepyrazine, cyclohexaneopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanequinoline, cyclopentanoisoquinoline, cyclohexaneisoquinoline, cyclopentanoindole, cyclohexaneindole, cyclopentanebenzimidazole, cyclohexanebenzimidazole cyclopentanebenzoxazole, cyclohexanebenzoxazole, cyclopentaneimidazole, cyclohexaneimidazole, cyclopentanethiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of f-enylcr; -nallilu and lye-tertiarycyclyl selected from the group consisting of pyridinyl, pyriraidinyl, pyrazinyl, pyridazinyl , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, branched or unbranched Ci_6 alkyl optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclic moiety is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di-alkyl (Ci_3) amino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety is selected from the group described herein above in this paragraph, NH2C (O), a mono- or di-alkyl (Ci-3) aminocarbonyl, alkyl Ci-4- OC (O), alkyl Cj.-5-C (O) -C 1-4 branched or unbranched alkyl, an amino-Ci-5 alkyl / mono- or di-alkyl (Ci- 3) amino-Ci-5 alkyl, R 9 -Ci-alkyl 5, Rio-Ci_5 alkoxy, R11-C (O) -alkyl Cx-s, and R12-C1-5 alkyl- (R13) N; c) a cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, in which the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three Ci-3 alkyl groups; d) a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three Ci-3 alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) a branched or unbranched Cx.6 alkyl, optionally partially or wholly halogenated; or Ri and R2 taken together, can optionally form a fused phenyl or pyridinyl ring; each of R8 and R13 is independently selected from the group consisting of: hydrogen and branched or unbranched C1-4 alkyl, optionally partially or fully halogenated each of R, R5, R6, R7, R9 / Rio, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; m is 0, 1 or 2; W is 0 or S and its pharmaceutically acceptable derivatives. 10. Use according to claim 4, wherein the p38 kinase inhibitor is a compound of formula 5a W M H H 5a wherein: Ari is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ari is optionally substituted with one or more Ri, R2 or R3; Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole, each of which being optionally substituted with zero to three groups R2; is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three Ci_alkyl, Ci-4alkoxy or Ci_4alkylamino chains, each being branched or unbranched; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydrorrialeimidyl, piperidinyl, benzimidazole, 3H-imidazo [4,5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three Ci-4 alkyl, Ci_4 alkoxy, hydroxy, nitrile, amino, mono- or di- (Ci-3 alkyl) amino, mono- or di- (alkyl) groups. Ci_3-amino) carbonyl, NH2C (0), alkyl-1-6-S (0) or halogen, is: a bond or a chain of saturated or unsaturated, branched or unbranched Ci-4 carbons, optionally partially or fully halogenated , wherein one or more C atoms are optionally replaced by 0, N, or S (0) m and wherein Y is optionally substituted independently with one to two oxo, nitrile, phenyl, hydroxy or one or more alkyl groups Ci-4 optionally substituted with one or more halogen atoms is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocyclyl selected from piperazinyl , tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo [2.2.1] heptanyl, pentamethylene sulfuryl, pentamethylene sulfoxydyl, pentamethylene sulfonyl, cetramethienium sulturium, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl , 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z groups is optionally substituted with one to three halogen groups, Ci-6-alkyl / Ci-6-alkoxy / Ci-3-alkoxy-3-Ci-6-alkoxy-C6-alkoxycarbonyl, aroyl, heteroaroyl, heterocyclyl-acyl Ci_3 wherein the heteroaryl and heterocyclyl are as defined hereinbefore in this paragraph C 1 acyl, oxo, hydroxy, pyridinyl-Ci_3 alkyl, imidazolyl-Ci-3 alkyl, tetrahydrofuranyl-C 1-3 alkyl, nitrile-C: -3 alkyl, nitrile, carboxy, phenyl in which the phenyl ring is optionally substitute with one to two halogen groups, Ci_6 alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, S (0) m amino, Ci-SS (0) alkyl or phenyl-S (0) m wherein the phenyl ring is optionally substituted with one to two halogen groups, alkoxy 1-6, hydroxy, halogen or mono- or di- (Ci_3 alkyl) amino; Z is optionally substituted with one to three amino, aminocarbonyl or amino-Cx_3 alkyl groups in which the optionally-mono-N-optionally-substituted-N-is-amino-C-6-amino-atom with C 1-6 amino-alkyl, Ci-3 alkyl, arylC0-3 alkyl, Ci-5 alkoxy Ci-3 alkyl / Ci_5 alkoxy, aroyl, Ci_3 acyl, Ci-3-S (0) m- or aryl-C0-3-S alkyl (0) m-, wherein each of the aforementioned alkyl and aryl, attached to the amino group, is optionally substituted with one to two halogen groups, Ci_6 alkyl, Ci_s alkoxy, hydroxy or mono- or di- (alkyl) Ci-3) amino; Z is optionally substituted with one to three aryl, heterocyclyl or heteroaryl groups as described above in this paragraph, each