ME01360B - Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors - Google Patents

Description

Description

The present invention relates to triazolopyridinylsulfanyl derivatives. More precisely, the present invention relates to pyrazolyl-[(triazolopyridinylsulfanyl)-benzyl]-urea derivatives and procedures for obtaining them, intermediates used in the obtaining procedure, compositions containing them and the use of these derivatives.

The triazolopyridinylsulfanyl derivatives of the present invention are inhibitors of p38 mitogen-activated protein kinase ("p38 MAPK", "p38 kinase" or "p38"), especially p38a kinase, and are inhibitors of tumor necrosis factor ("TNF") production, especially TNFa. They find numerous therapeutic applications, especially in the treatment of allergic and non-allergic airway diseases, i.e. obstructive or inflammatory airway diseases such as chronic obstructive pulmonary disease ("COPD").

Mitogen-activated protein kinases (MAPs) form a family of proline-directed serine/threonine kinases that activate substrates by dual phosphorylation. Kinases are activated by a variety of signals, including nutritional and osmotic stress, UV light, growth factors, endotoxin, and inflammatory cytokines. The p38 MAP kinase group is a MAP family of different isoforms, including p38a, p38p, and p38y. These kinases are responsible for the phosphorylation and activation of transcription factors (eg, ATF2, CHOP, and MEF2C), as well as other kinases (eg, MAPKAP-2 and MAPKAP-3). p38 isoforms are activated by bacterial lipopolysaccharide, physical or chemical stress, and pro-inflammatory cytokines, including tumor necrosis factor ("TNF") and interleukin-1 ("IL-1"). Phosphorylation products of p38 mediate the production of inflammatory cytokines, including TNF.

TNF is a cytokine produced primarily by the activation of monocytes and macrophages.

Increased or unregulated production of TNF (especially TNF) mediates numerous diseases and it is hypothesized that TNF may generally contribute to the effects of inflammation.

IL-8 is another pro-inflammatory cytokine, produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. This cytokine is associated with conditions involving inflammation. IL-1 is produced by activated monocytes and macrophages, and involvement in inflammatory responses. IL-1 is involved in numerous pathophysiological responses, including rheumatoid arthritis, fever, and decreased bone resorption.

TNF, IL-1, and IL-8 affect a variety of cells and tissues, and are important inflammatory mediators in a wide variety of conditions. Compounds that inhibit p38 kinase will also inhibit IL-1, IL-8, and TNF synthesis in human monocytes.

P38 kinase inhibitors are well known to those of ordinary skill in the art. J. Med. Chem. 2002, 45, 2994-3008 discloses certain pyrazole urea compounds as inhibitors of p38 kinase. International patent application PCT/IB02/00424 (WO 02/072579) describes triazolopyridine as inhibitors of MAP kinases, preferably p38 kinase.

International Patent Application PCT/US02/36699 (WO 03/044021) describes substituted indolizine-like compounds that are useful in the treatment of diseases such as those mediated by TNF, IL-1R, IL-6 and/or IL-8.

International patent application PCT/EP01/00790 (WO 01/57038) describes heterocyclic compounds claimed to be PARP inhibitors.

International patent application PCT IB2004/000363 (WO 2004/072072), publication date August 26, 2004, describes triazolo-pyridines useful as anti-inflammatory compounds for the treatment of certain diseases.

The compounds of the present invention are potentially useful for the treatment of a wide range of disorders. In addition to the treatment of obstructive or inflammatory airway disease, it is believed that the compounds of the present invention can be used to treat TNF/p38 mediated diseases such as: asthma, chronic or acute bronchoconstriction, bronchitis, acute lung injury and bronchiectasis, general inflammation (e.g. inflammatory disease bowel), arthritis, neuroinflammation, pain, fever, fibrotic diseases, pulmonary disorders and diseases (eg, hyperoxic alveolar injury), cardiovascular disease, post-ischemic reperfusion injury and congestive heart failure, cardiomyopathy, stroke, ischemia, reperfusion injury, renal reperfusion injury, brain edema, neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver diseases and nephritis, gastrointestinal conditions, ulcerative diseases, ophthalmic diseases, ophthalmological conditions, glaucoma, acute eye tissue injuries and ocular trauma, diabetes, diabetic nephropathy, skin diseases, myalgia due to influenza infection, endotoxic shock, toxic shock syndrome, autoimmune diseases, graft rejection, bone resorption disease, multiple sclerosis, psoriasis, disorders of the female reproductive system, pathological (but non-malignant) conditions, such as hemaginomas , nasopharyngeal anglofibroma, and avascular bone necrosis, benign and malignant tumors/neoplasia including cancer, leukemia, lymphoma, systemic lupus erythematosus (SLE), angiogenesis including neoplasia, hemorrhage, coagulation, radiation injury, and/or metastases. Chronic release of active TNF can cause cachexia and TNF can be lethal

TNF also mediates infectious diseases. These include, for example, malaria, mycobacterial infection and meningitis. And also include viral infections, such as HIV, influenza virus, and herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (FISV-2), cytomegalovirus (CMV), varicella -zoster virus (VZV),

Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies (Aujeszky's disease), and rhinotracheitis, among others .

Treatment of obstructive or inflammatory airway disease is the preferred use. All forms of obstructive or inflammatory airway diseases can potentially be treated with the compounds of the present invention, and in particular obstructive or inflammatory airway diseases selected from the group consisting of chronic eosinophilic pneumonia, COPD, COPD including chronic bronchitis, pulmonary emphysema or dyspnea associated or unrelated to COPD , COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyper-reactivity as a consequence of other drug therapies, and airway disease associated with pulmonary hypertension.

There is a need for new TNF inhibitors / p38 kinase inhibitors that are good drug candidates. Preferably, the new TNF inhibitors/p38 kinase inhibitors show good potency, high levels of selectivity compared to other related protein kinases, have properties that are particularly suitable for providing efficient (effective) inhalation treatment, are suitable for the treatment of allergic and non-allergic respiratory diseases ( especially obstructive or inflammatory airway diseases), are non-toxic and exhibit few side effects, have physical properties suitable for administration by inhalation, exist in a physical form that is convenient and non-hygroscopic, and/or are easily formulated.

According to one aspect of the present invention, there is provided a compound of formula (I):

Or pharmaceutically acceptable salts and/or solvates thereof (including hydrates) where: R 1 is CH 3 , SCH 3 and SCH 2 CH 3 , CH 2 CH 3 , H or CH 2 SCH 3 ;

R1a is CH3 or CH2CH3;

R 2 is heteroaryl, heterocyclyl, aryl, or carbocyclyl;

R3 je heteroaril, heterociklil, aril, carbociklil ili R7;

R 7 is (C 1 -C 6 alkyl (optionally substituted with one or more substituents independently selected from OH, halo, NR 5 R 6 , (C 1 -C 6 )alkoxy, -S(O)p(C 1 -C 6 )alkyl, CO 2 H, CONR 5 R 6 , heteroaryl, heterocyclyl, aryl, carbocyclyl , aryloxy, carbocyclyloxy, heteroaryloxy and heterocyclyloxy); p is 0, 1 or 2;

R 5 and R 6 are each independently selected from H and (C 1 -C 4 )alkyl, said (C 1 -C 4 )alkyl being optionally substituted with one or more substituents independently selected from OH and halo, or R 5 and R 6 , together with a nitrogen for which are bonded to form a piperazinyl, piperidinyl, morpholinyl or pyrrolidinyl group, (given piperazinyl, piperidinyl, morpholinyl and pyrrolidinyl is optionally substituted by one or more OH)

each "aryl" independently means phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with one or more substituents independently selected from halo, -CN, -CO 2 H, OH, CONR 5 R 6 , R 8 and R 9 ;

each R8 is independently selected from (C1-C6)alkyl, (C1-C6)alkyl, -C02(C1-C6)alkyl, -S(O)p(C1-C6)alkyl, -CO(C1-C6)alkyl and ( C3-C7)cycloalkyl;

each R8 is optionally substituted with one or more substituents independently selected from: (C1-C6) alkoxy (optionally substituted with one or more substituents independently selected from OH, halo, CO2H, CONR5R6 and NR5R6),

-S(0)p(CrC6)alkyl (optionally substituted with one or more substituents independently selected from OH, halo, CO2H, CONR5R6 and NR5R6),

OH,

halo,

NR5R6,

co2h,

CONR5R6, i

R9;

each R 9 is heteroaryl 2 , heterocyclyl 2 , aryl 2 , carbocyclyl 2 , aryl 2 oxy, carbocyclyl 2 oxy, heteroarylPoxy or heterocyclylPoxy;

"aryl2", means phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, OH, and CONR5R6,

"carbocyclyl" means a mono- or bicyclic, saturated or partially unsaturated ring system containing 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, OH, CONR5R6, R8 and R9; "carbocyclyl2" means a mono- or bicyclic, saturated or partially unsaturated ring system containing from 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, OH and CONR5R6;

primers "carbocyclyl" and "carbocyclyl2" in the group poput: indanyl, indenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and tetrahydronaphthyl;

each "heterocyclyl", and "heterocyclyl2", independently, means a 3- to 10-membered, saturated or partially unsaturated, mono- or bicyclic group with 1, 2, 3 or 4 ring heteroatoms independently selected from N, O, and S.

Examples of "heterocyclyl" and "heterocyclyl2" are groups such as:

tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranil, tetrahydrothiopyranil, piperidinil, 1,4dioxanil, 1,4-oxathianil, morpholinil, 1,4-dithianil, piperazinil, 3,4-dihydro-2H-pyranil, 5,6-dihydro-2H- pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, dihydroindolyl and dihydrobenzofuranyl.

each "heteroaryl", and each "heteroaryl2", independently, means a 5- to 10-membered, mono- or bicyclic, aromatic group with 1, 2, 3, or 4 ring heteroatoms, independently of N, O, and S (wherein the number of S atoms in the ring does not exceed 1, and the total number of O atoms in the ring does not exceed 1), and includes the following groups:

pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl,1-oxa-2, 4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2, 5-diazolyl, 1 -thia-3,4-diazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiofenil, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2, 3-c]pyridinyl, pyrolo[3,2-cjpyridinyl, pyrolo[3,2-b]pyridinyl, imidazo[4,6-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3- djpyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, purinyl, indolinyl, imidazol[1,2-a]pyridinyl, imidazo[ 1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrolo[1-2,b] pyridazinil, imidazo[1,2-c]pyrimidinyl, hinolinil, isohinolinil, cinnolinil, hinazolinil, hinoxalinil, phthalazinil, 1,6-naphthiridinil, 1,7-naphthiridinil, 1,8-naphthiridinil, 1,5-naphthiridinil, 2,6-naphthiridinil, 2,7-naphthiridinil, pyrido[3,2-d]pyrimidinyl, pyrido[4, 3-d]pyrimidinyl, pyrido[3,4-djpyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pirimido[5,4- djpyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl;

each "heterocyclyl" and each "heteroaryl" group is, independently, optionally substituted at one or more

carbon atoms in the ring with one or more substituents independently donated by halo, -CN, -CO2H, OH, CONR5R6, R8 and R9, and optionally substituted on one or more nitrogen atoms in the ring with one or more substituents independently selected from H and (C 1 -C 6 )alkyl;

each "heterocyclyl2" and each "heteroaryl2" group is independently, optionally substituted on one or more ring carbon atoms with one or more substituents independently selected from halo, -CN, -CO2H, OH, and CONR5R6, and optionally substituted on one or more nitrogen atoms in the ring, one or more substituents independently selected from H and (C1-C6)alkyl;

"Alkyl" and "Alkoxy" groups, including groups containing the indicated residues, may be straight-chain or branched, where the number of carbon atoms permits. "(C 1 -C 4 )alkyl or "(C 1 -C 4 )alkyl" means a straight-chain group or a branched group, respectively, containing from 1 to 4 or from 1 to 6 carbon atoms. This also applies when they bear a substituent or occur as substituents or other radicals, for example in (CrC6alkyloxy radicals, -C02(CrC6)alkyl radicals, -CO(CrC6)alkyl radicals, or -S(0)p(C1-C6)alkyl radicals. Examples of corresponding (C1-C4) alkyl or (C 1 -C 6 alkyl radicals) are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl. ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy, pentyloxy and hexyloxy.

"halogen" or "halo" means a halogen atom selected from the group consisting of fluorine, chlorine and

brom.

It should be noted that all references to "treating", "treating" or "treating" include curative, palliative and/or prophylactic treatment.

"compounds of the invention" or "compound of the invention" as used herein includes compounds, or a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and includes all polymorphs and their crystalline forms, prodrugs and isomers (including optical, geometric and tautomeric isomers), and their mixtures, as defined below and isotopically labeled compounds of formula I.

Compounds of formula (I) p38 inhibitors/TNF production inhibitors have been found to be particularly useful for the treatment of diseases, disorders or conditions mediated by TNF, and/or p38, and are particularly useful for administration by inhalation.

Preferably, R 1 is CH 3 , SCH 3 , SCH 2 CH 3 or CH 2 SCH 3 , and more preferably R 1 is CH 3 or SCH 3 .

In an alternative embodiment, R 1 is preferably CH 3 , SCH 3 , CH 2 CH 3 or CH 2 SCH 3 , and more preferably R 1 is CH 3 , CH 2 CH 3 or CH 2 SCH 3 .

Preferably, R 1a is CH 3 .

Preferably, R 2 is pyridyl, tetrahydronaphthyl or aryl, wherein said pyridyl, tetrahydronaphthyl and aryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halo,

-CN,

-co2h

OH,

CONR5R6

(C 1 -C 6 )alkyl (given (C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from OH, NR 5 R 6 , aryl 2 and halo),

-S(0)p(Ci-C6)alkyl (given -S(0)p(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

(CrC6)Alkoxy (given (CrC6)Alkoxy is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

-C02(C1C6)alkyl (given -C02(C-i-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

(C3-C7)cycloalkyl (given (C3-C7)cycloalkyl is optionally substituted with one or more substituents

independently selected from OH and halo), pyridyl, and

aril2,

Preferably, R2 is:

3-pyridyl (optionally substituted with one or more substituents independently selected from OH, -

S(CrC6)alkyl, (CrC6alkyl, CF3 i halo),

or

phenyl (optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, OH, -S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, CN, CF 3 and halo).

More preferably, R 2 is phenyl (optionally substituted with one or more substituents independently selected from methyl, ethyl, OH, CN, CF 3 , Cl, F, -SCH 3 and -OCH 3 ).

Further, preferably R 2 is 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl, 3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl or 4-hydroxy-3-chlorophenyl .

In an alternative embodiment, R 2 is preferably pyridyl or aryl,

Each of the indicated pyridyl and aryl is optionally substituted with one or more substituents

independently selected from the group consisting of:

halo,

-CN,

-C02H

OH,

CONR5R6

(C 1 -C 6 )alkyl (given (C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from OH, NR 5 R 6 and halo),

(C 1 -C 6 )Alkoxy (given (C 1 -C 6 )Alkoxy is optionally substituted with one or more substituents independently selected from OH, CO 2 H, aryl 2 and halo),

Even better, R2 is:

3-pyridyl (optionally substituted with one or more substituents independently selected from OH, (Ci-C6)alkyl, (C1-C6) alkoxy and CF3), phenyl (optionally substituted with one or more substituents independently selected from (Cr C6) alkyl, OH , -S(Ci-C6)alkyl (where the given -S(C1-C6)alkyl is optionally substituted with OH), (CV C6)alkoxy (where the given (C1-C6)alkyl is optionally substituted with OH) , CN, CF3 and halo).

Further, it is preferred that R 2 , phenyl is optionally substituted with one or more substituents independently selected from (C 1 -C 4 )alkyl, OH , -S(C 1 -C 4 )alkyl (wherein given -S(C 1 -C 4 )alkyl is optionally substituted with OH), (C1-C4)Alkoxy (where the given (Cr-C4)Alkoxy is optionally substituted with OH), CN, CF3 and halo).

It is further preferred that R 2 is phenyl (optionally substituted with one or more substituents independently selected from methyl, ethyl, OH, CN, CF 3 , Cl, F and -OCH 2 CH 2 OH).

More preferably, R 2 is phenyl substituted with one or two substituents independently selected from OH, Cl, CN, methyl and -OCH 2 CH 2 OH.

Preferably, when R 2 is substituted phenyl, the substitution is at the 3- and/or 4-positions of the given phenyl.

In another preferred embodiment, when R2 is phenyl substituted with a hydroxyethoxy substituent, said hydroxyethoxy substituent is at the 3-position of the (meta)phenyl.

In a particularly preferred embodiment of the invention, R2 is substituted phenyl according to one of the embodiments or preferences given here, where R2 is phenyl, substituted with at least one hydroxy substituent, or at least one hydroxyethoxy substituent, and preferably at least one hydroxy substituent.

In a preferred embodiment of the invention, R2 is phenyl substituted with:

3-chloro and 4-hydroxy, 3-cyano and 4-hydroxy, 3-hydroxy, 4-hydroxy, 3-hydroxyethoxy, 3-hydroxy and

4-chloro, or 3-hydroxy and 4-cyano.

In another embodiment, R 2 is preferably 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl, 4-methylphenyl, 3-methylphenyl, -OCH 2 CH 2 OH or 4-hydroxy-3-chlorophenyl.

Preferably, R 3 is pyridyl or aryl, wherein each pyridyl and aryl is optionally substituted with one or

more

of substituents independently selected from the group consisting of: halo,

-CN,

-co2h

OH,

CONR5R6

(C 1 -C 6 )alkyl (given (C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from OH, NR 5 R 6 , aryl 2 and halo),

-S(0)p(CrC6)alkyl (given -S(0)p(CrC6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo), (CrC6)alkoxy (given (C1-C6Alkoxy is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

-C02(CrC6)alkyl (given -C02(CrC6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

(C3-C7)cycloalkyl (given (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halo), pyridyl, and aryl2,

or, alternatively, R 3 is preferably (C 1 -C 6 )alkyl, optionally substituted with one or more substituents independently selected from OH, halo, and (C 1 -C 6 )alkoxy.

More preferably, R 3 is aryl, optionally substituted with one or more substituents independently selected from the group consisting of: halo,

OH,

(CrC6)alkyl (given (CrC6 alkyl is optionally substituted with one or more substituents independently selected from OH and halo),

(C 1 -C 6 ) alkoxy (given (C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from OH and halo), or R 3 is (C 1 -C 6 )alkyl.

More preferably, R 3 is phenyl (optionally substituted with one or more substituents independently selected from: Cl, F, OH, methyl, ethyl, isopropyl, CF 3 , methoxy, ethoxy (given methoxy and ethoxy are each optionally substituted with OH), or R 3 is isopropyl.

In an alternative embodiment, R 3 is preferably pyridyl or aryl, wherein each pyridyl and aryl is optionally substituted with one or more substituents independently selected from the group consisting of: halo,

-CN,

-C02H

OH,

CONR5R6

(C^C^alkyl (given (C1C6)alkyl is optionally substituted with one or more substituents independently selected from OH, NR5R6, aryl2 and halo),

-S(0)p(C1-C6)alkyl (given -S(0)p(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo),

(C 1 -C 6 )alkoxy (given (C 1 -C 6 )alkyl optionally substituted with one or more substituents independently selected from OH, aryl 2 and halo), -CO 2 (C 1 -C 6 )alkyl (given -CO 1 2 (C 1 -C 6 )alkyl is optionally substituted one or more substituents independently selected from OH, aryl2 and halo),

(C3-C7)cycloalkyl (given (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halo),

or, alternatively, R 3 is preferably (C 1 -C 6 )alkyl, optionally substituted with one or more substituents independently selected from OH, halo, and (C 1 -C 6 )alkyloxy.

More preferably, R 3 is aryl, optionally substituted with one or more substituents independently selected from the group consisting of: halo,

OH,

CN,

(CrC6)alkyl (given (CrC6)alkyl is optionally substituted with one or more substituents independently selected from OH and halo),

(CT-CeAlkoxy (the given (CrC6)Alkoxy is optionally substituted with one or more substituents independently selected from OH and halo),

-S-(C1-C6)alkyl (given -S-(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH and halo), or R3 is (C1-C6)alkyl.

Even more preferably, R3 is phenyl (optionally substituted with one or more substituents independently selected from: CN, Cl, F, OH, methyl, ethyl, isopropyl, CF3, -S-(C1-C4)alkyl (given -S-(C1 -C4)alkyl is optionally substituted with OH), methoxy, ethoxy (given ethoxy is optionally substituted with OH), or R3 is isopropyl.

Preferably, R 3 is phenyl substituted with one or two substituents independently selected from Cl, F, CN, OH, -S-methyl, OCH 3 , -SCH 2 CH 2 OH and -OCH 2 CH 2 OH.

In a particularly preferred embodiment of the present invention, R3 is substituted phenyl according to one of the embodiments or preferences, where R3 is phenyl substituted with at least one hydroxy substituent, or at least one hydroxyethoxy substituent, preferably with at least one hydroxy substituent.

In the following particularly preferred embodiment of the present invention, R3 is phenyl substituted with:

2-hydroxy and 5-chloro,

2-hydroxy and 3-chloro,

3-hydroxy and 2-chloro,

5-hydroxy and 2-chloro,

3-cyano and 4-hydroxy,

2-hydroxy, or 2-OCH2CH2OH.

Preferably, when R3 is substituted phenyl and at least one substituent is -S-(CrC6)alkyl, -S-(CrC4)alkyl or -SCH2CH2OH, -S-(CrC6)alkyl, -S-tCrC4alkyl or -SCH2CH2OH located in the ortho position (position 2-) of phenyl.

Preferably, R 3 is phenyl substituted with at least one substituent independently selected from -S-methyl and -SCH 2 CH 2 OH, where the given -S-methyl or -SCH 2 CH 2 OH is in the ortho position (position 2) of the phenyl.

Preferably, R 5 and R 6 are independently selected from H, methyl and ethyl.

Preferably, “aryl” and “aryl 2 ” are phenyl (optionally substituted with one or more substituents independently selected from halo, -CN, OH, and R 8 ).

Preferably, R 8 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl or (C 3 -C 7 )cycloalkyl (each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 3 -C 7 )cycloalkyl is optionally substituted with one or more substituents independently selected from OH and hello).

Poželjno, R8 group su CF3, methyl, methoxy, ethyl, ethoxy, -OCH2CH2OH, -SCH2CH2OH, S-Me and cyclopropyl.

Preferably, p is 0.

Preferably, R 9 is heteroaryl 2 , heterocyclyl 2 , aryl 2 , aryl 2 oxy or heteroaryl 2 oxy;

More preferably, R 9 is heteroaryl 2 or aryl 2 .

Preferably, R 9 is pyridyl or phenyl (given pyridyl or phenyl is optionally substituted with one or more OH or halo).

Even better, R 9 is phenyl.

The next particularly preferred embodiment of the present invention is a compound of formula (I) according to one of the embodiments or preferences given here, where at least one of R2 and R3 is substituted phenyl, where phenyl is substituted with at least one hydroxy substituent or at least one hydroxyethoxy substituent, preferably at least one hydroxy substituent.

Preferably, "carbocyclyl" and "carbocyclyl2" are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (each cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is optionally substituted with one or more OH).

Preferably, "heterocyclyl" and "heterocyclyl2" are each independently selected from pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-dithianyl, and piperazinyl (each pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-dithianyl, and piperazinyl optionally substituted with one or more OH).

Preferably, "heteroaryl" and "heteroaryl2" are each independently selected from pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, and pyrazinyl (each pyrazolyl, imidazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, and pyrazinyl are sekrumen supstituisan jednim ili više OH).

More preferably, "heteroaryl" is pyridyl or isoquinolinyl, each optionally substituted with one or more

OH.

According to another embodiment, the compound of formula (I), or its pharmaceutically acceptable salt and/or solvate (including hydrate) where:

R 1 is CH 3 , SCH 3 and CH 2 CH 3 or CH 2 SCH 3 ;

R 1a is CH 3 ;

R2 is pyridyl, isoquinolinyl or phenyl, said phenyl being optionally substituted with one or more substituents independently selected from SCH3, Cl, F, Br, ethyl, methyl, methoxy, OH, benzyloxy, CF3, CO2H, CO2Et,

CN, -OCO2H, hydroxyethoxy, i -C(O)NHCH3; i

R 3 is isopropyl or phenyl, said phenyl being optionally substituted with one or more substituents independently selected from Cl, OH, F, benzyloxy, methoxy, hydroxyethoxy, isopropyl, methyl, ethyl, SCH 3 , CO 2 H, hydroxyethylthio and CN; is preferred.

According to the following embodiment, the compound of formula (I), or its pharmaceutically acceptable salt and/or solvate (including hydrate), where:

R 1 is CH 3 , SCH 3 , or CH 2 SCH 3 ;

R 1a is CH 3 ;

R 2 is phenyl, said phenyl being optionally substituted with one or more substituents independently selected from SCH 3 , Cl, OH, CN and hydroxyethoxy; and

R 3 is isopropyl or phenyl, said phenyl being optionally substituted with one or more substituents independently selected from Cl, OH, hydroxyethoxy, SCH 3 , hydroxyethylthio and CN; is more preferable.

In a further embodiment there is provided a compound of formula (I) wherein each R1, R1a, R2 and R3 substituent is independently selected from the substituents as defined in the given preferred or alternative embodiments, including any combination of the indicated preferred alternative or preferred embodiments.

A preferred group of compounds wherein each substituent is as defined in the examples below.

Preferably, the compound of formula (I) is selected from the compounds as indicated in the examples below.

A preferred group of compounds is one where each substituent is as defined in list 1 below.

Preferably, the compound of formula (I) is selected from list 1:

list 1:

N-{3-tert-Butyl-1-[4-(metilthio)fenil]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo{4 ,3-a]pyridin-6-yl)thio]benzyl}urea,

N-{3-tert-butil-1-[3-(metilthio)fenil]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo[4 ,3-a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(3,4-dichlorophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1f2,4]triazolo[4,3 -

a]pyridin-6-yl)thio]benzyl}urea,

ethyl 4-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino) -karbonyl]amino}-1H-pyrazol-1-yl)benzoate,

ethyl 3-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino) -karbonyl]amino}-1H-pyrazol-1-yl)benzoate,

N-[3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-

a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-

a]pyridin-6-yl)thio]benzyl}urea,

N-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ii)-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridine- 6-

il)thio]benzyl}urea,

N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2>4]triazolo[4,3- a]pyridine-

6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-

a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a]pyridin6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3- a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2, 4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N' -(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-{3-[ 1,1-Dimethyl-2-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3 -a]pyridin-6-yl)thio]benzyl}urea, N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl ]-N'-{2-[(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-i!)thio]benzyl}urea,

N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N'-{3-[1-metil-1-( methylthio)ethyl3-1-fenil-1H-pyrazol-5-yl}urea,

N-{1-[2-(benzyloxy)fenil]-3-[1-metil-1-(metilthio)etil]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[ 1,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N-{1-(4-chlorfenil)-3-[1-metil-1-(metilthio)ethyl ]-1H-pyrazol-5-yl}-N'-12-[{3-isopropyl[1,2,4]triazolo[4,3a]pyridin-6-yl)thio]benzyl}urea,

N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-i!)thio]benzyl}-N'-{3-[1-methyl-1- (methylthio)ethyl]-1-

[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

[1-methyl1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea,

N-[2-({3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N'-{3-[ 1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-ii]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-

a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-Butyl-1-(4-hydroxy-3-methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a]pyridin6-yl)thio]benzyl}urea,

N-{1 -(3-Hydroxyfenil)-3-[1 -metil-1 -(metilthio)etil]-1 H -pyrazol-5-yl}-N'-{2-[(3-isopropyl[1, 2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-(2-{[3-(2-hydroxyfenil)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzil)-N'-{3-[1-metil -1-(methylthio)ethyl]-1 fenil-1 H -pyrazol-5-yl}urea,

N-{1-(4-hlorfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol~5-yl}-N'-(2-{[3-(2-

hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-ii]thio}benzyl)urea,

N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3-[1-methyl -1-(methylthio)ethyl]1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea

3-(3-tert-Butyl-5-{3-[2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-ureido}- pyrazol-1-yl)-benzoic acid,

4- (3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl ]amino}-1Hpyrazol-1-yl)benzojeva kiselina, N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3- isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio] benzyl}urea,

N-[3-tert-Butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3- a]pyridin-6-yl)thio]benzylurea,

N-(3-tert-butyl-1-pyridin-3-yl-1H-pyrazol-5-yl)-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3- a]pyridine-6-

il)thio]benzyl}urea,

N-(2-{[3-(2-hydroxyfenil)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzil)-N'-{3-[1-metil -1-(methylthio)ethyl]-1 pyridin-3-yl-1 H -pyrazol-5-yl}urea,

N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N'-[3-[1-methyl-1-( methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,

N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[ 4,3-

a]pyridin-6yl]thio}benzyl)urea,

N-(2-{[3-(2-Hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3-[1-methyl -1-(methylthio)ethyl]1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,

N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3- [1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,

N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N'-[3-[1-methyl-1-( methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,

N-[3-tert-Butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[ 4,3-

a]pyridin-6yl]thio}benzyl)urea,

N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3-[1-methyl -1-(methylthio)ethyl]1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,

N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[ 3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea, N-[3-tert-Butyl-1-(3-methylphenyl) -1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl] thio}benzyl)urea, N-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N'-(2-{[3-( 2-hydroxyphenyl)[1,2,4]triazolo [4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1-methyl-1-

(methylthio)ethyl]-1-fenil-1H-pyrazol-5-yl}urea,

N-[3-[1,1 -dimethyl-2-(metilthio)ethyl]-1 -(4-metilfenil)-1 H -pyrazol-5-yl]-N'-(2-{[3-(2 -hydroxyfenil)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-[3-[1,1-dimethyl-2-(metilthio)ethyl]- 1-(3-metilfenil)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenii)[1,2,4]triazolo[4,3-a]pyridin-6 -yl]thio}benzyl)urea, N-[3-[1,1-dimethyl-2-(metilthio)ethyl]-1-(4-hydroxyfenil)-1 H-pyrazol-5-yl]-N'- {2-[(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-[1,1-dimethyl-2-( methylthio)ethyl]-1-(3-hydroxyfenil)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin- 6-yl)thio]benzyl}urea,

N-[3-tert-Butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazoyl [4l3-

a]pyridin-6yl]thio}benzyl)urea,

N-[3-tert-Butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2, 4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-hiorfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxy- 4-methylfenil)

[1.2.4] triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-ethylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[ 4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-ethylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-

methylphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzi!)urea,

N-{1-(3-ethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxy -4-methylphenyl)

[1.2.4] triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{3-tert-butyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4 ]triazolo[4,3-a]pyridin-6-yl]thiolbenzyl)urea, N-{3-tert-butyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N' -(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1-methyl-1-

(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

N-{2-[(3-isopropyl[1>2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N'-{3-[1-methyl-1-( methylthio)ethyl]-1-

[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3-[1-methyl -1-

(methylthio)ethyl]1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

N-{3-tert-butyl!-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-

hidroksiphenil)[1,2,4]triazole[4,3-a] pyridin-6-yl]thio}benzyl)urea,

N-{3-tert-butyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxy-4-

methylphenylHl^^triazolo^.S-aJpyridin-e-ylthioJbenziOurea,

N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1-methyl-1-

(methylthio)ethyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,

N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methithio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1, 2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-

hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6--yl]thio}benzyl)ureaI

N-[3-tert-butyl-1-(4-cyclopropylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-

hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzit)urea,

N-[3-tert-butyl-1-(4-cyclopropylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-

methylphenyl)[1,2,4]triazole [4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxy- 4-

methylphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2 ,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-{1-(3-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxyphenyl) )

[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-cyclopropylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-

hidroksiphenil)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-cyclopropylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-

methylphenyl)[1,2,4]triazole [4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3-cyclopropylphenyl)~3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxy- 4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3,5-dimethylfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1 ,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-{1-(3,5-dimethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2- hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-[3-tert-butyl-1-(3,5-dimethylphenyl)-1H- pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N -[3-tert-butyl-1-(3,5-dimethylphenyl!)-1H-pyrazol-5-yl]-N'-{2-{[3-(2-hydroxy-4-methylphenyl)[1, 2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3,5-dimethylfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2- hydroxy-4-

methylphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-hydroxyfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[( 3-isopropyl[1,2 ,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chlorphenyl)[1,2,4]triazolo[ 4,3-a]pyridin-6yl]thio}benzyl)urea,

N-{1 -(4-hydroxyphenit)-3-[1 -metil-1 -(metilthio)etil]-1 H-pyrazol-5-yl}-N'-(2-{[3-(2-metilfenil) )[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[ 4,3-

a]pyridin-6yl]thio}benzyl)urea,

N-{1-(3-hydroxyfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-

methylphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzi!)urea,

N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[ 4.3

a]pyridin-6yl)tio]benzylurea,

N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3- isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H -pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3-hlor-4-hydroxyfenil)-3-[1-metil-(metilthio)ethyl]-1H-pyrazol-5-yl}-N’-(2-{[3-(2-

methylphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[ 4.3

a]pyridin~6yl)thio]benzyl}irea,

N-{11-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl [1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H- pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3- (2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-hydroxy-3-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl [1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(4-hydroxy-3-methylphenyl)-1H- pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-hydroxy-3-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3- (2-methylphenyl) [1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-[3-tert-butyl-1-(3-hydroxy-4- methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin6-yl)thio]benzyl}urea,

N-{1-(3-hydroxy-4-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-12-[(3-isopropyl[ 1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(3-hydroxy-4-methylphenyl)-1H-pyrazole -5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(3-hydroxy-4-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-( 2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

IM-[3-tert-butyl-1-(4-ethyl-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[ 4,3-

a]pyridin-6yl)tio]benzylurea,

N-{1-(4-ethyl-3-hydroxyfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N’-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-[3-tert-butyl-1-(4-ethyl-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-

hlorphenyl)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-{1-(4-ethyl-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-( 2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzii)-N'-[3- [1-methyl-

1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,

N-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3- [1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea, N-[3-tert-butyl-1-(3-methylphenyl)-1H- pyrazol-5-yl]-N'-(2-{[3-(2-chlor-4-hydroxyfenil)[1,2,4]triazolo[4,3-a] pyridin-6-yl]thio}benzyl )urea,

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3- [1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-[3- [1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea, N-[3-tert-butyl-1-(3-methylphenyl)-1H- pyrazol-5-yl]-N'-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a] pyridin-6-yl]thio}benzyl )urea,

N-[3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-phenyl[1,2,4]triazolo[4,3- a]pyridine-6-

il)thio]benzyl}urea,

N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-phenyl[1,2,4]triazolo[4,3- a]pyridine-6-

il)thio]benzyl}urea,

N-{1 -(4-hydroxyfenil)-3-[1 -metil-1 -(metilthio)ethyl]-1 H -pyrazol-5-yl}-N'-{2-[(3-fenil[1, 2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,

N-{3-(2-hydroxy-1,1-dimethylethyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-( 2-

hidroksiphenil)[1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-

(methylsulfinyl)phenyl][1,2,4]triazolo[4,3-aj pyridin-6-yl}thio)benzyl]urea,

N-[3-[1,1-dimethyl-2-(methylsulfinyl)ethyl]-1-(3-fluorophenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-

hidroksifenil) [1,2,4]triazole[4,3-a]pyridin-6-yl]thio}benzyl)urea,

i

N-{1-(3-hydroxyfenil)-3-[1 -metil-1 -(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-fenil[1,2 ,4]triazolo[4,3-a] pyridin-6-yl)thio]benzyl}urea, i nihoje soli i/ili solvati.

