KR20070032066A - Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors - Google Patents

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (including hydrates) thereof; And TNF-mediated diseases, disorders or symptoms, or p38-mediated diseases, disorders or symptoms, specifically allergic and nonallergic airway diseases, more specifically obstructive or inflammatory airway disease, preferably chronic obstructive lung It relates to the use of a compound of formula (I) in the treatment of a disease:

Formula I

Description

TRIAZOLOPYRIDINYLSULFANYL DERIVATIVES AS P38 MAP KINASE INHIBITORS as a P38 MAP Kinase Inhibitor

The present invention relates to triazolopyridinylsulfanyl derivatives. More specifically, the present invention relates to pyrazolyl-[(triazolopyridinylsulfanyl) -benzyl] -urea derivatives, methods for their preparation, intermediates used for their preparation, compositions containing such derivatives and the use of such derivatives will be.

 Triazolopyridinylsulfanyl derivatives of the present invention are inhibitors of p38 mitogen activating protein kinases ("p38 MAPK (MARK)", "p38 kinase" or "p38"), in particular p38α kinase, and tumor necrosis factor ( "TNF") is an inhibitor of production, in particular TNFα. They have numerous therapeutic uses, and in particular have numerous therapeutic uses in allergic and nonallergic airway diseases, more particularly in obstructive or inflammatory airway diseases such as chronic obstructive pulmonary disease ("COPD").

Mitogen activating protein kinases (MAPs) constitute a family of proline-based serine / threonine kinases that activate substrates by double phosphorylation. Kinases are activated by a variety of signals, including nutrient and osmotic stress, UV light, growth factors, endotoxins and inflammatory cytokines. The p38 MAP kinase family is a MAP family consisting of various isoforms, including p38α, p38β and p38γ. These kinases, as well as other kinases (eg MAPKAP-2 and MAPKAP-3), are involved in the phosphorylation and activation of transcription factors (eg ATF2, CHOP and MEF2C). The p38 isotype is activated by bacterial lipopolysaccharide, physical and chemical stress, and pre-inflammatory cytokines, including tumor necrosis factor ("TNF") and interleukin-1 ("IL-1"). The product of p38 phosphorylation mediates the production of inflammatory cytokines including TNF.

TNF is a cytokine produced primarily by activated monocytes and phagocytes. Excessive or unregulated TNF production (particularly TNF-α) has been involved in mediating numerous diseases, and TNF generally appears to cause or contribute to an inflammatory effect.

IL-8 is another preinflammatory cytokine produced by monocytes, fibroblasts, endothelial cells and keratinocytes. The cytokines are associated with symptoms including inflammation. IL-1 is produced by activated monocytes and phagocytes and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses, including rheumatoid arthritis, decreased heat and bone resorption.

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

p38 kinase inhibitors are well known to those skilled in the art. J. Med. Chem. 2002, 45, 2994-3008, disclose specific pyrazole urea compounds as p38 kinase inhibitors. International patent application PCT / IB02 / 00424 (WO 02/072579) discloses triazolopyridine as an inhibitor of MAP kinase, preferably p38 kinase.

International Patent Application PCT IB2004 / 000363 (WO 2004/072072), published August 26, 2004, discloses triazolo-pyridine useful as an anti-inflammatory compound for treating certain diseases. This document is incorporated by reference in its entirety.

The compounds of the present invention may have useful efficacy in the treatment of a wide variety of disorders. In addition to the treatment of obstructive or inflammatory airway diseases, the compounds of the present invention may be used for asthma, chronic or acute bronchial contraction, bronchitis, acute lung injury and bronchiectasis, general inflammation (eg, inflammatory bowel disease), arthritis, neuritis, pain, fever , Fibrotic disease, pulmonary disorder or disease (e.g., peroxic alveolar injury), cardiovascular disease, post-ischemic reperfusion injury and congestive heart failure, cardiomyopathy, stroke, ischemia, reperfusion injury, kidney reperfusion injury, cerebral edema, neurotrauma and Brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease and nephritis, gastrointestinal symptoms, ulcer disease, eye disease, ophthalmic symptoms, glaucoma, acute damage to eye tissue and ocular trauma, diabetes, diabetic nephropathy, skin related symptoms , Muscle pain caused by infection, influenza, endotoxin shock, toxic shock syndrome, autoimmune disease, rejection of transplant, bone resorption disease, multiple sclerosis, psoriasis, female reproductive system Vulgaris, pathological (non-malignant) symptoms such as hemangiomas, hemangiofibromas of the nasopharyngeal pharynx, and benign and malignant tumors / neoplasms including bone avascular necrosis, leukemia, lymphoma, systemic lupus erythematosus (SLE), renal It can be used to treat TNF / p38 mediated diseases such as living organisms, including angiogenesis, bleeding, coagulation, radiation damage and / or metastasis. Chronic release of active TNF can cause cachexia and anorexia, and TNF can be fatal.

 TNF has also been associated with infectious diseases. These infectious diseases include, for example, malaria, mycobacterium infection and meningitis. These infectious diseases are also particularly viral infections such as HIV, influenza virus, and herpes simplex virus 1-type (HSV-1), herpes simplex virus 2-type (HSV-2), cytomegalovirus (CMV), varicella zoster Virus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8), rabies and rhinitis Herpes virus.

Treatment of obstructive or inflammatory airway disease is a preferred use. All forms of obstructive or inflammatory airway disease, particularly COPD with eosinophilic pneumonia, COPD, chronic bronchitis, emphysema or dyspnea associated with or without COPD, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbating airway hyperresponsiveness as a result of other drug treatments, and pulmonary hypertension related airway disease can be efficaciously treated by the compounds of the present invention.

There is a need to provide novel TNF inhibitors / p38 kinase inhibitors that are good drug candidates. Preferably, the novel TNF inhibitor / p38 kinase inhibitor exhibits good efficacy, a high level of selectivity over other related protein kinases, and is particularly suitable for providing effective treatment via the inhalation route, allergic and non Suitable for the treatment of allergic airway disease (especially obstructive or inflammatory airway disease), non-toxic, rarely adverse side effects, suitable for administration by inhalation, present in stable and non-hygroscopic physical form / Or is easily formulated.

Exemplary PXRD patterns of the compounds of Examples 80, 26, 93, 73, 63, and 60 are shown in FIGS. 1-6 that include a 15% silicon internal reference reference.

1 shows an exemplary PXRD pattern of the compound of Example 80. FIG.

2 shows exemplary PXRD patterns of the compound of Example 26. FIG.

3 shows exemplary PXRD patterns of the compound of Example 93. FIG.

4 shows exemplary PXRD patterns of the compound of Example 73. FIG.

5 shows an exemplary PXRD pattern of the compound of Example 63.

6 shows exemplary PXRD patterns of the compound of Example 60. FIG.

According to one aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (including hydrates) thereof:

Where

R ¹ is CH ₃ , S (O) _p CH ₃ , S (O) _p CH ₂ CH ₃ , CH ₂ CH ₃ , H or CH ₂ S (O) _p CH ₃ ;

R ^1a is CH ₃ or CH ₂ CH ₃ , wherein CH ₃ and CH ₂ CH ₃ are each unsubstituted or substituted with one or more hydroxy substituents;

R ² is heteroaryl, heterocyclyl, aryl or carbocyclyl;

R ³ is heteroaryl, heterocyclyl, aryl, carbocyclyl or R ⁷ ;

R ⁷ is 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, heterocycle (C ₁ -C ₆ ) alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of aryl, aryl, carbocyclyl, aryloxy, carbocyclyloxy, heteroaryloxy and heterocyclyloxy ;

p is 0, 1 or 2;

R ⁵ and R ⁶ are each independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl, wherein (C ₁ -C ₄ ) alkyl is one or more substituents independently selected from the group consisting of OH and halo Substituted or unsubstituted with, or

R ⁵ and R ⁶ together with the nitrogen to which they are attached form a piperazinyl, piperidinyl, morpholinyl or pyrrolidinyl group, wherein the piperazinyl, piperidinyl, morpholinyl and pyrrolidinyl are each 1 Is substituted or unsubstituted with at least one OH;

"Aryl" each independently means phenyl or naphthyl, said phenyl or naphthyl consisting of halo, -CN, -CO ₂ H, OH, CONR ⁵ R ⁶ , NR ⁵ R ⁶ , R ⁸ and R ⁹ Unsubstituted or substituted with one or more substituents independently selected from the group, preferably said phenyl or naphthyl is a group consisting of halo, -CN, -CO ₂ H, OH, CONR ⁵ R ⁶ , R ⁸ and R ⁹ Or is unsubstituted with one or more substituents independently selected from;

R ⁸ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -CO ₂ (C ₁ -C ₆ ) alkyl, -S (O) _p (C ₁ -C ₆ ) alkyl, -CO Each independently selected from the group consisting of (C ₁ -C ₆ ) alkyl and (C ₃ -C ₇ ) cycloalkyl;

R ⁸ is (C ₁ -C ₆ ) alkoxy (unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, halo, CO ₂ H, CONR ⁵ R ⁶ and NR ⁵ R ⁶ ), -S _{(O) p (C 1 -C} 6) Al keel (OH, halo, CO ₂ H, CONR ⁵ R ⁶ and NR ⁵ R ⁶ is not substituted with one or more substituents independently selected from the group consisting of substituted), Or are each unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, halo, NR ⁵ R ⁶ , CO ₂ H, CONR ⁵ R ⁶ and R ⁹ ;

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

"Aryl ² " means phenyl or naphthyl, said phenyl or naphthyl being one or more independently selected from the group consisting of halo, -CN, -CO ₂ H, OH, NR ⁵ R ⁶ and CONR ⁵ R ⁶ Or is not substituted with a substituent, preferably the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, OH and CONR ⁵ R ⁶ ;

"Carbocyclyl" is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, OH, NR ⁵ R ⁶ , CONR ⁵ R ⁶ , R ⁸ and R ⁹ , Preferably 3 to 10 ring carbon atoms, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, OH, CONR ⁵ R ⁶ , R ⁸ and R ⁹ Monocyclic or bicyclic saturated or partially unsaturated ring systems containing a sugar;

"Carbocyclyl ² " is unsubstituted, preferably halo, with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, NR ⁵ R ⁶ , OH and CONR ⁵ R ⁶ Monocyclic or bicyclic saturated or partially unsaturated rings containing 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from the group consisting of -CN, CO ₂ H, OH and CONR ⁵ R ⁶ System;

Examples of “carbocyclyl” and “carbocyclyl ² ” are groups such as indanyl, indenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and tetrahydronaphthyl;

“Heterocyclyl” and “Heterocyclyl ² ” are each independently 3-membered to include 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of N, O and S. A 10-membered saturated or partially unsaturated monocyclic or bicyclic group. Examples of "heterocyclyl" and "heterocyclyl ² " include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl , 1,4-oxatianyl, morpholinyl, 1,4-ditianyl, piperazinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H -Groups such as pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, dihydroindolyl and dihydrobenzofuranyl.