of which in turn is optionally substituted with halogen. C1-6 alkyl or Ci-6 alkoxy; Z is hydroxy, hydroxy-Ci_3 alkyl, halogen, nitrile, amino in which the N atom is optionally mono- or di-substituted independently with amino-C1-alkyl alkyl, aryl-C1-3 alkyl, Ci-5- alkoxy C1-3 alkyl, C1-5 alkoxy, aroyl, Ci_3 acyl, C1-3-S (O) m-, aryl-C0-3-S (O) m-, nitrile-C1- alkyl or C1-6 alkoxy 3-Ci-3 alkyl, each of the aforementioned alkyl and aryl groups attached to the amino group is optionally substituted with one to two halogen groups, Ci_6 alkyl, Ci_6 alkoxy, hydroxy or mono- or di- (Ci alkyl) -3) -amino, alkoxy CT-fi-h tpmari 1 -alt Uo-Gu rr heteroaryl-C 0-3 alkyl or heterocyclyl-C 0-3 alkyl, in which the heteroaryl and heterocyclyl are described above in this paragraph, Z is C 1-6 branched or unbranched alkyl, C 1-6 alkoxy, Ci-3-amino acyl, nitrile-C 1-6 alkyl, Ci_6-S (0) alkyl or > and phenyl-S (0) m, wherein the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy or mono- or di- (alkyl Ca-3) amino; is: a) a branched or unbranched Ci_10 alkyl, optionally partially or wholly halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclyl groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furry, isoxazolyl and isothiazolyl; each of said phenyl, naphthyl or heterocyclyl being selected from the group described hereinabove, and being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched Ci_6 alkyl, which optionally is partially or fully halogenated, C3-8 cycloalkyl / C5_8 cycloalkenyl, hydroxy, nitrile, CX-3-oxy alkyl, which is optionally partially or fully halogenated, NH2C (0) and dialkyl (Ci_3) aminocarbonyl; a C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or wholly halogenated and optionally substituted with one to three Ci_3 alkyl groups, or a a group analogous to said cycloalkyl group, wherein from one to three ring-membered groups are replaced by groups independently selected from the group consisting of O, S, CHOH, > C = 0, > C = S and NH; a branched C3-10 alkenyl, optionally partially or fully halogenated and optionally substituted with one to three branched or unbranched Ci-5 alkyl groups, phenyl, naphthyl or heterocyclyl, each of said heterocyclyl groups being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of said groups being phenyl, naphthyl or het-.pmri < -1 i 1 or substituted with -T-a-5"groups selected from the group consisting of halogen, branched or unbranched Ci-6 alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, NH2C (0) and mono- or di-alkyl (Ci-3) aminocarbonyl; a C5-7 cycloalkenyl selected from the group consisting of it consists of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three Ci_3; e) nitrile alkyl groups; of) branched or unbranched Ci-6-carbonyl alkoxy, alkyl Branched or unbranched Ci-6-aminocarbonyl, Ci-6-carbonylamino-Ci-3 alkyl branched or unbranched, is: a branched or unbranched Ci-6 alkyl, optional partially or wholly halogenated and optionally substituted with nitrile, or R 2 is acetyl-1-alkoxy-er--branched or unbranched, optionally partially or wholly halogenated, halogen, methoxycarbonyl or phenylsulfonyl; is: a) a phenyl, naphthyl or heterocyclyl 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, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naf ipyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein said phenyl, naphthyl or heterocyclyl group is optionally substituted with one to five groups selected from the group consisting of of a phenyl, naphthyl, heterocyclyl selected from the group described hereinabove in this paragraph, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl , phenyl-Ci-5 alkyl, naphthyl-alkyl uilo-halogen; -hydroxy, ~ oxo, nitrile, Ci-3 alkoxy optionally partially or wholly halogenated, Ci-3 alkoxy Ci-5 alkyl, thio-Ci-3 alkyl, thio-Ci-3 alkyl Ci-5 alkyl , phenyloxy, naphthyloxy, heteroaryloxy in which the heterocyclic moiety is selected from the group described hereinabove in this paragraph, nitro, amino, mono- or di- (1-3C) alkylamino, phenylamino, naphthylamino, heterocyclylamino in which the heterocyclic moiety it is selected from the group described hereinabove in this paragraph, NH2C (0), a mono- or di (C1-3) alkyl-aminocarbonyl, alkyl CX.5-C (0) -alkyl Ci-4, amino-alkyl C1-s, mono- or di-alkyl (Cx-3) amino-Ci-5-alkyl, amino-S (0) i, di- (Ci-3) alkylamino-S (0) 2, R4-Ci-alkyl 5 / R5-Ci-5 alkoxy, R6-C (O) -Ci-5 alkyl and R7-Ci-5- alkyl (R8) N, carboxy-mono- or di-alkyl (Ci-5) -amino; a condensed 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, and the cyclohexane pyrimidine, cyclopentanepyrazine, cyclohexaneopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanequinoline, iclopentanoisoquinoline, cyclohexaneisoquinoline, cyclopentanoindole, cyclohexaneindole, iclopentanobenzimidazole, cyclohexanebenzimidazole, cyclopentanebenzoxazole, cyclohexanebenzoxazole, cyclopentaneimidazole, cyclohexaneimidazole, lopentanothiophene 