Pharmaceutically acceptable salts of compounds of formula (I) include addition salts of acids and bases.

Suitable acid addition salts are obtained from acids that form non-toxic salts. Examples include the following salts: acetates, aspartates, benzoates, besylates, bicarbonates/carbonates, bisulfates/sulfates, borates, camsylates, citrates, edisylates, ezylates, formates, tumarates, gluceptates, gluconates, glucuronates, hexafluorophosphates, hibenzates, hydrochlorides/chlorides, hydrobromides /bromides, hydroiodides/iodides, isethionates, lactates, malates, maleates, malonates, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, rotates, oxalates, palmitates, pamoates, phosphates/hydrogen phosphates/dihydrogen phosphates, saccharates, stearates , succinates, tartrates, tosylates, adipates, cyclamates, tannates, pyroglutamates, xinafoates (1-hydroxynaphthalene-2-carboxylate) and trifluoroacetates.

The corresponding base salts are obtained from bases that form non-toxic salts.

Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases can also be obtained, for example, hemisulfate and hemicalcium salts.

A review of suitable salts is provided in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and VVermuth (Wiley-VCH, VVeinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) can be obtained according to one or more of the following procedures:

(i) by reacting a compound of formula (I) with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from an appropriate precursor compound of formula (I) or by ring-opening an appropriate cyclic precursor, for example, a lactone or lactam, using an appropriate acid or base; or

(iii) by converting one salt of a compound of formula (I) into another by reaction with a suitable acid or base or by means of a suitable ion exchange column.

All three reactions usually take place in solution. The resulting salt can be settled and collected by filtration or can be regenerated by evaporation of the solvent. The degree of ionization in the obtained salt can vary from fully ionized to non-ionized.

The compounds of the present invention can be in unsolvated or solvated form. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the solvent, water, is given.

The scope of the present invention includes complexes such as clathrates, drug-host inclusion complexes, where, contrary to the above-mentioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric concentrations. Also included are drug complexes containing two or more organic and/or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized. A review of these complexes is provided in J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975).

Hereinafter, all references to compounds of formula (I) include references to their salts, solvates, hydrates and complexes and to solvates and complexes of salts.

The compounds of the present invention include compounds of formula (I) as defined above, including their polymorphs and crystal forms, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined below and isotopically-labelled compounds of formula (I ).

As indicated, so-called 'pro-drugs' of compounds of formula (I) are also included within the scope of the invention. Thus determined derivatives of the compounds of formula (I) which themselves show little or no pharmacological activity, can, when administered into or on the body, be converted into compounds of formula (I) with the desired activity, on rpiemr, by hydrolytic cleavage. These derivatives are labeled as 'prodrugs'. Additional information on the use of prodrugs can be found in Pro-drugs as a Novel Delivery System, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs of the present invention can, for example, be obtained by replacing the appropriate functional group present in the compound of formula (I) with certain groups known to the person skilled in the art as 'pro-groups' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the invention include the case when:

(i) a compound of formula I containing a carboxyl functional group (-COOH), an ester thereof, for example, a compound where the hydrogen of the carboxyl functional group of a compound of formula (I) is replaced by (CrC8)alkyl;

(ii) the compound of formula (I) contains a (-OH) functional group, its ether, for example, a compound where the hydrogen of the alcohol functional group of the compound of formula (I) is replaced by (C^Ce) alkanoyloxymethyl; and

(iii) the compound of formula (I) contains a primary or secondary amino functional group (-NH2 or -NHR where R ^ H), its amide, for example, a compound where it may be the case that one or both hydrogens of the amino functional group of the compound of formula ( I) is/are replaced by (Cr C10)alkanoyl.

Further examples of substitution groups in accordance with the following examples and examples of other types of prodrugs can be found in the references given above.

Furthermore, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

The scope of the present invention also includes metabolites of compounds of formula (I), which are compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include the case of:

(i) when the compound of formula (I) contains a (C1-C6)alkyl group, its hydroxy(C1-C6)alkyl derivative. For example, when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (-CH3 -> -CH2OH);

(ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (-OR -> -OH);

(iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (NR5R6 -> -NHR5 or -NHR6);

(iv) when the compound of formula (I) contains a secondary amino group, its primary derivative (-NHR5 -> -NH2);

(v) when the compound of formula (I) contains a phenyl group, its phenol derivative (-Ph -> - PhOH);

(vi) when the compound of formula (I) contains an amide group, its carboxylic acid derivative (cacarboxylic derivative) (-CONH2 -> COOH); and

(vii) when the compound of formula (I) contains an S-(Cn-C6)alkyl group, its S(O)(C1C6)alkyl derivative. For example, when the compound of formula (I) contains an S-methyl group, its S(O)methyl derivative, and when the compound of formula (I) contains an alkyl-S-alkyl group, its alkyl-S(O)-alkyl derivative.

In the next aspect of the present invention, active metabolites of compounds of formula (I) are provided, where "active" means having an IC50 (TNFa screen) of less than 1000nM, and preferably an IC50 (TNFa screen) of less than 100nM. Preferably, a compound of formula (I) is provided which contains an S(O)(C1C6)alkyl group, or a hydroxy group.

Compounds of formula (I) containing one or more asymmetric carbon atoms can occur in two or more stereoisomers. When structural isomers are interconvertible across a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This may be a form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or a so-called valence tautomerism in compounds containing an aromatic group. It follows that one compound can exhibit several types of isomerism.

The scope of the present invention includes all stereoisomers, geometric isomers and tautomeric forms of compounds of formula (I), including compounds exhibiting multiple types of isomerism, and mixtures of one or more of them. Also included are addition salts of acids or bases where the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Conventional techniques for obtaining/isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate salt or derivative) by, for example, chiral high pressure chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or in the case where the compound of formula (I) contains an acidic or basic group, a base or an acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization and one or both diastereomers converted to the corresponding pure enantiomer(s) according to techniques known to one of ordinary skill in the art.

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically-enriched form by chromatography, usually HPLC, on an asymmetric resin with a mobile dose consisting of a hydrocarbon, usually heptane or hexane, containing from 0 to 50 wt. % of isopropanol, usually from 2% to 20%, and from 0 to 5 % alkylamine, usually 0.1% diethylamine. An enriched mixture is obtained by concentrating the eluate.

Stereoisomeric conglomerates can be separated by conventional techniques known to one of ordinary skill in the art, see, e.g., Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wiien (Wiley, New York, 1994).

The subject invention also includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) where one or more atoms have been replaced by atoms with the same atomic number, but a different atomic weight or mass number than that which can be found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen isotopes such as 2H and 3H, carbon such as 11C, 13C and 14C, chlorine such as 36CI, fluorine such as 18F, nitrogen such as 13N and 15N, oxygen , popu 150, 170 and 1sO, and sulfur, such as 35S.

Certain isotopically labeled compounds of formula (I), for example, those containing a radioactive isotope, are useful in studies of drug and/or substrate distribution in tissues. Radioactive isotopes of tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for these purposes due to their ease of incorporation and detection methods.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may lead to certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases.

Substitution with positron-emitting isotopes, such as 11C, 18F, 150, and 13N, can be useful in Positron Emission Topography assays to determine receptor substrate occupancy.

Isotopically labeled compounds of formula (I) can generally be obtained by conventional techniques known to one of ordinary skill in the art or by processes analogous to those described in the accompanying Examples and Preparations using the appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

Pharmaceutically acceptable solvates according to the subject include those where, for example, the crystallization solvent is isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.

The present invention also includes novel intermediates as defined, salts, solvates and complexes thereof and all solvates and complexes of salts as defined herein for compounds of formula (I). The invention includes all polymorphs of the above-mentioned species and their crystalline forms.

When preparing compounds of formula (I) according to the present invention, the option remains open to one of ordinary skill in the art to routinely select the form of the intermediate compound which provides the best combination of characteristics. These characteristics are the melting point, solubility, processing and yield of the intermediate form and the resulting ease with which the product can be purified after isolation.

The crystal structures of the compounds of Examples 80, 26, 93, 73, 63 and 60 were analyzed by powder X-ray diffractometry ("PXRD").

Illustrative PXRD patterns for these compounds are given in Figures 1-6 containing 15% silica as an internal reference standard.

Pictured by : Case 80 Figure 4: Case 73

Figure 2: Example 26 Figure 5: Example 63

Figure 3: Example 93 Figure 6: Example 60

X-ray analysis data were recorded at room temperature using a Bruker AXS D4 powder X-ray diffractometer (Cu Ka radiation) with automatic sample changer, theta-theta goniometer, automatic beam divergence slits, secondary monochromator and scintillation counter. Samples were prepared for analysis by mixing the compound with silicon powder as a reference standard in an amount of 15 wt. %. The powder was placed on a sample holder with a diameter of 12 mm. The sample was rotated while irradiating with copper Ka1 X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube set at 40kV/40mA. Analyzes were performed with the goniometer set to continuous operation mode, for 5 seconds at a step of 0.02° in the theta range from 2° to 55°. The obtained peaks are adjusted according to the reference standard (ICDD reference number 001-0791).

The average crystallographer will appreciate the fact that the relative intensities of the various peaks given in the Tables and Figures may vary due to a number of factors such as the effect of the orientation of the crystal in the X-ray beam or the purity of the annealed material or the degree of crystallinity of the sample. Peak positions may also shift due to variations in sample weight, but peak positions remain essentially as defined in the figures. The average crystallographer will also appreciate the fact that measurements at different wavelengths will lead to different shifts according to Bragg's equation - n. = 2d son.

These PXRD gratings obtained at alternative wavelengths are considered as an alternative representation of the PXRD gratings of the crystalline materials of the present invention and as such are encompassed by the present invention.

Tables 1-6 give the corresponding principal diffraction peaks as 20 values and intensities of the compounds excluding those peaks attributable to the reference standard. All 20 values are +/- 0.1 degrees.

Table 1 gives peaks for Example 80 with a relative intensity greater than 33.0%.

Table 2 gives the peaks for Example 26 with a relative intensity greater than 36.5%.

Table 3 gives peaks for Example 93 with a relative intensity greater than 15.5%.

Table 4 gives peaks for Example 73 with a relative intensity greater than 34.0%.

Table 5 gives peaks for Example 63 with a relative intensity greater than 35.7%.

Table 6 gives peaks for Example 60 with a relative intensity greater than 36.4%.

In a further aspect of the invention, there is provided a compound of Example No. 80, 26, 93, 73, 63 or 60, having a crystal structure as illustrated in the Figures and/or as defined in the Tables. The invention is in no way limited by solid forms.

Compounds of formula (I) can be prepared in a known manner and in various ways. The following are ways that illustrate the way to obtain these compounds; the average person will appreciate the fact that the paths may be equally feasible. In the following schemes, unless otherwise indicated, the substituents are as previously defined with reference to compounds of formula (I), and

"PdCl2(dppf).CH2CI2" is 1,1-bis(diphenylphosphino)ferrocene palladium(II) chloride 1:1 dichloromethane complex,

"DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene; "BOC" means tert-butoxycarbonyl;

"CBz" means benzyloxycarbonyl "Et" means ethyl "Me" means methyl "Pd" means palladium, and "eq" means molar equivalent(s)

"iPr" stands for isopropyl.

Shema 1

Compounds of general formula (II) are either commercially available or can be prepared as given in Scheme 2.

Compounds of general formula (III) are either commercially available (eg when R1a=Me and R1=Me) or can be prepared as given in Scheme 3.

Compounds of general formula (IV) can be obtained from compounds of formula (II) and (III) according to the process step i - cyclocondensation of compound (II) and compound (III) optionally in the presence of a suitable acid catalyst such as hydrochloric acid, optionally in in the presence of a suitable base such as Hunig's base, triethylamine or pyridine, in a suitable solvent such as methanol or ethanol, at elevated temperature, for 3-24 hours. Typical conditions include 1.0-1.3 equivalents of compound (II) and 1.0-1.1 equivalents of compound (III) in the presence of hydrochloric acid, in ethanol, with heating under reflux for 3-24 hours.

Additionally, compounds of general formula (IV) can be obtained by direct condensation of a compound of formula (VII) with a compound of formula (III), in EtOH/HCl.

Compounds of general formula (V) can be prepared as shown in Scheme 4.

Compounds of formula (I) can be obtained from compounds (IV) and (V) according to step ii) of the process -urea is obtained by reacting compound (IV) in the presence of a suitable source

carbonyls such as N,N'-carbonyldiimidazole, phenylchloroformates or bis(trichloromethyl) carbonates and appropriate bases such as Hunig's base or pyridine, in a suitable solvent such as dichloromethane or 1,4 dioxane, under ambient conditions, for 48 hours , after which compound (V) was added. Typical conditions include either:

a) 1.0 equivalent of compound (IV) and 5.0-6.0 equivalents of N,N'-carbonyldiimidazole in dichloromethane, under ambient conditions for 24 hours,

b) 0.25-0.80 equivalents of compound (V), 0.25-1.25 equivalents of Hiinig's base in dichloromethane or 1,4 dioxane, under ambient conditions for 24 hours, or

c) 1 equivalent of compound (IV) and 1 equivalent of phenylchloroformate in THF/pyridine, after which 0.8-1 equivalent of compound (V) in DMSO was added.

When R 2 is aryl or heteroaryl, compounds of general formula (II) can be prepared as shown in Scheme 2.

When R 2 -Br is not available, the compound of formula (II) can be obtained from the appropriate aniline derivative, by diazotization and then reduction, under the letters that are well known in the chemical literature.

PG is a suitable protecting group such as BOC or CBz, preferably BOC.

When R 2 is, or contains, phenol, one of ordinary skill will appreciate the fact that a protecting group, usually benzyloxy or methyloxy, must be used.

Compounds of general formula (VI) are commercially available.

Compounds of general formula (II) can be obtained from compounds of general formula (VI), via compound (VII), according to steps (iii) and (iv) of the process.

Step (iii) - is performed by obtaining a suitable organometallic reagent, e.g. arylMgBr, heteroarylMgBr, arylLi, or heteroarylLi, optionally obtained in situ under standard Grignard conditions or by reaction with a suitable alkyl lithium, e.g. nBuLi, in a suitable solvent, such as tetrahydrofuran or diethyl ether, at a temperature of about -100° C to 25°C, for 1-18 hours. Intermediate compound (VII) was obtained by successive nucleophilic attacks of an adequately protected diazocarboxylate compound, preferably di-tert-butyldiazocarboxylate, with arylMgBr/heteroarylMgBr/arylLi/heteroarylLi, in a suitable solvent such as tetrahydrofuran or diethyl ether, at -78°C for 0.5-1.0 hours.

Step (iv) - Deprotection of compound (VII) according to standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz.

When PG = BOC, typical conditions include saturating intermediate (VII) with a suitable acid such as hydrochloric acid or trifluoroacetic acid, in a suitable solvent such as isopropyl alcohol, 1,4-dioxane or diethyl ether, under ambient conditions for 2-18 hours.

Preferably, compounds of general formula (II) can be obtained from compounds of formula (VI) by combining steps iii) and iv) in a one-pot synthesis. Typical conditions include:

a) 1.0 equivalents of compound (VI), 1.1 equivalents of magnesium filings, one crystal of iodine in tetrahydrofuran, at room temperature, for 18 hours, after which di-tert-butyldiazocarboxylate was added at -78°C, for 30 minutes.

b) saturation with gaseous hydrogen chloride in isopropyl alcohol, under ambient conditions, during 0.5-1.0 hours.

When R 2 represents heterocyclyl or carbocyclyl, compounds of general formula (II) can be prepared according to scheme 2.1.

Step (xvii)-Compounds of formula (XXVII) can be obtained from compounds of formula (VI) by reaction with a suitably protected hydrazine (eg BOC-NHNH2) in the presence of a suitable alkali metal base (eg K2CO3 or Na2CO3) in a suitable solvent such as acetonitrile or N,N-dimethylformamide at a temperature between room and 60°C for up to 48 hours.

Compounds of formula (II) can be obtained from compounds of formula (XXVII) according to the procedures previously described for step iv.

Compounds of general formula (III) can be obtained according to schemes 3.1 and 3.2.

When R1 = -(CH2)nSRb, compounds of formula (III) can be obtained as given in scheme 3.1.

Rb represents methyl or ethyl. n represents 0 or 1.

Shema 3.1

LG is a corresponding outgoing group, e.g. OR' or Cl, preferably OR'.

R' represents C1C4 alkyl, preferably C1C2 alkyl.

When R-Et or Me, compounds of formula (VIII) are commercially available.

When n=1, compounds of formula (IXA) can be obtained from compounds of formula (VIII) according to process step v by -nucleophilic substitution. The reaction proceeds via the formation of an intermediate containing the appropriate leaving group.

LG', such as mesylate or tosylate by reacting compound (VIII) with mesyl chloride/anhydride or tosyl chloride, in the presence of a suitable base such as Hunig's base, triethylamine or pyridine, in a suitable solvent such as dichloromethane or diethyl ether, on low temperature for 1-2 hours. After concentration in vacuo, 1,4-dioxane or toluene and sodium methanethiol salt were added, heating under reflux for 24 hours. Typical conditions include:

a) I.Eq of compound (VIII), 1.0-1.2 eq of Hunig's base, and 1.1 eq of methane sulfonyl chloride in dichloromethane, at 0°C for 1-2 hours.

b) 1.1 eq sodium methanethiol salt in 1,4-dioxane, with heating under reflux for 24 hours.

When n=0, compounds of formula (IXA) are commercially available.

The compound (III) can be obtained from the compound of the formula (IXA) according to step vi of the process - reaction with acetonitrile (X). Treatment of (X) with a suitable base such as sodium hydride or lithium diisopropylamide, followed by reaction of the intermediate anion with compound (IXA), in a suitable solvent such as tetrahydrofuran, at elevated temperature for 3 hours to give compounds of formula (III). Typical conditions include 1.3 eq acetonitrile,

1.3 eq of sodium hydride (60% dispersion in mineral oil) and 1.0 eq of compound (IXA) in tetrahydrofuran, heated under reflux for 3 hours.

When R 1a represents H, CH 3 or CH 2 CH 3 , compounds of formula (III) can be obtained as given in Scheme 3.2.

Shema 3.2

LG is a suitable outgoing group, e.g. OR' or Cl, preferably OR'. R represents C 1 -C 2 alkyl, preferably C 1 -C 2 alkyl.

Compounds of formula (III) can be obtained from compounds of formula (IXB) according to process step vi, as previously described.

Compounds of formula (IXB) are either commercially available or can be obtained according to the procedures of Julia et. al. Staring. Soc. Chim. Fr. 1996; 133(1); 15-24, or Chuit et. al. Tetrahedron 1980; 36(16), 2305-10.

Compounds of formula (V) can be prepared as shown in Scheme 4

Shema 4

When Y=halogen and preferably bromine, compounds of general formula (XI) are commercially available.

Compounds of formula (XII) can be obtained from compounds of formula (XI) according to process step vii - reaction with hydrazine monohydrate, optionally in a suitable solvent such as methanol or ethanol, at elevated temperature for 18-72 hours. Typical conditions include 1.0 eq of compound (XI) and an excess of hydrazine monohydrate heated at 70°C for 72 hours.

Compounds of formula (XIV) can be obtained from compounds of formula (XII) according to step viii of the process - by reaction with degrossing alkyl chloride R3C(0)CI (XIII), in the presence of a suitable base such as Hunig's base, triethylamine or pyridine in a suitable solvent

such as dichloromethane or diethyl ether, at low temperature for 1-2 hours. Typical conditions include 1.Eq of compound (XII), 1.Eq of R 3 C(0)CI (XIII) and 5.0 eq of Hunig's base in dichloromethane, at a temperature between 0-5°C for 1-2 hours.

Compounds of formula (XV) can be obtained from compounds of formula (XIV) according to step ix of the -cyclization process. This is achieved by using a decomposing dehydration reagent such as phosphorus oxychloride or phosphorus (V) oxide in sulfuric acid, at an elevated temperature for 18-24 hours. Typical conditions involve 1.0 equivalent of compound (XIV) in excess phosphorus oxychloride at 75°C for 18-24 hours.

Alternatively, compounds of formula (XV) may be obtained directly from compounds of formula (XV).

(XII) according to step ix of the process. This cyclization is achieved by reaction with an excess of the compound

(XIII) and heating, for example at 95°C, for 18-24 hours.

Compounds of formula (XVII) can be obtained from compounds of formula (XV) according to process step x - Pd-catalyzed cross-coupling reaction with 2-mercaptobenzyl alcohol (XVI), in the presence of a suitable catalyst such as PdCI2 (dppf).CH2CI2, in the presence of a suitable base such as cesium carbonate or potassium carbonate, in a suitable solvent such as N,N-dimethylformamide or 1,4-dioxane, at elevated temperature for 2-48 hours. Typical conditions include 1.Oeq of compound (XV), 1.2-1.4eq of cesium carbonate, 1.3eq of 2-mercaptobenzyl alcohol (XVI) and 0.1eq of PdCI2 (dppf) CH2CI2 in N,N-dimethylformamide, at elevated temperature for 18 hours.

Compounds of formula (XVIII) can be obtained from compounds of formula (XVII) according to step xi of the process - preparation of azides. These are prepared by reacting compound (XVII) with a suitable base such as DBU or sodium hydride, followed by reaction with a suitable azide such as diphenylphosphoryl azide in a suitable solvent such as toluene or tetrahydrofuran, at a temperature between 0-25°C for 18-24 hours. Typical conditions include 1.0 eq of compound (XVII), 1.2 eq DBU and 1.2 eq diphenylphosphoryl azide in toluene at 0-25°C for 24 hours.

Compounds of formula (V) can be obtained from compounds of formula (XVIII) according to process step xii - reduction of compound (XVIII) with a suitable reducing agent such as triphenyl phosphine/water, stannous chloride or catalytic hydrogenation, in a suitable solvent such as tetrahydrofuran or ethanol, between ambient temperature and elevated temperature. Typical conditions include 1 eq of compound (XVIII), 1.2 eq of triphenylphosphine and 1.2 eq of water in tetrahydrofuran at room temperature for 40 hours and at 50°C for 5 hours.

Alternatively, compounds of formula (V) can also be prepared as shown in Scheme 5

Compounds of formula (XII) can be prepared as described in Scheme 4.

Compounds of formula (XIX) are either commercially available or can be prepared as described in Scheme 6.

Compounds of formula (XX) can be obtained from compounds of formula (XII) and (XIX) according to step xiii of the process - by condensation of hydrazine (XII) and aldehyde (XIX) in a suitable solvent such as methanol, ethanol or toluene, at an elevated temperature for 0.5 -1 hour. Typical conditions include 1 eq of compound (XII) and 1 eq of compound (XIX) in ethanol, with heating at reflux for 0.5-1.0 hours.

Compounds of formula (XV) can be obtained from compounds of formula (XX) according to process step xiv - cyclization of compound (XX) in the presence of a suitable oxidizing reagent such as (diacetoxyiodo)benzene, cerium (IV) ammonium nitrate or 2,3-dichloro -5,6-dicyano-1,4-benzoquinone in a suitable solvent such as ethyl acetate, dichloromethane or acetonitrile, under ambient conditions for 18-24 hours. Typical conditions involve 1.0 eq of compound (XX) and 1.2 eq of (diacetoxyiodo)benzene in dichloromethane, at room temperature for 24 hours.

Alternatively, compounds of formula (XV) can be obtained from compound (XII) according to process steps xiii and xiv - one-pot synthesis. Typical conditions include 1 eq of compound (XII) and 1 eq of compound (XIX) in ethanol, heated at reflux for 0.5-1.0 hour, followed by the addition of 1.2 eq of (diacetoxyiodo)benzene and dichloromethane, at room temperature for 24 hours.

Compounds of formula (XVII) can be prepared from compounds of formula (XV) and (XVI) according to process step x, as described in Scheme 4.

Compounds of formula (XVIII) can be obtained from compounds of formula (XVII) according to step xi of the process as described in Scheme 4.

Compounds of formula (V) may be prepared from compounds of formula (XVIII) according to process step xii, as described in Scheme 4.

Alternatively, compounds of formula (V) can also be obtained from compounds of formula (XVII) according to process step xviii. The reaction proceeds via the formation of an intermediate containing a suitable leaving group such as mesylate or tosylate by reacting compound (VIII) with mesyl chloride/anhydride or tosyl chloride, in the presence of a suitable base such as Hunig's base, triethylamine or pyridine, in a suitable solvent such as dichloromethane or diethyl ether, at lower temperatures to ambient temperature, for 1-4 hours. The resulting intermediate is then treated with an appropriate source of ammonia, typically 7M ammonia in methanol, under ambient conditions for 18-72 hours. Typical conditions include 1.0 equiv of compound (XVII), 3.0-4.0 equiv of Hunig's base, and 2.0-3.0 equiv of methanesulfonyl anhydride in dichloromethane, at 25°C for 1-4 hours. An excess of 7M ammonia in methanol was added and the reaction was stirred at ambient temperature for 18-72 hours.

Alternatively, compounds of formula (V) can be obtained from compounds of formula (XV) and compounds of formula (XXVI!) where PG is a protecting group, such as BOC. Typical conditions include 1 eq compound (XV), 1.2 eq compound (XXVII), 1.2 eq anhydrous cesium carbonate, 3 eq cesium fluoride, 0.1 eq PdCI2(dppf).CH2CI2 in dimethylformamide as solvent at 80-100 °C for 2-48 h. the product of this reaction is then exposed by acid removal of the BOC group to give compounds of formula (V).

Compounds of formula (XXVII) can be obtained from compounds of formula (XXVIII) according to process step xix (Scheme 5.1). This reaction takes place by inserting a palladium-containing sulfide into the aromatic-bromine bond. Typical conditions include 1 eq compound (XXVIII), 1 eq potassium tri(isopropyl)silylsulfide (obtained from 1 eq potassium tert-butoxide and 1 eq triisopropylsilanethiol in toluene), 1 eq PdCI2(dppf).CH2CI2 in toluene as solvent at 100 X during 0.5 to 2 h.

Shema 5.1

When R 3 is or contains phenol, one of ordinary skill in the art will appreciate the fact that it is necessary to use a protecting group, usually benzyloxy or methyloxy.

Compounds of formula (XXIV) are commercially available Compounds of formula (XXV) can be obtained from compounds of formula (XXIV) by process step xv - reduction with a suitable reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or sodium borohydride in a suitable solvent such as tetrahydrofuran or methanol, at an elevated temperature for 6-18 hours. Typical conditions include 1.0eq of compound (XXIV) and 1.0-1.2eq. of lithium aluminum hydride in tetrahydrofuran, at reflux for 6 hours.

Compounds of formula (XIX) can be obtained from compounds of formula (XXV) according to step xvi of the -oxidation process with a suitable oxidizing agent such as manganese dioxide, potassium permanganate or oxalyl chloride/dimethylsulfoxide, in a suitable solvent such as acetone, dichloromethane or dimethylsulfoxide, at temperatures from -80 to +80°C for 3-18 hours. Typical conditions include 1 eq of compound (XXV) and 0.5 eq of manganese dioxide in acetone, heating under reflux for 3 hours.

Alternatively, compounds of formula (XIX) can be obtained from commercial compounds of formula (XXVI) according to process step xvii - reduction of nitriles with diisobutylaluminum hydride in

a suitable solvent such as tetrahydrofuran, at low temp. Typical conditions include

a) 1.0 equivalent of compound (XXVI) and 1.0-2.0 equivalent of diisobutylaluminum hydride in tetrahydrofuran, at -78°C for 1 hour,

b) excess hydrochloric acid and water at 0°C.

One of ordinary skill will appreciate that it may be necessary or desirable in any step of the synthesis of a compound of formula (I) to protect one or more sensitive groups in the molecule so as to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect phenolic groups. The protecting groups used to obtain the compounds of formula (I) can be used in a conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis', Theodora W Green and Peter G M Wuts, Third Edition, (John Wiley and Sons, 1999), especially Chapter 2, pages 17-245 ("Protection for the Hydroxyl Group"). Alternatively, protected phenols are commercially available. Removal of these groups can be achieved using conventional methods.

It will also be apparent that compounds of formula (I) can be converted to alternative compounds of formula (I) by standard chemical reactions and transformations. For example, when X (where X is a group as given in the Examples and Preparations) is an ester, compounds of formula (I) can undergo saponification to give carboxylic acid derivatives. When X= aryloxy, compound (I) can be subjected to de-alkylation using boron tribromide or HBr/acetic acid to give the corresponding phenol. Furthermore, when X=OH, the hydroxy alkoxy derivatives can be obtained by reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran followed by deprotection of the primary alcohols, using boron tribromide or para-toluenesulfonic acid.