“Heteroaryl” and “heteroaryl ² ” each independently include 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of N, O and S, wherein a ring S atom Total number of ring O atoms does not exceed 1) 5 to 10 membered monocyclic or bicyclic aromatic 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, benzothiophenyl, indolyl, benz Imidazolyl, indazolyl, benzotriazolyl, Rolo [2,3-b] pyridinyl, pyrrolo [2,3-c] pyridinyl, pyrrolo [3,2-c] pyridinyl, pyrrolo [3,2-b] pyridinyl, imidazole [ 4,5-b] pyridinyl, imidazole [4,5-c] pyridinyl, pyrazolo [4,3-d] pyridinyl, pyrazolo [4,3-c] pyridinyl, pyrazolo [3, 4-c] pyridinyl, pyrazolo [3,4-b] pyridinyl, isoindolyl, purinyl, indolininyl, imidazole [1,2-a] pyridinyl, imidazo [1,5-a ] Pyridinyl, pyrazolo [1,5-a] pyridinyl, pyrrolo [1,2-b] pyridazinyl, imidazo [1,2-c] pyrimidinyl, quinolinyl, isoquinolinyl, shin Nolinyl, quinazolinyl, quinoxalineyl, phthalazine, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6 -Naphthyridinyl, 2,7-naphthyridinyl, pyrido [3,2-d] pyrimidinyl, pyrido [4,3-d] pyrimidinyl, pyrido [3,4-d] pyrimi Dinyl, pyrido [2,3-d] pyrimidinyl, pyrido [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl, pyrimido [5,4-d] pyrimid Dean , Pyrazinio [2,3-b] pyrazinyl and pyrimido [4,5-d] pyrimidinyl groups;

“Heterocyclyl” and “heteroaryl” groups each independently represent halo, —CN, —CO ₂ H, OH, NR ⁵ R ⁶ , CONR ⁵ R ⁶ , R ^8, and R ⁹ on one or more ring carbon atoms Unsubstituted or substituted with one or more substituents independently selected from the group consisting of, or preferably on one or more ring carbon atoms, -CN, -CO ₂ H, OH, CONR ⁵ R ⁶ , R ⁸ and R ⁹ Not substituted or substituted with one or more substituents independently selected from the group consisting of: substituted or substituted with one or more substituents independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl on one or more ring nitrogen atoms Not;

"Heterocyclyl ² " and "heteroaryl ² " groups are each independently independent from the group consisting of halo, -CN, -CO ₂ H, NR ⁵ R ⁶ , OH and CONR ⁵ R ⁶ on one or more ring carbon atoms One or more substituents independently or unsubstituted with one or more substituents selected from, or preferably independently selected from the group consisting of halo, -CN, -CO ₂ H, OH and CONR ⁵ R ⁶ on one or more ring carbon atoms Unsubstituted or substituted with a substituent and unsubstituted with one or more substituents independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl on one or more ring nitrogen atoms.

"Alkyl" and "alkoxy" groups, including groups containing such moieties, may be straight or branched chains having acceptable carbon atoms. "(C ₁ -C ₄ ) alkyl" or "(C ₁ -C ₆ ) alkyl" means a straight or branched chain group containing 1 to 4 or 1 to 6 carbon atoms, respectively. They may also have substituents or other radicals such as (C ₁ -C ₆ ) alkoxy radicals, —CO ₂ (C ₁ -C ₆ ) alkyl radicals, —CO (C ₁ -C ₆ ) alkyl radicals or —S ( O) also applies when present as a substituent on a _p (C ₁ -C ₆ ) alkyl radical. Examples of suitable (C ₁ -C ₄ ) 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. Examples of suitable (C ₁ -C ₆ ) alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy, pentyl Oxy and hexyloxy.

"Halogen" or "halo" is intended to mean a halogen atom selected from the group consisting of fluorine, chlorine and bromine.

It is to be understood that all references herein to “treatment”, “treat” or “treating” include healing, palliative and / or prophylactic treatment.

As used herein, "compounds of the present invention" or "compound of the present invention" means compounds or compounds of formula (I), pharmaceutically acceptable salts and / or solvates thereof, as defined below. All of its polymorphs, crystalline phases, prodrugs and isomers (including optical, geometric and tautomers) and mixtures thereof, and isotopically labeled compounds of formula (I).

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

In another aspect of the invention R ¹ is CH ₃ , 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 , R ³ , R ⁷ , p, R ⁵ , R ⁶ , "aryl", R ⁸ , R ⁹ , "aryl ² ", "carbocyclyl", "carbocyclyl ² ", "heterocyclyl", "heterocycle Reel ² "," heteroaryl "and" heteroaryl ² "are all provided as compounds as defined above, or a pharmaceutically acceptable salt and / or solvate (including hydrates) thereof.

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

In another embodiment, preferably R ¹ is CH ₃ , SCH ₃ , CH ₂ CH ₃ or CH ₂ SCH ₃ , 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 and the pyridyl, tetrahydronaphthyl and aryl are halo, —CN, —CO ₂ H, OH, CONR ⁵ R ⁶ , (C ₁ -C ₆ ) alkyl (this (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, NR ⁵ R ⁶ , aryl ² and halo), -S (O) _p (C ₁ -C ₆ ) alkyl (this -S (O) _p (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), (C ₁ -C ₆ ) alkoxy (wherein (C ₁ -C ₆ ) alkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), -CO ₂ (C ₁ -C ₆ ) alkyl, wherein -CO ₂ (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo , (C ₃ -C ₇ ) cycloalkyl (which (C ₃ -C ₇ ) cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo), pyridyl and aryl ² Unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

More preferably, R ² is one or more substituents independently selected from the group consisting of 3-pyridyl (OH, —S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, CF ₃ and halo Substituted or unsubstituted), or phenyl ((C ₁ -C ₆ ) alkyl, OH, -S (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, CN, CF ₃ and halo Unsubstituted or substituted with one or more substituents independently selected from.

Even more preferably, R ² is phenyl (methyl, ethyl, OH, CN, CF _3, Cl, F, -SCH ₃ and -OCH not substituted or substituted from the group consisting of ₃ with one or more substituents independently selected) to be.

Even more 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 another embodiment, R ² is preferably pyridyl or aryl, wherein each of the pyridyl and aryl is halo, —CN, —CO ₂ H, OH, CONR ⁵ R ⁶ , (C ₁ -C ₆ ) alkyl ( The (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, NR ⁵ R ⁶ and halo, and (C ₁ -C ₆ ) alkoxy (wherein (C ₁ -C ₆₎ alkoxy is OH, CO ₂ H, aryl ² and halo does not imchihwan with one or more substituents independently selected from the group consisting of substituted) value with one or more substituents independently selected from the group consisting of unsubstituted or Unsubstituted, more preferably R ² is substituted with one or more substituents independently selected from the group consisting of 3-pyridyl (OH, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and CF ₃ Or unsubstituted) or -S (C ₁ -C unsubstituted or substituted with phenyl ((C ₁ -C ₆ ) alkyl, OH, OH) ₆ ) alkyl, unsubstituted or unsubstituted with (C ₁ -C ₆ ) alkoxy, unsubstituted or substituted with one or more substituents independently selected from the group consisting of CN, CF ₃ and halo.

Even more preferably, R ² is (C ₁ -C ₄ ) alkyl, OH, —S (C ₁ -C ₄ ) alkyl (wherein -S (C ₁ -C ₄ ) alkyl is substituted or unsubstituted with OH) , (C ₁ -C ₄ ) alkoxy (wherein (C ₁ -C ₄ ) alkoxy is optionally substituted with OH), CN, CF ₃ and halo substituted or substituted with one or more substituents independently selected from the group consisting of Unsubstituted phenyl.

Even more preferably, R ² is phenyl (substituted or unsubstituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, CN, CF ₃ , Cl, F and -OCH ₂ CH ₂ OH). .

Even more preferably, R ² is phenyl substituted with one or two substituents independently selected from the group consisting of OH, Cl, CN, methyl and —OCH ₂ CH ₂ OH.

Preferably, when R ² is substituted phenyl, the substitution is in the 3- and / or 4- position of the phenyl.

In another preferred embodiment, the hydroxyethoxy substituent is at the 3 (meth) position of phenyl when R ² is phenyl substituted with a hydroxyethoxy substituent.

In a particularly preferred aspect of the invention, R ² is substituted phenyl according to any of the embodiments or preferred embodiments herein, wherein R ² phenyl is one or more hydroxy substituents or one or more hydroxyethoxy substituents, More preferably it is substituted with one or more hydroxy substituents.

In a preferred embodiment of the invention, R ² is 3-chloro and 4-hydroxy, 3-cyano and 4-hydroxy, 3-hydroxy, 4-hydroxy, 3-hydroxyethoxy, 3-hydroxy And phenyl substituted with 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 pyridyl and aryl are each halo, —CN, —CO ₂ H, OH, CONR ⁵ R ⁶ , (C ₁ -C ₆ ) alkyl (wherein (C _1- ) C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, NR ⁵ R ⁶ , aryl ² and halo), -S (O) _p (C ₁ -C ₆ ) alkyl ( The —S (O) _p (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), (C ₁ -C ₆ ) alkoxy ( The (C ₁ -C ₆ ) alkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), —CO ₂ (C ₁ -C ₆ ) alkyl (wherein -CO ₂ (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo, (C ₃ -C ₇ ) cycloalkyl (wherein (C _3- C ₇ Cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo), pyridyl and aryl ² or unsubstituted with one or more substituents independently selected from the group consisting of, or R ³ is preferably OH, halo and (C ₁ -C ₆₎ that is from the group consisting of alkoxy optionally substituted with one or more substituents independently selected from (C ₁ -C ₆₎ alkyl.