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, iraidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, branched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, halogen, nitrile, Ci_3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy in which the remainder The heterocyclic compound is selected from the group described hereinabove, nitro, amino, mono- or di (C1-3) alkyl amino, phenylamino. naphthylamino-r heterocyclylamino in which the heterocyclic radical is selected from the group described hereinabove, NH2C (0), a mono- or di-alkyl (Ci_3) -aminocarbonyl, alkyl d-4-0C (0), alkyl Ci-5 -C (0) - branched or unbranched Ci-4 alkyl, an amino-C1-5alkyl mono- or di-alkyl (Ci-3) amino-Ci-5alkyl, R9-C1-5alkyl, i0 -alkoxy Ci-E, Rn-C (O) -alkyl C1-s and R12-alkyl Ci-5- (Ri3) N; a cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and is optionally substituted with one to three C grupos alkyl groups; d) a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three alkyl groups Ca-3; e) acetyl, aroyl, Ci_6-carbonyl alkoxy Ci_6 alkyl or phenylsulfonyl; or f) a branched or unbranched Ci-alkyl, optionally partially or wholly halogenated; or Ri and R2 taken together, optionally form a fused phenyl or pyridinyl ring; each of R8 and 13 is independently selected from the group consisting of: hydrogen and branched or unbranched Ci_4 alkyl, optionally partially or fully halogenated; each of R4 / R5, R6 / R7, R9, io, Rn and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole; m is 0, 1 or 2; W is O or S; wherein X is directly linked to one or two -Y-Z, and their pharmaceutically acceptable derivatives. eleven . Use according to claim characterized in that the kinase inhibiting agent p3 is a compound of formula 6 in which: G is: an aromatic carbocycle Ce- ?? or a saturated or unsaturated C3_io aromatic carbocycle; a heter "3 ri -] - Q - d - 6- ±? - members containing 1 or more heteroatoms chosen from 0, N and S, a 5-8 membered monocyclic heterocyclyl containing one or more heteroatoms chosen from 0, N and S or an 8-11 membered bicyclic heterocyclyl, which contains one or more heteroatoms chosen from 0, N and S, in which G is substituted with one or more Ri, R2 or R3, is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl. dihydrobenzothienyl, indanyl, indenyl or indolyl, each of which being optionally substituted with one or more R4 or R5; is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or with one to three Ci-4 alkyl, Ci_ alkoxy or Ci_-amino aryl; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4, 5-b] pyridine, is: a bond or a saturated or unsaturated, branched or unbranched Ci_4 carbon chain, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by O, N or S (0) m and wherein Y is optionally substituted independently with one to two oxo groups, phenyl or one or more Ci-4 alkyl groups optionally substituted with one or more halogen atoms; is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each of which being optionally substituted with one to three halogen groups, Ci_6 alkyl, Ci_6 alkoxy, hydroxy, amino , mono- or di- (alkyl Ci-3) amino, alkyl Ci_é-S (0) m, CN, CONH2, COOH or phenylamino in which the phenyl ring is optionally substituted with one to two halogen groups, Ci- 6 or Ci_6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, cyclohexanolyl, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, each of which being optionally substituted with one to three nitrile groups, 0 to 6 alkyl, Ci 6 alkoxy / hydroxy, amino, mono- or di - (C 1-3 alkyl) amino C 1-3 alkyl, CONH 2, phenylamino C 1-3 alkyl or C 1-3 alkoxy C 1-3 alkyl; halogen, C 1-4 alkyl, nitrile, amino, hydroxy, C 1-6 alkoxy, NH 2 C (0), mono- or di (C 1-3 alkyl) aminocarbonyl, mono- or di (C 1-6 alkyl) amino, a secondary or tertiary amine wherein the amino nitrogen is covalently linked to C1_3alkyl or C1-5alkoxyalkyl, pyridinyl C1_3alkyl, imidazolyl C1_3alkyl, tetrahydrofuranyl_C1_3alkyl, nitrile-C1-3alkyl, carboxamido-C1_3alkyl , phenyl, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_s alkoxy, hydroxy or mono- or di- (Ci-3 alkyl) amino, Ci_6-S (0) alkyl or phenyl-S ( 0) m / in which the phenyl ring is optionally substituted with one to two halogen groups, C 1-6 alkoxy (hydroxy, halogen or mono- or di- (C 1 -C 3) alkyl; Ci-6 alkyl-S ( 0) m / and phenyl-S (0) m, in which the phenyl ring is optionally substituted with one to two halogen, alkoxyo- or dino- or di- (Ci-3 alkyl) amino; i is independently: a Ci-io alkyl optionally partially or fully halogenated, and optionally substituted by one to three C3-10 cycloalkanyl groups, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned groups being optionally substituted with one to five groups selected from halogen, Ci-6 alkyl optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy optionally partially or fully halogenated or NH2C (0), mono- or di (Ci_3 alkyl) amino, and mono- or di (Ci_3 alkyl) aminocarbonyl; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, each