In the following embodiment of the present invention, there is provided a process for obtaining compounds of formula (I), where the substituents are as defined in claim 1 and the description relating to the processes, which include the steps:

and: cyclocondensation of compounds of formula (II) and compounds of formula (III) to obtain compounds of formula (IV):

and/or

ii: obtaining urea, by reacting the compound of formula (IV) with the compound of formula (V), in the presence of

of a suitable carbonyl source.

In the next embodiment of the invention, a process for obtaining compounds of formula (V) is given, where the substituents are as defined in the description relating to the processes, and includes the following steps:

xi: obtaining an azide, by reacting a compound of formula (XVII) with a suitable base, followed by reaction with a suitable azide, whereby a compound of formula (XVIII) is formed

and/or

xii: reduction of a compound of formula (XVIII) to a compound of formula (V)

In the following embodiment of the invention, new processes are described and provided as herein

described.

In a further embodiment of the invention, there is provided an intermediate compound of formula (IV), (V), (XVII) or (XVIII), wherein the substituents are as described herein.

In another embodiment, a new intermediate compound of the formula as described herein is provided.

A further aspect of the invention is a compound of formula (I) as described herein, or a salt and/or solvate thereof, for use in medicine.

A further aspect of the invention is a compound of formula (I) as described herein, or a salt and/or solvate thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of:

1. asthma of any type, etiology or pathogenesis, especially asthma which is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, external asthma caused by environmental factors, essential asthma of unknown or non-obvious cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, asthma caused (induced) by physical exercise, asthma caused by allergen, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whinging syndrome in children and bronchiolitis,

2. chronic or acute bronchoconstriction, chronic bronchitis, obstruction of small airways, and emphysema,

3. obstructive or inflammatory respiratory diseases of any type, etiology or pathogenesis, especially obstructive or inflammatory lung disease which is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD which includes chronic bronchitis, pulmonary emphysema or dyspnoea associated or not associated with COPD, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyper-reactivity following therapy with other therapies, and airway disease associated with pulmonary hypertension,

4. bronchitis of any type, etiology or pathogenesis, especially bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidonic bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis and vesicular bronchitis,

5. acute lung injury,

6. bronchiectasis of any type, etiology or pathogenesis, especially bronchiectasis which is a selected member of the group consisting of cylindrical bronchiectasis, scular bronchiectasis, spindle-shaped bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

A further aspect of the present invention is the use of a compound of formula (I) as described herein, or a salt and/or solvate thereof, for the manufacture of a medicament for the treatment of the diseases, disorders, or conditions previously provided in paragraphs 1-6.

A further aspect of the present invention is the use of a compound of formula (I) as described herein, or a salt and/or solvate thereof, for the manufacture of a medicament for the treatment of p38-mediated diseases, disorders or conditions and TNF-mediated diseases, disorders or conditions.

A further aspect of the invention is a compound of formula (I) as described herein, or salts and/or solvates thereof, for use in the treatment of p38-mediated diseases, disorders or conditions or TNF-mediated diseases, disorders, or conditions.

The present invention provides a method for treating a mammal, including a human, with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

More specifically, the subject invention provides a method of treating p38-mediated diseases, disorders, or conditions or TNF-mediated diseases, disorders, or conditions in mammals, including humans, and in particular the aforementioned diseases, disorders, or conditions, comprising administering to the mammal an effective amount of a compound of the formula (I), or its salts and/or solvates.

Preferably, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of obstructive or inflammatory lung disease of any type, etiology or pathogenesis, and in particular obstructive or inflammatory airway disease which is a member selected from the group consisting of consist of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or unrelated to COPD, COPD that is characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of hyper- airway reactivity after therapy with another drug and airway disease associated with pulmonary hypertension, or asthma of any type, etiology or pathogenesis, and in particular asthma selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, internal asthma caused by pathophysiological disorders, external asthma caused by environmental factors, essential asthma of unknown or non-obvious cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, induced asthma by physical exercise, asthma caused by allergen, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whinging syndrome in children and bronchiolitis,

Preferably, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of chronic obstructive pulmonary disease (COPD).

Preferably, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of obstructive or inflammatory airway disease of any type, etiology, or pathogenesis, and in particular obstructive or inflammatory airway disease selected from groups consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, pulmonary emphysema or dyspnea associated or unrelated to COPD, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyper-reactivity after therapy with another drug and airway disease associated with pulmonary hypertension, or asthma of any type, etiology or pathogenesis, and especially asthma that belongs to the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma induced by pathophysiological disorders, extrinsic asthma induced by environmental factors, essential asthma of unknown or non-obvious cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, induced asthma ) by physical exercise, asthma caused by allergen, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whinging syndrome in children and bronchiolitis,

Preferably, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD).

As used herein, the term "TNF-mediated disease", or "TNF-mediated disorder" or "TNF-mediated condition" refers to any disease, disorder, or condition (especially any pathological condition), respectively, where TNF plays a role, either by controlling TNF itself, or by TNF inducing the release of another monokine, such as, for example, IL-1, IL-6, and/or IL-8. Therefore, a disease state where, for example, IL-1 is a major component and whose production or action is exacerbated or reduced in response to TNF, would be considered a TNF-mediated disorder.

As used herein, the term "p38-mediated disease", or "p38-mediated disorder" or "p38-mediated condition" refers to any disease, disorder, or condition (especially any pathological condition), respectively, where p38 plays a role, either by control

p38 itself, or that p38 induces the release of another monokine, such as, for example, IL-1, IL-6, and/or IL-8. A disease state where, for example, IL-1 is a major component and its production or action is impaired or is secreted in response to p38, would be considered a p38-mediated disorder.

The compounds of the invention can be used for the treatment of TNF-positive diseases, disorders, or conditions, or p38-mediated diseases, disorders, or conditions, particularly the allergic and non-allergic airway diseases described above, as well as for the treatment of p38- or TNF- mediated states such as:

(a) inflammation;

(b) arthritis, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus arthritis, juvenile arthritis, osteoarthritis, and gouty arthritis;

(c) neuroinflammation;

(d) pain (ie, use of the compound as an analgesic), such as neuropathic pain;

(e) fever (i.e., use of the compound as an antipyretic);

(f) pulmonary sarcosis, and silicosis;

(g) cardiovascular diseases, such as atherosclerosis, myocardial infarction (such as post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, and complications associated with hypertension and/or cardiac arrest such as vascular organ damage ;

(h) cardiomyopathy;

(i) stroke, such as ischemic hemorrhagic stroke;

(j) ischemia, such as cerebral ischemia and ischemia resulting from cardiac/coronary bypass;

(k) reperfusion injury;

(l) renal reperfusion injury;

(m) brain edema;

(n) neurotrauma and brain trauma, such as closed head injury;

(o) neurodegenerative disorders;

(p) disorders of the central nervous system (this includes, for example, disorders with an inflammatory or apoptotic component), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injuries, and peripheral neuropathy;

(q) liver diseases and nephritis;

(r) gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis;

(s) ulcerative diseases, such as peptic ulcer;

(t) ophthalmic diseases, such as retinitis, retinopathies (such as diabetic retinopathy), uveitis, ocular photophobia, nonglaucomatous optic nerve strophy, and age-related macular degeneration (ARMD) (such as ARMD-atrophic form;

(u) ophthalmic conditions, such as corneal graft rejection, ocular neovascularization, retinal neovascularization (such as neovascularization following injury or infection), and retrolental fibroplasia;

(v) glaucoma, such as primary open-angle glaucoma (POAG), juvenile onset primary open-angle glaucoma, angle-closure glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular hypertension, Reiger's syndrome, normal pressure glaucoma, neovascular glaucoma, ocular inflammation, and corticosteroid-induced glaucoma;

(w) acute ocular tissue injury and ocular trauma, such as post-traumatic glaucoma, traumatic optic neuropathy, and central retinal artery occlusion (CRAO);

(x) diabetes;

(y) diabetic nephropathy;

(z) skin-related conditions, such as psoriasis, eczema, burns, dermatitis, keloid formation, scarring, and angiogenic disorders;

(aa) viral and bacterial infections, such as sepsis, septic shock, gram negative sepsis, malaria, meningitis, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex ), pneumonia, rhinovirus infections, and herpes virus;

(bb) myalgias due to infection;

(cc) influence;

(dd) endotoxic shock;

(ee) toxic shock syndrome;

(ff) autoimmune disease, such as graft vs. host and allograft rejection;

(gg) diseases of bone resorption, such as osteoporosis;

(hh) multiple sclerosis;

(ii) disorder of the female reproductive system, such as endometriosis;

(jj) pathological, but non-malignant, conditions, such as hemaginomas (infantile hemaginomas), nasopharyngeal angiofibroma, and avascular bone necrosis;

(kk) benign and malignant tumors/neoplasia including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasia derived from epithelial cells, (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as oral cancer , mouth cancer, esophageal cancer, small intestine cancer, and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell cancer and cancer basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells in the body;

(II) leukemia;

(mm) lymphoma, B cell lymphoma;

(nn) systemic lupus erythematosus (SLE);

(oo) angiogenesis including neoplasia;

(pp) metastases;

(qq) fibrozna bolest;

(rr) hemorrhage;

(ss) coagulation;

(tt) acute phase responses similar to those seen with infections and spes and during shock, (eg, (uu) septic shock, hemodynamic shock, etc.);

(in) anorexia;

(ww) mycobacterial infection;

(xx) pseudorabies (Aujeszky's disease),

(yy) rhinotraheitis,

(zz) HIV,

(aaa) flu virus,

(bbb) herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2),

(ccc) citomegalovirus (CMV),

(ddd) varicella-zoster virus (VZV),

(eee) Epstein-Barr virus,

(fff) human herpesvirus-6 (HHV-6),

(ggg) human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8).

In the next embodiment of the invention, there is provided a compound of formula (I), or its salt and/or solvate, for use in the course of a disease, disorder, or condition, selected from the previously given list (a) to (ggg).

The next embodiment of the invention is the use of the compound of formula (I), or its salt and/or solvate, for the production of a drug for the treatment of diseases, disorders, or conditions selected from the previously given same (a) to (ggg).

A further embodiment of the invention is a method for the treatment of a disease, disorder, or condition selected from the previously given list (a) to (ggg), in a mammal, including a human, and includes administering to a given mammal an effective amount of a compound of formula (I) or its salt and/ or solvates.

The compounds of the invention can also be used to treat p38- or TNF-mediated diseases such as smoking-induced airway inflammation, inflammation-promoted cough, to control myogenesis, to treat mucin overproduction, and/or to treat mucus hypersecretion.

As TNF-ft has similar structural homology to TNF-a (also known as cachectin), and because each induces similar biological responses and binds to the same cellular receptor, the synthesis of TNF-a and TNF-H tends to be inhibited by the compound in question. of the invention so are referred to herein collectively as TNF" unless otherwise indicated.

A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, as given above, can be administered as a medicine according to the invention, to animals, preferably mammals, and especially to humans.

The compound can be administered per se, in a mixture with one or more other compounds of the invention, or in the form of a pharmaceutical preparation, which, as an active component, contains an effective dose of at least one compound of the invention, in addition to the usual pharmaceutical harmless excipients and/or additives.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained, for example, as solid cakes, powders, or films by processes such as deposition, crystallization, freeze drying, spray drying or vapor drying. Microwave or radio frequency can be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). Generally, they are administered as formulations in combination with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipients largely depends on factors such as the route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the distribution of the compounds of the present invention and procedures for their preparation will be apparent to one of ordinary skill in the art. These compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Pronal compounds can be administered orally. Oral administration may involve ingestion, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration are solid formulations such as tablets, capsules containing particles, liquids or powders, lozenges (including those filled with liquid), chewable tablets, multi- and nano-particulates, gels, solid solutions, liposomes, films, ovules, sprays and liquid formulations.

Liquid formulations are suspensions, solutions, syrups and elixirs. These formulations can be used as fillers for soft or hard capsules, and usually contain a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example, from a container.

The compounds of the invention can also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

For the dosage form of tablets, depending on the dose, the drug can make up from 1 wt. % to 80 wt. % dosage form, better than 5 wt. % to 60 wt. % dosage form. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include starch sodium glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, sodium alginate. Generally, the disintegrant contains from 1 wt. % to 25 wt %, preferably 5 wt. % to 20 wt. % dosage form.

Binders are generally used to add cohesive qualities to a tablet formulation. Suitable binders are microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets may optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silica and talc. When present, surfactants can make up from 0.2 wt. % to 5 wt. % tablets, and gliders can make up from 0.2 wt. % to 1 wt. % tablets.

The tablets also contain glidants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally consist of 0.25 wt. % to 10 wt. %, preferably from 0.5 wt. % to 3 wt. % tablets.

Other possible ingredients are antioxidants, colors, aromas, preservatives and taste masking agents.

Primer tablets contain up to about 80% of the drug, from about 10 wt. % to about 90 wt. % binder, of about 0 wt. % to about 85 wt. % diluent, from about 2 wt. % to about 10 wt. % disintegrant, and from about 0.25 wt. % to about 10 wt. % sliding agent.

The mixture for tableting can be directly compressed or rolled into tablets. The tableting mixture or portions of the mixture may alternatively be granulated by wet-, dry-, or melt granulation, melt freezing, or extruded prior to tableting. The final formulation may contain one or more layers and may be coated or uncoated; and it can be encapsulated.

The tablet formulation is described in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Oral films for human consumption or for veterinary use are water-soluble or water-swellable, flexible thin films that may be fast-dissolving or mucoadhesive and typically contain a compound of the invention, a film-forming polymer, a solvent, a humectant, a plasticizer, a stabilizer or an emulsifier, a viscosity modifying agent, and a solvent. Some formulation components may have more than one function.

The compounds of the present invention may be water soluble or insoluble. Water-soluble compounds usually contain from 1 wt. % to 80 wt. %, or from 20 wt. % to 50 wt. %, dissolved substances. Less soluble compounds can comprise a larger part of the composition, usually up to 88 wt. % solute. Alternatively, the pronal compounds may be in the form of multiparticulate granules.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range of 0.01 to 99 wt. %, and better in the range of 30 to 80 wt. %.

Other possible ingredients are antioxidants, colors, flavorings and enhancers, preservatives, saliva stimulating agents, cooling agents, co-solvents (including oils), emollients, fillers, anti-foaming agents, surface active agents (surfactants) and taste masking agents.

Films according to the invention are usually obtained by spray drying thin aqueous films deposited on a smooth substrate or paper. This can be done in a conventional dryer or tunnel dryer, usually a combined liner dryer, or by freeze drying or vacuum drying.

Solid formulations for oral administration can be formulated to be immediate and/or modified release. Modified-release formulations include delayed-, continuous-, pulse-, controlled-, target-, and programmed-release.

Suitable modified formulations for the purposes of the present invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high-energy dispersions and osmotic and coated sixes can be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention can be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable means for parenteral administration are needle (including microneedle) injectors, needleless injectors and infusion techniques.

The compounds of the invention can also be administered topically to the skin or mucosa, such as dermally or transdermally.

The compounds of the invention can also be administered intranasally or by inhalation, typically in dry powder form (either alone, or as a mixture, for example, in a dry mixture with lactose, or as a mixed particulate component, for example, mixed with phospholipids, such as phosphatidylcholine). from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an electrohydronic atomizer to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1 ,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, for example, chitosan or cyclodextrin.

A pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound of the invention such as ethanol, an aqueous ethanol solution, or a suitable alternative agent for dispersing, dissolving, or prolonging the release of the active agent, propellant(s) as a solvent, and a surfactant of choice, such as sorbitan trioleate, oleic acid, or oligolactic acid.

Before use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for distribution by inhalation (typically less than 5 microns). This can be achieved by a suitable pulverization process, such as spiral jet milling, fluidized bed milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made from, for example, gelatin or hydroxypropylmethylcellulose), blister packs and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the pronal compound, a suitable powder base such as lactose or starch, and performance modifiers such as l- leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in monohydrate form, preferably the latter. Other suitable excipients are dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1mg to 20mg of the compound of the invention per actuation, and the actuation volume may vary from 1ml to 100ml. A typical formulation may contain a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol are glycerol and polyethylene glycol.

Suitable flavorings, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to these formulations of the present invention for inhalation/intranasal administration.

Formulations for inhalation/intranasal administration can be formulated to be immediate and/or modified release using, for example, PGLA. Modified-release formulations include delayed-, sustained-, pulse-, controlled-, target-, and programmed-release.

In the case of suvig inhalation powders and aerosols, the dosage unit is determined by a valve that distributes (delivers) a metered dose of colilin. Units according to the invention are typically set up to administer a metered dose or "puff" containing from 0.001 mg to 10 mg of a compound of the invention. The total daily dose will usually range from 0.001 mg to 40 mg which may be administered in a single dose, or, more commonly, as separate doses spread over the day.

In another embodiment of the invention, the compounds of the invention are preferably administered by inhalation. Preferably, the compounds of the invention are administered by inhalation using a dry powder inhaler (pump) or metered dose inhaler, preferably a dry powder inhaler.

The compounds of the invention can be administered rectally or vaginally, for example, in the form of suppositories (suppositories), pessaries, or enemas.

The compounds of the invention may also be administered directly to the eye or ear, typically as drops of a micronized suspension or as a solution in isotonic sterile pH-adjusted saline.

The compounds of the invention can be combined with suitable soluble macromolecular entities (units), such as cyclodextrin and its corresponding derivatives or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the previously mentioned methods of administration.

It has been found that drug-cyclodextrin complexes, for example, can be generally useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent, or solvent. The most commonly used for this purpose are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

In another embodiment of the invention, a pharmaceutical composition is provided which contains a compound of formula (I), or a salt and/or solvate thereof, and a pharmaceutically acceptable diluent, carrier or adjuvant.

In a further aspect of the invention, there is provided a compote, which contains:

a. A compound of formula (I), or a salt and/or solvate thereof

b. instructions for the treatment of obstructive or inflammatory lung disease,

i

c. a package containing a and b.

Preferably, the obstructive or inflammatory lung disease is COPD.

In an alternative embodiment, the instructions in b are for the treatment of asthma.

Since it may be desirable to administer a combination of an active compound, for example, for the treatment of an indicated disease or condition, the present invention contemplates that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, can be combined in the form of a kit which is suitable for co-administration of the composition.

Thus, another aspect of the invention is a kit containing two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention according to the invention and a means for separate storage of the indicated compositions, such as a container, a divided vial, or a divided foil package. An example of such a set is the well-known blister pack, which is used for packing tablets, capsules, etc.

A kit according to the invention may be particularly suitable for administering different dosage forms, for example parenterally, for administering separate compositions at different intervals, or for titrating separate compositions against each other. To comply with the regulation, the kit usually contains instructions for administration and can be in the form of a so-called memory aid.

For administration to human patients, the total dose of a compound of the invention is usually in the range of 0.01 mg to 10 mg depending, of course, on the route of administration. For example, the inhaled dose can be from 0.01 mg to 5 mg. The total daily dose, which can be administered as a single or multiple divided doses, may exceed the limits given here, according to the doctor's instructions.

These doses are based on an average human subject weighing about 65kg to 70kg. The doctor will simply be able to determine the doses for subjects whose weight does not belong to this scope, such as children and the elderly.

According to another embodiment of the present invention, the compounds of the invention can be used in combination with one or more additional therapeutic agents for co-administration to a patient to obtain some particularly desired therapeutic effects and end results such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue breakdown, (v) signs and symptoms such as dyspnea, cough. Other and other additional therapeutic agents may also be a compound of the invention, or one or more TNF inhibitors and/or p38 inhibitors known in the art. More typically, the second and other therapeutic agents will be selected from a different class of therapeutic agents.

As used herein, the terms "co-administration", "co-administered" and "in combination with", refer to the compounds of the invention and one or more other therapeutic agents, have the meaning and refer to the following:

• simultaneous administration of a given combination of compounds of the invention and therapeutic agents to a patient in need thereof, when the given components are formulated together into a single dosage form that releases the given components in essence simultaneously to the given patient,

substantially simultaneous administration of a given combination of a compound of the invention and a therapeutic agent(s) to a patient in need of treatment, wherein the indicated components are separately formulated in separate dosage forms taken by the indicated patient substantially simultaneously to the given patient, wherein the indicated components are released substantially simultaneously at the same time in the patient's body,

• sequential administration of this combination of a compound of the invention and a therapeutic agent(s) to a patient in need of treatment, when these components are formulated separately from each other in separate dosage forms that the patient takes one after the other with a significant time interval between each administration, wherein indicated components released essentially at different times in the patient's body, i

• sequential administration of this combination of the compound of the invention and the therapeutic agent(s) to the patient, when the given components are formulated together in a single dosage form that releases the given components in a controlled manner, whereby they are administered simultaneously, consecutively and/or overlapping at the same time and/ or different times to the patient, where each part can be administered in the same or different ways.

Suitable examples of other therapeutic agents that may be used in combination with the compound(s) of the invention, or pharmaceutically acceptable salts, solvates or compositions thereof, include, but are in no way limited to:

(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,

(b) Leukotriene antagonists (LTRAs) including LTB4, LTC4, LTD4, and LTE4 antagonists,

(c) Histamine receptor antagonists including H1 and H3 antagonists,

(d) a1- and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for use as decongestants,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,

(g) Theophylline,

(h) Sodium cromoglycate,

(i) COX inhibitors, non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),

(j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated corticoid receptor agonists)

(k) Monoclonal antibodies active against endogenous inflammatory entities,

(l) β2 agonists, including long-acting β2 agonists,

(m) adhesion molecule inhibitors including VLA-4 antagonists,

(n) Kinin-B1-i B2-receptor antagoniste,

(o) Immunosuppressive agents,

(p) Matrix metalloprotease inhibitors (MMPs),

(q) Tahikinin NK1, NK2 i NK3 receptor antagonist,

(r) Elastase inhibitors,

(s) Adenosine A2a receptor agonists,

(t) Inhibitore urokinaze,

(u) Compounds that act on dopamine receptors, e.g. D2 agonists,

(v) Modulators of the NFkB pathway, eg IKK inhibitors,

(w) modulators of cytokine signaling pathways such as syk kinases, or JAK kinase inhibitors,

(x) Agents which may be classified as mucolytics or antitussives, i

(y) Antibiotike.

According to the present invention, the combination of the compound of the invention with:

-H3 antagonist,

-Muscarinic M3 receptor antagonists,

- PDE4 inhibitors,

-glucocorticosteroids,

- Adenosine A2a receptor agonists,

-p2 agonistima

- Modulators of cytokine signaling pathways such as syk kinase, or

-Leukotriene antagonists (LTRAs), including antagonists LTB4, LTC4, LTD4, and LTE4, are preferred.

According to the invention, the combination of the compounds of the invention with:

- glucocorticosteroids, especially inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunizolid, triamquinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate and mometasone furoate monohydrate,

-muscarinic M3 receptor antagonists or anticholinergic agents, including especially ipratropium salts, more specifically ipratropium bromide, tiotropium salts, i.e. tiotropium bromide, oxitropium salts, i.e. oxitropium bromide, perenzepine, and telenzepine,

-or β2 agonists, especially long-acting 0.2 agonists, including salmeterol, formoterol, QAB-149 and CHF-4226. are also preferred.

Preferably, the compounds of the invention exhibit slow offset binding kinetics for p38.

In another preferred embodiment, when the compounds are administered by inhalation, they are rapidly metabolized by movement from the lungs.

Even better, pronal compounds are metabolized to compounds that are less active than the administered compound.

In another embodiment of the invention, there is provided a compound, use, method or composition substantially as described herein.

Prove: on TNFa screen

The anti-inflammatory properties of the compounds of the invention are demonstrated by their ability to inhibit the release of TNFα from human peripheral blood mononuclear cells. Venous blood was collected from healthy volunteers and mononuclear cells were purified by centrifugation through Histopaque (Ficoll) adsorbent. The production of TNFa from these cells is stimulated by the addition of lipopolysaccharide. After 18 hours of incubation in the presence of LPS, the cell supernatant was removed and the concentration of TNFa in the supernatant was determined by ELISA. The addition of the compounds of the invention reduces the amount of TNFa produced. An IC50 was determined which is equal to the concentration of compound that gives 50% inhibition of TNFα production as compared to LPS stimulated control wells.

Examples were tested in the assay described above and found to have an IC50 (TNFα screen) of less than 1000nM, and for most compounds tested, were found to have an IC50 (TNFα screen) of less than 100nM.

Examples tested were found to have an IC50 (p38 probe) of less than 1000nM, and for most compounds tested, they were found to have an IC50 (p38 probe) of less than 100nM.

In the present invention, the term "active", "potent, strong" or "strength" means that the compounds of formula (I) exhibit TNF activity that is less than 1000 nM as measured by the TNF assay described herein.

Proba with p38 kinazu:

Cloning of human p38a:

The coding region of human p38a cD NK was obtained by PCR amplification of RNA isolated from the human monocytic THP.1 cell line. The first strand of cDNA was synthesized from total RNA as follows: 2 pg of RNA was hybridized with 100 ng of random hexameric primers (primers) in 10 µl of the reaction mixture by heating to 70° C. for 10 minutes and then keeping it on ice for 2 minutes. cDNA was then synthesized by adding 1 µl RNAsin (Promega, Madison Wis.), 2 µl 50 mM dNTPs, 4 µl 5X buffer, 2 µl 100 mM DTT, and 1 µl (200 U) Superscript IIT AMV reverse transcriptase. Random primers, dNTPs, and Superscript IIT reagents were purchased from Life-Technologies, Gaithersburg, Mass.

The reaction was incubated at 42°C. during 1 hour. Amplification of p38 cDNA was performed by aliquoting 5 µl of reverse transcriptase reaction mixture into 100 µl of PCR reaction mixture containing the following: 80 µl of dH20, 2 µl of 50 mM dNTPs, 1 µl each of left and right (■eng\.forward and reverse) limiter (50 pmol/pl), 10 pl of 10X buffer and 1 pl of ExpandT polymerase (Boehringer Mannheim). PCR primers, purchased from Genosys, incorporated sites for Bam Hl in the 5' and 3' ends of the amplified fragment. The sequences of the left and right primers were 5'-ATCGAGGATTCATGTCTCAGGAGAGGCCCA-3' and 5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3', respectively. PCR amplification was carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles of 1 minute at 94° C., 1 minute at 60° C. and 2 minutes at 68° C. After amplification, excess limiters and unincorporated dNTPs were removed were from the amplified fragment using VVizardT PCR prep (Promega) and treated with Bam H1 (New England Biolabs). Bam HISTONE-treated fragments were ligated using T-4 DNA ligase (New England Biolabs) to pGEX 2T plasmid DNA (PharmaciaBiotech) also treated with BamHI, as described in T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). Chemically competent E. coli DH10B cells, obtained from Life-Technologies, were transformed with the ligation reaction mixture, according to the manufacturer's instructions. Plasmid DNA was isolated from the harvested bacterial colonies using the Promega VVizardT miniprep kit. Plasmids containing the corresponding Bam H1 fragment were sequenced in a DNA Thermal Cycler (Perkin Elmer) with PrismT (Applied Biosystems Ine.). cDNA clones encoding both isoforms of human p38a have been identified (Lee et al. Nature 372, 739). one of the clones that contained the cDNA for p38a-2 (CSB-2), inserted into the PGEX 2T cloning site, 31 of the GST coding region was designated pMON 35802. The sequence obtained for this clone completely matched the cDNA clone published by Lee et al. dr.. This expression plasmid enables the production of the fused protein GST-p38a.

Expression in humane p38a

Plasmid pMON 35802 expresses the GST/p38a fusion protein in E. coli strain DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grown overnight in Luria Broth (LB) containing 100 mg/ml ampicillin. The next day, 500 ml of fresh LB was inoculated with 10 ml of the overnight culture, and continued in a 2-liter dish at 37° C. with constant shaking until the literature reached an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by the addition of isopropyl b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. Cultures were shaken for three hours at room temperature, cells were collected by centrifugation. Cell pellets were stored frozen until protein purification.

Purification of P38 Kinase-alpha

All chemicals were obtained from Sigma Chemical Co. unless otherwise indicated. Twenty grams of E. coli cell pellets were collected from five fermentations in 1 L vessels resuspended in PBS (140 mM NaCl, 2.7 mM KCl, 10 mM Na.sub.2 HPO.sub.4, 1.8 mM KH.sub. 2 PO.sub.4, pH 7.3) to 200 ml. The cell suspension was adjusted to 5 mM DTT by addition of 2 M DTT and then divided equally into five 50 ml conical Falcon tubes. Cells were nicked (Ultrasonics model W375) with a 1 cm probe 3 times, 1 minute (pulsing) on ice. Lysed cell material was removed by centrifugation (12,000 x g, 15 minutes) and the clear supernatant was applied to glutathione-sepharose resin (Pharmacia).

Glutathione-Sepharoza Afinitna hromatografiia

Twelve ml of 50% glutathione sepharose-PBS suspension was added to 200 ml of clear supernatant and incubated for 30 minutes at room temperature. The resin was collected by centrifugation (600 times g, 5 min) and washed 2 times with 150 ml of PBS/1% Triton X-100, and then 4 times with 40 ml of PBS. To cleave p38 kinase from the GST-p38 fusion protein, glutathione-sepharose resin was resuspended in 6 ml of PBS containing 250 units of thrombin protease (Pharmacia, specific activity >7500 units/mg) and mixed gently for 4 hours at room temperature. Glutathione-sepharose resin was removed by centrifugation (600 times.g, 5 min) and washed 2 times with 6 ml of PBS each. PBS wash fractions and digesta supernatant containing p38 kinase protein were collected and adjusted to 0.3 mM PMSF.

Mono Q Anion izmenjivaćka hromatografiia

Thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. The thrombin-cleaved sample was diluted 2-fold with Buffer A (25 mM

HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchange column equilibrated with Buffer A. The column was eluted with 160 ml of 0.1 M-0.6 M NaCI/Buffer A gradient (flow rate: 2 ml/minute). The p38 kinase peak eluted with 200 mM NaCl was collected and concentrated to 3-4 ml using a Filtron 10 concentrator (Filtron Corp.).

Sefakril S100 Gel Filtraciona hromatografiia

A concentrated sample of Mono Q~p38 kinase was purified by gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacril S100 column equilibrated with buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol)). The protein was eluted from the column using Buffer B at a flow rate of 0.5 ml/minute and the protein was detected by measuring the absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were collected and frozen at -80° C. A typical yield of purified E. coli protein from 5 L fermentation vessels is 35 mg of p38 kinase.

Kinetic tests Association kinetics:

SKF-86002 (from Calbiochem; KD -200nM) gives an increase in fluorescence after binding to p38a (followed by excitation at 340nm and emission at 420nm). SKF-86002 (1-2jaM) was preincubated with p38a (20-60nM) for 5-10min at room temperature in a buffer consisting of 20mM Bis-Tris, 2mM EDTA, 500mM NaCl, 0.01% NaN3, 0.15% NOG and 5 % DMSO. A sample compound (20-100nM) was then added and the change in fluorescence was monitored. As SKF dissociates from the p38a binding site, SKF is replaced with a sample compound and a decrease in fluorescence is observed on a time scale proportional to the rate of compound association. Using the known binding kinetics of SKF-86002, the association rate of the compound was measured.

Dissociation kinetics:

A sample of compound (50 or 100nM) was preincubated with p38a (37nM protein or 21nM as determined by active site titration) overnight at room temperature in a buffer consisting of 20mM Bis-Tris, 2mM EDTA, 0.01% NaN3, 0.15% NOG, 500mM NaCl and 5% DMSO. The following day, SKF 86002 was added to a final concentration of 50 µM. An increase in fluorescence after binding of SKF 86002 to p38a was observed, which was followed by excitation at 340 nm and emission at 420 nm, and the rate of dissociation was measured.

Results and:

The following results were obtained using the TNF screen described here.