More preferably, R ³ is halo, OH, (C ₁ -C ₆ ) alkyl (wherein (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo ), And (C ₁ -C ₆ ) alkoxy, wherein (C ₁ -C ₆ ) alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of OH and halo) Aryl unsubstituted or substituted with one or more substituents selected, or R ³ is (C ₁ -C ₆ ) alkyl.

Still more preferably, R ³ is unsubstituted or substituted with one or more substituents independently selected from the group consisting of phenyl (Cl, F, OH, methyl, ethyl, isopropyl, CF ₃ , methoxy, ethoxy, wherein Methoxy and ethoxy are each substituted or unsubstituted with OH), or R ³ is isopropyl.

In another embodiment, R ³ is preferably pyridyl or aryl and said pyridyl and aryl are halo, —CN, —CO ₂ H, OH, CONR ⁵ R ⁶ , (C ₁ -C ₆ ) alkyl (the above (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, NR ⁵ R ⁶ , aryl ² and halo), -S (O) _p (C ₁ -C ₆ ) alkyl (wherein -S (O) _p (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), (C ₁ -C ₆ ) alkoxy (the (C ₁ -C ₆ ) alkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, aryl ² and halo), -CO ₂ (C ₁ -C ₆ ) alkyl (said -CO ₂ (C ₁ -C ₆₎ alkyl is not substituted by OH, aryl ² and halo one or more substituents independently selected from the group consisting of substituted), and (C ₃ -C ₇₎ cycloalkyl Kill with one or more substituents independently selected from the group consisting of (said (C ₃ -C ₇₎ cycloalkyl is OH and halo groups are not substituted or substituted with one or more substituents independently selected from the group consisting of) optionally substituted or, or R ³ is preferably OH, halo and (C ₁ -C ₆₎ that is from the group consisting of alkoxy optionally substituted with one or more substituents independently selected from (C ₁ -C ₆₎ alkyl.

More preferably, R ³ is substituted or substituted with one or more substituents independently selected from the group consisting of halo, OH, CN, (C ₁ -C ₆ ) alkyl (wherein (C ₁ -C ₆ ) alkyl is OH and halo Or (C ₁ -C ₆ ) alkoxy, wherein (C ₁ -C ₆ ) alkoxy is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo), -S- (C ₁ -C ₆ ) alkyl (wherein -S- (C ₁ -C ₆ ) alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo) Aryl unsubstituted or substituted with any of the above substituents, or R ³ is (C ₁ -C ₆ ) alkyl.

Even more preferably, R ³ is —S— (C ₁ -C ₄ ) alkyl, methoxy, unsubstituted or substituted with phenyl (CN, Cl, F, OH, methyl, ethyl, isopropyl, CF ₃ , OH, Unsubstituted or substituted with one or more substituents independently selected from the group consisting of ethoxy unsubstituted or substituted with OH), or R ³ is isopropyl.

Even more preferably, R ³ is Cl, F, CN, OH, -S- _{methyl, OCH 3, -SCH 2 CH 2} OH and -OCH 1 or 2 substituents independently selected from the group consisting of ₂ CH ₂ OH Phenyl substituted by

In a particularly preferred embodiment of the invention, R ³ is substituted phenyl according to any of the embodiments or preferred embodiments herein, wherein R ³ phenyl is one or more hydroxy substituents, or one or more hydroxyethoxy substituents , More preferably with one or more hydroxy substituents.

In another particularly preferred embodiment of the invention, R ³ is 2-hydroxy and 5-chloro, 2-hydroxy and 3-chloro, 3-hydroxy and 2-chloro, 5-hydroxy and 2-chloro, 3 -Cyano and phenyl substituted with 4-hydroxy, 2-hydroxy, or 2-OCH ₂ CH ₂ OH.

Preferably, when R ³ is substituted phenyl and at least one substituent is -S- (C ₁ -C ₆ ) alkyl, -S- (C ₁ -C ₄ ) alkyl or -SCH ₂ CH ₂ OH, -S -(C ₁ -C ₆ ) alkyl, -S- (C ₁ -C ₄ ) alkyl or -SCH ₂ CH ₂ OH is at the ortho position (2-position) of phenyl.

More preferably, R ³ is phenyl substituted with one or more substituents independently selected from the group consisting of -S-methyl and -SCH ₂ CH ₂ OH, wherein -S-methyl or -SCH ₂ CH ₂ OH is selected from It is at the ortho position (2-position).

Preferably, R ⁵ and R ⁶ are independently selected from the group consisting of H, methyl and ethyl.

Preferably, "aryl" and "aryl ² " are phenyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, OH and R ⁸ .

Preferably, R ⁸ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or (C ₃ -C ₇ ) cycloalkyl ((C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) Alkoxy and (C ₃ -C ₇ ) cycloalkyl each is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo.

More preferred R ⁸ groups are CF _3, methyl, methoxy, ethyl, _{ethoxy, -OCH 2 CH 2 OH, -SCH} 2 CH 2 OH, the S-Me and cyclopropyl.

Preferably, p is zero.

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 .

Even more preferably, R ⁹ is pyridyl or phenyl, wherein the pyridyl or phenyl is unsubstituted or substituted by one or more OH or halo.

Even more preferably, R ⁹ is phenyl.

Another particularly preferred aspect of the invention is a compound of formula I according to any of the embodiments or preferred embodiments herein, wherein at least one of R ² and R ³ is substituted phenyl and said substituted phenyl is 1 Substituted with one or more hydroxy substituents or one or more hydroxyethoxy substituents, more preferably with one or more hydroxy substituents.

Preferably, "carbocyclyl" and "carbocyclyl ² " are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (each of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are unsubstituted or substituted with one or more OHs). Each group is independently selected.

Preferably, "heterocyclyl" and "heterocyclyl ² " are pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-ditianyl and piperazinyl (Pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-ditianyl and piperazinyl are unsubstituted or substituted with one or more OH) Are each independently selected from

Preferably, "heteroaryl" and "heteroaryl ² " are pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl and pyrazinyl (pyrazolyl, imidazolyl, tetra Zolyl, pyridinyl, pyridazinyl, pyrimidinyl, isoquinolinyl and pyrazinyl are each independently selected from the group consisting of one or more OHs.

More preferably, "heteroaryl" is pyridyl or isoquinolinyl, each unsubstituted or substituted with one or more OH.

In another embodiment, R ¹ is CH ₃ , SCH ₃ , CH ₂ CH ₃ or CH ₂ SCH ₃ ; R ^1a is CH ₃ ; R ² is pyridyl, isoquinolinyl or phenyl, said phenyl is SCH ₃ , Cl, F, Br, ethyl, methyl, methoxy, OH, benzyloxy, CF ₃ , CO ₂ H, CO ₂ Et, CN, Unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OCO ₂ H, hydroxyethoxy and -C (O) NHCH ₃ ; R ³ is isopropyl or phenyl, said phenyl being Cl, OH, F, benzyloxy, methoxy, hydroxyethoxy, isopropyl, methyl, ethyl, SCH ₃ , CO ₂ H, hydroxyethylthio and CN Preference is given to compounds of the formula (I) or pharmaceutically acceptable salts and / or solvates (including hydrates), which are unsubstituted or substituted with one or more substituents independently selected from the group consisting of: According to a further embodiment, R ¹ is CH ₃ , SCH ₃ or CH ₂ SCH ₃ ; R ^1a is CH ₃ ; R ² is phenyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of SCH ₃ , Cl, OH, CN and hydroxyethoxy; Is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cl, OH, hydroxyethoxy, SCH ₃ , hydroxyethylthio and CN, wherein R ³ is isopropyl or phenyl More preferred are the compounds or their pharmaceutically acceptable salts and / or solvates (including hydrates).

In another embodiment, the groups R ¹ , R ^1a , R ² and R ³ each consists of substituents as defined in any of the preferred or other embodiments herein, including any combination of preferred or other embodiments herein. Independently from.

Preferred groups of compounds are those in which each substituent is described in the examples below.

Preferably, the compound of formula (I) is selected from the group consisting of compounds as described in the Examples below.

Preferred groups of compounds are those wherein each substituent is listed in Listing ¹ below:

Preferably, the compound of formula (I) is selected from the group consisting of the compounds set forth in Listing ¹ :

^{Listing 1} :

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- (3,4-dichlorophenyl) -1H-pyrazol-5-yl] -N '-{2-[(3-isopropyl [1,2,4] 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) carbonyl] 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) carbonyl] 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-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] 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-isopropyl [1,2,4 ] Triazolo [4,3-a] pyridin-6-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-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-1H-pyrazol-5-yl} urea,

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

N- {1- (3-hydroxyphenyl) -3- [1-methyl-1- (methylthio) ethyl] -1H-pyrazol-5-yl} -N '-{2-[(3-iso Propyl [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-phenyl-1H-pyrazol-5-yl} urea,

N- {1- (4-Chlorophenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-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) 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} -1 H-pyrazol-1-yl) benzoic acid,

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] benzyl} urea,

N- (3-tert-butyl-1-pyridin-3-yl-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] -1-pyridin-3-yl-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- (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-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-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-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- (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-hydr Oxyphenyl) [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-phenyl-1H-pyrazol-5-yl} urea,

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

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

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

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} benzyl) urea,

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

N- [3-tert-butyl-1- (3-cyclopropylphenyl) -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-cyclopropylphenyl) -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-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-dimethylphenyl) -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- (3,5-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-dimethylphenyl) -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- (4-hydroxyphenyl) -3- [1-methyl-1- (methylthio) ethyl] -1H-pyrazol-5-yl} -N '-{2-[(3-iso Propyl [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-6-yl] thio} benzyl) urea,

N- {1- (4-hydroxyphenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-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-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-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- [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- {1- (3-Chloro-4-hydroxyphenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-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-Chloro-4-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- [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- {1- (4-Chloro-3-hydroxyphenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-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] -1 H-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] 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-isopropyl [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- (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,

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

N- {3- (2-hydroxy-1,1-dimethylethyl) -1- [3- (2-hydroxyethoxy) phenyl] -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-hydroxyphenyl) -1H-pyrazol-5-yl] -N '-[2-({3- [2- (methylsulfinyl) phenyl] [ 1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] urea,

N- [3- [1,1-dimethyl-2- (methylsulfinyl) ethyl] -1- (3-pullorophenyl) -1H-pyrazol-5-yl] -N '-(2- {[3- (2-hydroxyphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea, and

N- {1- (3-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 and salts and / or solvates thereof.