of which being optionally partially or wholly halogenated and optionally substituted with one to three Ci_3 alkyl groups optionally partially or wholly halogenated, CN, hydroxyC1-3 alkyl or aryl; or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by O, S (0) m, CHOH, > C = 0, > C = S or NH; optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3 alkyl or aryl; or a group analogous to said cycloaryl group, wherein one to two methine ring groups are independently replaced by N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or completely halogenated and optionally substituted with one to three C1-3 alkyl groups optionally halogenated partially or totally, CN, hydroxy-C1 -3 or aryl; or a group analogous to said cycloalkyl group, wherein one to three ring methylene groups are independently replaced by O, S (0) m / CHOH, > C = 0, > C = S or NH; a C3-i0 alkenyl branched or unbranched, each being optionally partially or completely halogenated, and optionally substituted with one to three alkyl groups Ci_5 branched or unbranched, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl , imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned groups being substituted with optionally is partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, alkyl C! _3-oi which is optionally partially or fully halogenated, NH2C (0), mono- or di (C 1-3 alkyl) aminocarbonyl; the C3-i0 alkenyl being branched or unbranched, optionally interrupted by one or more heteroatoms chosen from O, N and S (0) m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three Ci-3 alkyl nitrile, halogen; methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; silyl containing three alkyl groups optionally halogenated Ci- partially or completely, - a carbon chain of 3-6 alkynyl, branched or unbranched optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, H or S (0) m and wherein said alkynyl group is optionally substituted independently with one to two oxo, pyrrolidinyl groups, or one or more alkyl groups optionally substituted with one or more halogen atoms , nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di- (Ci-3 alkyl) amino optionally substituted with one or more halogen atoms; each of R2, R and R5 is a branched or unbranched Ci-6 alkyl, optionally partially or fully halogenated, acetyl, aroyl, branched or unbranched C1-4 alkoxy, each of which being optionally partially or wholly halogenated, halogen, nitrile, methoxycarbonyl, C, i.-3-S (0) m alkyl optionally partially or fully halogenated, or phenylsulfonyl; Ci_6 alkoxy, hydroxy, amino, or mono- or di- (Ci-4 alkyl) amino, nitrile, halogen; 0R5; nitro; or mono- or di- (C 1-4 alkyl) amino-S (0) 2 optionally partially or fully halogenated, or H2NS02; each R3 is independently: phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazoj i 1 n, | tirerr ±± furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl , quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned groups is optionally substituted with one to three groups phenyl, naphthyl, heterocyclyl or heteroaryl as previously described in this paragraphbranched or unbranched Ci-6 alkyl, which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Cx-s alkyl, naphthyl-Ci_5 alkyl, halogen, hydroxy, oxo, nitrile, C 1-3 -alkyl optionally halogenated partially or wholly, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyl-oxy in which the heterocyclyl or heteroaryl moiety is as previously described in this paragraph, nitro, amino, mono- or di- (C 1-3 alkyl) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH 2 C (O), a mono- or di- (Ci-alkyl) amino-S (0) 2, di- (C1-3 alkyl) amino-S (0) 2, R7-Ci_5 alkyl, R8-C1-5 alkoxy, R9-C (O) -Ci-5 alkyl, R10- alkyl Ci-5 (Rn) N, carboxy-mono- or di- (Ci-5 alkyl) -amino; an aryl condensate selected from benzocyclobutanyl, indanyl, indenyl, yl dihidronaf, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, ciclohexanopiridinilo, ciclopentanopirimidinilo, ciclohexanopirimidinilo, ciclopentanopirazinilo, ciclohexanopirazinilo, ciclopentanopiridazinilo, ciclohexanopiridazinilo, ciclopentanoquinolinilo, ciclohexanoquinolinilo, ciclopentanoisoquinolinilo, ciclohexanoisoquinolinilo, cyclopentanoindolyl, cyclohexaneindolyl, cyclopentanebenzimidazolyl, cyclohexanebenzimidazolyl, cyclopentanebenzoxazolyl, cyclohexanebenzoxazolyl, cyclopentanoimidazolyl, cyclohexaneimidazolyl, 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, isoxazolylc-Ls feia ^ oiircr; alkylated Ci_6 which is optionally partially or fully halogenated, halogen, nitrile, Ci_3-oxy alkyl which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, nitro , amino, mono- or di- (Ci_3 alkyl) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclyl-amino in which the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH2C (0), mono- or di- (C 1 -C 3 alkyl) aminocarbonyl, C 1 -C 0 alkyl (0), C 1 -C 5 alkyl (O) -Ci 4 alkyl, amino C 1 -C 5 alkyl, mono- or di-alkyl (Ci 3) amino-Ci-S