Primeri i dobiiania

Nuclear magnetic resonance (NMR) data were obtained on Varian Unity lnova-400, Varian Unity lnova-300 or Bruker AC300 spectrometers and are expressed in parts per million relative to tetramethylsilane. Mass spectral (MS) data were obtained on a Finnigan Mat. TSQ 7000 or Fisons Instruments Trio 1000. The listed calculated and observed ions refer to the isotopic compositions of the lowest mass. For silica gel column chromatography, Kieselgel 60, 230-400 mesh, from E. Merck, Darmstadt, was used, unless otherwise indicated. Kieselgel 60 F254 plates from E. Merck were used for TLC, and compounds were visualized using UV light, 5% aqueous potassium permanganate, or Dragendorff's reagent (sprayed with aqueous sodium nitrite). The water content was determined on a Mitsubishi CA100 (Coulometric Karl Fisher Titrator). Other measurements were made using standard equipment. PdCI2(dppf).CH2CI2 is a 1,1-bis(diphenylphosphino)ferrocene palladium(II) chloride 1:1 dichloromethane complex. DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene.

Killing 1

methyl ester 2.2-Dimetil-3-metilsulfanil-propionic acid

N,N-Diisopropylethylamine (15.5g, 0.12mol) was added to a solution of methyl 2,2-dimethyl-3-hydroxypropionate (13.2g, 0.1mol) in dichloromethane (150mL) and the solution was cooled to 0°C. Then methane sulfonyl chloride (12.6g, 0.11mol) was added dropwise and the mixture was stirred at 0°C for 90 minutes. The reaction mixture was then diluted with 0.5M hydrochloric acid (100mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2x50mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Methanethiol sodium salt (7.7g, 0.11moi) was added to a solution of the residue in dioxane (100L) and the mixture heated under reflux for 24 hours. The mixture was then diluted with ethyl acetate (250 mL), washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on a silica gel column, eluting with a mixture of dichlorometapentane 50:50 to 100:0, gave the desired compound as a pale yellow oil in a yield of 24%, 3.85g.

Killing 2

4.4-Pimetil-5-methylsulfanyl-3-oxo-pentanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 1.20g, 30mmol) in tetrahydrofuran (20mL) was brought to reflux. A solution of the product from Preparation 1 (3.84g, 23.7mmol) in acetonitrile (1.56mL, 30mmol) was added and the mixture was heated at reflux for 3 hours. The cooled reaction mixture was then diluted with water, added 2M hydrochloric acid (30mL) and extracted with dichloromethane (3x50mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane to give the title compound as a pale yellow oil in 67% yield, 2.70g.

Killing 3

4-Methyl-4-methylsulfanyl-3-oxo-pentanenitrile

The desired compound was obtained from ethyl 2-methyl-2-(methylthio)propionate and acetonitrile, according to a procedure similar to that for obtaining 2, as a colorless oil in a yield of 81%.

Killing 4

(3-Methylsulfanyl-phenyl)-hydrazine

Magnesium filings (0.79g, 33mmol) and one crystal of iodine were added to a solution of 3-bromothioanilazole (6.11g, 30mmol) in tetrahydrofuran (50mL) and the mixture was stirred at room temperature for 18 hours. The mixture was cooled to -78°C and di-tert-butyldiazocarboxylate (6.91 g, 30 mmol) was added. The mixture was stirred at -78°C for 30 minutes and then 1 M citric acid (40 mL) was added. The reaction mixture was allowed to warm to room temperature and then extracted with ethyl acetate (250 mL). The organic solution was washed with brine and water, dried over magnesium sulfate and concentrated in vacuo. The residue was redissolved in isopropyl alcohol (200 mL) and the solution was saturated with hydrogen chloride gas. The mixture was then allowed to cool to room temperature and concentrated in vacuo. Water was added to the residue, its basicity was increased with an additional saturated solution of sodium hydrogen carbonate and extracted with a mixture of dichlorometammethanol, 90:10, (4x50mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography, eluting with dichlorometammethanol, 100:0 to 70:30, to give the desired compound as a dark orange liquid, in 36% yield.

Killing 5

di-tert-Butyl 1-(4-methoxy-3-methylphenyl)hydrazine-1,2-dicarboxylate

"Butyllithium (2.5M in hexane, 23.9mL, 59.75mmol) was added to a solution of 4-bromo-2-methylanisole (10g, 49.74mmol) in tetrahydrofuran (150ml_) cooled to -78°C, the mixture was stirred at this temperature for 1 hour. Di-tert-butyldiazocarboxylate (13.74g, 59.68mmol) in tetrahydrofuran (50ml_) was then added dropwise and the mixture was stirred at -78°C for one hour and then for 2 hours at room temperature. The reaction was diluted with water (25ml_ ), concentrated in vacuo to a small volume, and diethyl ether (300 mL_) and brine (300 mL) were added. The aqueous layer was separated and re-extracted with diethyl ether (2x100 mL), the combined organic solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with heptane:ethyl acetate, 75:25, the desired compound was obtained as a pale yellow solid in a yield of 62%, 10.93g.

Killing 6

14-Methoxy-3-methylphenyl)hydrazine hydrochloride

4M Hydrochloric acid in 1,4-dioxane (37.5 mL, 150 mmol) was added dropwise to a solution of the product from the preparation of 5 (10.75 g, 30.50 mmol) in 1,4-dioxane (12.5 mL) and the mixture was stirred for 48 hours at room temperature. temperature. The mixture was then concentrated in vacuo and the residue was stirred in diethyl ether at 0°C for 30 minutes. The precipitate was filtered, washed with diethyl ether, the solid residue was dried in vacuum at 40°C for 6 hours, giving the desired compound in a yield of 94%, 5.43g.

Killing 7

3-tert-Butyl-1-r4-(methylthio)phenyl1-1H-pyrazol-5-amine

Concentrated hydrochloric acid (1ml) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2g, 10.5mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44g, 11.5mmol) in ethanol (30ml) and the mixture was heated with reflux 18 hours. The cooled mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a mixture of dichlorometammethanol, 100:0 to 97:3 to give the title compound as a yellow oil which crystallized on standing (2.59g, 95% yield).

Refutations 8 to 19

The following compounds, the general formulas of which are presented in the following text, were obtained according to a procedure similar to that for the preparation of 7, starting from the corresponding hydrazines and nitriles as starting materials. Reactions were monitored by tlc analysis and heated under reflux for 3-24 hours.

Yields 14-19 : Purification was performed by chromatography on a silica gel column, eluting with dichlorometamethyl acetate, 80:20.

Killing 20

5-tert-Butyl-2-phenyl-2H-pyrazol-3-ylamine

N,N-Diisopropylethylamine (1.7mL, 7.99mmol) was added to a mixture of phenylhydrazine hydrochloride (1.5g, 10.39mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0g, 7.99mmol) in ethanol (15mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to a small volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with heptamethyl acetate, 75:25, to give the title compound as a pale orange oil which crystallized on standing (1.21 g, 70% yield).

Rebuttals 21 to 24

The following compounds, the general formulas given in the following text, were obtained according to procedures similar to those described for the preparation of 20, starting from the corresponding hydrazine and nitrile as starting materials. Reactions were monitored by tlc analysis and heated under reflux for 3-24 hours.

Killing 25

(5-Bromo-pyridin-2-yl)-hydrazine

2-Chloro-5-bromopyridine (64g, 333mmol) was suspended in hydrazine monohydrate (250mL) and the mixture was heated for 72 hours at 70°C. the reaction mixture was then diluted

Killing 26

4-Chloro-3-hydroxymethyl-phenol

Lithium aluminum hydride (1 M in diethyl ether, 25 mL, 25 mmol) was added to an ice-cooled solution of 2-chloro-5-hydroxy-benzoic acid (4 g, 23.2 mmol) in tetrahydrofuran (200 mL) and the mixture was heated at reflux for 6 h. The mixture was then diluted with a water/tetrahydrofuran mixture, 1 M hydrochloric acid was added, and extracted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated in vacuo to give the title compound in quantitative yield, 4.3g.

Killing 27

2-Chloro-5-hydroxy-benzaldehyde

Manganese dioxide (11 g, 125 mmol) was added to a suspension of the product from the preparation of 26 (4 g, 25.2 mmol) in acetone (25 mL) and the mixture was heated to reflux for 3 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane:methanol, 95:5, passed through a pad of silica and concentrated in vacuo to give the desired compound as a solid residue in 81% yield, 3.17g

Killing 28

2-Chloro-4-hydroxy-benzaldehyde

Piisobutylaluminum hydride (1 M in hexane, 240 mL, 240 mmol) was added to a solution of 2-chloro-4-hydroxybenzonitrile (15 g, 97.7 mmol) in tetrahydrofuran (200 mL), cooled to -78 °C, and the mixture was stirred at room temperature for 1 h. at room temperature for 18 hours. The mixture was then cooled to 0°C and 1 M hydrochloric acid (80 mL) was added dropwise. The reaction mixture was diluted with water (200 mL) and filtered, thoroughly washed with ethyl acetate (x2). The filtrate layers were separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with dichloromethane gave the desired compound in the form of a solid substance in a yield of 84%, 12.92g.

Killing 29

N'-(5-bromo-pyridin-2-in-hydrazide isobutyric acid).

N,N-Piisopropylethylamine (137g, 1.06mol) was added to a suspension of preparation 25 (40g, 213mmol) in dichloromethane (100ml) and the solution was cooled to 0°C. Isobutyryl chloride (22.7g, 213mmol) was then added dropwise and the mixture was stirred for 2 hours at 0°C. Reactionary

Killing 30

2-(Benzyloxy)benzaldehyde (5-bromopyridin-2-yl)hydrazone

A mixture of 2-benzyloxybenzaldehyde and the product from the preparation of 25 (10g, 53.2mmol) in ethanol (350mL) was heated for 15 minutes at 80°C. The resulting precipitate was filtered, washed thoroughly with ethanol, and dried in vacuo for 18 hours to give the desired compound as a white solid in 94% yield.

Killing 31

6-Bromo-3-isopropyl-M,2,4'ltriazolof4,3-a1pyridine

A suspension of the product from the preparation of 29 (16g, 62mmol) in phosphorus oxychloride (320ml_) was heated for 18 hours at 75°C. the reaction mixture was concentrated in vacuo and the residue was dissolved in water, its basicity was increased by the addition of 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solutions were dried over sodium sulfate and concentrated in vacuo. Trituration of the residue in ethyl acetate/methanol, 98:2, gave the desired compound in a yield of 75%, 11.23g.

Killing 32

3-(6-Bromo-[1,2,41triazolof4,3-a1pyridin-3-in-4-chloro-phenol

A mixture of the products from the preparation of 27 (3.1 g, 19.7 mmol) and 25 (3.7 g, 19.7 mmol) in ethanol (75 mL) was heated under reflux for 1 hour. The mixture was then cooled to room temperature, diluted with ethanol (75 mL) and iodobenzene diacetate (6.30 g, 19.7 mmol) was added. the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, triturated with a mixture of ethyl acetate and methanol and filtered. The residue was further purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane:methanol, 90:10, giving the desired compound in a yield of 15%, 0.95g

Killing 33

4-(6-Bromo-n.2.41triazolor4,3-a1pyridin-3-i0-3-chloro-phenol

The desired compound was obtained from the product from the preparation of 28 and 25, according to a procedure similar to that described for the preparation of 32, as a solid in a yield of 78%.

Killing 34

3-f2-(Benziloksi)fenin-6-bromon.2,41triazolo[4.3-alpiridin

The desired compound was obtained from the product from preparation 30, according to a procedure similar to that for obtaining 33. The desired compound was further purified by chromatography on a silica gel column, eluting with ethyl acetate:dichloromethane, 50:50, and then triturating with diethyl ether/ethyl acetate to give the desired compound as a solid substance in a yield of 88%.

Killing 35

f2-(3-lzopropil-n.2.41triazolo[4,3-a1piridin-6-ilsulfanilHenill-metanol)

2-Mercaptobenzyl alcohol (12.8g, 91 mmol) was added to a mixture of the product from the preparation of 31 (19.8g, 70mmol), cesium carbonate (31.9g, 98mmol) and the adduct 1,1'-bis(diphenylphosphino)ferrocendichloropalladium(l!) of dichloromethane (5.7g, 7.0mmol) in N,N-dimethylformamide (175ml) and the reaction mixture was heated at 90°C for 21 hours. The mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic solution was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate:methanol, 98:2, and triethylamine (one drop per 100 mL of organic solution), to give the title compound as a brown solid. in a yield of 33%, 7 years.

Killing 36

4-Chloro-3-(6-ff2-hydroxymethyl)phenyl1thio)H,2,41triazolof4,3-alpyridin-3-yl)phenol

The desired compound was obtained from the product of the preparation of 32 and 2-mercaptobenzyl alcohol, according to a procedure similar to that described for the preparation of 35, as a pale brown solid in a yield of 62%.

Killing 37

3-Chlor-4-(6-((2-(hydroxymethyl)pheninthio)) f1 2..triazolof4.3-a1pyridin-3-yl)phenol

The desired compound was obtained from the product of the preparation of 33 and 2-mercaptobenzyl alcohol, according to a procedure similar to that described for the preparation of 35, as a pale brown foam in a yield of 41%.

Killing 38

f2-(f3-f2-(Benzyloxy)phenyl1[1.2.4ltriazolof4.3-a1pyridin-6-yl)thio)pheninmethanol The desired compound was obtained from the product of the preparation of 34 and 2-mercaptobenzyl alcohol, according to a procedure similar to that described for the preparation of 35 , as a brown firm riser in the yield of 57.

Killing 39

6-(2-Azidomethyl-phenylsulfanyl)-3-isopropyl-[1,2,41triazolof4,3-a1pyridine

1,8-Diazabicyclo[5.4.0]undec-7-ene (6.4g, 42.1mmol) was added to a cold suspension of the product from the preparation of 35 (10.5g, 35.1mmol) and diphenylphosphoryl azide (11.6g, 42.1mmol) in toluene (60mL) and the mixture was stirred at 0°C for 3 hours at room temperature for 18 hours. Dilute sodium hydrogen carbonate solution was then added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium of sulfate and concentrated in vacuo Purification by chromatography on a silica gel column, eluting with ethyl acetate:methanol, 98:2, and triethylamine (one drop per 100 ml of organic solution), gave the desired compound as a brown oil in a yield of 79%, 9g.

Killing 40

3- (6-{f2-(Azidometil)fenintio)f1.2.41triazolof4.3-alpiridin-3-il)-4-hlorfenil difenil fosfat

The desired compound was obtained from the product from the preparation of 36, according to a procedure similar to that described for the preparation of 39, in a yield of 84%.

Killing 41

4- (6-{r2-(Azidometi0fenintio)f1.2.41triazolor4.3-ajpiridin-3-i0-3-hlorfenol

The title compound was obtained from the product of the preparation of 37, following a procedure similar to that described for the preparation of 39, as a pale brown foam better in 58% yield.

Killing 42

6-fr2-(azidometil)fenintio)-3-f2-(benziloksi)feninf1.2,41triazolo[4.3-alpiridin

The desired compound was obtained from the product of the preparation of 38, following a procedure similar to that described for the preparation of 39, as a liquid in 45% yield.

Killing 43

{2-r(3-lzopropilH,2.41triazolof4.3-atpiridin-6-i0tio1benzil)amin hidrohlorid

Triphenylphosphine (10.6g, 40.3mmol) and water (0.73mL, 40.3mmol) were added to a solution of the product from preparation 39 (10.8g, 33.6mmol) in tetrahydrofuran (114mL) and the mixture was stirred at room temperature for 40 hours, then heated to 40°C for 5 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane and cooled in an ice bath. 1 M hydrochloric acid in diethyl ether (35 mL) was added dropwise and the mixture was stirred for 18 hours at room temperature. The precipitate was filtered and dried over phosphorus pentoxide to give the title compound as a gray solid in 65% yield, 7.24g.

Killing 44

3- (6-(f2-(Aminometil)fenil'ltioiri.2.41triazolof4.3-a1piridin-3-il)-4-hlorfenol hydrochlorid

The title compound was obtained from the product from the preparation of 40, following a procedure similar to that described for the preparation of 43. The crude product was redissolved in methanol and saturated with 1 M hydrochloric acid in diethyl ether to give the desired product in quantitative yield.

Killing 45

4- (6-{f2-(Aminometinfenil1tio)f1.2,41triazolof4,3-a1piridin-3-il)-3-hlorfenol hydrochlorid

The desired compound was obtained from the product of the preparation of 41, following a procedure similar to that described for the preparation of 43. The crude product was redissolved in methanol and saturated with a 1 M solution of hydrochloric acid in diethyl ether to give the desired product in 60% yield.

Killing 46

r2-((3-f2-(Benzyloxypheninf1.2,4ltriazolof4.3-a1pyridin-6-ylHio)benzamine hydrochloride The title compound was obtained from the product of preparation 42, according to a procedure similar to that described for the preparation of 43. The crude product was redissolved in methanol and saturated with 1 M hydrochloric acid in diethyl ether to give the desired product as a white solid in 78% yield.

Killing 47

4.4-Pimetil-3-oxohexan-nitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 3.18g, 79.4mmol) in tetrahydrofuran (60mL) was heated at 60°C for 1 hour. The reaction mixture was then cooled to room temperature, acetonitrile (4.2 mL, 79.4 mmol) and 2,2-dimethyl-butyric acid ethyl ester [(7.95 g, 61 mmol), J. Am. Chem. Soc., 1942, 64, 2964] in tetrahydrofuran (100 mL) and the mixture was stirred for 4 hours at 25°C. The mixture was then diluted with 1 M hydrochloric acid (100 mL) and the aqueous layer was separated and extracted with ethyl acetate. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was triturated with heptane to give the desired compound as a pale brown solid in a yield of 27%, 2.3g.

Killing 48

1-(Benzyloxy)-3-bromo-5-methylbenzene

A mixture of 3-bromo-5-methylphenol [(40.7g, 218mmol) J. Amer. Chem. Soc., 2003, 125, 7792)], benzyl bromide (28.6ml_, 239mmol) and potassium carbonate (90.2g, 653mmol) in acetone (1L) was heated under reflux for 2 hours. The cooled reaction mixture was acidified by the addition of 2M hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic solution was washed with brine (x3), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a red oil in quantitative yield.

Killing 49

Benzyl 5-(benzyloxy)-2-chlorobenzoate

The desired compound was obtained from 2-chloro-5-hydroxybenzoic acid (US2002/0037905 p15), according to the procedure described for the preparation of 48, as an oil in quantitative yield.

Killing 50

4-fBenziloks0-2-hlorbenzonitril

Potassium carbonate (66.3g, 480mmol) was added to a mixture of 2-chloro-4-hydroxybenzonitrile (25g, 160mmol) and benzyl bromide (19.3ml_, 161mmol) in acetonitrile (300ml_) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. Trituration of the residue with heptane gave the desired compound as a whitish solid in a yield of 99%, 38.65g.

Killing 51

4-(BenzyloxQ-2-chlorobenzaldehyde

The desired compound was obtained from the product from the preparation of 50, according to the procedure described for the preparation of 28, in a yield of 97%.

Killing 52

4-Bromo-1 -ethyl-2-methoxybenzene

Methyl iodide (3ml_, 47.3mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25g, 43mmol) and potassium carbonate (6.54g, 47.3mmol) in acetone (20mL) and the mixture was stirred at room temperature for 18 hours. . The reaction mixture was concentrated in vacuo to a small volume and diluted with water. The aqueous mixture was extracted with dichloromethane (3x50mL) and the combined organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10 mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140 mmol) were added and the reaction mixture was heated for 60 hours at 150°C. 1 M hydrochloric acid was then added to the reaction mixture and extracted with ethyl acetate (3x20mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified

Kugel Rohr fractional distillation (150°C/0.05mbar) affording the desired compound as a yellow oil (128mg).

Killing 53

N-(3-Chloro-4-methoxyphenyl-N'-(2.2-dimethylpropanoin--2.2-dimethylpropanohydrazide) The desired compound was obtained from 4-bromo-2-chloro-1-methoxy-benzene (J. Org. Chem.

1982, 47, 5270) and di-tert-butyldiazocarboxylate, according to a procedure similar to that described for obtaining 5, as a white powder in a yield of 43%.

Killing 54

di-tert-Butyl 1 -f3-(benzyloxy)-5-methylphenyl1hydrazine-1,2-dicarboxylate

The desired compound was obtained from the product from the preparation of 48 and di-tert-butyldiazocarboxylate,

according to the procedure described for the preparation of 5, as a yellow liquid in 84% yield.

Killing 55

di-terc-butyl 1-(3-ethyl-4-methoxyphenyl)hydrazine-1.2-dicarboxylate

The desired compound was obtained from 4-bromo-2-ethyl-1-methoxy-benzene and di-tert-butyldiazocarboxylate, according to the procedure described for the preparation of 53, as a solid in a yield of 53%.

Killing 56

di-terc-Butyl 1-(4-ethyl-3-methoxypheninehydrazine-1,2-dicarboxylate

The desired compound was obtained from the product from the preparation of 52 and di-tert-butyldiazocarboxylate, according to the procedure described for the preparation of 53, as a pale yellow oil in 40% yield.

Killing 57

(3-Chloro-4-methoxyphenyl)hydrazine hydrochloride

The desired compound was obtained from the product from the preparation of 53, according to the procedure described for the preparation of 6, as a whitish powder in a yield of 93%.

Killing 58

f3-(Benzyloxy)-5-methylpheninhydrazine hydrochloride

The desired compound was obtained from the product from the preparation of 54, according to the procedure described for the preparation of 6, as a solid substance in a yield of 59%.

Killing 59

(3-Ethyl-4-methoxyphenyl)hydrazine hydrochloride

The desired compound was obtained from the product from the preparation of 55, according to the procedure described for the preparation of 6, as a solid in quantitative yield.

Killing 60

(4-Ethyl-3-methoxyphenhydrazine hydrochloride

The desired compound was obtained from the product from the preparation of 56, according to the procedure described for the preparation of 6, as an off-white solid in 85% yield.

Rebuttals 61 to 86, 88 and 89

The following compounds, the general formulas given below, were obtained according to a procedure similar to that described for the preparation of 7, using commercially available hydrazine and commercially available nitrile as starting materials. When starting materials are not commercially available, syntheses are given in the text. Reactions were monitored by tlc analysis and heated under reflux for 3-24 hours.

Ref. 83: was obtained from the product from the preparation of 3 and (3-ethylphenyl)-hydrazine hydrochloride (EP 177242, p31).

Ref. 84: The crude product was purified by silica gel column chromatography, eluting with pentamethyl acetate, 100:0 to 60:40.

Ref. 86: The crude product was purified by silica gel column chromatography, eluting with hexamethyl acetate, 91:9 to 83:17.

Killing 87

('4-Chloro-3-methoxyphenyl)hydrazine

Concentrated hydrochloric acid (12mL) and a solution of sodium nitrite (1.7g, 24.4mmol) in water (8mL) were added to a solution of 4-chloro-3-methoxyaniline (3.86g, 24.4mmol) in water (8mL), at -10° C. The mixture was stirred for 30 minutes and then added to a solution of stannous chloride (14.89g, 66mmol) in concentrated hydrochloric acid (24mL) and water (24mL), cooled to 0°C. the reaction mixture was stirred for 18 hours, allowing the temperature to rise to 25°C. The resulting precipitate was filtered and the solid residue was re-crystallized from heptane/ethyl acetate (33:66) to give the target compound as a white solid in 72% yield, 3g

Killing 90

3-tert-Butyl-1-pyridin-3-yl-1H-pyrazol-5-amine

The desired compound was obtained from 4,4-dimethyl-3-oxopentane nitrile and 3-pyridinohydrazide (US2002/0143176, p22), according to the same procedure described for obtaining 7, as an orange oil in a yield of 50%.

Killing 91

3-tert-Butyl-1-pyridin-2-yl-1H-pyrazol-5-amine

The desired compound was obtained from 4,4-dimethyl-3-oxopentane nitrile and 2-hydrazinopyridine, according to the procedure described for obtaining 7, as a solid substance in a yield of 99%.

Killing 92

1-f4-(benzyloxyphenin-3-ri-methyl-1-(methylthio)ethin-1H-pyrazol-5-amine

Concentrated hydrochloric acid (2mL) was added dropwise to a suspension of [4-(benzyloxy)phenylhydrazine hydrochloride (3.19g, 12.74mmol) and product 3 (2g, 12.74mmol) in ethanol (50mL) and the mixture was heated under reflux 2 an hour. Then water (5ml_) was added and the reaction mixture was heated under reflux for another 16 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The compound was purified by silica gel column chromatography, eluting with dichloromethane:ethyl acetate, 100:0 to 85:15, to give the desired compound as an orange oil that crystallized on standing, (2.79g, 62% yield).

Preoarations 93 do 97

The following compounds, the general formulas given below, were obtained according to a procedure similar to that described for the preparation of 20, using commercially available hydrazine and commercially available nitrile as starting materials. When starting materials are not commercially available, syntheses are given in the text. The reactions were monitored by tlc analysis and were heated under relux for 3-24 hours.

Refutation 93: The crude compound was triturated with heptane:diethyl ether 66:33.

Killing 98

f4-(5-Amino-3-tert-butyl-1H-pyrazol-1-iopheninmethanol

Lithium aluminum hydride (1M in tetrahydrofuran, 1.83mL, 1.83mmol) was added to an ice-cold solution of 4-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-benzoic acid methyl ester [(0.25g, 0.92mmol), WO2004060306, p134] in tetrahydrofuran (5mL), and the mixture was stirred at 0°C for 1 hour. The reaction mixture was then diluted with water (0.35ml_) and 1M sodium hydroxide solution (0.35mL) was added followed by more water (1mL). The mixture was then extracted with diethyl ether (10 mL) and the organic solution was dried over sodium sulfate and concentrated in vacuo to give the title compound as a red oil, 98% yield, 220.1 mg.

Killing 99

3-tert-Butyl-1-r4-({tert-butyl(dimethylsilyloxy)methylphenin-1H-pyrazol-5-amine

A mixture of the product from preparation 98 (0.5g, 2.04mmol), tert-butyldimethylsilyl chloride (0.34g, 2.25mmol) and imidazole (0.18g, 2.55mmol) in N,N-dimethylformamide (2ml_) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with methanol (1ml) and stirred for 15 minutes at room temperature. The mixture was further diluted with sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (3x15 mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with heptamethyl acetate, 85:15, 75:25, to give the title compound as a colorless solid in 30% yield,

220.5mg.

Killing 100

3-tert-Butyl-1-(3-(tert-butyl(dimethylsilinoxy)-4-methylphenyl-1H-pyrazol-5-arnine)

The desired compound was obtained from 5-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-2-methyl-phenol hydrochloride (WO 03/005999, p81-p82) and tert- butyldimethylsilyl chloride, according to the procedure described for obtaining 99, as a solid substance in a yield of 86%.

Killing 101

3- (5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenol

Boron tribromide (1M in dichloromethane, 12ml_, 12mmol) was added dropwise to an ice-cold solution of the product from preparation 63 (1.28g, 4mmol) in dichloromethane (50mL) and the mixture was stirred for 30 minutes, allowing the temperature to rise to 25°C. . The reaction mixture was then diluted with methanol (20 mL) and water, its basicity was increased by the addition of 0.88 ammonia and extracted with dichloromethane (3x50 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:ethyl acetate, 100:0 to 80:20, to give the title compound as a pale yellow foam in 89% yield. , 825 mg.

Killing 102

4- (5-Amino-3-H-metil-1-(metiltiofetill-1H-piazol-1-il)fenol

The desired compound was obtained from the product from the preparation of 76, following a procedure similar to that described for the preparation of 101, as a white solid in 40% yield.

Killing 103

N-f 1 -f4-(Benzyloxy)phenyl1-3-tert-butyl-1H-pyrazol-5-yl)benzamide

The desired compound was obtained from the product of 244 and phenyl chloroformate, according to the procedure described for the preparation of 116, as a brown oil in quantitative yield.

Killing 104

1-(4-tert-Bulyl(dimethylsilinoxy)phenin-3-F1-methyl-1-fmethylthio)ethyn-1H-pyrazol-5-amine

The desired compound was obtained from the product of the preparation of 102 and tert-butyldimethylsilyl chloride, according to the procedure described for the preparation of 99, as a yellow oil in a yield of 48%.

Killing 105

1-(3-{tert-Butyl(dimethinsilinoxy)phenyl)-3-f1-methyl-1-(methylthio)ethyn-1H-pyrazol-5-amine

The desired compound was obtained from the product of the preparation of 110 and tert-butyldimethylsilyl chloride, according to the procedure described to obtain 99, as a red oil in a yield of 49%.

Killing 106

3-tert-Butyl-1-(3-frtert-butyl(dimethylPsilinoxy}phenyl)-1H-pyrazol-5-amine

The desired compound was obtained from the product of the preparation of 101 and tert-butyldimethylsilyl chloride according to the procedure described for the preparation of 99, as a colorless oil, in a yield of 34%.

Killing 107

3-(5-Amino-3-H.1-dimethyl-2-(methylthio)ethyl-1H-pyrazol-1-yl)phenol

The desired compound was obtained from the product of Preparation 72, according to the procedure described for Preparation 101, as a yellow solid in 18% yield.

Killing 108

3-f5-Amino-3-(1,1-dimethylpropyl)-1H-pyrazol-1-Nlphenol

A solution of boron tribromide (1.7mL, 17.9mmol) in dichloromethane (20mL) was added dropwise to an ice-cold solution of the product from Preparation 70 (1.20g, 3.6mmol) in dichloromethane (15mL) and the mixture was stirred for 90 minutes, allowing the temperature to rise. up to 25°C. Then, dimethylamine (40% in water, 5 mL) was added dropwise and the mixture was stirred for 1 hour at room temperature. The aqueous layer was separated, extracted with ethyl acetate and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with heptane:ethyl acetate, 100:0 to 50:50, gave the desired compound as a yellow foam in a yield of 49%, 390mg.

Killing 109

2- (6-([2-(Aminomethi0phenyl1thio)f1.2.41triazolor4.3-alpyridin-3-yl)phenol

The product from preparation 46 (3.43g, 7.22mmol) was suspended in hydrobromic acid (5.7M in glacial acetic acid, 7mL, 40mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether (150 mL), stirred at room temperature for 15 minutes and then filtered. The residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution and the resulting precipitate was filtered and redissolved in dichloromethane:methanol, (90:10, 400mL). The aqueous layer of the filtrate was separated and extracted three times with dichloromethane:methanol, (90:10). The extracts were combined with a solution of the residue which had been dissolved, dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with diethyl ether gave the desired compound as a solid residue in a yield of 96%, 2.40g.

Killing 110

3-(5-Amino-3-f1-metil-1-(metilthio)ethyl1-1H-pyrazol-1-iDphenol

The desired compound was obtained from the product from the preparation of 87, according to the procedure described for the preparation of 109, as a white foam in a yield of 44%.

Killing 111

3-tert-Butyl-1-{3-f2-(tetrahydro-2H-pyran-2-yloxy)ethoxy1phenyl}-1H-pyrazol-5-amine

A mixture of the product from the preparation of 101 (750mg, 3.25mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.02g, 4.88mmol) and potassium carbonate (690mg, 5mmol) in N,N-dimethylformamide (10mL) was stirred at 60°C, 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water (x2) and brine. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichlorometamethyl acetate, 100:0 to 85:15, to give the desired compound as a yellow oil in 71% yield.

Killing 112

3-f1-Methyl-1-(methylthio)ethyn-1-(3-f2-(tetrahydro-2H-pyran-2-yloxy)ethoxy1phenyl>-1H-pyrazol-5-

in

The desired compound was obtained from the product of the preparation of 110 and 2-(2-bromoethoxy)tetrahydro2H-pyran, according to the procedure described for the preparation of 111, as an orange oil in a yield of 94%.

Killing 113

3-f1.1-Pimetil-2-(metiltio1etilH3-f2-(tetrahidro-2H-piran-2-iloks0etoksi1fenil)-1H-pirazol-5-

in

The desired compound was obtained from the product of the preparation of 107 and 2-(2-bromoethoxy)tetrahydro-2H-pyran, according to the procedure described for the preparation of 111, as a yellow oil in a yield of 71%.

Killing 114

3-(1.1-Pimethypropyl)-1-(3-r2-(tetrahydro-2H-pyran-2-yloxy)ethoxy1phenyl)-1H-pyrazol-5-amine The desired compound was obtained from the product from the preparation of 108 and 2-(2 -bromoethoxy)tetrahydro-2H-pyran, according to the procedure described for obtaining 111, as a yellow oil in a yield of 71%.