Pharmaceutically acceptable salts of compounds of formula I include acid addition salts and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetates, aspartates, benzoates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, disylates, ecylates, formates, fumarates, gluceptates , Gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, maleate , Malonate, mesylate, methylsulfate, naphthylate, 2-leadsate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharide Stearate, Succinate, Tartrate, Tosylate, Adipate, Cyclame Agent, carbon titanate, blood glutamate benzoate, through port Eight include acetate salt (1-hydroxy-naphthalene-2-carboxylate) and trifluoroacetate.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trometamine and zinc salts.

Hemisalts of acids and bases can be formed, such as hemisulphate and hemicalcium salts.

See Handbook of Pharmaceutical Salts: Properties, Selection, and Use , Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) for an overview of suitable salts.

Pharmaceutically acceptable salts of compounds of formula (I) include the following three methods: (i) reacting a compound of formula (I) with a desired acid or base, (ii) an acid- or base-labile protecting group Removing from a suitable precursor of or opening a suitable cyclic precursor such as lactone or lactam with the desired acid or base, or (iii) reacting one salt of a compound of formula (I) with a suitable acid or base, or It may be prepared by one of the methods of converting to another salt by a suitable ion exchange column.

The three methods are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by solvent evaporation. The degree of ionization of the resulting salt may vary from fully ionized to rarely ionized.

The compounds of the present invention may exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe molecular complexes comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

Complexes such as clathrates and drug-host insertion complexes in which the drug and host are present in stoichiometric or non-stoichiometric amounts as opposed to the solvates described above are included within the scope of the invention. Also included are complexes of drugs containing two or more organic and / or inorganic components which may be present in stoichiometric or non stoichiometric amounts. The resulting complex may be ionized, partially ionized or not ionized. See J Pharm Sci , 64 (8), 1269-1288, Haleblian (August 1975) for an overview of these complexes.

Hereinafter, the compounds of formula (I) all include salts, solvates, hydrates and complexes thereof, and solvates and complexes of salts thereof.

The compounds of the present invention are formula (I) as defined above, including all polymorphs, crystalline phases, prodrugs and isomers (including optical, geometric and tautomers), and isotopically labeled compounds of formula (I) as defined below. It includes a compound of.

As mentioned above, so-called "prodrugs" of compounds of formula I are within the scope of the present invention. Thus, certain derivatives of the compounds of formula (I), which, when administered into or on the body, may themselves have little or no pharmacokinetic activity, may be converted into compounds of formula (I) having the desired activity, such as by hydrolytic cleavage. have. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella); And Bioreversible Carriers in Drug Design , Pergamon Press, 1987 (ed. EBRoche, American Pharmaceutical Association).

Prodrugs according to the invention are referred to as "pro-moieties" as described, for example, in the appropriate functional groups present in compounds of formula (I), for example in Design of Prodrugs , H. Bundgaard (Elsevier, 1985). It can be produced by replacing with a specific residue known to those skilled in the art.

Some examples of prodrugs in accordance with the present invention (i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), the hydrogen of its esters, such as carboxylic acid functional groups of the compounds of formula I (C ₁ -C ₈₎ Compounds replaced with alkyl; (ii) where the compound of formula (I) contains an alcohol functional group (—OH), the ether thereof, such as a compound in which hydrogen of the alcohol functional group of the compound of formula (I) is replaced with (C ₁ -C ₆ ) alkanoyloxymethyl; And (iii) where the compound of formula (I) contains a primary or secondary amino functional group (-NH ₂ or -NHR (R is not H)), an amide thereof, such as the amino of the compound of formula (I) One or both hydrogen groups of the functional group include compounds in which (C ₁ -C ₁₀ ) alkanoils have been replaced.

Further examples of alternative groups according to the above examples and examples of other prodrug types can be found in the above-mentioned literature.

In addition, some compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the present invention are metabolites of the compounds of formula (I), ie compounds formed in vivo upon drug administration. Some examples of metabolites according to the present invention include (i) when the compound of formula (I) contains a (C ₁ -C ₆ ) alkyl group, a hydroxy (C ₁ -C ₆ ) alkyl derivative thereof, such as a compound of formula (I) When it contains a methyl group, its hydroxymethyl derivative (-CH ₃ ->-CH ₂ OH); (ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (OR->OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR ⁵ R ^6- > NHR ⁵ or -NHR ⁶ ); (iv) where the compound of formula I contains a secondary amino group, a primary derivative thereof (-NHR ^5- > -NH ₂ ); (v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph->PhOH); (vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH _2- >COOH); And (vii) where the compound of formula (I) contains an S- (C ₁ -C ₆ ) alkyl group, the S (O) (C ₁ -C ₆ ) alkyl derivative thereof, such as a compound of formula (I) contains an S-methyl group Where the S (O) methyl derivative thereof and the compound of formula (I) include alkyl-S (O) -alkyl derivatives if they contain alkyl-S-alkyl groups.

In another aspect of the invention there is provided an active metabolite of a compound of formula (I), where "activity" means having an IC ₅₀ (TNFα screen) of less than 1000 nM, preferably an IC ₅₀ (TNFα screen) of less than 100 nM. do. Preferably, compounds of formula I are provided which contain S (O) (C ₁ -C ₆ ) alkyl groups or hydroxy groups.

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more isomers. Tautomerization can occur when structural isomers can be interconverted through a low energy barrier. It may, for example, have a so-called valence transfer form in a compound containing an aromatic moiety or a proton transfer in a compound of formula (I) containing an imino, keto or oxime group. A single compound may exhibit more than one type of isomerization.

All stereoisomers, geometric isomers and tautomeric forms of compounds of Formula (I), including compounds exhibiting more than one type of isomerization, and mixtures of one or more thereof are included within the scope of the present invention. Also included are acid addition salts or base salts, such as d-lactate or l-lysine, or racemic compounds such as dl-tartrate or dl-arginine, in which the counterion is optically active.

Conventional methods of preparing / isolating individual enantiomers have been achieved by the resolution of racemates (or racemates of salts or derivatives thereof) using chiral synthesis, such as chiral high pressure liquid chromatography (HPLC), from optically pure suitable precursors. It includes.

Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or if the compound of formula I contains an acidic or basic moiety or a base such as 1-phenylethylamine or tartaric acid or Can react with acids. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization and one or both of the diastereomers are converted to the corresponding pure enantiomer (s) by methods well known to those skilled in the art. Can be.

Chiral compounds of the invention (and chiral precursors thereof) are hydrocarbons, typically containing 0 to 50% by volume of isopropanol, typically 2 to 20% by volume and 0 to 5% by weight of alkylamine, typically 0.1% of diethylamine. It can be obtained in enantiomeric rich form by chromatography on asymmetric resins, typically HPLC, by means of a mobile phase consisting of heptane or hexane. The eluent is concentrated to give a concentrated mixture.

Stereoisomeric conglomerates may be separated by conventional methods known to those skilled in the art, see, for example, Stereochemistry of Organic Compounds , EL Eliel and SHWilen, Wiley, New York, 1994.

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) in which one or more atoms have the same atomic number but are replaced with atoms other than those found generally in nature.

Examples of suitable isotopes for insertion into compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, isotopes of carbon such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine such as ³⁶ Cl, Isotopes of fluorine such as ¹⁸ F, isotopes of nitrogen such as ¹³ N and ¹⁵ N, isotopes of oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, isotopes of sulfur such as ³⁵ S.

Some isotopically-labelled compounds of formula (I), such as those into which radioisotopes have been inserted, are useful for drug and / or matrix tissue distribution studies. Radioisotope tritium, ie ³ H and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in terms of ease of insertion and ease of detection means.

Substitution with heavy isotopes, such as deuterium, i.e. ² H, may provide some therapeutic benefits resulting from greater metabolic stability, such as increased or reduced dosage requirements in vivo, and may therefore be desirable in some situations. have.

Substitution by positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

Isotope-labeled compounds of Formula (I) are generally prepared by conventional techniques known to those skilled in the art, or by using the appropriate examples of isotopically labeled reagents in place of previously used non-labeled reagents, and It may be prepared by a method similar to that described in the preparation examples.

Pharmaceutically acceptable solvates in accordance with the present invention, the crystallization solvent, for example, D ₂ O, d ₆ - include those which may be substituted by isotopes with acetone, d ₆ -DMSO.

In addition, the scope of the present invention includes novel intermediates as defined herein, all salts, solvates and complexes thereof, and all solvates and complexes of salts as defined herein for compounds of Formula (I). The present invention includes all polymorphs and crystalline phases of the compounds described above.

When preparing the compounds of formula (I) according to the invention, it is acceptable to those skilled in the art to conventionally select the form of the intermediate compound that provides the best combination of features of this purpose. These features include the melting point, solubility, processability and yield of intermediate forms, and consequently the easy purification of the product upon isolation.

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

Exemplary PXRD patterns of such compounds are shown in FIGS. 1-6 that include a 15% silicon internal reference reference.

1: Example 80

2: Example 26

3: Example 93

4: Example 73

5: Example 63

6: Example 60

X-ray diffraction data was obtained using a Bruker AXS D4 powder X-ray diffractometer (Cu Kα radiation) equipped with an automatic sample changer, theta-theta goniometer, automatic beam divergence slit, second monochromator and scintillation counter. Collect at room temperature. Samples were prepared for analysis by mixing the compound with a 15 wt% content of silicon powder internal reference. The powder was placed on a 12 mm diameter silicon wafer specimen holder. The sample was rotated while irradiating copper Kα1 X-rays (wavelength = 1.5406 Hz) in an X-ray test tube operating at 40 kV / 40 mA. The analysis was carried out using a goniometer operating in a continuous manner set at 5 second intervals per 0.02 ° step over a 2 theta range of 2 ° to 55 °. The peaks obtained were aligned against the silicon reference reference (ICDD Ref. No. 001-0791).