alkyl, R12-Ci_5i alkyl R13-C1-5 alkoxy, Ri4-C (O) -C1-5 alkyl or Ri5-Ci-5- alkyl (Ri6) N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which being optionally partially or fully halogenated and optionally substituted with one to three C1_3alkyl groups or a group analogous to said cycloalkyl group, wherein one of three methylene ring groups are independently replaced by 0, S, CHOH, > C = 0, > C = S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups; alkyl Ci-4-phenyl-C (O) -alkyl Ci_4-, alkyl Ci-4-C (0) -alkyl Ci_4- or alkyl C1-4-phenyl-S (0) m-C1-4alkyl-; C 1-6 alkyl or C 1-6 alkoxy branched or unbranched, each of which optionally being partially or fully halogenated or optionally substituted with Ri 7; ORis or Ci-S alkyl optionally substituted with 0R18; amino or mono- or di- (Ci-5 alkyl) amino optionally substituted with Ri9; R20C (O) N (R2i) -, R220- or R23R24NC (0) -; R26 (CH2) mC (0) N (R21) - or R26C (0) (CH2) mN (R21) -; C2-alkenyl substituted with R23R24NC (O) -; a C3-6 alkynyl carbon chain, branched or unbranched, optionally partially or wholly halogenated, in which one or more methylene groups are optionally replaced by O, NH, S (0) m and wherein said alkynyl group is optionally substituted independently with one to two oxo, pyrrolidinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, one or more C 1 alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, ) amino optionally substituted with one or more halogen atoms; or aroyl; I 6 is a C 1-4 alkyl optionally partially or fully halogenated and optionally substituted with R 26; each of R7, R8, 9 / i2 »R13, i4 # R15 / i7 # R19 / R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di- (C 1-4 alkyl) amino optionally halogenated partially or wholly; each of R1X and Ri6 is independently: hydrogen or a C1-alkyl optionally halogenated partially or wholly; Rie independently is: hydrogen or a C 4 alkyl optionally substituted independently with oxo or R 25; R20 is independently: a CX-io alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; R21 is independently: each of the 22, R23 and 2 is independently: hydrogen, a Ci_6 alkyl optionally partially or fully halogenated, said Ci_6 alkyl is optionally interrupted by one or more 0, N or S, said C1-6 alkyl also being optionally substituted in a manner independently with mono- or di- (C 1-3 alkyl) aminocarbonyl, phenyl, pyridinyl, amino or mono- or di- (C 1-4 alkylamino) each of which optionally is partially or fully halogenated and optionally substituted with mono- or di- - (Cx-3 alkyl) amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 or 2; W is O or S and its pharmaceutically acceptable derivatives. 12. Use according to claim 4, wherein the kinase inhibitor p38 is a compound of formula 7 in which: E is a ca-befie-e-sp group with heteroatom chosen from -0-, -NH- and -S-; G is: an aromatic carbocycle C6_i0 or non-aromatic carbocycle C3-10, saturated or unsaturated; a 6-14 membered heteroaryl, monocyclic, bicyclic or tricyclic, containing 1 or more heteroatoms chosen from 0, N and S; a 6-8 membered monocyclic heterocyclyl, which contains one or more heteroatoms chosen from 0, N, and S; or an 8-11 membered bicyclic heterocyclyl, which contains one or more heteroatoms chosen from 0, N, and S; wherein G is optionally substituted with one or more Rlr R2 or R3; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl, each of which being optionally substituted with one or more R4 or R5; X is: a Cl-ojL-¾u-ilo s cTcTo ^ Tquen C5-8 optionally substituted with one to two oxo groups or with one to three chains of Ci-4 alkyl, Ci_4 alkoxy or Ci-4-amino alkyl, each being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4, 5-b] pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three Ci-4 alkyl, Ci-4 alkoxy, hydroxy, nitrile, amino, mono- or di- (Ci_3) amino, mono- or di- (alkyl) groups Ci-3-amino) carbonyl, NH 2 C (O), Ci-6-S (0) alkyl or halogen; a carbon chain or chain of Ci_4 saturated or unsaturated, branched or unbranched, optionally partially or completely halogenated, in which one or more C atoms are optionally replaced by O, or S (0) m and wherein Y is optionally substituted independently with one to two oxo, nitrile, phenyl groups or one or more Ci-4 alkyl optionally substituted with one or more halogen atoms; piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocyclyl selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-azabicyclo [2.2.1] heptanyl, pentamethylene sulfuryl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfuryl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxydyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen groups, Ci_6 alkyl, Ci-6 alkoxy, Ci-3 alkoxy Ci-3 alkyl, Ci-6-alkoxycarbonyl, aroyl, Ci-3 acyl , oxo, hydroxy, pyridinylC1-3alkyl, imidazolyl-C1_3alkyl tetrahydrofuranyl-C1_3alkyl, nitrile-Ci_3alkyl, nitrile, carboxy, phenyl in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy or mono- or di- (Ci_3 alkyl) amino, Ci_6-S (0) m alkyl, or phenyl-S (0) m in which the phenyl ring is optionally its cn-1 a two halogen groups, alkoxy-6, hydroxy, halogen or mono- or di- (Ci-3 alkyl) amino; Z is optionally substituted with one to three amino or amino-Ci_3 alkyl groups in which the N atom is optionally mono- or di-substituted independently with amino-Ci_6 alkyl, Ci-3 alkyl, arylC0-3 alkyl , C 1 -3 alkoxy C 1-3 alkyl, C 1-5 akoyl alkoxy, Ci 3 acyl, C 1-3 alkylsulp (0) m- or aryl C 0-3-S (O) m-, each the aforementioned alkyl and aryl groups attached to the amino group is optionally substituted with one to two halogen groups, C 1-6 alkyl or C 1-6 alkoxy; Z is optionally substituted with one to three aryl, heterocyclyl or heteroaryl groups as previously described in this paragraph each of which in turn is optionally substituted with halogen, Ci-6 alkyl or Ci-6 alkoxy; or Z is hydroxy, halogen, nitrile, amino in which the atom of N is optionally mono- or di-substituted independently with acyl Ci-3, alkyl Ci-6 or alkoxy Ci-3alkyl Ci-3, alkyl Ci-6 branched or unbranched, alkoxy Ci-6, acyl Ci_3-amino, nitrile-Ci_4alkyl, alkyl? ^ - ???) and phenyl-S (0) m, in which the phenyl ring is optionally substituted with one to two halogen groups, Ci_6 alkoxy, hydroxy or nio_io ^ J ^ uii-ß? T ^ - ^ -? Tp? T ?? each Ri is independently: a Ci-io-branched or unbranched alkyl, optionally partially or wholly halogenated, in which one or more C atoms are optionally independently replaced by O, or S (0) m, and wherein said alkyl Ci-io is optionally substituted with one to three C3-i0 cycloalkyl groups, hydroxy, oxo-phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned groups being optionally substituted with one to five groups selected from halogen, Ci-S alkyl optionally being partially or fully halogenated, C3_8 cycloalkanyl, C5_8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy optionally partial or fully halogenated or NH2C (O), mono- or di (Ci-3 alkyl) -amino, and mono- or di- (Ci-3 alkyl) -aminocarbonyl; is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, to said cycloalkyl group, wherein one to three ring methylene groups are independently replaced by O, S (0) m, CHOH, > C = 0, > C = S or NH; phenyloxy or benzyloxy, each of which being optionally partially or wholly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy-Ci_3 alkyl or aryl; or a group analogous to said cycloaryl group, wherein one to two methine ring groups are independently replaced by N; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which being optionally partially or wholly halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or wholly halogenated, nitrile, hydroxy-Ci alkyl -3 or aryl; or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by O, S (0) m, CHOH, > C = 0, > C = S or NH; C3-10 alkenyl branched or unbranched, each being optionally partially or fully halogenated, and optionally substituted with one to three alkyl groups C1-5 branched or unbranched, unbranched, unsaturated, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned groups being substituted with one to five halogen groups, Ci_6 alkyl optionally being partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, Ci_3-oxy alkyl which is optionally partially or fully halogenated, NH2C (0), mono- or di (C 1-3 alkyl) aminocarbonyl; the C3-i0 alkenyl being branched or unbranched, optionally interrupted by one or more heteroatoms chosen from O, N and S (0) m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein said cycloalkenyl group is optionally substituted with one to three alkyl groups oxo, nitrile, halogen; silyl containing three Ci_alkyl groups optionally partially or wholly halogenated; or a C3-6 alkynyl carbon chain, branched or unbranched, optionally halogenated partially or wholly, which is optionally replaced by 0, NH or S (0) m and wherein t said alkynyl group is optionally substituted independently with each other two oxo, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl groups, one or more Ci_4 groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (alkyl) Ci_3) amino optionally substituted with one or more halogen atoms; each of R2 / R4 and R5 is a branched or unbranched Ci-6 alkyl, optionally partially or fully halogenated, Ci-6 acyl, aroyl, branched or unbranched C1-4 alkoxy, each being optionally partially halogenated or totally, halogen, methoxycarbonyl, Ci-3-S (0) M alkyl optionally partially or fully halogenated, or phenyl- S (0) M; 0R6, Ci-6 alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S (0) M- in which the N atom is optionally mono- or di-substituted independently with Ci-6 alkyl or arylC0-3 alkyl, or amino in which the N atom is optionally mono - or di-substituted independently with Ci-3 alkyl, arylC0-3 alkyl, acyl QL-6, alkyl Ci-6-S (0) M- or aryl-alkyl C0-3-S (O) M-, each of the alkyl and aryl groups before- ^ m fig ^ n two ~~ eñ this " subparagraph is optionally partially or fully halogenated and optionally