Killing 115

3-f1-Methyl-1-(methylthio)ethin-1-f4-|2-(tetrahydro-2H-pyran-2-yloxyethoxy1phenyl>-1H-pyrazol-5-

in

The desired compound was obtained from the product of the preparation of 102 and 2-(2-bromoethoxy)tetrahydro-2H-pyran, according to the procedure described for the preparation of 111, as a yellow oil in a yield of 82%.

Killing 116

Phenyl (3-tert-butyl-1-f3-r2-(tetrahydro-2H-pyran-2-yloxy)ethoxyphenyl)-1H-pyrazol-5-iocarbamate

Phenylchloroformate (1.94g, 12.4mmol) was added to an ice-cold solution of the product from the preparation of 111 (4.05g, 11.3mmol) and pyridine (1.09mL, 13.5mmol) in tetrahydrofuran (50mL), the mixture was stirred for 5 minutes at 0°C and at room temperature, 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, 5% citric acid and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo to give the desired compound as a yellow oil in 86% yield, 5.22g.

Killing 117

Fenil (3-f1-metil-1-(metiltiotetin-1-(3-f2-(tetrahidro-2H-piran-2-iloks0etoksi1fenil)-1H-pirazol-5-iOkarbamat)

The desired compound was obtained from the product of the preparation of 112 and phenylchloroformate, according to the procedure described for the preparation of 116, as an orange oil in quantitative yield.

Killing 118

Phenyl f1-f3-(benzyloxyphenin-3-tert-butyl-1H-pyrazol-5-yl)carbamate

The desired compound was obtained from the product from the preparation of 63 and phenylchloroformate, according to the procedure described for the preparation of 116, as a brown solid in a yield of 94%.

Killing 119

Phenyl r3-tert-butyl-1-(3-fftert-butyl(dimethinsilinoxy)phenin-1H-pyrazol-5-yl1carbamate

The desired compound was obtained from the product of the preparation of 106 and phenylchloroformate, according to the procedure described for the preparation of 116, as a clear oil in quantitative yield.

Killing 120

Phenyl 1-(3-tert-butyl(dimethyl)silyloxy)phenyl-3-11-methyl-1-(methylthio)ethyl 1-1H-pyrazole-5-dicarbamate

The desired compound was obtained from the product of the preparation of 105 and phenylchloroformate, following a procedure similar to that described for the preparation of 116, as a red oil in quantitative yield.

Killing 121

N-r2-({3-2-(benzyloxy)phenylH.2,41triazolof4,3-alpyridin-6-yl)thio)benzyl1-N'-r3-tert-butyl-1-(4-

fluorofenil)-1H-pirazol-5-inurea

The product from preparation 61 (117mg, 0.50mmol) was added to a solution of N,N'-carbonyldiimidazole (405mg, 2.50mmol) in dichloromethane (20mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and extracted with dichloromethane (3x20mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The product from preparation 46 (142mg, 0.30mmol) was added to a solution of the residue and N-ethyldiisopropylamine (129mg, 1mmol) in dichloromethane (10mL) and the mixture was stirred for 45 minutes at room temperature. The reaction mixture was then diluted with ethyl acetate, washed with 0.5M hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate and methanol, 100:0 to 90:10, giving the desired compound as a glassy substance in a yield of 90%, 189mg.

Killing 122

N-f2-({3-2-(benziloksi)fenilf1,2.4'|triazolof4.3-a1Piridin-6-il)tio)benzin-N'-(3-terc-butil-1-f3-f2-

(Tetrahydro2H-pyran-2-yloxy)ethoxy1phenyl)-1H-pyrazol-5-yl)urea

The product from preparation 111 (180mg, 0.50mmol) was added to a solution of N,N'-carbonyldiimidazole (405mg, 2.50mmol) in dichloromethane (20mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with water and extracted with dichloromethane (3x20mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The product from preparation 46 (167mg, 0.35mmol) was added to a solution of the residue and N-ethyldiisopropylamine (0.17mL, 1mmol) in dichloromethane (10mL) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N citric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate.methanol, 95:5, giving the desired compound in a yield of 95%, 273 mg.

Rebuttals 123 to 166

The following compounds, general formulas given below, were obtained by a procedure similar to that described for the preparation of 121, starting from the appropriate amine, N,N'-carbonyldiimidazole and the appropriate aminopyrazole as starting materials, which are available by the syntheses described here or are commercially available. Reactions were monitored by tlc analysis and stirred at room temperature for 20-72 hours.

Refs 124, 132 and 133: The crude compounds were purified by silica gel column chromatography, eluting with dichloromethane:7M methanolic ammonia, 100:0 to 97.5:2.5. This was followed by further purification by reverse phase chromatography on a C18 silica gel column, eluting with water/7M methanolic ammonia (98:2):acetonitrile/7M methanolic ammonia (98:2), 75:25 to 25:75.

Ref 134: The crude compound was purified by silica gel column chromatography, eluting with dichloromethane: 7M methanolic ammonia/dichloromethane (10:90), 100:0 to 50:50. This is followed by further purification by trituration with dichloromethane:methanol:diethyl ether.

Rebuttal 160: prepared from the products of recovery 17 and 206

Refutation 163: Prepared from the products of Preparations 104 and 214

Refutations 165 and 166: were prepared from the corresponding aminopyrazoles and products from

obtaining 208. The crude compounds were purified by chromatography on a silica gel column,

eluting with hexamethyl acetate, 90:10, and then with pentamethyl acetate, 80:20 to 20:80,

and then ethyl acetatemethanol, 100:0 to 50:50.

Killing 167

N-f2-(f3-2-(benziloksi)fenilf1.2,41triazolof4.3-a1piridin-6-il)tio)benzin-N’-(3-terc-butil-1-

pyridin-3-yl-1H-pyrazol-5-iourea

The desired compound was obtained from the products from the preparation of 46 and 90, according to the procedure described for the preparation of 121, in a yield of 15%.

Killing 168

SN-lž-fO-Ž-benzyloxyjphenylfl.Ž^ltriazoloK.S-alpyridin-e-iDthiojbenzyl-N'-O-tert-butyl-l-

pyridin-2-yl-1H-pyrazol-5-yl)urea

The desired compound was obtained from the product from the preparation of 46 and 91, according to the procedure described for the preparation of 121, in a yield of 63%.

Killing 169

N-f2-((3-2-benziloks0fenilf1.2,41triazolof4.3-a1piridin-6-il)tio)benzin-N’-(3-f1.1-dimetil-2-

(Methylthio)ethyl-1-(3-f2-(tetrahydro-2H-pyran-2-yloxy)ethoxy1phenyl)-1H-pyrazol-5-ylurea

Pyridine (64mL, 0.8mmol) and phenylchloroformate (110mg, 0.70mmol) were sequentially added to an ice-cold solution of product 113 (250mg, 0.62mmol) in tetrahydrofuran (10mL) and the mixture was stirred at 0°C for 10 minutes and room temperature, 40 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (5mL), the product from preparation 46 (332mg, 0.70mmol) and N,N-ethyldiisopropylamine (0.17mL, 1mmol) were added and the mixture was stirred at 50°C for 90 minutes. The reaction mixture was cooled to room temperature, diluted with water and washed with 0.1 M citric acid, saturated sodium hydrogen carbonate solution. The organic solution was dried over dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow foam in quantitative yield, 614mg.

Killing 170

N-f2-({3-2-benziloks0fenilH,2.4ltriazolof4.3-a1piridin-6-il)tio)benzifl-N’-(3-(1.1-dimetilpropiQ-

1-f2-(tetrahydro2H-pyran-2-ilox0ethoxy]fenil)-1H-pyrazol-5-i0urea

The desired compound was obtained from the product of the preparation of 114 and 46, according to the procedure described for the preparation of 169. The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:ethyl acetate, 100:0 to 30:70, to give the desired product as a white foam in a yield of 59%.

Killing 171

N-(1-f3-(BenziloksQfenil1-3-tert-butyl-1H-pyrazol-5-yl}-N'-(2~ff3-(2-

metilfeninf1.2,41triazolo[4.3-alpiridin-6-in ItiolbenziOurea

The desired compound was obtained from the product from the preparation of 63 and 206, according to the procedure described for the preparation of 169. The crude compound was purified by column chromatography on a 12g ISCO silica cartridge, eluting with ethyl acetate, giving the desired product in 43% yield.

Killing 172

N-(2Tf3-(2-Hydroxyphenyl)f1,2,41triazolof4,3-apyridin-6-yl1thio)benzyl)-N'-f3-[1-methyl-1-

(methylthio)ethini-(4-metilphenin-1H-pyrazol-5-inurea).

The desired compound was obtained from the product from the preparation of 85 and 109, according to the procedure described for the preparation of 169. The crude compound was purified by column chromatography

silica gel, eluting with dichloromethane, 95:5, giving the desired product in 33% yield.

Killing 173

N-(2-f(3-lzopropiiri,2.4ltriazolo[4.3-a1pyridin-6-yl)thio1benzyl}-N'-(3-f1-methyl-1-(methylthio)ethyl1-1-

(3-r2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy1phenylHH-pyrazol-5-yl)urea

A mixture of the product from Example 26 (89mg, 0.15mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (36mg, 0.17mmol) and potassium carbonate (28mg, 0.2mmol) in N,N-dimethylformamide (2mL) was mixed at room temperature for 18 hours and heated for 12 hours at 60°C. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was then dried over magnesium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography, eluting with dichlorometammethanol:0.88 ammonia, 100:0:0 to 94:6:1, to give the desired glassy compound in 67% yield. .

Killing 174

N-f1-f3-(Benziloksi)fenin-3-terc-butil-1H-pirazol-5-il)-N’-{2-f(3-f2-f2-(tetrahidro-2H-piran-2-

yloxy)ethoxy]phenyl)(1,2,4-triazolof4,3-a1pyridin-6-yl)thiolbenzyl)urea

The desired compound was obtained from the product of the preparation of 123 and 2-(2-bromoethoxy)tetrahydro-2H-pyran, according to the procedure described for the preparation of 111, as a white foam in a yield of 75%.

Killing 175

N-f3-tert-Butyl-1-f4-f2-(tetrahydro-2H-pyran-2-yloxyethoxy1phenyl)-1H-pyrazol-5-yl)-N'-(2-ff3-(2-chlorophenin .2, 41 triazolor4,3-a1pyridin-6-intio}benzyl)urea

The desired compound was obtained from the product of the preparation of 257 and 2-(2-bromoethoxy)tetrahydro-2H-pyran, according to the procedure described for the preparation of 111, as a pale yellow foam in a yield of 45%.

Killing 176

f5-(Benzyloxy)-2-chloropheninmethanol

The desired compound was obtained from the product from the preparation of 49, according to the procedure described for the preparation of 26. The crude compound was triturated with diethyl ether to give the desired product as a white solid in 91% yield.

Killing 177

5-(Benzyloxy)-2-chlorobenzaldehyde

The desired compound was obtained from the product of preparation 176, according to a similar procedure

to that described for the preparation of 27. The crude compound was recrystallized from isopropyl ether to give

the desired product as a solid substance in a yield of 67%.

Rebuttals 178 to 183

The following compounds, the general formulas given below, were obtained according to a procedure similar to that described for the preparation of 30, starting from the preparation 25 of the corresponding commercially available aldehyde. To obtain 182, the starting material 4-benzyloxy-2-chlorobenzaldehyde was prepared as described in J. Chem. Soc. Perkin Trans 1990, (2), 253.

Killing 184

6-Bromo-3-(2-etilfenil)n.2.4'ltriazolof4,3-alpiridin

(Piacetoxyiodo)benzene (6.95g, 22mmol) was added to a solution of the product from the preparation of 178 (5.46g, 18mmol) in dichloromethane (200mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with ethyl acetate:dichloromethane, 50:50, to give the title compound as a solid in quantitative yield.

Killing 185

6-Bromo-3-(2-hlorfenil)f1.2,41triazolof4,3-a1piridin

The title compound was obtained from the product from the preparation of 181, following the procedure described for the preparation of 184. The crude compound was further purified by trituration with ethyl acetate to give the desired product in 73% yield.

Killing 186

6-Bromo-3-r2-(metiltio)feninf1.2.41triazolof4.3.-a1piridin

(Diacetoxyiodo)benzene (500mg, 1.55mmol) was added to an ice-cooled solution of the product from the preparation of 180 (500mg, 1.55mmol) and the mixture was stirred for 6 hours, allowing the temperature to rise to 25°C. More (diacetoxyiodo)benzene (500mg, 1.55mmol) was added and stirring was continued for 18 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with ethyl acetate to give the title compound as a white solid in 68% yield.

Killing 187

6-Bromo-3-(2-methylphenyl)f1.2.4ltriazolo[4.3-alpyridine

Ammonium cerium nitrate (35g, 63.76mmol) was added to a solution of the product from the preparation of 179 (9.25g, 31.88mmol) in ethanol (190mL) and dichloromethane (60ml) and the mixture was stirred for 72 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic solution was separated, washed with water (4x100mL), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with pentane:ethyl acetate, 75:25, and then dichloromethaneethanol, 50:50, gave the desired compound in a yield of 21%, 1.94g.

Killing 188

6-Bromo-3-(2-fluorofeninf1.2.41triazolor4.3-a1piridin

The desired compound was obtained from 2-fluorobenzaldehyde and the product from the preparation of 25, according to the procedure described for the preparation of 32, as a white powder in a yield of 54%.

Killing 189

6-Bromo-3-f2-metoksifenil)H.2,41triazolof4.3-a]piridin

A mixture of 2-methoxybenzaldehyde (10g, 73.4mmol) and the product from the preparation of 25 (13.8g, 73.4mmol) in dichloromethane (10mL) and ethanol (100ml) was heated at 65°C for 5 minutes. The mixture was then cooled to room temperature and filtered. The residue was redissolved in dichloromethane (50mL) and ethanol (50mL), iodobenzene diacetate (23.66g, 73.4mmol) was added and the reaction mixture was stirred at room temperature for 90 minutes. The mixture was concentrated in vacuo and the residue was triturated three times with diethyl ether to give the title compound as a white solid in 64% yield, 14.2g.

Killing 190

6-Bromo-3-(2-chloro-3-methoxyphenyl)f1,2,41triazolor4,3-alpyridine

A mixture of 2-chloro-3-methoxybenzaldehyde [(10g, 58.6mmol), WO 2005/007165, p47] and the product from the preparation of 25 (11.13g, 58.6mmol) in ethanol (70mL) was heated at 70°C for 2.5 hours. Iodobenzene diacetate (24.5g, 76mmol) was added and the reaction mixture was diluted with ethanol (40mL) and stirred at room temperature for 18 hours. The precipitate was filtered, washed thoroughly with ethanol and dried in vacuo to give the desired compound as a solid precipitate in 64% yield, 12.70g

Killing 191

3-F5-(Benzyloxy)-2-chlorophenin-6-bromoft,2.4]triazolof4.3-a]pyridine

The desired compound was obtained from the product from the preparation of 177, following a procedure similar to that described for the preparation of 190, as a solid in 60% yield.

Killing 192

3-[4-(Benzyloxy)-2-chlorophenin-6-bromof1,2,41triazolof4,3-alpyridine

A mixture of the product from the preparation of 182 (53.4g, 128mmol!) and iodobenzene diacetate (41.3g, 128mmol) in dichloromethane (50mL) and ethyl acetate (50mL) was stirred at room temperature for 18 hours. The pale yellow precipitate was filtered off, yielding the first portion of the desired compound. The filtrate was then treated with dichloromethane (5QmL) and diethyl ether (100ml_) and the resulting yellow precipitate was filtered to give a new amount of the desired compound, the total yield of the desired compound was 37.1g (70%).

Killing 193

3-f2-(Benziloksi)-2-hlorfenill-6-bromof1.2.4ltriazolo[4.3-a1piridin

A suspension of the product from the preparation of 183 (6.2g, 14.8mmol) in dichloromethane (300mL) and ethanol (100mL) was heated to 40°C. Iodobenzene diacetate (6.39g, 19.24mmol) was added and the mixture was stirred at 40°C for 10 minutes and then allowed to cool to room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (400 mL), washed with 5% sodium bisulfite solution (300 mL) and water (300 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was then triturated with diethyl ether to give the desired compound as a white solid in a yield of 92%, 5.7g.

Rebuttals 194 to 203

The following compounds, the general formulas given below, were prepared according to a procedure similar to that described for the preparation of 35, starting from the appropriate starting materials and 2-mercaptobenzyl alcohol.

Refutation 195: The crude compound was purified by silica gel column chromatography, eluting with ethyl acetate-dichloromethane, 50:50, then dichloromethane:methanol, 95:5. Refutation 196: The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:ethyl acetate, 40:60 to 0:100.

Refutation of 197, 198 and 202: The crude compounds were triturated with diethyl ether

Killing 204

(2-ff3-(2-Ethylpheninf1.2,41triazolo[4.3-alpiridin-6-yl1benzinamin hydrochloride

Methanesulfonic acid anhydride (5g, 29mmol) was added to the solution of the product obtained from 194 (3.5g, 9.7mmol) and N,N-ethyldiisopropylamine (6.8ml, 38.8mmol)

dichloromethane (100 mL) and the mixture was stirred at room temperature for 90 minutes. A solution of 7M methanolic ammonia (140 mL) was added and the mixture was stirred at sonboy temperature for 72 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (200mL) and washed with sodium hydrogen carbonate solution (2x200mL) and 2M hydrochloric acid (4x50mL). Fractions from the washes were combined, 2M sodium hydroxide solution was added to pH8 and extracted with dichloromethane (3x100mL).

The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue redissolved in dichloromethane. The resulting solution was cooled in an ice bath and hydrogen chloride gas was blown through until saturation. The reaction mixture was then concentrated in vacuo and the residue azeotroped with diethyl ether, then dichloromethane to give the title compound as an orange foam in 43% yield, 1.66g.

Killing 205

55 (2-{r3-(2-ChloropheniDH.2,41triazolof4,3-alpyridin-6-inthio)benzinamine hydrochloride

Methanesulfonic anhydride (4.99g, 28.66mmol) was added to an ice-cooled solution of the product from the preparation of 199 (5.27g, 14.33mmol) and N,N-ethyldiisopropylamine (7.4mL, 42.99mmol) in dichloromethane (150mL) and the mixture was stirred for 10 minutes. stirred at 0°C and at room temperature, 4 hours. A solution of 7M Methanolic ammonia (143mL) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (150 mL) and washed with sodium hydrogen carbonate solution (150 mL) and 2M hydrochloric acid (3x70 mL). Fractions from the washes were combined, 2M sodium hydroxide solution (250mL) was added and extracted with dichloromethane (4x125mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, to give an orange foam. This foam was then dissolved in dichloromethane (15mL) and acidified with hydrochloric acid (4M in dioxane, 3.1mL). The mixture was azeotroped with methanol and dichloromethane, and the residue was triturated with diethyl ether to give the title compound as a white solid in 48% yield, 2.82g

Killing 206

(2-ff3-f2-metilfenil)f1,2,4ltriazolo[4,3-a]piridin-6-intio}benzil)amin

Methanesulfonic acid anhydride (2.7g, 15.49mmol) was added to a solution of product 195 (1.8g, 5.18mmol) and N,N-ethyldiisopropylamine (3.6mL, 20.72mmol) in dichloromethane (50mL) and the mixture was stirred at room temperature. 1 hour. A 7M methanolic solution of ammonia (140 mL) was added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then washed with sodium hydrogen carbonate solution, brine and 2M hydrochloric acid (3x100mL). Fractions from the washes were combined, the basicity was increased by the addition of 2M sodium hydroxide to pH8 and extracted with dichloromethane (5x150mL). The combined organic solution was dried over sodium sulfate and concentrated in vacuo to give the title compound as an orange gum in 55% yield, 982mg.

Killing 207

[2-(f3-r2-(Methylthio)pheninf1,2,41triazolof4,3-a|pyridin-6-yl}thiojbenzinamin

The desired compound was obtained from the product of the preparation of 196, according to the procedure described for the preparation of 206, as a pale orange foam in a yield of 49%.

Killing 208

l2-(f3-f2-(Benziloksi)-5-hlorfeninn.2.41triazolof4.3-a|piridin-6-ilftio)benzinamin

The desired compound was obtained from the product from the preparation of 203, according to the procedure described for the preparation of 206. The crude compound was purified by chromatography on a silica gel column, eluting with dichloromethane:methanol:0.88 ammonia, 97:3:0.2 to 95:5:0.5, giving the desired compound as a pale brown gum in 52% yield.

Killing 209

6-(r2-(Azidometi0phenylthio}-3-(2-fluorophenyl)ri.2.41triazolof4.3-a|pyridine

The desired compound was obtained from the product from the preparation of 197 and diphenylphosphoryl azide, according to the procedure described for the preparation of 39, in a yield of 95%.

Killing 210

6-fr2-(Azidometil)fenintio)-3-(2-metoksifeni0f1.2.41triazolor4.3-alpiridin

The desired compound was obtained from the product of the preparation of 198 and diphenylphosphoryl azide, according to a procedure similar to that described for the preparation of 39, in a yield of 86%.

Killing 211

6-{r2-(azidomethyl)pheninthio}-3-(2-chloro-3-methoxypheni0f1.2.41triazolof4.3-a1pyridine

The title compound was obtained from the product of the preparation of 200 and diphenylphosphoryl azide, following a procedure similar to that described for the preparation of 39. The crude compound was triturated with dichloromethane/diethyl ether to give the desired product in 59% yield.

Killing 212

6-ff2-(Azidometi0pheninthio}-3-f4-(benzyloxy)-2-chloropheninf1.2.41triazolof4,3-alpyridine

Killing 213

64f2-(Azidometi0pheninthio}-3-r5-(benzyloxyV2-chlorophenylin.2.41triazolof4,3-alpyridine)

The desired compound was obtained from the product of the preparation of 202 and diphenylphosphoryl azide, following a procedure similar to that described for the preparation of 39, in quantitative yield.

Killing 214

(2-ff3-(2-Fluorophenyl)f1,2,41triazolof4,3-ajpyridin-6-ylthio)benzyl)amine hydrochloride

Triphenylphosphine (8.53g, 32.5mmol) and water (0.58mL, 32.5mmol) were added to a solution of 209 (10.2g, 27.1mmol) in tetrahydrofuran (100mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (200mL). Hydrochloric acid (4M in dioxane, 8mL) was added dropwise and the mixture was stirred for 72 hours at room temperature. The precipitate was filtered and triturated with dichloromethane to give the desired compound as a solid in a yield of 35%, 3.7g.

Killing 215

f2ff3-(2-Methoxyphenyl)f1,2,41triazolof4,3-a1pyridin-6-yl1thio)benzi0amine hydrochloride

The desired compound was obtained from the product from the preparation of 210, according to the procedure described for the preparation of 214, as a solid in a yield of 52%.

Killing 216

(2ff3-(2-Chloro-methoxyphenyl)[1,2.4ltriazolof4.3-alpyridin-6-yl1thio)benzi0amine hydrochloride

The desired compound was obtained from the product from the preparation of 211, according to the procedure described for the preparation of 214, as a solid in a yield of 72%.

Killing 217

f2(f3-f4-(benzyloxy0-2-chloropheninf1,2,41triazolof4,3-a1pyridin-6-yl)thio1benzyl1amine hydrochloride The title compound was obtained from the product from the preparation of 212, following a procedure similar to that described for the preparation of 214, as a solid in yield of 64%.

Killing 218

f2-({3-f5-(Benziloksiy-2-hlorfeninf1.2.41triazolo[4.3-ajpiridin-6-il)tio)benzinamin

Killing 219

N-(3-tert-Butyl-1-{3-f2-(tetrahydro-2H-pyran-2-iloksi)etoksnfenil}-1H-pyrazol-5-iiy-N'-(2-(f3-(2- fluorofeniPH .2.41 triazolof4.3-a1pyridin-6-il1tio)benzinurea

A mixture of product 214 (360mg, 0.93mmol), product 116 (446mg, 0.93mmol!) and N,N-ethyldiisopropylamine (0.39mL, 2.23mmol) in dimethylsulfoxide (4mL) was stirred at room temperature for 72 hours and 60°C, 1 hour. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (50ml) and washed with 0.5M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane, 99:1 to 93:7, to give the title compound as a light brown oil in 33% yield, 223mg.

Killing 220

N-(3-tert-Butyl-1-(3-F2-(tetrahydro-2H-pyran-2-yloxy0ethoxflphenyl)-1H-pyrazol-5-yl)-N'-(2-(f3-(2-chlorophenylM). .2,41 triazolor4,3-a]pyridin-6-ylTthio)benzi0urea

The desired compound was obtained from the products from the preparation of 205 and 116, according to a procedure similar to that described for the preparation of 219, as a white foam in a yield of 45%.

Killing 221

N-(3-tert-butyl-1~f3-f2-(tetrahydro-2H-pyran-2-yloxyethoxyphenylphenirHH-pyrazol-5-iP-N'-(2~ff3-(2 isopropylphenyl)ri.2.41triazolo[4.3 -alpyridin-6-illtio>beninurea

The desired compound was obtained from the product from the preparation of 237 and 116, according to the procedure described for the preparation of 219, as a white foam and in a yield of 37%.

Killing 222

N-(3-tert-Butyl-1-13-r2-(tetrahydro-2H-pyran-2-yloxy1ethoxyphenyl)-1H-pyrazol-5-ylV-N'-(2-fr3-(2-methoxyphenyl) H.2.41 triazolor4.3-alpyridin-6-inthio}benzinurea

The desired compound was obtained from the product from the preparation of 215 and 116, according to the procedure described for the preparation of 219, as a white foam in a yield of 46%.

Killing 223

N-f1-r3-(Benzyloxyl)phenyl-3-tert-butyl-1H-pyrazol-5-yl)-N'-(2-ff3-(2-chlorophenin-f1.2.41triazolof4,3-a1pyridin-6- il1 thiolbenzihurea

Killing 224

N-11-f3-(Benzyloxyl)phenyl-3-tert-butyl-1H-pyrazol-5-yl)-N'-[2-tf3-2-

(benzyloxyphenylH,2,41triazolo4,3-a1pyridine6-thio)benzyl)urea

The desired compound was obtained from the product from the preparation of 118 and 46, according to the procedure described for the preparation of 219, as a yellow solid in a yield of 58%.

Killing 225

N-(1-(3-(fter-Butyl(dimethyl)silinoxyl)fenil)-3-n-metil-1-(metilthio)ethin-1H-pyrazol-5-yl)-N'-(2-r( 3-isopropyl M.2.41triazolof4.3-a1pyridin-6-dithio1benzyl)urea

The desired compound was obtained from the product from the preparation of 120 and 43, according to the procedure described for the preparation of 219, as a white foam in a yield of 69%.

Killing 226

N-(1-f3-(fter-Butyl(dimethyl)silinoxyl}pheniO-3-f1-methyl-1-(methylthio)ethin-1H-pyrazol-5-yl}-N'-(2-

([3-(2-fluorophenil)H.2.41triazolof4.3-a1piridin-6-illtio1benzil)urea

The desired compound was obtained from the product from the preparation of 120 and 214, according to the procedure described for the preparation of 219, as a whitish foam in a yield of 48%.

Killing 227

N-{1-(3-{tert-Butyl(dimethylsilyloxyl}phenyl)-3-H -methyl-1-(methylthio)ethyl-1H-pyrazol-5-yl}-N'-(2-([3-( 2-Methoxyphenyl(1.2.41triazolof4.3-a1pyridin-6-yl1thio)benzyl)urea The desired compound was obtained from the product from the preparation of 120 and 215, according to the procedure described for the preparation of 219, as a white foam in a yield of 53%.

Killing 228

N-(1-f3-(Benzyloxyl)phenin-3-f1-methyl-1-(methylthio)ethin-1H-pyrazol-5-yl}-N'-(2-(f3-(2-ethylpheniOH ,2.41triazol f4,3-a1pyridin-6-inthio)benzyl)urea

The desired compound was obtained from the product of the preparation of 204 and the preparation of 17, according to the procedure described for the preparation of 121, and in a yield of 41%.

Killing 229

N-(1-f3-(Benziloksiljfenill-3-terc-butil-1H-pirazol-5-il)-N'-f2-((3-f2-

(metiltio)feninf1,2,41triazolof4.3-ajpiridin6-ilHio)benzinurea

Killing 230

N-(1-4-(Benzyloxy)phenin-3-f1-methyl-1-(methylthio)ethyl-1H-pyrazol-5-yl)-N,-(2-{f3-(2-methylpheniOH .2, 41triazolo[4,3-alpyridin-6-inthio]benzyl)urea

The desired compound was obtained from the product from the preparation of 92 and 206, according to the procedure described for the preparation of 121, in a yield of 19%.

Killing 231

N-f2-((3-f4TBenziloksi)-2-hlorfeninf1.2.4ltriazolof4.3-alpiridin-6-il}benzin-N’-f3-terc-butil-1-

(3.4-difluoropheniQ-1H-pirazol-5-il1urea

The desired compound was obtained from the product from the preparation of 95 and 217 according to the procedure described for the preparation of 121, as a brown powder in a yield of 59%.

Killing 232

N-f2-({3-f5-(Benziloksi)-2-hlorfenillf1.2.4ltriazolof4.3-alDiridin-6-il}tio)benzill-N’-f3-terc-butil-

1-(3.4-difluorofeni0-1H-pirazol-5-inurea

The desired compound was obtained from the product from the preparation of 218 and 95, according to the procedure described for the preparation of 121, as a white powder in a yield of 40%.

Killing 234

6-Bromo-3-(2-isopropylphenyl)f1.2,41triazolor4,3-a1pyridine

The desired compound was obtained from the product of the preparation of 25 and 2-isopropylbenzaldehyde, according to the procedure described for the preparation of 189. The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 95:5, to give the desired product as a yellow liquid in a yield of 35%.

Killing 235

f3-(2-lisopropylphenyl)f1,2.41triazolof4,3-alpyridin-6-ylmethanol

The desired compound was obtained from the product of the preparation of 234 and 2-mercaptobenzyl alcohol, according to the procedure described for the preparation of 35. The crude compound was purified by chromatography on a silica gel column, eluting with dichloromethane methanol 95:5, giving the desired product as a dark brown oil in a yield of 45 %.

Killing 236

6-fr2-(Azidometi)phenylthio>-3-(2-isopropylpheni0f1,2,41triazolof4,3-alpyridine

Killing 237

(2-{f3-(2-lisopropylphenyl)1,2,41tria2olor4.3-alpyridin-6-inthio)benzi0amine hydrochloride

The desired compound was obtained from the product from the preparation of 236, according to the procedure described for the preparation of 214, as a white solid in a yield of 805.

Killing 238

N-(2-if3-(2-Fluorophenyl-2,41triazolo4,3-a1pyridin-6-thio)enzi0-N'-(3-H-methyl-1-(methylthioethyl)-1 {3-[2-(tetrahydro- 2H-pyran-2-yloxyethoxy)phenyl-1H-pyrazol-5-yl)urea

A mixture of the product from the preparation of 117 (399mg, 0.78mmol), the product from the preparation of 214 (307mg, 0.78mmol) and N,N-ethyldiisopropylamine (0.30mL, 1.70mmol) in dimethylsulfoxide (2mL) was stirred for 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate (50ml) and washed with 0.5M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethanemethanol, 100:0 to 95:5, to give the title compound as a white foam in 40% yield, 266mg.

Killing 239

N-(2-ff3-(2-Methoxyphenyl)f1,2,41triazolof4,3-alpyridin-6-ylthio)benzi0-N'-(3-H-methyl-1-(methylthio)ethyl1-1f3-f2-(tetrahydro -2H-pyran-2-yloxyethoxyphenyl)-1H-pyrazol-5-iourea The desired compound was obtained from the product from the preparation of 117 and 215, according to the procedure described for the preparation of 238, as a white foam in a yield of 45%.