As known to the skilled crystalgraphers, the relative intensities of the various peaks recorded in the tables and figures below are due to numerous factors such as the effect of crystal orientation in the X-ray beam or the purity of the material to be analyzed or the crystallinity of the sample. Can change. In addition, the peak position may shift due to the variation in the sample weight, but the peak position is substantially as defined in the figure. The skilled crystallologist knows that measurements using different wavelengths result in different shifts according to the Bragg equation nλ = 2dsinθ.

Additional such PXRD patterns generated using other wavelengths are considered to be another representative of the PXRD patterns of the crystalline materials of the present invention and are themselves within the scope of the present invention.

Tables 1-6 list the intensities of the compounds excluding corresponding major diffraction peaks in terms of 2θ values, and peaks that may be provided for the silicon reference reference. All 2θ values are in the +/- 0.1 ° range.

Table 1 lists the peaks of Example 80 with relative intensities greater than 33.0%.

Table 2 lists the peaks of Example 26 with relative intensities greater than 36.5%.

Table 3 lists the peaks of Example 93 with relative intensities greater than 15.5%.

Table 4 lists the peaks of Example 73 with relative intensities greater than 34.0%.

Table 5 lists the peaks of Example 63 with relative intensities greater than 35.7%.

Table 6 lists the peaks of Example 60 with relative intensities greater than 36.4%.

In another aspect of the invention, there is provided a compound of Example 80, 26, 93, 73, 63 or 60 having a crystal structure illustrated in the figures and / or defined in the tables herein. The present invention is not limited to the above solid form.

Compounds of formula (I) can be prepared in a variety of ways, in known manner. The following pathways illustrate various methods of preparing the compounds; Those skilled in the art will appreciate that other routes are also possible. Unless otherwise indicated in the following schemes, substituents are as defined above for the compounds of Formula (I) above and “PdCl ₂ (dppf). CH ₂ Cl ₂ ” is 1,1-bis (diphenylphosphino) ferrocene Palladium (II) chloride 1: 1 dichloromethane complex, “BU” is 1,8-diazabicyclo [5.4.0] undes-7-ene, and “BOC” is tert-butoxycarbonyl "CBz" means benzyloxycarbonyl, "Et" means ethyl, "Me" means methyl, "Pd" means palladium, "eq" means molar equivalents ( ) And "iPr" means isopropyl.

Compounds of formula (II) can be purchased commercially or prepared as described in Scheme 2.

Compounds of formula III can be purchased commercially (eg when R ^1a = Me and R ¹ = Me) or can be prepared as shown in Scheme 3.

The compound of formula IV is prepared in (i) process step, i.e. in the presence of a suitable base such as H ㆌ nig base, triethylamine or pyridine in a suitable solvent such as methanol or ethanol for 3 to 24 hours at elevated temperature. And may be prepared from compounds of formula II and compounds of formula III by cyclic condensation of compounds of formula II and compounds of formula III in the presence of a suitable acid catalyst such as hydrochloric acid. Typical conditions include 1.0 to 1.3 equivalents of compound of formula II and 1.0 to 1.1 equivalents of compound of formula III in the presence of hydrochloric acid in ethanol heated at reflux for 3 to 24 hours.

In addition, compounds of formula IV can be obtained by condensation of compounds of formula VII and compounds of formula III directly in EtOH / HCl.

Compounds of formula V can be prepared according to Scheme 4.

Compounds of formula (I) may be selected from N, N'-carbonyldiimidazole, phenylchloroform, and suitable bases such as Hunich base or pyridine in a suitable solvent such as dichloromethane or 1,4-dioxane for 48 hours under ambient conditions. The compound of formula IV by a process step of (ii) reacting the compound of formula IV in the presence of a suitable carbonyl source such as mate or bis (trichloromethyl) carbonate followed by addition of the compound of formula V to form urea; and It can be prepared from a compound of formula (V). Typical conditions are a) 1.0 equivalent of the compound of formula IV and 5.0 to 6.0 equivalents of N, N'-carbonyldiimidazole in dichloromethane for 24 hours under ambient conditions, b) dichloromethane for 24 hours under ambient conditions. Or 0.25 to 0.80 equivalents of compound of formula V and 0.25-1.25 equivalents of Hunich base in 1,4-dioxane, or c) 1 equivalent of compound IV of formula IV and 1 equivalent of phenylchloroformmate in THF / pyridine and then formulated in DMSO 0.8 to 1 equivalent of compound of V.

When R ² is aryl or heteroaryl, compounds of formula II can be prepared as shown in Scheme 2:

Where R ² -Br is not available, compounds of formula (II) can be prepared from the corresponding aniline derivatives by diazoation and subsequent reduction using conditions well known in the chemical literature.

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

If R ² is phenol or contains phenol, those skilled in the art will recognize that it may be necessary to use a protecting group, typically benzyloxy or methyloxy.

Compounds of formula VI are commercially available.

Compounds of formula (II) can be prepared via compounds (VII) from compounds of formula (VI) by process steps (iii) and (iv).

step (iii) forms a suitable organometallic reagent, such as arylMgBr, heteroarylMgBr, arylLi or heteroarylLi, optionally prepared in the same reaction system under standard Grignard conditions, or from 1 to 100 to 25 ° C. By reaction with a suitable alkyllithium, such as ⁿ BuLi, in a suitable solvent such as tetrahydrofuran or diethyl ether for 18 hours. Intermediate compound (VII) is a suitably protected diazocarboxylate compound, preferably di-tert-butyldiazocarboxylate, in a suitable solvent such as tetrahydrofuran or diethyl ether at −78 ° C. for 0.5 to 1.0 hour. Is formed by successive nucleophilic attack with aryl MgBr / heteroaryl MgBr / arylLi / heteroarylLi.

(iv) Step is deprotection of compound (VII) using standard methodology as described in "Protecting Groups in Organic Synthesis", TW Greene and P. Wuts. When PG = BOC, typical conditions are intermediates 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 for 2 to 18 hours under ambient conditions. VII).

More preferably, the compound of formula (II) can be prepared from the compound of formula (VI) by the combination of steps (iii) and (iv) in the synthesis of the one-pot. Typical conditions are: a) 1.0 equivalent of Compound (VI) in tetrahydrofuran, 1.1 equivalents of magnesium debris and 1 iodine crystal for 18 hours at room temperature followed by di-tert-butyldiazocarboxylate for 30 minutes at -78 ° C. Addition, b) saturation with hydrochloric acid gas in isopropyl alcohol for 0.5-1.0 h under ambient conditions.

When R ² represents heterocyclyl or carbocyclyl, the compounds of formula II can be prepared according to the following scheme 2a:

(xvii) step-the compound of formula XXVII is a suitable alkali metal base (e.g., K ₂ CO ₃ or Na _{2 in a} suitable solvent such as acetonitrile or N, N-dimethylformamide for up to 48 hours at ambient temperature to 60 ° C) From compounds of formula VI by reaction with a suitable protected hydrazine (eg, BOC-NHNH ₂ ) in the presence of CO ₃ ).

Compounds of formula (II) can be prepared from compounds of formula (XXVII) using the method already described for step (iv).

Compounds of formula III can be prepared according to Schemes 3a and 3b.

When R ¹ =-(CH ₂ ) _n SR ^b , the compound of formula III can be prepared as described in Scheme 3a. R ^b represents methyl or ethyl. n represents 0 or 1.

LG is a suitable leaving group such as OR 'or Cl, preferably OR'.

R 'represents C ₁ -C ₄ alkyl, or preferably C ₁ -C ₂ alkyl.

When R '= Et or Me, the compound of formula VIII is commercially available.

When n = 1, compounds of formula (IXA) can be prepared from compounds of formula (VIII) by (v) step-nucleophilic substitution. The reaction is carried out for 1 to 2 hours at low temperature in the presence of a suitable base, such as Wienerach base, triethylamine or pyridine, in a suitable solvent, such as dichloromethane or diethyl ether, of compound (VIII) and mesyl chloride / anhydride or tosyl chloride. The reaction proceeds through the formation of an intermediate containing a suitable leaving group LG 'such as mesylate or tosylate. After concentration in vacuo, 1,4-dioxane or toluene and methanethiol sodium salts were added while heating at reflux for 24 h. Typical conditions are: a) 1.0 equivalent of compound (VIII) in dichloromethane at 0 ° C. for 1.0 hour, 1.0-1.2 equivalents of Wiener base and 1.1 equivalents of methane sulfonyl chloride, and b) heated under reflux for 24 hours. While 1.1 equivalent of methanethiol sodium salt in 1,4-dioxane.

When n = 0, the compound of formula IXA is commercially available.

Compound (III) may be prepared from a compound of Formula (IXA) by process step (vi), which is a reaction with acetonitrile (X). Treatment of compound (X) with a suitable base such as sodium hydride or lithium diisopropylamide followed by quenching the intermediate anion with compound (IXA) in a suitable solvent such as tetrahydrofuran at elevated temperature for 3 hours gives a compound of formula III do. Typical conditions include 1.3 equivalents of acetonitrile in tetrahydrofuran heated at reflux for 3 hours, 1.3 equivalents of sodium hydride (60% dispersion in mineral oil) and 1.0 equivalents of compound (IXA).

When R ^1a is H, CH ₃ or CH ₂ CH ₃ , the compound of formula III can be prepared as shown in Scheme 3b.

LG is a suitable leaving group such as OR 'or Cl, preferably OR'.

R 'represents C ₁ -C ₄ alkyl, preferably C ₁ -C ₂ alkyl.

Compounds of formula III can be prepared from compounds of formula IXB by the process step (vi) as described above.

Compounds of formula (IXB) are commercially available or are disclosed in Julia et al., Bull. 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 below.

When Y = halogen, preferably bromine, the compound of formula XI is commercially available.

Compounds of formula (XII) may be prepared from compounds of formula (XI) by process step (vii), which is a reaction step with hydrazine monohydrate in a suitable solvent such as methanol or ethanol for 18 to 72 hours at elevated temperature. Typical conditions include 1.0 equivalent of Compound (XI) and excess hydrazine monohydrate heated to 70 ° C. for 72 hours.