substituted with one to two Ci-6 alkyl or Ci-6 alkoxy groups, each R3 is independently: phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, [1, 3, 4] oxadiazole, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzothiofuranyl, cinolinyl, pterinidinyl, phthalazinyl, naphypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned groups is optionally substituted by one to three phenyl, naphthyl, heterocyclyl or heteroaryl, as previously described in this paragraph, Ci_6 branched or unbranched, optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-Ci-5 alkyl, naphthyl Ci-5 alkyl, halogen, hydroxy, oxo , nitrile, Ci_3 alkoxy optionally partially or fully halogenated, phenylovi, n-if < - ?? mH, | heteroaryloxy or heterocyclyloxy in which the heterocyclic or heteroaryl moiety is as described above in this paragraph, nitro, amino, mono- or di- (Ci-3 alkyl) -amino, phenylamino, naphthylamino, heteroaryl- or heterocyclic-amino wherein the heteroaryl or heterocyclyl moiety is as previously described in this paragraph, NH2C (0), a mono- or di- (Ci-3 alkyl) -aminocarbonyl, C1-5-alkyl (0) -alkyl Ci-4 , amino-Ci_5alkyl, mono- or di- (Ci_5alkyl) amino, mono- or di- (C1-3alkyl) amino-C1-5alkyl, amino-S (0) 2, di- (C1-3alkyl) amino-S (0) 2 7-Ci-5 alkyl, R8-C 1-5 alkoxy, R9-C (0) -C1-5 alkyl, Rio-Ci-5- alkyl (Rn) N, carboxy-mono- or di- (C 1-5 alkyl) -amino; an aryl condensate selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, ciclohexanopiridinilo, ciclopentanopirimidinilo, ciclohexanopirimidinilo, ciclopentanopirazinilo, ciclohexanopirazinilo, ciclopentanopiridazinilo, ciclohexanopiridazinilo, ciclopentanoquinolinilo, ciclohexanoquinolinilo, ciclopentanoisoquinolinilo, ciclohexanoisoquinolinilo to ±? 1 ???? a ??? 1 ??? 1? 1 ?? "7" cyclohexaneindolyl, cyclopentanebenzimidazolyl, cyclohexanebenzimidazolyl, cyclopentanebenzoxazolyl, cyclohexanebenzoxazolyl, cyclopentanoimidazolyl, cyclohexaneimidazolyl, 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, Ci_6 alkyl groups optionally partial or fully halogenated, halogen, nitrile, Ci_3-oxy alkyl which is optionally partially or fully halogenated, phenyloxy, naphthyloxy. heteroaryloxy or heterocyclyloxy in which the heteroaryl or heterocyclyl moiety is as described above in this paragraph, nitro, amino, mono- or di- (Ci-3 alkyl) amino, phenylamino, naphthylamino, heteroaryl- or heterocyclic-amino in which the remainder heteroaryl or heterocyclyl is as previously described in this paragraph, NH2C (0), mono- or di- (C1-3alkyl) -aminocarbonyl, alkylCi-0C (0), alkyl Ci_5-C (0) -alkyl C1 -4, amino-Ci-5 alkyl, mono- or di-alkyl (Ci-3) amino-Ci-5-alkyl, Ri2-Ci-5-alkyl, Ri3-Ci-5-alkoxy, Ri4-C (O) -alkyl Ci-5 or Ri5-Ci_5 alkyl - (RiS) N; cyclopropanyl, cyclobutanyl, pyridinyl-cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3alkyl groups, or a group analogous to said cycloalkyl group, in which one to three ring methylene groups are independently replaced by O, S, CHOH, >; C = 0, > C = S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci-2 alkyl groups; alkyl Ci-4-phenyl-C (O) -alkyl Ci- -, alkyl Ci-4-C (0) -alkyl Cx_4- or alkyl Ci_4-phenyl-S (O) m- alkyl Ci_4-; a Ci-6 alkyl or Ci-6 alkoxy branched or unbranched each of which is optionally partially or fully halogenated or optionally substituted with Ri7; ORis or Ci-6 alkyl optionally substituted with 0Ri8; amino or mono- or di- (Ci_5 alkyl) amino optionally substituted with R19; R20C (O) N (R2i) -, R220- or R23R24NC (O) -; R2S (CH2) mC (0) N (R21) -, R23R24NC (0) - C1-3 alkoxy or R26C (0) (CH2) mN (R21) -; C2_6 alkenyl substituted with R23R2 NC (0) -; &numsp &numsp &numsp a C2-6 alkynyl chain, branched or unbranched, optionally halo-inked &tt-fully, in which one or more methylene groups are optionally replaced by O, NH, S (0) m and wherein said alkynyl group is optionally substituted independently with one to two oxo, pyrrolidinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl groups, one or more ¾_4 alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino , piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (alkyl Ci-) amino optionally substituted with one or more halogen atoms; acyl Ci-6 or aroyl; s a: Ca_4 alkyl optionally halogenated partially or wholly and optionally substituted with R26; each of the R7 R8, R9, Ri0, Ri2, Ri3, Ri4 # Ri5 # Ri ?, 19 25 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; each of Rn and Ri6 is independently: hydrogen or Ci_4 alkyl optionally partially or fully halogenated; RiB is indepe dí g »ai ^ pmnn1-n · hydrogen or Ci-4 alkyl optionally substituted independently with oxo or R25; R20 is independently: Ci-10 alkyl optionally partially or fully halogenated, phenyl or pyridinyl; R21 is independently: hydrogen or Cx.3 alkyl optionally partially or fully halogenated; each of R22 # R23 and 24 is independently: hydrogen, Ci_6 alkyl optionally partially or fully halogenated, said Ci-6 alkyl is optionally interrupted by one or more O, N or S, said Ci_6 alkyl being optionally independently substituted as well with mono- or di- (Ci_3 alkyl) aminocarbonyl, phenyl, pyridinyl, amino or mono- or di- (Ci- 4 alkyl) araino, each of which optionally being partially or fully halogenated and optionally substituted with mono- or di- - (Ci-3 alkyl) amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; m = 0, 1 or 2; W is O or S and its pharmaceutically acceptable derivatives. 