Killing 240

1-f3-(Benzyloxy)phenin-3-(1,1-dimethylpropyl-1H-pyrazol-5-amine)

The desired compound was obtained from the product of the preparation of 47 and 3-benzyloxyphenylhydrazine hydrochloride, according to the procedure described for the preparation of 7. The crude compound was triturated with diethyl ether to give the desired product as a pink solid in 91% yield.

Killing 241

3-f5-Amino-3-( 1,1 -dimetilproqil)-1 H-pirazol-1 -illfenol

The desired compound was obtained from the product from the preparation of 240, according to the procedure described for example 99, as a yellow foam in a yield of 49%.

Killing 242

1-(3-(F-tert-butyl(dimethinsilinoxy)phenyl N3-(1,1-dimethylpropyl)-1H-pyrazol-5-amine)

The desired compound was obtained from the product of the preparation of 241 and tert-butyldimethylsilyl chloride, according to the procedure described for the preparation of 99, as a solid in a yield of

69%.

Killing 243

N-f1-3-(fterc-Butil(dimetil)silinoksilfenil)-3-(1.1-dimetilpropil-1H-pirazol-5-ill-N’-f2-((3-f2-

(methylthio)pheninn.2.ntriazolor4.3-alpyridin-6-yl)thio)benzinurea

The desired compound was obtained from the product from the preparation of 242 and 207, according to the procedure described for the preparation of 169, in a yield of 47%.

Killing 244

1 -f4-(Benzyloxyphenin-3-tert-butyl-1H-pyrazol-5-amine

The desired compound was obtained from 4,4-dimethyl-3-oxopentane nitrile and 4-benzyloxyphenylhydrazine hydrochloride, according to the procedure described for the preparation of 7, as a pale pink powder, in quantitative yield.

Killing 245

4-(5-Amino-3-tert-bulyl-1H-pyrazoi-1-iOphenol

The desired compound was obtained from the product from the preparation of 244, according to the procedure described for example 99, as a brown powder in a yield of 72%.

Killing 246

3-tert-Butyl-1-(4-(tert-butyl(dimethylsilyloxy}phenyl)-1H-pyrazol-5-amine)

The desired compound was obtained from the product of the preparation of 245 and tert-butyldimethylsilyl chloride, according to the procedure described for the preparation of 99, as a white solid in 18% yield.

Killing 247

Phenyl f3-tert-butyl-1-(4-{tert-butyl(dimethyl)silinoxy)phenyl)-1H-pyrazole-5-incarbamate

The desired compound was obtained from the product of the preparation of 246 and phenylchloroformate, according to the procedure described for the preparation of 116 in quantitative yield.

Killing 248

N-f3-tert-Butyl-1-(4-(fter-butyl(dimethylsilinoxy)phenylV1H-pyrazol-5-yn-N-(2-{[3-(2-fluorooheninn.2.41triazolo r4.3-alpyridine- 6-intio)benzi0urea

The desired compound was obtained from the product from the preparation of 214 and 247, according to the procedure described for the preparation of 219, as a colorless glassy substance in a yield of 93%.

Killing 249

4-(Metiltio1benzaldehid (5-bromopiridin-2-inhidrazon

The desired compound was obtained from the product of the preparation of 25 and 4-(methylthio)benzaldehyde, according to the procedure described for the preparation of 30, as a pale yellow solid in a yield of 92%.

Killing 250

6-Bromo-3-f4-(methylthio)pheninn.2,41triazolo[4.3-ajpyridine

The desired compound was obtained from the product from the preparation of 249, according to the procedure described for the preparation of 184, as a white solid in a yield of 72%.

Killing 251

r2-({3-r4-(Methylthio)pheninf1.2.41triazolor4,3-alpyridin-6-yl)thio)pheninmethanol

The desired compound was obtained from the product of the preparation of 250 and 2-mercaptobenzyl alcohol, according to the procedure described for the preparation of 35, as a white solid in a yield of 58%.

Killing 252

f2-((3-f4-(methylthio1phenyl1H,2,41triazolof4.3-alDiridin-6-yl>thio)benzylamine hydrobromide)

Thionyl bromide (235mL, 3.03mmol) was added to an ice-cold solution of the product from preparation 251 (384mg, 1.01mmol) in dichloromethane (10mL) and the mixture was stirred for 1 hour. the reaction mixture was then concentrated in vacuo and the resulting residue was redissolved in dichloromethane. The solution was cooled to 0°C, a solution of 7M methanolic ammonia (15mL) was added dropwise and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue was diluted with dichloromethane, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with methanol:ethyl acetate, 20:80 to 50:50, gave the desired compound as a pale yellow solid in a yield of 40%, 154mg.

Killing 253

N-(1-f3-(benzyloxy)phenyl1-3-tert-butyl-1H-pyrazol-5-yl}-N-f2-f (3-f4-('methylthio)phenyl)1,2,41triazolof4,3- alpyridin6-yl)thio)benzylurea

The desired compound was obtained from the product of preparations 252 and 63, according to the procedure described for the preparation of 121, as a white solid in a yield of 65%.

Killing 254

N-f2-({3-r2-(Benziloksi)feninf1.2,41triazolof4.3-a1piridin-6-il)tio)benzill-N-f3-terc-butil-1-(3-

fluorophenyl)-1H-pyrazol-5-yl]urea

The desired compound was obtained from the product of the preparation of 62 and 46, according to the procedure described for the preparation of 121. The crude compound was triturated with diethyl ether to give the desired product as a solid in 85% yield.

Killing 255

N-(2-{r3-(2-isopropylphenyl)f1,2,41triazolof4,3-alpyridin-6-inthio)benzi0-N'-(3-ri-methyl-1-

(methylthioethene-1(3-[2-(tetrahydro-2H-pyran-2-yloxnetoxy1phenyl>-1H-pyrazole-5-inurea) The desired compound was obtained from the product from the preparation of 237 and 117, according to the procedure described for the preparation of 219, as a white foam in a yield of 48%.

Killing 256

N-(1-f4-(Benzyloxyphenyl-3-tert-butyl-1H-pyrazol-5-yl)-N-(2-(r3-(2-chlorophenyl)ri.2,41triazolof4.3-alpyridin-6- in thiolbenziDurea

The desired compound was obtained from the product from the preparation of 103 and 205, according to the procedure described for the preparation of 219, as a foam in a yield of 74%.

Killing 257

N-f3-tert-Butyl-1-(4-hydroxyfenil)-1H-pyrazol-5-yl]-N'-(2-(f3-(2-chlorofenil)n.2.41triazolof4.3-alpyridin-6- intio) benziOurea

The desired compound was obtained from the product from the preparation of 256, according to the procedure described for the preparation of 101. The crude compound was further purified by trituration with diethyl ether to give the desired compound as a white solid in 47% yield.

First 1

N-{3-tert-Butyl-1-r4-(methylthio)phenyl-1H-pyrazol-5-yl)-N'-(-2-f(3-isopropyl[1.2,41triazolof4,3-ajpyridiniOthiolbenzyl)urea

The product from preparation 7 (0.13g, 0.50mmol) was added to a solution of N,N'-carbonyldiimidazole (0.49g, 3.00mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then diluted with brine, and stirred vigorously for 15 minutes. The aqueous layer was separated and extracted with dichloromethane (3x15mL) and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The product from preparation 43 (0.15g, 0.49mmol) was added to a solution of the residue and N-ethyldiisopropylamine (65mg, 0.50mmol!) in f,4-dioxane (10mL) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate, washed with water (25mL) and brine (25mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with dichloromethane:7M ammonia in methanol, 100:0 to 97.5:2.5. Appropriate fractions were concentrated in vacuo and the residue was repurified on a Flashmaster® silica gel column eluting with dichloromethane:7M ammonia in methanol, 100:0 to 97.5:2.5 to give the title compound.

1H NMR (300MHz, CDCI3) d: 1.20(đ, 6H), 1.40(s, 9H), 2.29(s, 3H), 3.15(m, 1H), 4.50(d, 2H), 6.30(s, 1H), 6.72(d, 1 H),6.80(d, 2H), 7.05(d, 2H), 7.21 (m, 5H), 7.48(d, 1H), 7.65(s, 1H), 8.15(s, 1 H) LRMS: m/z API-ES 586.7 [MH]+

Primeri 2 do 12

The following compounds, general formulas given in the following text, were obtained according to a procedure similar to that described for example 1, starting from the product of the preparation of 43, N,N'-carbonyldiimidazole and the corresponding pyrazole starting material. Reactions were monitored by tlc analysis and stirred at room temperature for 20-48 hours.

Example 3: the reaction was carried out only in dichloromethane. Purification performed on a Biotage® silica column, elution with ethyl acetate.

Example 4: the reaction was carried out only in dichloromethane. Purification performed on an ISCO companion® silica column, eluting with pentane:ethyl acetate, 100:0, 50:50, 20:80.

Example 5: Purification carried out on an ISCO companion® silica column eluting with ethyl acetate.

Example 9: The crude product was further purified by recrystallization from dichloromethane/diethyl ether to give the title compound.

Example 11: The crude compound was further purified on a Flashmaster® silica column, eluting with ethyl acetate.

First 13

N-f3-tert-Butyl-1-(4-methylphenyl-1H-pyrazol-5-iH-N'-(2-(f3-(2-chloro-4-

hydroxyphenyl0M.2,41triazolo[4,3-alpyridin6-yl1thio}benzinurea

The desired compound was obtained from the product from the preparation of 21 and 45, according to a procedure similar to that described for example 1, as a white foam in a yield of 54%.

1H NMR (300MHz, CDCI3) 5: 1.30(s, 9H), 2.40(s, 3H), 4.45(d, 2H), 6.30(s, 1 H), 6.85(dd, 1 H), 7.00(d, 1 H), 7.15(d, 1 H), 7.20-7.32(m, 10H), 7.40(d, 1 H), 7.65(s, 1 H), 7.70(d, 1 H) LRMS: m/z API-ES 638.5 [MH]+

First 14

N-f3-tert-Butyl-1-(4-methyloheni0-1H-pyrazol-5-yl1-N'-(2-ff3-(2-chlor-5-

hydroxyphenyl) (1,2,4-triazolof4,3-a1-pyridin6-ylthio)benzyl)urea

The desired compound was obtained from the product from the preparation of 21 and 44, according to a procedure similar to that described for example 1, in a yield of 51%.

1H NMR (300MHz, DMSO-d6) 8: 1.25(s, 9H), 2.30(s, 3H), 4.35(d, 2H), 6.20(s, 1H), 6.95-7.10(m, 3H), 7.20-7.40(m, 9H), 7.45(d, 1 H), 7.85(d, 1H), 7.99(s, 1H), 8.20(s, 1H) LRMS: m/z API-ES 638.5 [MH]+

First 15

N-13-f1.1-Dimetil-2-(metilthio)ethin-1-fenil-1H-pyrazol-5-yl>-N'-{2-r(3-isopropylH .2.41triazolof4.3-a1pyridin-6 -i0 thiolbenzylurea

The product from preparation 15 (209mg, 0.000mmol) was added to a solution of N,N'-carbonyldiimidazole (810mg, 5.00mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with water and extracted with dichloromethane (3x25mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The product from preparation 43 (215mg, 0.64mmol) was added to a solution of the residue and N-ethyldiisopropylamine (129mg, 1mmol) in dichloromethane (10mL) and the mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with 0.1 M hydrochloric acid (25 mL) and extracted with dichloromethane (3x25 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:methanol, 100:0 to 85:15. Appropriate fractions were concentrated in vacuo and the residue was crystallized from ethyl acetate to give the title compound in 55% yield, 206mg.

1H NMR (400MHz, DMSO-d6) 5: 1.29{s, 6H), 1.34(d, 6H), 1.97(s, 3H), 2.77(s, 2H),

3.55(m, 1H), 4.40(d, 2H), 6.29(s, 1H), 7.02(t, 1 H), 7.10(d, 1H), 7.26(m, 4H), 7.38(t, 1H), 7.46(m, 4H), 7.70(6, 1 H), 8.35(s, 1 H), 8.60(s, 1 H) LRMS: m/z APCI 586 [MH]+ Mikroanaliza: C33H35N7OS2. 0.2H2O zahteva (%): C 63.17; H 6.05; N 16.63; nađeno (%) C 63.03; H 6.00, N 16.42.

Primer 16 do 20

The following compounds, general formulas given below, were obtained according to a procedure similar to that described for Example 15, starting from the product of the preparation of 43, N,N'-carbonyldiimidazole and the corresponding pyrazole starting material. Reactions were monitored by tic analysis and stirred at room temperature for 0.5-18 hours.

Primeri 21 do 23

The following compounds, the general formulas given below, were obtained according to a procedure similar to that described for example 15, starting from the product of the preparation of 46 N,N'-carbonyldiimidazole and the corresponding pyrazole starting material. The reactions were monitored by tlc analysis and stirred at room temperature for 0.5-18 hours.

First 24

N-f3-tert-Butyl-1-(3-hydroxyfenil)-1H-pyrazol-5-ill-N'-{2-f(3-isopropiin.2,4ltriazolor4.3-alpiridin-6-inthiolbenzil) urea

A solution of the product from Example 12 (0.26g, 0.45mmol) in dichloromethane (5.5mL) was cooled to 10°C, boron tribromide (1 M in dichloromethane, 5.5mL, 5.50mmol) was added and the mixture was stirred at room temperature, 18 hours. Ethylenediamine solution (15% in water, 25mL) was added dropwise and the mixture was acidified to pH1 by adding 6M hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate (3x20mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel column chromatography, eluting with dichloromethane, 96:4 to 92:8, and then trituration with dichloromethane/diethyl ether gave the desired compound in a yield of 35%, 88mg.

1H NMR (300MHz, CDCI3) 5: 1.20(s, 9H), 1.40(d, 6H), 3.60(m, 1 H), 4.40(d, 2H), 6.20(s, 1 H), 6.75(d, 1 H), 6.85(m, 2H), 7.20(m, 2H), 7.30(m, 5H), 7.72(d, 1 H), 8.30(s, 1 H), 8.60(s, 1 H), 9.70(s, 1H) LRMS: m/z API-ES 556.8 [MH]+

First 25

N-f3-tert-Butyl-1-(4-hydroxy-3-methylphenyl)-1H-pyrazol-5-yn-N'-f2-r(3-isopropylM.2,4]triazolof4,3-a1pyridine-6 -yl)thiol benzylurea

The title compound was obtained from the product of Example 11, following a procedure similar to that described for Example 24. The crude compound was purified on a Flashmaster® silica column, eluting with dichloromethane: 7M ammonia in methanol, 100:0 to 95:5, to give the desired product in yield of 84%.

1H NMR (300MHz, DMSO-d6) d: 1,20(s, 9H), 1,35(d, 6H), 2.14(s, 3H), 3.55(m, 1 H), 4.60(d, 2H), 6.20(s, 1H), 6.80(d, 1H), 6.95-7.05(m, 2H), 7.10(m, 2H), 7.20-7.34(m, 4H), 7.70(d, 1 H), 8.10(s, 1 H), 8.60(s, 1H), 9.60(bs, 1 H) LRMS: m/z API-ES 570.6 [MH]+

First 26

N-(1-(3-Hydroxyfenil)-3-H-metil-1-(metilthio)ethin-1H-pyrazol-5-yl)-N'-f2-f(3-isopropylf 1.2.41triazolof4.3-a1pyridine -6-yl)thiobenzyl}urea

The desired compound was obtained from the product of example 18, according to a procedure similar to that described for example 24. The crude product was purified by chromatography on a silica gel column, eluting with ethyl acetate:methanol, 100:0 to 90:10. The corresponding fractions were concentrated in vacuo and the resulting residue was recrystallized from ethyl acetate to give the desired compound as a solid column in 55% yield.

’H NMR (400MHz, DMSO-d6) 5: 1.34(d, 6H), 1.57(s, 6H), 1.88(s, 3H), 3.56(m, 1H), 4.41 (d, 2H), 6.34(s, 1H), 6.79(d, 1 H), 6.88(m, 2H), 7.10(m, 2H), 7.23-7.30(m, 5H), 7.70(d, 1 H), 8.35(s, 1H), 8.60(s, 1H), 9.79(s, 1 H) LRMS: m/z APCI 588 [MH]+

Primeri 27 do 29

The following compounds, the general formulas of which are given below, were obtained according to a procedure similar to that described for example 24, starting from the appropriate urea starting material. The reactions were monitored by tic analysis and stirred at room temperature for 0.5-1.0 hours.

First 30

3-(3-tert-Butyl-5-(3-r2-(3-isopropii-f1.2.41triazolof4.3-a1pyridin-6-yl-sulfanyl)-benzin-ureido>-pyrazol-1-yl)-benzoieva acid

A mixture of the product from Example 5 (68.5 mg, 0.11 mmol) and a 2M solution of sodium hydroxide (1 mL) in dioxane (2 mL) was heated at 90°C for 18 hours. The solvent was evaporated under reduced pressure and the aqueous residue was diluted with water (10 mL), acidified with 1 M hydrochloric acid to pH 3, and extracted with ethyl acetate (2x1 mL).

The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol:acetic acid, 95:5:0.5. The relevant fractions were concentrated in vacuo and the residue was dried under vacuum at 50°C to give the desired compound in 27% yield, 16.8mg.

1H NMR (400MHz, CD3OD) 5: 1.31 (s, 9H), 1.41 (d, 6H), 3.48(m, 1 H), 4.49(s, 2H), 6.28(s, 1 H), 7.19(d, 1 H), 7.23-7.31 (m, 3H), 7.37(d, 1H), 7.52-7.65(m, 3H), 8.02(d, 1H), 8.11(s, 1 H), 8.27(s, 1 H) LRMS: m/z APCI 582 [MH]+ Mikroanaliza: C31H33N703S. 0.55 DCM zahteva (%): C 60.11; H 5.45; N 15.55; nađeno (%) C 59.76; H 5.57, N 15.42.

First 31

4-(3-tert-butil-5-H(f(f2-r(3-isopropylH.2,41triazolof4.3-alpyridin-6-iothio]benzyl}amino)karboninamino)-1H-pyrazol1-iobenzoieva kiselina

A mixture of the product from example 4 (130mg, 0.21 mmol) and a 2M solution of sodium hydroxide (1.5ml) in dioxane (3ml) was heated to 90°C for 16 hours. The mixture was then diluted with ethyl acetate (10 mL) and extracted with sodium hydroxide solution (2x5 mL). The aqueous solution was acidified to pH5 by the addition of 1 M hydrochloric acid and extracted with ethyl acetate (2x5mL). The organic solution was dried sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol:acetic acid, 95:5:0.5 to 90:10:1. Relevant fractions were concentrated in vacuo, and the residue was azeotroped with toluene and dried under vacuum at 50°C to give the title compound in 6% yield, 7mg.

1H NMR (400MHz, CD3OD) 5: 1.31 (s, 9H), 1.41 (d, 6H), 3.47(m, 1 H), 4.50(s, 2H), 6.28(s, 1 H), 7.20(d, 1 H), 7.24-7.39 (m, 4H), 7.53(d, 2H), 7.59(d, 1 H), 8.09(d, 2H), 8.27(s, 1 H) LRMS: m/z ES 607 [MNa]+

First 32

N-f3-tert-Butyl-1-(4-hydroxyfenil)-1H-pyrazol-5-iH-N'-(2-F(3-isopropilf1.2,41triazolo[4,3-ajpyridin-6-iOthiolbenzil) urea

The desired compound was obtained from the product of example 10, according to a procedure similar to that described for example 24, as a white powder in a yield of 46%.

1H NMR (400MHz, DMSO-d6) 5: 1.24(s, 9H), 1.35(d, 6H), 3.56(m, 1 H), 4.41 (d, 2H), 6.22(s, 1 H), 6.85(d, 2H), 7.03(m, 1H), 7.12(dd, 1H), 7.19-7.34(m, 6H), 7.71(d, 1H), 8.15(s, 1H), 8.60(s, 1H), 9.74(s, 1H); LRMS: m/z API-ES 556.4 [MH]+

First 33

N-r3-tert-Butyl-1-(3-chloro-4-methoxypheni0-1H-pyrazol-5-in-N'-{2-[(3-isopropylH .2.41triazolof4,3-ajpyridin-6-i0 thiolbenzylkirea)

The desired compound was obtained from the product of the preparation of 94 and 43, according to the procedure described for the preparation of 121. The crude compound was chromatographed on a silica gel column, eluting with dichloromethane: 7M methanolic ammonia, 100:0 to 97.5:2.5. This is followed by further purification by reverse phase chromatography on a C18 silica gel column,

eluting with water/7M methanolic ammonia (98:2):acetonitrile/7M methanolic ammonia (98:2), 75:25 to 25:75, gave the desired product as a white solid in 22% yield. 1HNMR(300MHz, CDCl3) δ: 1.25-1.47(m, 15H), 3.15(m, 1H), 3.79(s, 3H), 4.55(d, 2H), 6.30(s, 1H) 6.67(d, 1H) ,6.81(m, 2H), 7.07(m, 1H), 7.17-7.31(m, 4H), 7.36(m, 1H), 7.42(m, 1H), 7.66(s, 1H), 7.94(m, 1H ); LCMS m/z 604/606 [M+H] +

First 34

N-(3-tert-Butyl-1-pyridin-3-yl-1H-Dyrazol-5-yl)-N'-(2-K3-isopropyl,2,41triazolof4.3-a1pyridin-6-

iOtiolbenzillurea

The title compound was obtained from the product of the preparation of 90 and 43, following a procedure similar to that described for the preparation of 121. The crude compound was purified by column chromatography using a Biotage® silica gel cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 up to 95:5:0.5. The residue was further purified by silica gel column chromatography, eluting with ethyl acetatemethanol, 90:10, to give the desired product in 5% yield 1HNMR(400MHz, CD3OD) 5 : 1.32(s, 9H), 1.42(d, 6H), 3.49 (m, 1H), 4.50(s, 2H), 6.29(s, 1H), 7.21 (d, 1H), 7.26-7.40 (m, 4H), 7.54(m, 1H), 7.61 (d, 1H), 7.96(d, 1H), 8.31 (s, 1H), 8.55(d, 1H), 8.74(s, 1H); LRMS APCI m/z 541 [M+H]+

First 35

N-f3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl1-N'-(2-(f3-(2-chloro-3-

methoxypheni0n.2,41triazolof4.3-alpyridine6-inthio)benzyl)urea

The title compound was obtained from the product from the preparation of 21 in 216, following a procedure similar to that described for the preparation of 121. The crude compound was triturated with diethyl ether to give the desired product as a solid in 56% yield.

1HNMR(300MHz, CDCI3) 5: 1.29(s, 9H), 2.27(s, 3H), 3.96(s, 3H), 4.51 (d, 2H), 5.79(s, 1 H), 6.24(s, 1 H), 6.58(s, 1H), 6.97(m, 1 H), 7.07-7.38(m, 10H), 7.41-7.49(m, 1 H), 7.52(m, 1H), 7.70(s, 1 H); LCMS m/z 652.6 [M+H]+

First 36

N-r3-tert-Butyl-1-(4-methylphenyl-1H-pyrazol-5-yl1-N'-(2-(r3-(2-chloro-3-

hydroxypheni0ri.2.41triazolof4.3-alpyridin6-inthio)benzi0urea

The title compound was obtained from the product of Example 36, following a procedure similar to that described for Example 72. The crude compound was recrystallized from dichloromethane/methanol:diethyl ether as a solid in 23% yield.

1HNMR(300MHz, DMSO-d6) S: 1.29(s, 9H), 2.34(s, 3H), 4.35(d, 2H), 6.21 (m, 1 H), 6.95(m, 1 H), 7.11 (m, 1 H), 7.20-7.36 (m, 11 H), 7.88(m, 1 H), 8.01 (m, 1H), 8.22(m, 1H), 10.67(s, 1 H); LCMS m/z 638.6 [M+H]+

First 37

N-(1-r3-(2-Hydroxyethoxy)phenin-3-r1-methyl-1-(methylthio)ethin-1H-pyrazol-5-yl)-N'-(2-r(3-isopropion). 2.41triazolo f4,3-a1pyridin-6-inthio1benzylurea

para-Toluenesulfonic acid (20mg) was added to a solution of the product from the preparation of 173 (72mg, 0.1 mmol) in methanol (10mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with ethyl acetate and methanol, 100:0 to 90:10, gave the desired compound as a white solid in a yield of 98%, 62mg.

1HNMR(400MHz, DMSO-d6) 5: 1.34(d, 6H), 1.57(s, 6H), 1.89(s, 3H), 3.56(m, 1 H), 3.71 (m, 2H), 4.02(m, 2H), 4.41 (d, 2H), 4.88(t, 1 H), 6.36(s, 1 H), 6.97(d, 1 H), 7.03(m, 2H), 7.09(m, 2H), 7.24(m, 2H), 7.29(m, 2H), 7.39(m, 1 H), 7.69(d, 1 H), 8.06(s, 1 H), 8.38(s, 1 H); LRMS APCI m/z 632 [M+H]+

Primeri 38 do 42

The following compounds, the general formulas given below, were obtained according to a procedure similar to that described for Example 37, starting from the appropriate starting materials and para-toluenesulfonic acid.

First 43

N-(3-tert-ButiM-f3-(2-hydroxyethoxy)phenin-1H-pyrazol-5-ylV-N'-(2-ff3-(2-

fluorofeniOH .2.41triazolor4.3 a1piridin6-intio}benzi0urea

A solution of the product from the preparation of 219 (215 mg, 0.29 mmol) was dissolved in a mixture of acetic acid (4 mL), tetrahydrofuran (2 mL) and water (1 mL) and the obtained solution was heated for 18 hours at 60°C. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane, 99:1 to 92:8. The appropriate fractions were evaporated under reduced pressure and the residue was triturated with dichloromethane/diethyl ether to give the title compound as a white powder in 26% yield, 50.2mg. 1HNMR(400MHz, DMSO-d6) δ: 1.24(s, 9H), 3.68(m, 2H), 3.98(m, 2H), 4.37(m, 2H), 4.85(t, 1H), 6.22(s, 1 H), 6.92(m, 1 H), 7.00-7.11 {m, 3H), 7.21-7.44(m, 8H), 7.65(m, 1 H),

7.78(m, 1 H), 7.87{m, 1 H), 8.19(m, 1 H), 8.35(s, 1 H); LCMSm/z 652.6 [M+H]+

First 44

N-f3-tert-Butyl-1-f3-(2-hydroxyethoxy)phenyl1-1H-pyrazol-5-yl>-N'-(2-(r3-(2-

isopropylphenin,2,41triazolof4,3-alpyridin-6-inthio)benzi0urea

The desired compound was obtained from the product from the preparation of 221, according to the procedure described for example 43, as a white powder in a yield of 66%.

1HNMR(400MHz, DMSO-d6) 8: 1.07(d, 6H), 1.24(s, 9H), 2.75(m, 1H), 3.68(m, 2H),

4.00(m, 2H), 4.35(m, 2H), 4.86(t, 1H), 6.21(s, 1H), 6.90(m, 1H), 7.01(m, 3H), 7.16-7.36(m, 7H), 7.47(m, 1H), 7.58(m, 2H), 7.86(m, 2H), 8.31 (s, 1H); LCMS m/z 676.2 [M+H]+

First 45

N-(3-tert-Butyl-1-f3-(2-hydroxyethoxy)phenyl-1H-pyrazol-5-yl)-N'-f2-{f3-(2-

metoksifeni0ri.2,41triazolor4,3-alpiridin-6-illtio}benzi0urea

The desired compound was obtained from the product from preparation 222, according to the procedure described for example 43, as a white powder in a yield of 45%.

1HNMR(400MHz, DMSO-d6) 6: 1.25(s, 9H), 2.75(m, 1H), 3.68-3.70(m, 5H), 4.01(m, 2H), 4.35(m, 2H), 4.86(t, 1H), 6.22 (s, 1H), 6.94(m, 1H), 7.01(m, 3H), 7.13-7.34(m, 8H), 7.57(m, 2H), 7.85(m, 2H), 8.31(s, 1 H); LCMS m/z 664.6 [M+HJ+

First 46

N-r3-tert-Butyl-1-(4-fluorophenin-1H-pyrazol-5-in-N'-(2Tf3-(2-hydroxypheninf1.2.4jtriazolor4,3-a1pyridin-6-intio> benziOurea

Boron tribromide (1 Mu in dichloromethane, 1 ml_, 1 mmol) was added dropwise to an ice-cold solution of the product from the preparation of 121 (186mg, 0.27mmol) in dichloromethane (10mL) and the mixture was stirred for 10 minutes at 0°C. The reaction mixture was then diluted with dichloromethane (25mL) and water (25mL) and stirring was continued at 450°C for another 10 minutes. 0.88 Ammonia (5mL) was added and the aqueous layer was separated and extracted with dichloromethane (2x25mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with ethyl acetate:methanol, 100:0 to 95:5. The appropriate fractions were evaporated under reduced pressure and the residue was recrystallized from ethyl acetate. acetate to give the desired compound as a pale yellow oil in 48% yield, 78mg.

1HNMR(400MHz, DMSO-d6) 8: 1.23(s, 9H), 4.35(đ, 2H), 6.23(s, 1 H), 6.96(m, 1H), 7.00(t,

1 H), 7.05(d, 1 H), 7.04-7.55 (m, 7H), 7.43(m, 1H), 7.48(dd, 2H), 7.54(dd, 1H), 7.83(d,

1H), 8.05(s, 1H), 8.28(s, 1H), 10.44(s, 1 H); LRMS APCI m/z 608 [M+H]+

Primeri 47 do 69

The following compounds, general formulas shown below, were obtained by a procedure similar to that described for Example 46, starting from the appropriate starting material and 4-6 equivalents of boron tribromide.

Example 48: The crude compound was further purified by silica gel column chromatography, eluting with ethyl acetate:methanol, 100:0 to 95:5, after which it was triturated with the remaining diethyl ether,

Example 66: The crude compound was recrystallized from ethyl acetate/methanol.

First 70

N-(3-tert-Butyl-1-pyridin-3-yl-1H-pyrazol-5-yn-N'-(2-{f3-(2-hydroxyphenyl)M.2.41triazolor4.3-

alpyridine-6-yl1tio)benzyl)urea

The desired compound was obtained from the product from the preparation of 167, according to the procedure described for example 46, in a yield of 75%.

1HNMR(400MHz, CD3OD) 8: 1.32(s, 9H), 4.48(s, 2H), 6.30(s, 1H), 7.01 (m, 2H), 7.24-7.37(m, 5H), 7.44(m, 1H), 7.54 (m, 2H), 7.71(d, 1H), 7.84(s, 1H), 7.97(d, 1H), 8.52(d, 1H), 8.73(s, 1H); LRMS APCI m/z 591 [M+H]+

First 71

N-(3-tert-ButyH-pyridin-2-yl-1H-pyrazol-5-yl)-N'-(2-(r3-(2-hydroxypheniOH.2.41triazolof4.3-

alpiridin-6-intio)benzi0urea

The desired compound was obtained from the product from the preparation of 168, according to the procedure described for example 46, as a brown solid in a yield of 18%.

1HNMR(400MHz, DMSO-d6) 5: 1.25(s, 9H), 4.46(s, 2H), 6.49(s, 1H), 7.00(m, 1H), 7.23-7.30(m, 5H), 7.40-7.45(m, 2H), 7.54(d, 1H), 7.83-7.86(m, 2H), 7.94-8.00(m, 1H), 8.05(m, 1H), 8.11(s, 1H), 8.35(m, 1H), 10.45(s, 1H), 10.99(s, 1 H); LRMS APCI m/z 591 [M+H]+

First 72

N-r3-tert-Butyl-1-(4-methylpheni0-1H-pyrazol-5-ii1-N'-(2-{r3-(2-hydroxyfenil)H.2.41triazolor4.3-alpiridin-6-inthio) benzvurea

Boron tribromide (1M in dichloromethane, 5.05 mL, 5.05 mmol) was added dropwise to a solution of the product from the preparation of 124 (0.18 g, 0.25 mmol) in dichloromethane (2 mL), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with water (1.5mL) and stirring was continued for another 10 minutes before 1,2-diaminoethane (1.5mL) was added. The mixture was then stirred vigorously and acidified to pH1 by addition of 6M hydrochloric acid. The aqueous layer was separated and re-extracted with dichloromethane (5 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. By recrystallization of the residue from dichloromethane:methanol, 50:50, the desired compound was obtained as a white solid in a yield of 36%.