Compounds of formula (XIV) are suitable alkoyl chlorides R ³ C (O) in the presence of a suitable base such as Hunich base, triethylamine or pyridine in a suitable solvent such as dichloromethane or diethyl ether at low temperature for 1-2 hours. It can be prepared from a compound of formula (XII) by the process step (viii) which is a reaction with Cl (XIII). Typical conditions include 1.0 equivalents of compound (XII), 1.0 equivalents of R ³ C (O) Cl (XIII) and 5.0 equivalents of Wiener Base at dichloromethane at 0-5 ° C. for 1-2 hours.

Compounds of formula (XV) may be prepared from compounds of formula (XIV) by process step (ix), which is a cyclization step. This is accomplished using a suitable dehydrating agent such as phosphorus oxychloride or phosphorus (V) oxide in sulfuric acid at elevated temperatures for 18 to 24 hours. Typical conditions include 1.0 equivalent of excess phosphorus oxychloride compound (XIV) at 75 ° C. for 18-24 hours.

Alternatively, the compound of formula XV can be prepared directly from the compound of formula XII by the process step (ix). This cyclization is effected, for example, by reaction with excess compound (XIII) and heating at 95 ° C. for 18 to 24 hours.

Compounds of formula (XVII) may be reacted with PdCl ₂ (dppf) 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 to 48 hours. Can be prepared from compounds of formula XV by process step (x), which is a Pd catalyzed cross-coupling reaction step with 2-mercaptobenzyl alcohol (XVI) in the presence of a suitable catalyst such as CH ₂ Cl ₂ . . Typical conditions are 1.0 equivalent of compound (XV) in N, N-dimethylformamide, 1.2 to 1.4 equivalents of cesium carbonate, 1.3 equivalents of 2-mercaptobenzyl alcohol (XVI) and PdCl ₂ (dppf). 0.1 equivalent of CH ₂ Cl ₂ .

Compounds of formula (XVIII) may be prepared from compounds of formula (XVII) by azide formation, which is a process step (xi). This is suitable for the reaction of compound (XVII) with a suitable base such as DBU or sodium hydride and in a suitable solvent such as toluene or tetrahydrofuran at a temperature of 0-25 ° C. for 18-24 hours thereafter, such as diphenylphosphoryl azide. It proceeds by reaction with azide. Typical conditions include 1.0 equivalent of Compound (XVII), DBU 1.2 equivalents and diphenylphosphoryl azide 1.2 equivalents in toluene at 0-25 ° C. for 24 hours.

(Xii) is a reduction step of compound (XVIII) with a suitable reducing agent such as triphenylphosphine / water, tin chloride or catalytic hydrogenation in a suitable solvent such as tetrahydrofuran or ethanol at ambient temperature to elevated temperature Process steps can be prepared from compounds of formula (XVIII). Typical conditions include 1.0 equivalents of compound (XVIII), 1.2 equivalents of triphenylphosphine and 1.2 equivalents of water in tetrahydrofuran for 40 hours at room temperature and 5 hours at 50 ° C.

Alternatively, the compound of formula V can be prepared as shown in Scheme 5.

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

Compounds of formula XIX can be purchased commercially or prepared as described in Scheme 6.

The compound of formula (XX) is a compound of formula (XII) and a compound of formula (XIX) by process step (xiii) which is a condensation step of hydrazine (XII) and aldehyde (XIX) in a suitable solvent such as methanol, ethanol or toluene at elevated temperature for 0.5 to 1 hour It can be prepared from a compound. Typical conditions include one equivalent of compound (XII) and one equivalent of compound (XIX) in ethanol heated under reflux for 0.5 to 1.0 hour.

Compounds of formula (XV) are (diacetoxyiodo) benzene, cerium (IV) ammonium nitrate or 2,3-di in a suitable solvent such as ethyl acetate, dichloromethane or acetonitrile under ambient conditions for 18 to 24 hours. It can be prepared from a compound of formula (XX) by process step (xiv), which is a cyclization step of compound (XX) in the presence of a suitable oxidizing agent such as chloro-5,6-dicyano-1,4-benzoquinone. Typical conditions include 1.0 equivalent of Compound (XX) and 1.2 equivalents of (diacetoxydodo) benzene in dichloromethane at room temperature for 24 hours.

Alternatively, compounds of formula (XV) can be prepared from compound (XII) by process steps (xiii) and (xiv) in the same reaction vessel synthesis. Typical conditions include 1 equivalent of compound (XII) and 1 equivalent of compound (XIX) in ethanol heated at reflux for 0.5 to 1.0 hour, followed by 1.2 equivalents of diacetoxydodobenzene and dichloromethane at room temperature for 24 hours. Addition of 1.2 equivalents of phosphorus.

Compounds of formula (XVII) may be prepared from compounds of formulas (XV) and (XVI) by process step (x) as described in Scheme 4.

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

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

Alternatively, the compound of formula V may also be prepared from a compound of formula XVII by a process step (xviii). The reaction is carried out with a compound with mesyl chloride / anhydride or tosyl chloride in the presence of a suitable base such as Wiener, base, triethylamine or pyridine in a suitable solvent such as dichloromethane or diethyl ether at low to ambient temperature for 1 to 4 hours. The reaction of (VIII) proceeds through the formation of an intermediate containing a suitable leaving group such as mesylate or tosylate. The resulting intermediate is then treated with a suitable source of ammonia in methanol, typically 7M ammonia, under ambient conditions for 18 to 72 hours. Typical conditions include 1.0 equivalents of compound (XVII), 3.0-4.0 equivalents of Wiener Base and 2.0-3.0 equivalents of methane sulfonyl anhydride in dichloromethane at 25 ° C. for 1-4 hours. Excess 7M ammonia in methanol is added and the reaction is stirred at ambient temperature for 18-72 hours.

Alternatively, compounds of formula (V) may be prepared from compounds of formula (XXVII) and compounds of formula (XV) wherein PG is a protecting group such as BOC. Typical conditions include 1 equivalent of compound (XV), 1.2 equivalents of compound (XXVII), 1.2 equivalents of cesium carbonate, 3 equivalents of cesium fluoride, PdCl ₂ ( ₂ ) in dimethylformamide as solvent at 80-100 ° C. for 2 to 48 hours. dppf) .CH ₂ Cl ₂ 0.1 equivalent. The product of the reaction was then removed by acid-mediation of the BOC group to produce a compound of formula V.

Compounds of formula (XXVII) can be prepared from compounds of formula (XXVIII) by the process step (xix) (Scheme 5a). The reaction proceeds by introducing sulfide into the aromatic compound-bromine bond with a palladium-catalyst

Typical conditions include: 1 equivalent of compound (XXVIII) in toluene, potassium tri (isopropyl) silylsulfide (1 equivalent of potassium tert-butoxide in toluene and 1 equivalent of triisopropylsilanethiol as solvent at 100 ° C. for 0.5 to 2 hours. 1 equivalent) of PdCl ₂ (dppf) .CH ₂ Cl ₂ .

If R ³ is phenol or contains phenol, the skilled person will recognize that it may be necessary to use protecting groups, typically benzyloxy or methyloxy.

Compounds of formula (XXIV) are commercially available.

The compound of formula XXV is a reduction step (xv) 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 elevated temperature for 6-18 hours. It can be prepared from the compound of formula (XXIV) by the process step. Typical conditions include 1.0 equivalent of compound (XXIV) and 1.0 to 1.2 equivalents of lithium aluminum hydride in reflux for 6 hours at reflux.

Compounds of formula XIX are suitable oxidizing agents such as manganese dioxide, potassium permanganate or oxalyl chloride / dimethylsulfoxide in a suitable solvent such as acetone, dichloromethane or dimethylsulfoxide at -80 to + 80 ° C for 3 to 18 hours. It can be prepared from the compound of formula XXX by the (xvi) process step, which is an oxidation step by. Typical conditions include 1.0 equivalent of compound (XXV) and 0.5 equivalent of manganese dioxide in acetone heated under reflux for 3 hours.

Alternatively, compounds of formula (XIX) may be prepared from commercial compounds of formula (XXVI) by process step (xvii), which is a nitrile reduction step with diisobutylaluminum hydride in a suitable solvent such as tetrahydrofuran at low temperature. Typical conditions include a) 1.0 equivalent of compound (XXVI) and 1.0-2.0 equivalents of diisobutylaluminum hydride in tetrahydrofuran at −78 ° C. for 1 hour, and b) excess hydrochloric acid and water at 0 ° C.

The skilled artisan will recognize that protecting one or more sensitive groups in the molecule to prevent undesirable side effects may be necessary or desirable at any stage during the synthesis of the compound of formula (I). In particular, it may be necessary or desirable to protect phenolic groups. The protecting groups used in the preparation of the compounds of formula (I) can be used in conventional manner. See, eg, "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter GM Wuts, 3rd edition, John Wiley & Sons, 1999, especially Chapter 2, pp. 17-245 ("Protection for the Hydroxyl Group"). See description. Alternatively, the protected phenol can be purchased commercially. Removal of such groups can be accomplished using conventional methods.

It is also recognized that compounds of formula (I) may be converted to other compounds of formula (I) using standard chemical reactions and modifications. For example, when X (when X is a group as shown in the examples and preparations herein) is an ester, the compounds of formula (I) can provide carboxylic acid derivatives by saponification. When X is aryloxy, the compounds of formula (I) can provide the corresponding phenols by dealkylation using boron tribromide or HBr / acetic acid. In addition, when X is OH, the hydroxyalkoxy derivative is used for reaction with 2- (2-bromoethoxy) tetrahydro-2H-pyran followed by deprotection of the primary alcohol with boron tribromide or para-toluenesulfonic acid. Can be prepared by

In another embodiment of the invention, (i) preparing a compound of formula IV by cyclic condensation of a compound of formula II and a compound of formula III:

And / or

(ii) urea formation by reaction of a compound of formula IV with a compound of formula V in the presence of a suitable carbonyl source:

There is provided a process for the preparation of compounds of formula (I), wherein the substituents are defined in claim 1 and in the detailed description of the invention relating to the process of preparation.