13. Appropriate inhalational formulations for inhalation characterized in that they contain at least one p38 kinase inhibitor in a therapeutically effective amount to treat mucus hypersecretion. 1 . Pharmaceutical composition according to claim 13, characterized in that an individual administration corresponds to a dose of p38 kinase inhibitor of 100 to 10,000 g. 15. Pharmaceutical composition according to claim 13 or 14, characterized in that it is a formulation selected from inhalable powders, aerosols in measured amounts containing a propellant, and inhalable solutions or suspensions free of propellant. 16. Pharmaceutical composition according to claim 13, 14 or 15, characterized in that it is an inhalable powder containing the p38 kinase inhibitor agent in admixture with appropriate physiologically acceptable excipients selected from monosaccharides, disaccharides, oligo- and poly-saccharides, polyalcohols , salts, or mixtures of these excipients between them. Inhalable powder according to claim 16, characterized in that the excipient has a maximum average particle size of up to 250 μp ?, preferably between 10 and 150 μ ??. 18. Ca sjjXa &T-characterized because they contain an inhalable powder according to claim 16 or 17. 19. Pharmaceutical composition according to claim 15, characterized in that it is an inhalable powder containing only the p38 kinase inhibitor agent. as its ingredients. 20. Pharmaceutical composition according to claim 15, characterized in that it is an inhalable solution or suspension free of propellant containing water, ethanol, or a mixture of water and ethanol as solvent. 21. Pharmaceutical composition according to one of claims 13 to 20, characterized in that the p38 kinase inhibitor agent is selected from the group of compounds described in US Pat. US 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 from PCT Patent 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 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 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 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 0 / 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 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 01/29 041, WO 01/29042, WO 01/62731, WO 01/05744, OR 01/05745, OR 01/05746, WO 01/05749, OR 01/05751, WO 01/27315, OR 01/42189, WO 01 / 00208, WO 01/42241, WO 01/34605, WO 01/47897, O 01/64676, O 01/37837, WO 01/38312, OR 01/38313, WO 01/36403, WO 01/38314, WO 01 / 47921, WO 01/27089, German Patent Application DE 19842833, and Japanese Patent Application JP 2000 86657. 22. Pharmaceutical composition of onfroma with claim 21, characterized in that the p38 kinase inhibitor is selected from the group of compounds described 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 /] 0563. WO-75791 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. 23. Pharmaceutical composition according to claim 22, characterized in that the kinase inhibitor p38 is a compound of formula 1 wherein R] _, R2 and R4 can have the meanings given in claim 5. 24. Pharmaceutical composition according to claim 22, characterized in that the kinase inhibitor p38 is a compound of formula 2 wherein RA, Ar, m, n, and 1 can have the meanings given in claim 6. 25. Pharmaceutical-conrormiaaa composition with claim 22, characterized in that the p38 kinase inhibitor is a compound of formula 3a, 3b , 3c or 3d in which R1, R¿, J, ?? and Z¿ have the meanings given in claim 7. 26. Pharmaceutical composition according to claim 22, characterized in that the p38 kinase inhibitor is a compound of formula 4. in which Ari, Ar2, X, L and Q can have the meanings given in claim 8. 27. Pharmaceutical composition according to claim 22, characterized in that the inhibitory agent wherein Ari, Ar2, W, X, Y and Z can have the meanings given in claim 9. 28. Pharmaceutical composition according to claim 22, characterized in that the kinase inhibitor p38 is a compound of formula 5a wherein Arl7 Ar2, W, X, Y and Z can have the meanings given in claim 10. 29. Pharmaceutical composition according to claim 22, characterized in that the p38 kinase inhibitor is a compound of formula 6 WG ^ Ar-X-Y-ZIIHH 6 in which Ar, W, G, X, Y and Z can have the meanings given in claim 11. 30. Pharmaceutical composition according to claim 22, characterized in that the kinase inhibitor agent p38 is a compound of fñrmn La_3 in which Ar, W, G, E, X, Y and Z can have the meanings given in claim 12.
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