1HNMR(300MHz, DMSO-d6) 5: 1.29(s, 9H), 2.34(s, 3H), 4.39(d, 2H), 6.25(s, 1H), 7.02-7.59(m, 14H), 7.81-7.91 (m, 1 H), 8.08(s, 1 H), 8.28(s, 1 H), 10.53(s, 1 H); LCMS m/z 604.6 [M+H]+

Primeri 73 do 79

The following compounds, the general formulas shown below, were prepared according to a procedure similar to that described for Example 72, starting from the appropriate starting material and 4-6 equivalents of boron tribromide.

Example 73: The crude compound was further purified by recrystallization from dichloromethane/methanol:diethyl ether.

Example 74: The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 98:2 to 92:8.

Example 75: The crude compound was recrystallized from dichloromethane/methanol:diethyl ether Example 78: The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 97:3 to 94:6, then trituration with dichloromethane/methanol:diethyl ether. ether (x3).

Example 79: The crude compound was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 100:0 to 95:5, then triturated with dichloromethane.

First 80

N-(3-tert-Butyl-1-r3-(2-hydroxyethoxy)phenin-1H-pyrazol-5-yl)-N,-(2-f[3-(2-

hydroxyphenir,2.41triazolof4,3-pyridin-6-ylthio)benziPurea

Boron tribromide (1 M in dichloromethane, 1.6mL, 1.6mmol) was added dropwise to a solution of the product from preparation 122 (270mg, 0.33mmol) in dichloromethane (10mL), cooled to -78°C and the mixture was stirred for 90 minutes at this temperature. The reaction mixture was stirred for an additional 30 minutes, allowing the temperature to rise to 25°C, and then methanol (10 mL) and 0.88 ammonia (3 mL) were added. The mixture was acidified with 2M hydrochloric acid and extracted with dichloromethane (3x50mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane, 100:0 to 90:10. Appropriate fractions were evaporated under reduced pressure and the residue was recrystallized from ethyl acetate/methanol to give the title compound as a solid in 56% yield, 120mg.

1HNMR(400MHz, DMSO-d6) 8: 1.24(s, 9H), 3.70(m, 2H), 4.00(t, 2H), 4.37(d, 2H), 4.86(m, 1H), 6.25(s, 1H), 6.94(dd, 1H), 7.03(m, 5H), 7.19(m, 3H), 7.26(d, 2H), 7.36(t, 1 H), 7.54(d, 1 H), 7.83(d, 1 H), 8.06(s, 1 H), 8.32(s, 1H), 10.45(s, 1 H); LRMS APCI m/z 650 [M+H]+

First 81

N-f3-terc-Butil-1-(3-hydroksifenin-1H-pirazol-5-in-N’-r2-((3-f2-(2-

hidroksietoksi)pheninf1.2.4]triazolof4.3-a1pyridin~6-yl)thio)benzinurea

Boron tribromide (1 M in dichloromethane, 1.3 mL, 1.3 mmol) was added dropwise to a solution of the product from the preparation of 174 (214 mg, 0.26 mmol) in dichloromethane (10 mL), at -78 °C, and the mixture was stirred for 5 min at both temperatures. . The reaction mixture was then stirred for an additional 5 minutes allowing the temperature to reach 0°C. The mixture was cooled again to -78°C, methanol (5mL) was added and the temperature was allowed to rise to 25°C. the reaction mixture was then diluted with water and extracted with dichloromethane (3x40mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 93:7:1. The appropriate fractions were evaporated under reduced pressure and the residue recrystallized from ethyl acetate/methanol to give the title compound as a solid in 47% yield, 79mg.

1HNMR(400MHz, DMSO-d6) 5: 1.23(s, 9H), 3.52(m, 2H), 4.06(t, 2H), 4.36(d, 2H). 4.72(t,

1H), 6.22(s, 1H), 6.76(d, 1H), 6.88(m, 2H), 7.01 (t, 1H), 7.14(t, 1H), 7.17-7.28(m, 7H), 7.58(m, 2H), 7.82(d, 1H), 8.12(s, 1H), 8.28(s, 1 H), 9.73(s, 1 H); LRMS APCI m/z 650 [M+H]+

First 82

N-( 1 -(4-EthylphenylV3-r 1 -methyl-1 -(methylthioletill-1H-pyrazol-5-yl)-N'-(2-(f3-( 2-hydroxypheniOH ,2,41triazolo r4,3 -a1pyridin-6-inthio)benzinurea

The desired compound was obtained from the product from the preparation of 157, according to the procedure described for example 81, as a solid substance in a yield of 60%.

1HNMR(400MHz, CDCI3) 5: 1.19(t, 3H), 1.57(s, 6H), 1.88(s, 3H), 2.64(q, 2H), 4.37(d, 2H), 6.34(s, 1H), 7,03(m, 3H), 40 7.18-7.37(m, 9H), 7.43(m, 1H), 7.54(d, 1H), 8.06(s, 1H), 8.32(s, 1H), 10.46(s, 1H); LRMS APCi m/z 650 [M+H]+

First 83

N-(1-(3-Ethylphenyl)-3-f1-methyl-1-(methylthiojetin-1H-pyrazol-5-yl)-N'-(2-(r3-(2-hydroxypheniOH ,2.4Itriazolo 45 r4 .3-alpyridin-6-yl1thio)benzi0urea

1HNMR(400MHz, CDCI3) 5: 1.17(t, 3H), 1.57(s, 6H), 1.89(s, 3H), 2.64(q, 2H), 4.37(d, 2H), 6.35(s, 1H), 7.01 (m, 3H), 7.05(d, 1H), 7.19-7.29(m, 8H), 7.39(m, 1H), 7.44(d, 1H), 7.54(d, 1H), 8.06(s, 1H), 8.33(s, 1H)t 10.45(s, 1 H); LRMS APCI m/z 650 [M+H]+

First 84

N-(2-{[3-(2-Hydroxyphenyl)[1,2,41triazolof4,3-a1pyridin-6-ylthio]benziQ-N'-(1-(4-methoxy-3-

metilfenil)-3-ri-metil-1-(metilthio)ethin-1H-pyrazol-5-yl}urea

The desired compound was obtained from the product of preparation 159, according to the procedure described for Example 81. The crude compound was triturated with ethyl acetate to give the desired product as a solid in 43% yield.

1HNMR(400MHz, CDCI3) 5: 1.56(s, 6H), 1.88(s, 3H), 2.17(s, 3H), 3.81(s, 3H), 4.36(d, 2H), 6.32(s, 1H), 6.99-7.06(m, 4H), 7.18-7.26(m, 7H), 7.43(m, 1H), 7.54(d, 1H), 7.83(d, 1H), 8.06(s, 1H), 8.21(s, 1H), 10.45(s, 1H); LRMS APCI m/z 666 [M+H]+

First 85

N-1 1 -( 3-Chlorophenyl V-3-F 1 -methyl-1 -(methylthio)ethyl1-1 H-pyrazol-5-ill-N'-f 2-(f3-( 2-hydroxyphenyl)H.2, 41triazolo[4,3-alpyridin-6-inthio]benzyl)urea

The desired compound was obtained from the product of Preparation 154, according to the procedure described for Example 81. The crude compound was triturated with ethyl acetate to give the desired product as a solid in 44% yield.

1HNMR(400MHz, CDCI3) 6: 1.55(s, 6H), 1.88(s, 3H), 4.35(d, 2H), 6.35(s, 1H), 6.87-7.32(m, 8H), 7.34-7.62(m, 6H), 7.82 (d, 1 H), 8.05(s, 1 H), 8.50(s, 1 H), 10.50(s, 1H); LRMS APCI m/z 608/610 [M+H]+

First 86

N-(2-(f3-(5-Hlor-2-hydroxyfenil)F1.2.41triazolor4.3-a1pyridin-6-inthio)benzyl)-N'-r3-n-metil-1-(metilthioletill 1-(3 -methylpheni0-1H-pyrazol-5-inurea

1HNMR(400MHz, DMSO-d6) 8: 1.56(s, 6H), 1.87(s, 3H), 2.34(s, 3H), 4.36(d, 2H), 6.35(s, 1H), 7.02(m, 1H), 7.05(d, 1 H), 7.22(m, 8H), 7.36(m, 1 H), 7.47(m, 1 H), 7.55(s, 1 H), 7.83(d, 1 H), 8.10(s, 1H), 8.31 (s, 1 H), 10.75(s, 1 H); LRMS APCI m/z 608/610 [M+H]+

First 87

N-(2-(f3-(5-Chloro-2-hydroxyphenyl)f1,2,41triazolof4,3-a1pyridin-6-ylthio)benzyl)-N'-r3-H-methyl-1-(methylthioletill 1 -(4 -methylphenyl)-H-pyrazol-5-iriurea

The desired compound was obtained from the product of preparation 166, according to the procedure described for Example 81. The crude compound was triturated with ethyl acetate/methanol to give the desired product as a solid in a 24% yield of solids.

1HNMR(400MHz, DMSO-d6) 5: 1.56(s, 6H), 1.87(s, 3H), 2.34(s, 3H), 4.36(d, 2H), 6.33(s, 1 H), 7.01 (m, 1H), 7.05(d, 1 H), 7.25(m, 9H), 7.47(m, 1 H), 7.54(s, 1 H), 7.83(d, 1 H),

8.11(s, 1H), 8.27(s, 1 H), 10.75(s, 1 H); LRMS APCI m/z 608/610 [M+H]+

First 88

N-(2-(f3-(5-Chloro-2-hydroxyphenyl)

2-(metilthio)ethyn-1-(4-metilfenil)-1H-pyrazol-5-ylurea

The desired compound was obtained from the product of preparation 149, according to the procedure described for Example 81. The crude compound was triturated with ethyl acetate/methanol to give the desired product as a solid in 52% yield.

1HNMR(400MHz, DMSO-d6) 8: 1.26(s, 6H), 1.95(s, 3H), 2.33(s, 3H), 2.77(s, 2H), 4.36(d, 2H), 6.27(s, 1H), 6.98(m, 1 20 H), 7.06(d, 1 H), 7.16-7.35(m, 9H), 7.47(d, 1 H), 7.55(s, 1 H), 7.84(d, 1 H), 8.12(s, 1 H), 8.27(s, 1 H), 10.78(s, 1 H); LRMS APCI m/z 684/686 [M+H]+

First 89

25 N-(2-(f3-(2-Ethylpheni0f1.2.41triazolof4.3-alpyridin-6-inthio)benzi0-N'-(1-(3-hydroxyfenil)-3-f1-metil-1-(metilthio) ethyn-1H-pyrazol-5-yl)urea

A solution of the product from the preparation of 228 (280mg, 0.38mmol) in dichloromethane (6ml_) was cooled to -78°C. Boron tribromide (1 M in dichloromethane, 1.9 mL, 1.9 mmol) was added dropwise and the mixture was stirred for 20 minutes. The reaction mixture was diluted with methanol (10 mL) and allowed to rise to 25°C. The mixture was concentrated in vacuo and the residue redissolved in dichloromethane and washed with 0.88 ammonia (2x1 OmL). The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 99.75:0.25 to 95:5, to give the title compound in 59% yield, 146mg.

1HNMR(400MHz, CDCI3) 8: 0.96(t, 3H), 1.59(s, 6H), 1.88(s, 3H), 2.38(q, 2H), 4.43(s, 2H), 6.42-6.45(m, 2H), 6.76(m, 2H), 6.85(m, 1H), 6.95(d, 1H), 7.10-7.37(m, 8H), 7.37(m, 1H), 7.45 (m, 1H), 7.54(s, 1H), 8.28(s, 1 H); LRMS APCI m/z 650 [M+H]+

First 90

N-f1-(4-Hydroxyphenyl)-3-f1-rnetyl-1-(rnetylthio)ethin-1H-pyrazol-5-yl)-N'-(2~ff3-(2-methylpheniOM .2.41triazolo f4,3 -alpyridin-6-yl1thio)benzi0urea

The title compound was obtained from the product of Preparation 230, following a procedure similar to that described for Example 89, as a solid in 10% yield.

1HNMR(400MHz, CD3OD) 5: 1.61(s, 6H), 1.90(s, 3H), 2.17(s, 3H), 4.45(s, 2H), 6.36(s, 1 H), 6.87(d, 2H), 7.19-7.52(m, 11 H), 7.66(s, 1 H), 7.73(d, 1 H); LRMS APCI m/z 636 [M+HJ+

First 91

N-(1-(3-Hydroxyphenyl)-3-ri-methyl-1-(methylthio)ethin-1H-pyrazol-5-yl>-N'-(2-fr3-(2-methylpheniOn,2,41triazolo f4 ,3-a1pyridin-6-intio}benzi0urea

The desired compound was obtained from the product of the preparation of 160, according to a procedure similar to that described for example 89, as a solid in a yield of 66%. 1HNMR(400MHz, CDCl3) δ: 1.62(s, 6H), 1.91 (s, 3H), 2.15(s, 3H), 4.47(s, 2H), 6.44(m, 1H), 6.48(s, 1H ), 6.76(s, 1H), 6.82(d, 1H), 6.93(m, 2H), 7.04(d, 1H), 7.18(m, 1H), 7.24-7.45(m, 9H), 7.58( s, 1H), 7.98(s, 1H); LRMS APCI m/z 636 [M+H]+

First 92

N-( 1 -(3,5-DimethylpheniO-3-f 1 -methyl-1 -(methylthioletill-1H-pyrazol-5-yl)-N'-( 2-f f3-f 2-hydroxypheniHH .2, 41triazo r4.3-a1pyridin-6-intio}benzi0urea

The desired compound was obtained from the product from preparation 164, according to the procedure

similar to that described for Example 89. The crude compound was triturated with ethyl

acetate/methanol to give the desired compound as a solid in 59% yield.

1HNMR(400MHz, DMSO-d6) 6: 1.37(s, 6H), 1.89(s, 3H), 2.30(s, 6H), 4.37(d, 2H), 6.44(s, 1H), 7.02(m, 6H), 7.10(m, 5H), 7.42(m, 1 H), 7.54(d, 1 H), 7.81 (d, 1H), 8.05(s, 1H), 8.30(s, 1H), 10.45(s, 1H); LRMS APCI m/z 650 [M+H]+

First 93

N-r3-tert-Butyl-1-(3-hydroxyphenyl-1H-pyrazol-5-yl1-N'-r2-({3-[2-(methylthiolfenillM ,2,41triazolof4,3-alpyridin-6-yl)thiolbenzylurea)

Boron tribromide (1 M in dichloromethane, 0.74mL, 0.74mmol) was added dropwise to a solution of the yield product 229 (107mg, 0.15mmol) in dichloromethane (5mL), at -78°C, and the mixture was stirred for 2 hours at this temperature. A methanolic solution of ammonia (7M, 5ml_) was added to the reaction mixture and allowed to warm to room temperature. The mixture was diluted with water and extracted with ethyl acetate, and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with ethyl acetate:methanol, 100:0 to 90:10, gave the desired compound as a pale yellow solid in a yield of 68%, 64mg. 1HNMR(400MHz, DMSO-d6) δ: 1.22(s, 9H), 2.38(s, 3H), 4.36(d, 2H), 6.21(s, 1H), 6.76(d,

1H), 6.86(d, 1H), 6.87(s, 1H), 7.00(m, 1 H), 7.23-7.34(m, 7H), 7.49-7.65(m, 3H), 7.83(s, 1 H), 7.88(d, 1H), 9.26(s, 1 H), 9.73(s, 1 H); LRMS APCI m/z 636 [M+H]+

First 94

N-f1-(4-Fluorophenyl)-3-n-methyl-1-(methylthio)ethyl1-1H-pyrazol-5-yl}-N'-(2-(f3-(2-hydroxyphenyl)[1.2,41triazolo (4,3-a1pyridin-6-ylthio}benzyl)urea

The desired compound was obtained from the product from the preparation of 152, according to the procedure described for example 93, as a solid substance in a yield of 41%.

1HNMR(400MHz, DMSO-d6) 5: 1.57(s, 6H), 1.88(s, 3H), 4.36(d, 2H), 6.34(s, 1H), 7.01(m, 2H), 7.05(d, 1H), 7.17-7.27 (m, 5H), 7.32(m, 2H), 7.43(m, 1H), 7.48-7.55(m, 3H), 7.84(d, 1H), 8.06(s, 1H), 8.33(s, 1H), 10.44(s, 1 H); LRMS APCI m/z 640 [M+H]+

First 95

N-(1-(3,4-Difluorophenyl-3-H-methyl-1-(methylthio)ethyl-1H-pyrazol-5-yl)-N'-(2-{f3-(2-hydroxyphenyl)f1,2, 41triazolo[4,3-alpyridin-6-ylthio]benzi0urea

The desired compound was obtained from the product from the preparation of 156, according to the procedure described for Example 93. The crude compound was further purified by HPLC on a Fenomenex Luna C18 system, eluting with acetonitrile: water/trifluoroacetic acid (5.95:0.1):acetonitrile, 100:0 to 0 :100, giving the desired product in 3% yield.

1HNMR(400MHz, CDCI3) 5: 1.65(s, 6H), 1.94(s, 3H), 4.52(d, 2H), 6.40(s, 1 H), 6.80(d, 1H), 6.91(m, 1 H), 7.00(s, 1H), 7.12(m, 1H), 7.19(m, 1H), 7.25-7.42(m, 9H), 7.61(m, 2H), 8.71 (s, 1 H)

First 96

25 N-f1-(3-Fluorophenyl)-3-H-methyl-1-(methylthio)ethin-1H-pyrazol-5-yl)-N'-(2-ir3-(2-hydroxypheninf1,2,4ltriazolo f4). 3-α1pyridin-6-inthio)benzylurea

Boron tribromide (1 M in dichloromethane, 0.85 ml_, 0.85 mmol) was added dropwise to a solution of the product from the preparation of 153 (150 mg, 0.21 mmol) in dichloromethane (10 mL), cooled to -40°C, and the mixture was stirred for 20 min at this temperature. Methanol (5 mL) diluted with water (30 mL) and dichloromethane (30 mL) were added to the reaction mixture and the mixture was allowed to warm to room temperature. The mixture was increased in basicity by the addition of 0.88 ammonia (5ml) and extracted with dichloromethane (3x30ml). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol, 100:0 to 95:5, to give the title compound as a white solid in 45% yield, 61 mg.

1HNMR(400MHz, DMSO-d6) 8: 1.58(s, 6H), 1.89(s, 3H), 4.36(d, 2H), 6.37(s, 1 H), 7.00(m, 1H), 7.04(m, 2H), 7.18-7.27 (m, 6H), 7.36(m, 2H), 7.43(m, 1 H), 7.53(m, 2H), 7.83(d, 1 H), 8.06(s, 1 H), 8.44(s, 1 H), 10.44(s, 1 H); LRMS APCI m/z 640 [M+HJ+

First 97

N-f3-tert-Butyl-1-(4-methoxyfenil)-1H-pyrazol-5-in-N'-(2-ff3-(2-hydroxyfenil)H.2.41triazolof4.3-a1pyridin-6-yl1 thiolbenziOurea

Boron tribromide (2M in dichloromethane, 0.63mL, 1.26mmol) was added dropwise to a solution of the product from the preparation of 138 (300mg, 0.42mmol) in dichloromethane (2.5mL) cooled to -45°C, and the mixture was stirred for 45 minutes at this temperature. More boron tribromide (2M in dichloromethane, 0.63mL, 1.26mmol) was then added and the mixture was stirred for 30 minutes at -45°C. Dimethylamine (40% in water, 2mL) was then added to the reaction mixture and the mixture was allowed to warm to room temperature. The mixture was diluted with water (10ml_) and dichloromethane (10ml_) and the biphasic system was acidified with 4M hydrochloric acid. The aqueous layer was separated and extracted with dichloromethane (3x1 mL), and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with dichloromethane, 100:0 to 90:10, then triturated with dichloromethane/diethyl ether to give the title compound as a white solid in 29% yield, 76.9mg.

1HNMR(300MHz, DMSO-d6) 5: 1.24(s, 9H), 3.77(s, 3H), 4.37(d, 2H), 6.21(s, 1H), 6.91-7.04(m, 5H), 7.17-7.41 (m, 8H), 7.51 (dd, 1H), 7.81(d, 1H), 7.92(s, 1H), 8.03(s, 1H), 10.60(brs, 1H); LCMS APCI m/z 620 [M+HJ+

First 98

N-r3-tert-Butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl1-N'-(2-(r3-(2-hydroxyphenyl)n,2,41triazolof4,3-a1pyridin-6-yl1 thiolbenzylurea

The title compound was obtained from the product of preparation 139, according to the procedure described for Example 97. The crude compound was further purified by reverse phase chromatography on a C18 silica gel column, eluting with water and acetonitrile, 67:33 to 33:67, after which it was triturated with dichloromethane /diethyl ether to give the desired product in 11% yield.

1HNMR(300MHz, DMSO-d6) 5: 1.25(s, 9H), 3.76(s, 3H), 4.37(d, 2H), 6.24(s, 1H), 6.90-7.06(m, 6H), 7.18-7.25(m, 5H), 7.32-7.45(m, 2H), 7.53(d, 1H), 7.82(s, 1H), 8.04(s, 1 H), 8.33(s, 1 H), 10.40(brs, 1 H); LCMS APCI m/z620 [M+HJ+

First 99

N-f3-(1.1-Dimethylpropi0-1-(4-methylphenyl)-1H-pyrazol-5-yn-N'-(2-(r3-(2-

hydroxypheni0ri.2.41triazolof4.3-alpyridin-6-thio)benzi0urea

The product from preparation 141 (203mg, 0.29mmol) was suspended in hydrobromic acid (5.7M in glacial acetic acid, 4mL, 22.8mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with diethyl ether gave the desired compound as a white solid in a yield of 81%, 144mg.

1HNMR(400MHz, DMSO-d6) 5: 0.73(t, 3H), 1.17 (s, 6H), 1.54(q, 2H), 2.32(s, 3H), 4.36(d, 2H), 6.19(s, 1 H), 6.98-7.06 (m, 2H), 7.15-7.33(m, 10H), 7.45(m, 1H), 7.55(d, 1H), 7.85(d, 1H), 8.06(s, 1H), 8.24(s, 1H), 10.47(s, 1 H); LRMS ESI m/z 618 [M+H]+

First 100

N-(3-(1.1-DimethylpropiP-1-f3-(2-hydroxyethoxy)phenin-1H-pyrazol-5-yl}-N'-(2-{f3-(2-hydroxypheninn ,2,41triazolo [4, 3-a1pyridin-6-yl1thio)benziPurea

The desired compound was obtained from the product of preparation 170, according to a procedure similar to that described for example 99, as a solid in a yield of 21%. 1HNMR(300MHz, DMSO-d6) δ: 0.76(t, 3H), 1.20(s, 6H), 1.56(q, 2H), 3.70(s, 2H), 4.01 (t, 2H), 4.37(d, 2H) ), 4.86(s, 1H), 6.21(s, 1H), 6.94(m, 1H), 7.05(m, 5H), 7.23(m, 5H), 7.38(m, 2H), 7.53(dd, 1H), 7.82(d, 1H), 8.05(s, 1H), 8.32(s, 1H), 10.43(s, 1H); LCMS m/z 665 [M+H] +

First 101

N-f3-tert-Butyl-1-(3-fluorophenin-1H-pyrazol-5-ill-N'-r2-g3-r2-(2-

hydroxyethoxyjphenyl1f1.2,41triazolof4,3-alpyridin6-yl)thiojbenzinurea

A mixture of the product from Example 47 (100mg, 0.17mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (30mL, 0.20mmol) and potassium carbonate (32mg, 0.25mmol) in N,N-dimethylformamide (3mL) was heated at 60°C for 18 hours. More 2-(2-bromoethoxy)tetrahydro-2H-pyran (15 mL, 0.10 mmol) was added and the mixture was heated at 60°C for 6 hours. The cooled reaction mixture was then diluted with ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in methanol (3mL), para-toluenesulfonic acid (20mg) was added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with water (3x10 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column, eluting with dichloromethane.methanol, 95:5 to 92:8. The residue was further purified by silica gel column chromatography, eluting with ethyl acetate:methanol, 97.5:2.5 to 95:5, to give the title compound as a solid in 23% yield, 24.5mg.

1HNMR(400MHz, CDCI3) d: 1.24(s, 9H), 3.70(m, 2H), 4.01(m, 2H), 4.37(d, 2H), 6.25(s,

1H), 6.68(m, 1H), 6.92(m, 2H), 7.00-7.07(m, 5H), 7.15(m, 1 H), 7.20-7.39(m, 4H), 7.53(m, 2H), 7.71 (m, 1 H), 7.79(s, 1 H)

First 102

N-(2-(r3-(2-Ethylpheniol)1.2.41triazolof4.3-a1pyridin-6-ylthio)benzine-N'-f1-[3-(2-

hydroxyethoxy)phenin-3-ri-methyl-1-(methylthio)ethyl-1-1H-pyrazol-5-yl)urea

The desired compound was obtained from the product of example 89, according to the procedure described for example 101, in a yield of 52%.

1HNMR(400MHz, CDCI3) 5: 1.01(t, 3H), 1.63(s, 6H), 1.92(s, 3H), 2.44(q, 2H), 3.72(m, 2H), 3.86(m, 2H), 4.46(d, 2H), 6.47(s, 1 H), 6.58(d, 1H), 6.90-7.36(m, 13H), 7.41 (d, 1H), 7.49(d, 1H), 7.49(t, 1H), 7.64(s, 1H), 8.03(s, 1 H); LRMS APCI m/z 695 [M+H]+

First 103

N-F2-((3-f2-f2-Hydroksietoks0fenilllT.2.41triazolof4.3-a1piridin-6-il)tio1benzin-N'-r3-ri-metil-1-(metiltioj etill-1-(4-metilfeni0-1) H-pirazol-5-illurea

The desired compound was obtained from the product of preparation 172, using a procedure similar to that described for example 101, in a yield of 34%.

1HNMR(400MHz, CDCI3) 5: 1.57(s, 6H), 1.89(s, 3H), 2.34(q, 2H), 3.52(m, 2H), 4.06(m, 2H), 4.36(d. 2H), 4.70(m, 1H), 6.33(s, 1H), 6.99(m, 1H), 7.10-7.34(m, 11H), 7.58(m, 2H), 7.81(d, 1H), 8.10(s, 1H), 8.25(s, 1H); LRMS APCI m/z 681 [M+H]+

First 104

N-(3-terc-Butyl-1-[3-(2-hydroxyethoxy)phenin-1H-pyrazol-5-yl)-N'-(2-{[3-(2-

etilahenil)f1.2.41triazolor4,3-alpiridin6-intiolbenzil)urea

A solution of the product from preparation 204 (360mg, 1 mmol) in dimethylsulfoxide (5mL) was added to a solution of the product from preparation 116 (490mg, 1mmol) and the mixture was stirred at room temperature for 18 hours and at 50°C for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (10 mL), and washed with 1 M hydrochloric acid (1 mL), water (10 mL), 1 M sodium hydroxide (10 mL), and brine (10 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol (5mL), para-toluenesulfonic acid (100mg) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (30 mL) and washed with water (2x1 mL). The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by chromatography on a silica gel column, eluting with ethyl acetate:methanol, 95:5, giving the desired compound in a 31% yield of 208.3mg.

1HNMR(400MHz, CDCI3) 5: 1.07(t, 3H), 1.31 (s, 9H), 2.52(q, 2H), 3.84(t, 2H), 4.01(t, 2H), 4.53(d, 2H), 6.13(brs, 1H), 6.33(s, 1 H), 6.75(d, 1 H), 7.01 (m, 3H), 7.21 (m, 3H), 7.26(m, 3H), 7.36(m, 3H), 7.45(d, 1H), 7.52(m, 1 H), 7.57(d, 1H), 7.71 (s, 1 H); LRMS APCI m/z 662 [M+H]+

First 105

N-13-tert-Butyl-1-r3-(2-hydroxyethoxy)phenyl-1H-pyrazol-5-yl>-N'-(2-(f3-(2-

methylpheni0f1.2.4ltriazolof4.3-alpyridin6-intio)benzyl)urea

The desired compound was obtained from the product from the preparation of 116 and 206, according to the procedure described for example 104, as a solid in a yield of 36%. 1HNMR(400MHz, CDCl3) d: 1.31(s, 9H), 2.21 (s, 3H), 3.83(m, 2H), 3.98(m, 2H), 4.53(d, 2H), 6.18(brs, 1H), 6.33(s, 1H), 6.72(d, 1H), 7.00(m, 3H), 7.09(brs, 1H), 7.20(m, 3H), 7.35(m, 6H), 7.45(d, 1H) , 7.52(d, 1H), 7.71 (s, 1H); LRMS APCI m/z 648 [M+H]+

First 106

N-13-tert-Butyl-1-f4-thydroxymethyl)phenyl-1H-pyrazol-5-yl}-N'-(2-f(3-isopropion.2.41triazolof4.3-alpyridin-6-iothiol)benziflurea

Tetraethylammonium fluoride dihydrate (60mg, 0.40mmol) was added to a solution of the product from the preparation of 136 (200mg, 0.29mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 6 hours. More tetraethylammonium fluoride dihydrate (60mg, 0.32mmol) was added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between 1 M hydrochloric acid (20 mL) and dichloromethane (20 mL). The aqueous layer was separated and extracted with dichloromethane (5x20mL), and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with dichloromethane:methanol, 99:1 to 92.5:7.5, and then trituration with dichloromethane/diethyl ether, gave the desired compound as a solid in a yield of 41%, 68.8mg. 1HNMR(300MHz, CDCl3) S: 1.27(s, 9H), 1.29(d, 6H), 3.18(m, 1H), 4.33(s, 2H), 4.46(d, 2H), 4.69(brs, 1H), 6.30(s, 1 H), 6.87(d, 1 H), 6.95(d, 2H), 7.07-7.25(m, 7H), 7.36(d, 1 H), 7.74(s, 1 H), 8.04( s, 1 H); LCMS m/z 570 [M+H]+

First 107

N41T3-Hydroxypheni0-3-ri-methyl-1-(methylthio)ethyl1-1H-pyrazol-5-yl)-N'-(2-(f3-(2-methoxypheni0f1.2.41triazolo r4.3-a1pyridin-6- il1tio}benzi0urea

The title compound was obtained from the product of Preparation 227, following a procedure similar to that described for Example 106, as a white solid in 65% yield. 1HNMR(400MHz, DMSO-d6) δ: 1.58(s, 6H), 1.89(s, 3H), 3.69(s, 3H),

4.38(d, 2H), 6.32(s, 1 H), 6.77(dd, 1 H), 6.86(m, 2H), 7.05(m, 1 H), 7.22(m, 8H), 7.56(m, 2H), 7.84(m, 2H), 8.32(s, 1 H), 9.77(s, 1 H); LCMS m/z 652 [M+H]+

First 108

N-[3-tert-Butyl-1-f3-hydroxy-4-methylphenyl)-1H-pyrazol-5-yn-N'-f2-K3-isopropylM,2,4]triazolo[4,3-a1pyridine-6 -i0tio1 benzylurea

Tetraethylammonium fluoride dihydrate (2.78g, 15.0mmol) was added to a solution of the product from preparation 137 (951mg, 1.39mmol) in tetrahydrofuran (10mL) and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was then concentrated in vacuo and the residue partitioned between 1 M hydrochloric acid (25 mL) and dichloromethane (25 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by chromatography on a silica gel column, eluting with dichloromethane, 95:5 to 90:10, and then trituration with dichloromethane/methanol:diethyl ether, gave the desired compound as a solid in a yield of 11%, 83.7mg.