In another embodiment of the invention, an azide forming step of (xi) reacting a compound of formula XVII with a suitable base followed by a suitable azide to form a compound of formula XVIII:

And / or

(xii) reducing the compound of formula XVIII to form a compound of formula V:

Provided is a process for preparing a compound of Formula (V), wherein the substituents are defined in the detailed description of the invention relating to the process for preparation.

In another aspect of the invention, a novel method as described herein is provided.

In another aspect 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 aspect of the invention, there is provided a novel intermediate compound of the formula as described herein.

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

Another aspect of the invention is a compound of Formula I, or a salt and / or solvate thereof, as described herein for use in treating a disease, disorder or condition selected from the group consisting of:

1. Asthma of any type, etiology or pathogenesis, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Endogenous asthma caused by external factors, exogenous asthma caused by external factors, unexplained or unclear essential asthma, non-atopic asthma, bronchitis asthma, emphysema, exercise-induced asthma, allergen-induced asthma, cold Asthma selected from the group consisting of air-induced asthma, occupational asthma, infectious asthma, non-allergic asthma, early asthma, whiskey infant syndrome and bronchiolitis caused by bacterial, fungal, antigenic or viral infections ,

2. chronic or acute bronchial contraction, chronic bronchitis, small airway obstruction and emphysema,

3. COPD with obstructive or inflammatory airway disease of all types, etiologies or pathogenesis, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or respiratory distress associated with or not associated with COPD. Obstructive or inflammatory airway disease, selected from the group consisting of COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness resulting from other medications and airway disease associated with pulmonary hypertension,

4. Bronchitis of any type, etiology or pathogenesis, especially acute bronchitis, acute laryngeal bronchitis, arachidous bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthma bronchitis, wet bronchitis, staphylococcus or streptococcal bronchitis, and Bronchitis selected from the group consisting of alveolar bronchitis,

5. acute lung injury, and

6. Bronchiectasis, cylindrical bronchiectasis, saculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicles of any type, etiology or pathogenesis follicular) bronchiectasis selected from the group consisting of bronchiectasis.

Another aspect of the invention is the use of a compound of formula (I), or a salt and / or solvate thereof, as described herein in the manufacture of a medicament for the treatment of the diseases, disorders or conditions disclosed in paragraphs 1 to 6 above.

Another aspect of the invention provides a compound of Formula I, or a salt and / or solvate thereof, as described herein in the manufacture of a medicament for treating a p38-mediated disease, disorder or condition, or TNF-mediated disease, disorder or condition. It is use.

Another aspect of the invention is a compound of formula (I), or salts and / or solvates thereof, described herein for use in treating p38-mediated disease, disorder or condition, or TNF-mediated disease, disorder or condition.

The present invention provides methods for treating mammals, including humans, using an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

More specifically, the present invention comprises administering an effective amount of a compound of formula (I) or a salt and / or solvate thereof to a mammal, including human, p38-mediated disease, disorder or condition, or TNF-mediated disease of the mammal. , A disorder or symptom, in particular a method for treating a disorder, disorder or symptom listed above.

Preferably, the present invention is a respiratory or inflammatory airway disease of any type, etiology or pathogenesis, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or respiratory tract associated with or not associated with COPD. COPD with difficulty, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), obstructive airway hyperresponsiveness resulting from other medications and airway disease associated with pulmonary hypertension. Or inflammatory airway disease; Or cause asthma of any type, etiology or pathogenesis, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Endogenous asthma, exogenous asthma caused by external factors, unknown or unclear essential asthma, non-atopic asthma, bronchitis asthma, emphysema, asthma-induced asthma, allergen-induced asthma, cold air induction Chemical formulas for use in the treatment of asthma selected from the group consisting of sexual asthma, occupational asthma, infectious asthma, non-allergic asthma, early asthma, infant wheezing syndrome and bronchiolitis caused by bacterial or fungal, antigenic or viral infections Provided are the compounds of I or pharmaceutically acceptable salts or solvates thereof.

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

Preferably, the present invention relates to obstructive or inflammatory airway disease of any type, etiology or pathogenesis, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or respiratory distress not associated with COPD. Obstructive or selected from the group consisting of COPD accompanying, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), airway hyperresponsiveness resulting from other medications and airway disease associated with pulmonary hypertension Inflammatory airway disease; Or cause asthma of any type, etiology or pathogenesis, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Endogenous asthma, exogenous asthma caused by external factors, unknown or unclear essential asthma, non-atopic asthma, bronchitis asthma, emphysema, asthma-induced asthma, allergen-induced asthma, cold air induction In the manufacture of a drug for the treatment of asthma selected from the group consisting of sexual asthma, occupational asthma, infectious asthma, non-allergic asthma, early asthma, infant wheezing syndrome and bronchiolitis caused by bacterial or fungal, antigenic or viral infections. To a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

More preferably, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in 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 symptoms" means that TNF inhibits TNF itself or by another monokine such as IL-1, IL-6 and And / or any disease, disorder or condition (particularly any pathological condition) that each plays a role by causing IL-8 to be released. Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to TNF is considered a disorder mediated by TNF.

As used herein, the term “p38-mediated disease” or “p38-mediated disorder” or “p38-mediated symptom” means that p38 inhibits p38 by itself or another monokine such as IL-1, IL-6 and And / or any disease, disorder or condition (particularly any pathological condition) that each plays a role by causing IL-8 to be released. Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to p38 is considered a disorder mediated by p38.

Compounds of the invention may be used in the treatment of TNF-mediated diseases, disorders or symptoms, or p38-mediated diseases, disorders or symptoms, in particular allergic and non-allergic airway diseases as described above, as well as p38-mediated or TNF- It can also be used to treat mediated symptoms:

(a) inflammation;

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

(c) neuroinflammatory;

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

(e) heat (ie, use of the compound as an antipyretic);

(f) pulmonary sarcoidosis and silicosis;

(g) complications associated with heart failure such as cardiovascular diseases such as atherosclerosis, myocardial infarction (eg, signs of myocardial infarction), thrombosis, congestive heart failure, heart reperfusion injury, and hypertension and / or vascular organ damage;

(h) cardiomyopathy;

(i) strokes such as ischemic and hemorrhagic strokes;

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

(k) reperfusion injury;

(l) kidney reperfusion injury;

(m) brain edema;

(n) neuro and brain trauma, such as obstructive head injury;

(o) neurodegenerative disorders;

(p) central nervous system disorders (including disorders with inflammatory or apoptotic symptoms) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury and peripheral neurodegeneration;

(q) liver disease and nephritis;

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

(s) ulcer diseases, such as gastric ulcer;

(t) eye diseases such as retinitis, retinopathy (eg diabetic retinopathy), uveitis, ocular phobia, nonglaucoma optic optic atrophy and old age macular degeneration (ARMD) (eg, ARMD-atrophic form);

(u) ophthalmic symptoms such as corneal graft rejection, ocular neovascularization, retinal neovascularization (such as angiogenesis after injury or infection) and posterior capsular fibrosis;

(v) Glaucoma, such as primary open-angle glaucoma (POAG), juvenile onset primary open-angle glaucoma, closed-angle glaucoma, pseudoscale glaucoma, anterior ischemic optic neuropathy (AION), hypertension, Reiger syndrome, normal pressure Glaucoma, neovascular glaucoma, eye inflammation and corticosteroid-induced glaucoma;

(w) acute damage to eye tissue and eye trauma such as post-traumatic glaucoma, traumatic optic neuropathy and retinal arterial occlusion (CRAO);

(x) diabetes;

(y) diabetic neurosis;

(z) skin related symptoms such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation and angiogenesis;

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

(bb) myalgias due to infection;

(cc) influenza;

(dd) endotoxin shock;

(ee) toxic shock syndrome;

(ff) autoimmune diseases such as graft versus host response and allograft rejection;

(gg) bone resorption diseases such as osteoporosis;

(hh) multiple sclerosis;

(ii) female reproductive system disorders such as endometriosis;

(jj) non-malignant pathological symptoms such as hemangiomas (including infantile hemangiomas), angiofibroma of the pharynx or bone avascular necrosis;

(kk) benign and malignant tumors / neoplastics, including cancer, such as colorectal cancer, brain cancer, bone cancer, epithelial cell induced neoplasms (epithelial carcinoma), such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancers such as lip cancer, oral cancer, esophageal cancer Intestinal cancer and gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancer, prostate cancer, renal cell carcinoma, and endothelial cells through the body Other known cancers that affect;

(ll) leukemia;

(mm) lymphomas such as B cell lymphoma;

(nn) systemic lupus erythematosus (SLE);

(oo) angiogenesis, including neoplasms;

(pp) metastasis;

(qq) fibrotic disease;

(rr) bleeding;

(ss) coagulation;

(tt) acute cyclic responses observed during infection and sepsis and acute cyclic responses observed during shock (eg, (uu) septic shock, hemodynamic shock, etc.);

(vv) anorexia;

(ww) mycobacterium infection;

(xx) false rabies;

(yy) rhinitis;

(zz) HIV;

(aaa) influenza virus;

(bbb) herpes viruses, including simple herpes virus 1-type (HSV-1), simple herpes virus 2-type (HSV-2);

(ccc) cytomegalovirus (CMV)

(ddd) Varicella zoster virus (VZV);

(eee) Epstein-Barr virus;

(fff) human herpes virus-6 (HHV-6);

(ggg) human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8).

In another embodiment of the invention there is a compound of formula (I) or a salt and / or solvate thereof for use in treating a disease, disorder or condition selected from the above lists (a) to (ggg).

Another aspect of the invention is the use of a compound of formula (I) or a salt and / or solvate thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from the lists (a) to (ggg) above.

Another aspect of the invention is a disease selected from the lists (a)-(ggg) above in a mammal comprising administering to a mammal, including a human, an effective amount of a compound of formula (I) or a salt and / or solvate thereof , To a method of treating a disorder or condition.

The compounds of the present invention may also be used for the treatment of p38-mediated or TNF-mediated diseases such as smoking-induced airway inflammation, coughs with enhanced inflammation, for the inhibition of angiogenesis, for the treatment of excess mucin production and / or over mucus It can also be used to treat secretion.