1HNMR(300MHz, DMSO-d6) 8: 1.24(s, 9H), 1.37(d, 6H), 2.15(s, 3H), 3.38(m, 1H), 4.42(d, 2H), 6.19(s, 1H), 6.74(d, 1H), 6.89(s, 1H), 7.10-7.13(m, 2H), 7.25-7.33(m, 4H), 7.47(m, 1H), 7.88(m, 2H), 8.30(s, 1H), 8.80(s, 1 H); LCMS m/z 570.6 [M+H]+

First 109

N-(2-ff3-(2-Fluoropheni0ri.2.41triazolof4.3-alpiridin-6-ylthio>benzyl)-N'-f1-(4-hydroxypheni0-3-f1-metil-1 -(metilthiojetill-l H- pyrazol-5-yl)urea

The desired compound was obtained from the product of Preparation 163, following a procedure similar to that described for Example 108, as a white solid in 26% yield.

1HNMR(300MHz, DMSO-d6) 5: 1.56(s, 6H), 1.88(s, 3H), 4.36(d, 2H), 6.30(s, 1H), 6.83(d, 2H), 7.00(m, 1H), 7.23(m, 7H), 7.44(m, 2H), 7.66(m, 1 H), 7.77(m, 1 H), 7.86(d, 1H), 8.16(d, 2H), 9.72(s, 1 H); LCMS m/z 640 [M+H]+

First 110

N-(1-(3-HydroksifeniD-3-H-metil-1-(metiltio)etin-1H-pvrazol-5-il}-N’-l2-[T3-

isopropyl 1.2.41triazolof4.3-alpyridin-6-inthiolbenzylurea

The desired compound was obtained from the product of the preparation of 225, according to a procedure similar to that described for example 108, as a white solid in a yield of 53%. 1HNMR(300MHz, DMSO-d6) δ: 1.24(s, 9H), 1.38(d, 6H), 3.58(m, 1H), 4.41(d, 2H), 6.23(s, 1H), 6.74(m, 1H ), 6.87(m, 2H), 7.01-7.17(m, 2H), 7.20-7.29(m, 5H), 7.67(m, 1H), 8.28(m, 1H), 8.58(m, 1H), 9.72(s, 1H); LCMS m/z 632.6 [M+H]+

First 111

N-(2-{[3-(2-Fluorofeni0f1.2.41triazolor4.3-alpiridin-6-intio>benzi0-N’-(1-(3-hidroksifeni0-3-f1-

methyl-1-(methylthio)ethin-1H-pyrazol-5-yl)urea

The desired compound was obtained from the product of preparation 226, according to a procedure similar to that described for example 108, as a white solid in a yield of 53%.

1HNMR(300MHz, DMSO-d6) 5: 1.57(s, 6H), 1.89(s, 3H), 4.38(d, 2H), 6.32(s, 1 H), 6.78(dd, 1 H), 6.86(m, 2H), 7.05(m, 1H), 7.28(m, 6H), 7.44(m, 2H), 7.67(m, 1H), 7.77(m, 1H), 7.87(d, 1H), 8.20(m, 1H), 8.31(s, 1 H), 9.77(s, 1H); LCMS m/z 640 [M+H]+

First 112

N-f3-(1.1-Dimetilpropil)-1-(3-hydroxypheni0-1H-pyrazol-5-yl-N'-r2-((3-[2-(metilthio)fenil1f1.2.4ltriazolorf4,3-aT pyridin- 6-yl)thio)benzinurea

The desired compound was obtained from the product from preparation 243, according to a procedure similar to that described for example 108, as a white solid in a yield of 31%. 1HNMR(300MHz, DMSO-d6) δ: 0.75(t, 3H), 1.19(s, 6H), 1.57(q, 2H), 2.40(s, 3H), 4.38(d, 2H), 6.20(s, 1H) ), 6.76(d, 1H), 6.87(m, 2H), 7.03(m, 1H), 7.24-7.37(m, 6H), 7.55(m, 2H), 7.61(m, 1H), 7.85-7.92( m, 2H), 8.30(m, 2H), 9.77(s, 1H); LCMS m/z 650 [M+H]+

First 113

N-f3-tert-Butyl-1-(4-hydroxyphenin-1H-pyrazol-5-yl1-N'-(2-(f3-(2-fluoropheni0f1.2.41triazolof4.3-alpyridin-6-inthio) benzylurea

The desired compound was obtained from the product from the preparation of 248, according to the procedure described for Example 108, as a white solid in a yield of 95%.

1HNMR(300MHz, DMSO-d6) 5 1.23(s, 9H), 4.37(đ, 2H), 6.14(s, 1H), 6.85(d, 2H), 7.18-7.30(m, 8H), 7.39-7.49(m, 2H), 7.68(m, 1H), 7.76-7.87(m, 2H), 8.19(s, 1 H), 8.38(s, 1 H), 9.87(s, 1 H); LCMS m/z608 [M+H]+

First 114

N-f3-tert-Butyl-1-(3-hydroxyfenil)-1H-pyrazol-5-yl1-N'-[2-({3-[4-(metilthiojfenillH ,2,41triazolof4.3-alpyridin-6- il1 thiojbenzylurea

The desired compound was obtained from the product from the preparation of 253, according to the procedure described for example 97, as a pale yellow solid in a yield of 78%. 1HNMR(400MHz, DMSO-d6) δ: 1.21(s, 9H), 2.53(s, 3H), 4.40(d, 2H), 6.21 (s, 1H), 6.75(d, 1H), 6.85(d, 1H) ), 6.88(s, 1H), 7.02(m, 1H), 7.20(d, 1H), 7.25(m, 2H), 7.31 (m, 3H), 7.43(d, 2H), 7.81 (d, 2H), 7.83(d, 1H), 8.27(s, 1H), 8.37(s, 1H), 9.73(s, 1H); LRMS APCI m/z 636 [M+H] +

First 115

N-(1-r3-(2-Hydroxyethoxy)phenin-3-H-methyl-1-(methylthio1etin-1H-pyrazol-5-yl)-N'-(2-(f3-(2-isopropylphenyl)f1.2.41 trizolof4,3-alpyridin-6-intio}benzyl)urea

para-toluenesulfonic acid (63mg, 3.3mmol) was added to a solution of the product from the preparation of 255 (262mg, 3.3mmol) in methanol (15mL) and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted with water, its basicity was increased by the addition of sodium hydrogen carbonate solution and the resulting precipitate was filtered to give the desired compound as a white solid in a yield of 76%.

1HNMR(300MHz, DMSO-d6)§: 1.09(d, 6H), 1.57(s, 6H), 1.89(s, 3H), 2.75(m, 1H), 3.69(s, 2H), 4.40(d, 2H), 4.34(d, 2H), 4.88(brs, 1H), 6.31 (s, 1H), 6.93(dd, 1H), 7.03(m, 2H), 7.26(m, 8H), 7.46(d, 1H), 7.56(d, 2H), 7.83(d, 2H), 8.63(s, 1 H); LCMS m/z 708 [M+H]+

The following compounds in list 2 can be obtained according to procedures analogous to those previously described. In the following embodiment, the preferred group of compounds is the one where each substituent is indicated in list 2 below.

Preferably, compound formula (I) is selected from list 2: N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({ 3-[2-(2-Hydroxyethoxy)phenyl][1,2,4]triazolo [4,3-a]pyridin-6-yl}thio)benzyl]urea N-[3-tert-butyl-1-( 3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo [4,3 -a]pyridin-6-yl}thio)benzyl]urea N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl!)-1H-pyrazol-5-yl]-N'-[2 -({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo [4,3-a]pyridin-6-ii}thio)benzyl]urea N-[3-tert-butyl- 1-(3-hior-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4, 3-a]pyridin-6-yl}thio)benzyl]urea

N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[ 4,3-a]pyridin-6-yl)thio]benzyl}urea

N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-i!)thio]benzyl}urea

N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-(2-hydroxyethoxy)phenyl] [1,2,4]triazolo [4,3-a]pyridin-6-yl}thio)benzyl]urea N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazole -5-yl]-N'-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo [4,3-a]pyridin-6-yl}thio)benzyl ]urea N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[4-(2-hydroxyethoxy) phenyl][1,2,4]triazolo [4,3-a]pyridin-6-yl}thio)benzyl]urea N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H -pyrazol-5-yl]-N'-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a] pyridin-6-yl}thio)benzyl ]urea

N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[ 4,3-a]pyridin-6-yl)thio]benzyl}urea

N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-hydroxyethyl)thio ]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl -1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3 -a]pyridin-6-yl}thio)benzyl]urea N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5- il}-N'-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N -{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[4 -(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N-{-(3-chloro-4-hydroxyphenyl)-3- [1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[2-(methylthio)phenyl] [1,2,4]triazolo[4 ,3-a]pyridin-6-yl}thio)benzyl]urea N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol- 5-yl}-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3- {2-[(2-Hydroxyethyl)thio]phenyl}[1,2,4]triazo[o[4,3-a]pyridin-6-yl)thio]benzyl}urea N-{1-(4-chlor -3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[2-(2-hydroxyethoxy)phenyl] [1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1- (methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a] pyridin-6-yl}thio)benzyl]urea N-{1-(4-chloro-3-hydroxyphenyl)-3-[1 -methyl-1 -(methylthio)ethyl]-1 H -pyrazol-5-yl} -N'-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N-{ 1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[2-( methylthio)phenyl] [1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N-{1-(4-chloro-3-hydroxyphenyl)-3-[1- methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyltyl^^Jtriazolo^.S-alpyridin-e-iOthiolbenzylJurea

N-{1-(4-hlor-3-hydroxyfenil)-3-[1-metil-1-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-{ 2-[(2-hydroxyethyl)thio]fenil}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1-(3-chloro-4-hydroxyfenil)-3-[1,1-dimethyl-2-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[2-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1 -(3-hlor-4-hydroxyfenil)-3-[1,1 -dimethyl-2-(metilthio)ethyl]-1 H -pyrazol-5-yl}-N'-[2-({ 3-[3-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1 -(3-hlor-4-hydroxyfenil)-3-[1,1 -dimethyl-2-(metilthio)ethyl]-1 H -pyrazol-5-yl}-N'-[2-({ 3-[4-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({ 3-[2-

(methylthio)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-hior-4-hydroxyfenil)-3-[1,1-dimethyl-2-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3 -

izopropyl[1,2,4]triazole[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1-(3-hlor-4-hydroxyfenil)-3-[1,1-dimethyl-2-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3 -{2-[(2

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3,a]pyridin-6-yl)thio]benzyl}urea

N-{1-(4-chloro-3-hydroxyfenil)-3-[1,1-dimethyl-2-(methithio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[2-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4>3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(4-chloro-3-hydroxyfenil)-3-[1,1-dimethyl-2-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[3-(2-

hidroksietoksi)phenil][1,2,4]triazo!o[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1 -(4-hlor-3-hydroxyfenil)-3-[1,1 -dimethyl-2-(metilthio)ethyl]-1 H -pyrazol-5-yl}-N'-[2-({ 3-[4-(2-

hidroksietoksi)fenii][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(4-chloro-3-hydroxyfenil)-3-[1,1-dimethyl-2-(metilthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[2-

(methylthio)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(4-hlor-3-hydroxyfenil)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl)-N'-{2-[(3 -

izopropyl[1,2,4]triazole[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1 -(4-hlor-3-hydroxyfenil)-3-[1,1 -dimethyl-2-(metilthio)ethyl]-1 H -pyrazol-5-yl}-N'-{2-[( 3-{2-[(2

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzy(}urea

N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-(2-

hidroksietoksi)phenyl] [1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-chloro-4-hydroxyfenil)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[3-(2-

hidroksietoksi)phenyl] [1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[4-(2 -

hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-ii}thio)benzyl]urea

N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-

(methylthio)phenyl][1,2,4]triazo!o[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-chlor-4-hydroxyfenil)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a] pyridin-6-yl)thio]benzyl}urea

N-[1-(3-chlor-4-hydroxyfenil)-3-(1,1-dimethylpropi!)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[( 2-

hydroxyethyl)thio]phenyl}[1,2,4]triazoio[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-ii]-N'-[2-({3-[2-(2- hydroxyethoxy)phenyl] [1,2,4]triazolo[4,3-a]pyridin-6Hl}thio)benzyl]urea N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1- dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[3-(2-hydroxyethoxy)phenyl] [1,2,4]triazolo[4>3-a]pyridine-6 -yl}thio)benzyl]urea N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-( {3-[4-(2-hydroxyethoxy)phenyl] [1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(4-chloro-3-hydroxyfenil)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-

(metilthio)fenil][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea N-[1-(4-chloro-3-hydroxyfenil)-3-(1 ,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a] pyridin-6-yl)thio]benzi !}urea

N-[1-(4-hlor-3-hydroxyfenil)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2 -

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-(2-

hidroksietoksi)phenyl][1,2,4]triazole [4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[3-(2-

hidroksietoksi)phenyl][1,2,4]triazole [4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[4-(2-

hidroksietoksi)phenyl][1,2,4]triazole [4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-

(methylthio)phenyl][1,2,4]triazole[4,3-a] pyridin-6-yl}thio)benzyl]urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-

izopropil[1,2,4]triazolo[4,3-a]piridin-6-if) tio]benzil}urea

N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[ 2-(2-

hidroksietoksi) phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[ 3-(2-

hidroksietoksi) phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[ 4-(2-

hidroksietoksi) phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3-[ 2-

(methylthio)phenyl] [1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1 -(3-cyano-4-hydroxyphenyl!)-3-[1 -methyl-1 -(methylthio)ethyl]-1 H -pyrazol-5-yl}-N'-{2-[(3 -{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[2-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[3-(2-

hydroxyethoxOfeniOfl.ž^jtriazolo^.S^pyridine-e-ylJthioJbenzylurea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[4-(2-

hidroksietoksi)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-[2-({3 -[2-

(methylthio)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3 -

isopropylll^^jtriazolo^.S-ajpyridine-e-iOtioJbenzylJurea

N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3 -{2-[(2-

hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridine,6-yl)thio]benzyl}urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-(2-

hydroxyethoxy)phenyl] [1,2,4Jtriazolo[4,3-ylpyridin-6-yl}thio)benzyl!]urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[3-(2-

hidroksietoksi)phenil] [1(2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[4-(2 -

hidroksietoksi)phenyl] [1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-[2-({3-[2-

(methylthio)phenyl][1,2,4]triazole[4,3-a]pyridin-6-yl}thio)benzyl]urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-{2-[(3-

izopropyl[1,2,4]triazole[4,3-a] pyridin-6-yl)thio]benzyl}urea

N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2 -hydroxyethyl)thio]phenyl} [1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea N-{3-tert-butyl-1-[3-(2- hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo [4,3-a]pyridin- 6-yl]thio}benzyl)urea N-{3-tert-butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3- (2-chloro-5-hydroxyphenyl)[1,2,4]triazolo [4,3-a]pyridin-6-yl]thio}benzyl)urea N-{3-tert-butyl-1-[4-( 2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo [4,3-a] pyridin-6-yl]thio}benzyl)urea N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[ 3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo [4,3-a]pyridin-6-yl]thio}benzyl)urea N-(2-{[3-(5-chloro -2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{1-[3-(2-hydroxyethoxy)phenyl]-3- [1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4 ,3-a]pyridin-6-yl]thio}benzyl)-N'-{1-[3-(2-

hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1>2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{1- [4-(2-

hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(2-hlor-5-hidroksifenii)[1l2,4]triazolo[4,3-a]piridin-6-il]tio}benzil)-N’-{1-[4-(2-

hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1,1-dimethyl

2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)fenil]-1H-pyrazol-5-yl}urea

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1,1-dimethyl 2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1,1-dimethyl 2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1,1-dimethyl

2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)fenil]-1H-pyrazol-5-yl}urea

N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-ii]thio}benzyl)-N'-{3- (1>1-

dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- (1,1-

dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- (1,1-

dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- (1.1 -

dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-{3-tert-butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(3-cyano-4-

hidroksiphenil)[1,2,4]triazole [4,3-a]pyridin-6-yl]thio}benzyl)urea

N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(3-cyano-4-

hidroksiphenil)[1,2,4)triazole [4,3-a]pyridin-6-yl]thio}benzyl)urea

N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1>214]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{1-[3 -(2-

hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{1- [4-(2-

hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

5 N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3 -[1,1-

dimethyl-2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- [1,1-

dimethyl-2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3- (1.1-

dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2l4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N'-{3-(1 ,1-

dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea

N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-ethylphenyl)[1,2,4]triazolo[ 4,3-a]pyridin-6-yl]thio}-benzyl)urea.

Claims (27)

1. Compound of formula (I), or its pharmaceutically acceptable salt and/or solvate (including hydrate); where R 1 is CH 3 1 SCH 3 > SCH 2 CH 3 , CH 2 CH 3 , H or CH 2 SCH 3 ; R 1a is CH 3 or CH 2 CH 3 ; R 2 is heteroaryl, heterocyclyl, aryl, or carbocyclyl; R 3 is heteroaryl, heterocyclyl, aryl, carbocyclyl or R 7 ; R 7 is (C 1 -C 8 alkyl optionally substituted with one or more substituents independently selected from OH, halo, NR 5 R 6 , (C 1 -C 8 )alkoxy, -S(O)p(C 1 -C 8 )alkyl, CO 2 H, CONR 5 R 6 , heteroaryl, heterocyclyl, aryl, carbocyclyl, aryloxy, carbocyclyloxy, heteroaryloxy and heterocyclyloxy; p is 0, 1 or 2; R 5 and R 6 are each independently selected from H and (C 1 -C 4 )alkyl, said (C 1 -C 4 )alkyl being optionally substituted with one or more substituents independently selected from OH and halo, or R5 and R6, together with the nitrogen to which they are attached form a piperazinyl, piperidinyl, morpholinyl, or pyrrolidinyl group, provided the piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl are each optionally substituted with one or more OH; "aryl" means phenyl! or naphthyl, given phenyl or naphthyl is optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, ON, CONR5R6, R7 and R8; R8 is selected from (C1C6alkyl, (C-1-C6)alkoxy, -CO^ C 1 -C 6 alkyl, -S(O)p(C 1 -C 6 )alkyl, -COCC 1 -C 6 alkyl and (C 3 -C 7 )cycloalkyl; each R 5 is optionally substituted with one or more substituents independently selected from: (C 1 -C 6 ) alkoxy optionally substituted with one or more substituents independently selected from OH, halo, CO2H, CONR5R6 and NR5R6. -S(O)p(C1C6)alkyl optionally substituted with one or more substituents independently selected from OH, halo, CO2H, CONR5R6 and NR5R6, OH, halo, NR5R6, CO2h, CONR5R6, and R9; R9 is heteroaryl1, heterocyclyl2, aryl1, carbocyclyl2, aryl1oxy, carbocyclyl2oxy, heteroaryl1oxy or heterocyclyl2oxy; "aryl1" means phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with one or more substituents independently selected from halo, -CN, CO2H, OH and CONR5R6; "carbocyclyl" means a mono- or bicyclic, saturated or partially unsaturated ring system containing 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, OH, CONR5R6, R8 and R9. "Carbocyclyl1" means a mono- or bicyclic, saturated or partially unsaturated ring system with 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halo, -CN, -CO2H, OH and CONR5R6; each "heterocyclyl", and "heterocyclyl1" independently, means 3- to 10-membered, a saturated or diethyl unsaturated, mono or bicyclic group with 1 to 4 ring heteroatoms, independently selected from N, O, and S, each "heteroaryl", and each "heteroaryl2", independently, means 5 to 10 membered, mono or bicyclic, an aromatic group containing from 1 to 4 ring heteroatoms independently selected from N, O, and S where the total number of S ring atoms does not exceed 1, and the total number of O ring atoms does not exceed 1. each "heterocyclyl" and each "heteroaryl " group is, independently, optionally substituted on one or more ring carbon atoms, with one or more substituents independently selected from halo, -CN, -CO2H, OH, CONR5R6, R8 and R9, and optionally substituted on one or more carbon atoms ring nitrogen with one or more substituents independently selected from H and (C 1 -C 8 )alkyl; each "heterocyclyl1" and each "heteroaryl2" group is, independently, optionally substituted on one or more ring carbon atoms, with one or more substituents independently selected from halo, -CN, -CO2H, OH, and CONR5R6, and optionally substituted on one or more nitrogen atoms in the ring, one or more substituents independently selected from H and (Cr C6)alkyl; 2. A compound, salt and/or solvate according to claim 1, characterized in that R1 is CH3, SCH3, SCH2CH3 or CH2SCH3. 3. A compound, salt and/or solvate according to claim 2, wherein R1 is CH3 or SCH3. 4. A compound, salt and/or solvate according to one of claims 1 to 3, characterized in that R1a is CH3. 5. A compound, salt and/or solvate according to one of claims 1 to 4, characterized in that R2 is selected from pyridyl, tetrahydronaphthyl and aryl, where each pyridyl, tetrahydronaphthyl and aryl is optionally substituted with one or more substituents independently selected from the group are: halo, -CN, -CO2H OH, CONR5R6 (C,-C6)alkyl, given (C,-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, NR5R6, aryl2 and halo, -S( 0)p(C1-C6)alkyl, given -S(0)p(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, (C1C6)alkoxy, given (C,- C6)Alkoxy is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, -O02(O,-C6)alkyl to give -C02(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, (C3-C7)cycloalkyl, said (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halo, pyridyl, and aryl2. 6. A compound, salt and/or solvate according to claim 5, characterized in that R2 is: 3-pyridyl optionally substituted with one or more substituents independently selected from OH, -S(C,-C6)alkyl, (Ci-C6) alkoxy, CF3 and halo, or phenyl optionally substituted with one or more substituents independently selected from (C,-C6)alkyl, OH,-S(Ci-C6)alkyl, (C,-C6)alkoxy, CN, CF3 and halo . 7. A compound, salt and/or solvate according to claim 8, characterized in that R2 is phenyl optionally substituted with one or more substituents independently selected from methyl, ethyl, OH, CN, CF3, Cl, F, -SCH3 and -OCH3. 8. Compound, salt and/or solvate according to claim 7, characterized in that R2 is 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl, 3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-hydroxy-3-methylphenyl , 3-methylphenyl or 4-hydroxy-3chlorophenyl. 9. A compound, salt and/or solvate according to one of claims 1 to 8, characterized in that R3 is pyridyl or aryl, each pyridyl and aryl optionally substituted with one or more substituents independently selected from the group consisting of: halo, -CN , -co2h OH, CONR5R6 (Cr-C6)alkyl, said (CrC6)alkyl is optionally substituted with one or more substituents independently selected from OH, NR5R6, aryl2 and halo. -S(0)p(Ci-C6)alkyl, given -S(0)p(Ci-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, (CrC6alkoxy, given (Cr- C6) alkoxy is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, -C02(C1-C6)alkyl, given -C02(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from OH, aryl2 and halo, (C3-C7)cycloalkyl, given (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halo, pyridyl, and aryl2, or R3 is (C3-C6)alkyl, optionally substituted one or more substituents independently selected from OH, halo, and (C 1 -C 6 ) alkoxy. 10. The compound, salt and/or solvate according to claim 9, characterized in that R3 is aryl, optionally substituted with one or more substituents independently selected from the group consisting of: halo, OH, (CrC6)alkyl, given (CrC6)alkyl is optionally substituted with one or more substituents independently selected from OH and halo, (CrC6alkoxy, given (CrC6)alkoxy is optionally substituted with one or more substituents independently selected from OH and halo, or R3 is (CrC6)alkyl. 11. The compound, salt and/or solvate according to claim 10, characterized in that R3 is phenyl optionally substituted with one or more substituents independently selected from: Cl, F, OH, methyl, ethyl, isopropyl, CF3, methoxy, ethoxy, each of the indicated methoxy and ethoxy is optionally substituted with OH, or R3 is isopropyl. 12. A compound, salt and/or solvate according to one of claims 1-11, characterized in that R5 and R6 are each independently selected from H, methyl and ethyl. 13. The compound, salt and/or solvate according to any of claims 1 to 9, characterized in that R3 is aryl, optionally substituted by one or more substituents independently selected from the group consisting of: halo, OH, CN, (CrC6)alkyl, given (C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from OH and halo, (C 1 -C 6 )alkyloxy, given (C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from OH and halo, -S-^- OOalkyl, given -S-(Ci-C6)alkyl is optionally substituted with one or more substituents independently selected from OH and halo, or R3 is (C^C6alkyl. 14. The compound, salt and/or solvate according to claim 13, characterized in that R3 is phenyl optionally substituted with one or more substituents independently selected from: CN, Cl, F, OH, methyl, ethyl, isopropyl, CF3, -S- (C1-C4)alkyl, wherein -S-(C1-C4)alkyl is optionally substituted with OH, methoxy or ethoxy, wherein ethoxy is optionally substituted with OH, or R3 is isopropyl. 15. A compound, salt and/or solvate according to claim 14, characterized in that R3 is phenyl substituted with one or two substituents independently selected from Cl, F, CN, OH, -S-methyl, methoxy, -SCH2CH2OH and -OCH2CH2OH. 16. A compound, salt and/or solvate according to one of claims 1 to 9, 13, 14 or 15, characterized in that R3 is phenyl substituted with at least one substituent independently selected from -S-methyl and -SCH2CH2OH, giving -S- methyl or -SCH2CH2OH is located at the ortho position of the phenyl. 17. Jedinjenje formula (I) or its pharmaceutically acceptable salt or solvate selected from N-{3-tert-Butyl-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}-N' -{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)-thio]benzyl}urea, N-{3-tert-butyl-1-[3 -(methylthio)phenyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)-thio ]benzyl}urea, N-[3-tert-butyl-1-(3l4-dichlorophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazo [4,3-a]pyridin-6-yl)thio]-benzyl}urea, ethyl 4-(3-tert-butii-5-{[({2-[(3-isopropyl[1,2,4] triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl]amino}-1H-pyrazol-1-yljbenzoate, ethyl 3-(3-tert-butyl-5-{[({ 2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)karbonyl]amino}-1H-pyrazol-1-yljbenzoate, N- [3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a] pyridin-6-yl)thio] benzyl}urea, N-[3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[ 1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzylurea, N-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-N'-{ 2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(4-methylphenyl) -1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio] benzylurea, N-[3 -tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin- 6-yl)thio]-benzyl}urea, N-[3-tert-butyl-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3 - isopropyl[1,2,4]triazolo[4,3-a]pyridin6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5- il]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]-benzylurea, N-[3-tert-Butyl-1 -(4-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a] -pyridin-6-yl]thio}benzyl)urea, N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-( 2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]-pyridin-6-yl]thio}benzyl)urea, N-{3-[1,1-Dimethyl-2- (methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl )thio]benzyl}urea, N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{2- [(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N-{2-[(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}-N'-{3-[1-methyl-1-(methylthio)ethyl]-1-phenyl H-pyrazol-5-yl}urea, N-{1-[2-(benzyloxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[ 1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl ]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl [1,2,4] triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N -{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N'-{3-[1-methyl-1-(methylthio )ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea, N-[2-( {3-[2-(benzyloxy) phenyl] [1,2,4] triazolo [4,3-a]pyridin-6-yl}thio)benzyl]-N'-{3-[1-methyl-1-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl} urea, N-[2-({3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N'-{1 -(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea, N-[2-( {3-[2-(benzyloxy)phenyl] [1,2,4]triazolo[4,3-a]pyridin-6-yl)thio)benzyl]-N'-{3-[1-methyl-1-(methylthio)ethyl]-1 -[4- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea, N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[ (3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio] benzyl}urea, N-[3-tert-Butyl-1-(4-hydroxy-3-methylphenyl) )-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin6-yl)thio]benzyl}urea, N-{ 1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4 ]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a] pyridin-6-yl]thio}benzyl)-N'-{3-[1-methyl-1 -(methylthio)ethyl]-1phenyl-1H-pyrazol-5-yl}urea, N-{1-(4- hlorfenil)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo [4,3-a]pyridin-6-yl]thio}benzyl)urea, N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin- 6-yl]thio}benzyl)-N'-{3-[1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea 3- (3-tert-Butyl-5-{3-[2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-ureido}-pyrazol- 1-yl)-benzojeva kiselina, 4-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl )thio]benzyl}amino)karbonyl]amino}-1Hpyrazol-1-yl)benzojeva kiselina, N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'- {2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio] benzyl}urea, N-[3-tert-Butyl-1-(3-methylphenyl) )-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a] pyridin-6-yl ]thio}benzyl)urea, N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2- [(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-Butyl-1-(4-chlorophenyl)-1H -pyrazol-5-yl]-N'-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6yl]thio}benzyl)urea, N- [3-tert-Butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4] triazolo[4,3-a] pyridin-6-yl]thio}benzyl)urea, N-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol- 5-yl}-N'-(2-{[3-(2-hydroxy-4-methylphenyl) [1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea , N-[3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo [4,3-a]pyridin-6yl]thio}benzyl)urea, N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{ [3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6yl]thio}benzyl)urea, N-[3-tert-butyl-1-(3-hior-4 -hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1l2>4]triazolo[4,3- a]pyridin-6yl)thio]benzyl}urea, N-{ 1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1, 2,4]-triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol- 5-yl]-N'-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, N-[ 3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-isopropyl[1,2,4]triazolo[4,3 - a]pyridin-6-yl)thio]benzyl}urea, N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2 -{[3-(2- hlorfenil)[1,2,4]triazolo[4,3-a]-pyridin-6-yl]thio}benzyl)urea, N-{1-(4-hydroxyphenyl)-3 -[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N'-{2-[(3-phenyl[1,2,4]triazolo[4,3-a]- pyridin-6-yl)thio]benzyl}urea, i N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[ (3-{2-[(2-Hydroxyethyl)thio]phenyl}[1,2,4]-triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea. 18. N-{3-tert-Butyl-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}-N'-{2-[(3-isopropyl[1,2,4]triazolo [4,3-a]pyridin-6-yl)thio] benzylurea, or a pharmaceutically acceptable salt and/or solvate thereof. 19. N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chloro-5-hydroxyphenyl)[1 ,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, or a pharmaceutically acceptable salt and/or solvate thereof. 20. N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-(2-{[3-(2-chlorophenyl)[1, 2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea, or a pharmaceutically acceptable salt and/or solvate thereof. 21. N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2- hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea, or a pharmaceutically acceptable salt and/or solvate thereof. 22. Compound and/or solvate according to one of claims 1 to 21, for use in medicine. 23. A compound, salt and/or solvate according to one of claims 1 to 21, for use in the treatment of a disease, disorder, or condition selected from the group consisting of: asthma of any type, etiology or pathogenesis, especially asthma selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, internal asthma caused by pathophysiological disorders, external asthma caused by environmental factors, essential asthma of unknown or non-obvious cause, non- atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, vising syndrome in children and bronchiolitis, •    chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction and emphysema, •    obstructive or inflammatory airway diseases of any type, etiology or pathogenesis, especially obstructive or inflammatory airway disease, belonging to the group that include chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema, or dyspnea associated or unrelated to COPD, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), worsening hyper - reactivity of the airways as a result of therapy with other drugs and diseases of the airways associated with pulmonary hypertension. •    bronchitis of any type, etiology or pathogenesis, and in particular bronchitis selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, acute laryngotracheal bronchitis, arachidonic bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis and vesicular bronchitis, •    acute lung injury, •    bronchiectasis of any type, etiology or pathogenesis, and especially bronchiectasis which is a selected member of the group consisting of cylindrical bronchiectasis, scular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis. 24. A compound, salt and/or solvate according to one of claims 1 to 21, for use according to claim 23, wherein the disease, disorder or condition is obstructive or inflammatory disease of the airways of any type of etiology or pathogenesis, in particular obstructive or inflammatory disease airways, which is selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, pulmonary emphysema or either dyspnea associated or unrelated to COPD, COPD characterized by irreversible, progressive airway obstruction, respiratory adult distress syndrome (ARDS), exacerbation of airway hyper-reactivity as a consequence of other drug therapies and airway disease associated with pulmonary hypertension. 25. A compound, salt and/or solvate according to any one of claims 1 to 21, for use according to claim 24, wherein the disease, disorder, or condition is chronic obstructive pulmonary disease (COPD). 26. Use of a compound, salt and/or solvate according to any one of claims 1 to 21, for the manufacture of a medicament for the treatment of a disease, disorder or condition as defined in claim 23, claim 24 or claim 25. 27. A pharmaceutical composition comprising a compound, salt and/or solvate according to one of claims 1 to 21, and a pharmaceutically acceptable diluent, carrier or adjuvant.