Synthesis of both TNF-α and TNF-β is important because TNF-β has close structural homology to TNF-α (also known as cathetine) and each induces a similar biological response and binds to the same cellular receptor. Tend to be inhibited by a compound of and therefore collectively referred to herein as "TNF", unless specifically stated otherwise.

The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates as mentioned above can be administered as medicaments according to the invention to animals, preferably to mammals, in particular to humans.

A compound is a pharmaceutical composition containing, as an active ingredient, an active dosage amount of one or more compounds of the present invention, as such, in a mixture with one or more other compounds of the present invention, or in addition to conventional pharmaceutically harmless excipients and / or additives It may be administered in the form of a formulation.

The compounds of the present invention for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying and evaporation drying. Oven or radio drying methods can be used for this purpose.

These 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 as any combination thereof). Generally, it is administered as a formulation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the present invention. The choice of excipient depends greatly on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be readily appreciated by those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences , 19th Edition (Mack Publishing Company, 1995).

The compounds of the present invention can be administered orally. Oral administration may include swallowing such that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used to introduce the compound directly from the mouth into the bloodstream.

Formulations suitable for oral administration include solid formulations such as tablets and capsules containing particulates, liquids or powders, lozenges (including liquid-filled), chewing agents, multi- and nano-particulates, gels, Solid solutions, liposomes, films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. The formulations can be used as fillers in soft and hard capsules and typically comprise carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspensions. . Liquid formulations may also be prepared by, for example, reconstituting a solid from a sacchet.

The compounds of the present invention may also be used in fast-soluble, belonging dosage forms as described in Expert Opinion in Therapeutic Patents , 11 (6), 981-986, Liang and Chen (2001).

For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to drugs, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl Cellulose, starch, pregelatinized starch and sodium alginate. Generally, disintegrants comprise from 1% to 25% by weight, preferably from 5% to 20% by weight of the dosage form.

Binders are generally used to impart tackiness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets also contain lactose (monohydrates, spray-dried monohydrates, anhydrides, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and divalent calcium phosphate dihydrate. It may also contain a diluent.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. The surfactant may, when present, constitute from 0.2% to 5% by weight of the tablet and the glider may constitute from 0.2% to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably from 0.5% to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavors, preservatives and taste-hiding agents.

Exemplary tablets include about 80% or less of the drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant and about 0.25% by weight of lubricant. About 10% by weight.

Tablet blends may be compressed directly or by roller to form tablets. The tablet blend or portion thereof may alternatively be wet-, dry- or melt-granulated, melt congealed or extruded prior to tableting. The final formulation may comprise one or more layers and may or may not be coated. Tablet formulations may be surrounded by capsules.

Tablet formulations are discussed in Pharmaceutical Dosage Forms : Tablets, Vol 1, H. Lieberman and L. Lachman, Marcel Dekker, New York, 1980.

Consumable oral films for use in humans or livestock can be rapidly dissolved or mucoadhesive and are typically compounds of the invention, film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifiers And typically a water soluble or water swellable thin film dosage form comprising a solvent. Some components of the formulation may perform more than one function.

The compounds of the present invention are either water soluble or water insoluble. Water soluble compounds typically comprise 1% to 80% by weight solute, more typically 20% to 50% by weight. Less soluble compounds may constitute a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compounds of the present invention may be in the form of composite particulate beads.

The film-forming polymer may be selected from polysaccharides, proteins or synthetic aqueous colloids and is typically present in the range of 0.01 to 99% by weight, more typically 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavor and flavor enhancers, preservatives, saliva stimulants, coolants, auxiliary solvents (including oils), emollients, fillers, antifoams, surfactants, and taste-hiding agents.

Films according to the invention are typically prepared by evaporating to dry peelable backing supports or thin aqueous films coated on paper. This can be done in a drying oven or tunnel, typically in a combined coater dryer or by lyophilization or vacuuming.

Solid dosage forms for oral administration may be formulated to be immediate and / or altered release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release and targeted release and programmed release.

Modified release formulations suitable for the purposes of the present invention are disclosed in US Pat. No. 6,106,864. Details of other suitable release techniques such as high energy dispersed and osmocoated particles can be found in Pharmaceutical Technology On-line , 25 (2), 1-14, Verma et al. (2001). The use of chewing rubber to achieve controlled release is described in WO 00/35298.

The compounds of the present invention may also be administered directly to the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intradural, intraventricular, intraurethral, substernal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needles (including microneedle) syringes, syringes without needles, and infusion techniques.

The compounds of the present invention may also be topically administered to the skin or mucosal layer, ie to the dermis or transdermal.

The compounds of the present invention are also typically in dry powder form (eg, alone, as a mixture of dry blends, for example with lactose, or as mixed component particles mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler. Pressurized vessel with or without suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane It may be administered intranasally or by inhalation, as a pump, spray or nebulizer (preferably nebulizer using electrohydrodynamics to produce fine mist) or as an aerosol spray from nebulizer. For intranasal use, the powder may comprise a bioadhesive such as, for example, chitosan or cyclodextrin.

Pressurized vessels, pumps, sprays, nebulizers or nebulizers are for example ethanol, aqueous ethanol, or alternatives suitable for dispersing, dissolving or prolonging the release of actives, propellant (s) as a solvent, and sorbitan trioleate, It contains a solution or suspension of the compound (s) of the invention comprising any surfactant such as oleic acid or oligolactic acid.

Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be done by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (eg, made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or blower are suitable powder bases such as the compounds of the invention, lactose or starch, and l- It may be formulated to contain a powder mix of performance modifiers such as leucine, mannitol or magnesium stearate. Lactose may be in anhydrous or monohydrate form, preferably in monohydrate form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers using electrofluidics to produce fine mist may contain between 1 μg and 20 mg of a compound of the invention in a single actuation, with a working volume of 1 μl to 100 μl. Can change from Typical formulations may include the compounds of the present invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents such as saccharin or saccharin sodium can be added to the formulations of the invention for inhalation / intranasal administration.

Formulations for inhalation / intranasal administration may be formulated for immediate and / or altered release, eg using PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve which delivers a metered amount. Units according to the invention are typically adjusted to administer a metered dose or "puff" containing from about 0.001 mg to about 10 mg of a compound of the invention. The overall daily dosage is typically in the range of about 0.001 mg to 40 mg, which may be administered in a single dosage or more generally as a divided dose over a day.

In another aspect of the invention, the compound of the invention is preferably administered by inhalation. More preferably, the compounds of the present invention are administered by dry powder inhaler or metered dose inhaler, most preferably dry powder inhaler.

The compounds of the present invention may be administered to the rectum or vagina, for example in the form of suppositories, pessaries or enemas.

The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of drops of a finely divided suspension or solution in isotonic, sterile saline, adjusted for pH.

Compounds of the present invention are soluble macromolecules such as cyclodextrins and their suitable derivatives or polyethylene glycol-containing polymers for improving solubility, degradation rate, taste-itch, bioavailability and / or stability for use in any of the foregoing modes of administration. May be combined with the monomer.

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. α-, β- and γ-cyclodextrins are most commonly used for this purpose, examples of which can be found in WO 91/11172, WO 94/02518 and WO 98/55148. have.

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

In another aspect of the invention, a. A compound of formula (I) or a salt and / or solvate thereof, b. Instructions for treating obstructive or inflammatory airway disease, c. A kit is provided that includes packaging for holding a and b.

Preferably the obstructive or inflammatory airway disease is COPD.

In another embodiment, the instructions for b are for treating asthma.

Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound according to the present invention, are coadministered with the composition. It is within the scope of the present invention that they can be conveniently combined in the form of a kit suitable for.

Thus, another aspect of the invention relates to two or more separate pharmaceutical compositions in which the at least one composition contains a compound according to the invention, and means for keeping the composition separate such as containers, divided bottles, divided It is a kit containing a foil packet. An example of such a kit is the familiar blister pack used to package tablets, capsules and the like.

Kits of the invention may be particularly suitable for administration in different dosage forms, for example parenteral, for administering separate compositions at different dosage intervals, or for titrating the separate compositions against one another. For ease of understanding, the kit typically includes instructions for administration and may have a so-called memory aid.

For administration to human patients, the total daily dosage of a compound of the invention typically ranges from 0.01 mg to 10 mg depending on the mode of administration. For example, an inhaled daily dose may only require 0.01 mg to 5 mg. The total daily dose may be administered in a single dose or in divided doses and may, as directed by the physician, deviate from the typical range provided herein.

The dosage is based on an average human patient having a weight of about 65 kg to 70 kg. For patients whose weight is outside this range, such as infants and the elderly, the doctor can easily determine the dosage.

According to another aspect of the invention, a compound of the invention comprises signs and symptoms, such as (i) bronchial contraction, (ii) inflammation, (iii) allergy, (ic) tissue destruction, (v) shortness of breath, cough It may also be used in combination with one or more additional therapeutic agents to be coadministered to a patient to achieve some specifically desired therapeutic outcome, such as but not limited to the treatment of pathologically related disease progression. The additional one or more second therapeutic agents may be a compound of the invention or one or more TNF inhibitors and / or p38 inhibitors known in the art. More typically, the one or more second therapeutic agents are selected from different kinds of therapeutic agents.

As used herein, the terms “coadministered”, “coadministered” and “combined” in connection with a compound of the present invention and one or more other therapeutic agents are intended to mean the following and refer to and include the following :

When the combination of the compound (s) and therapeutic agent (s) of the invention is formulated in a single dosage form and released substantially simultaneously to a patient in need of treatment, the compound (s) and therapeutic agents of the invention in said patient Simultaneous administration of the combination of (s),

The combination of the compound (s) and therapeutic agent (s) of the invention are formulated in separate dosage forms from one another so that they are ingested substantially simultaneously by the patient in need thereof so that the components are released to the patient substantially simultaneously. If substantially simultaneous administration of the combination of the compound (s) and therapeutic agent (s) of the invention in said patient,

The compound (s) and therapeutic agent (s) of the invention are formulated in separate dosage forms from one another so that the components are ingested successively with sufficient time intervals between each administration by the patient in need of such treatment so that the Continuous release of the combination of the compound (s) and therapeutic agent (s) of the invention in said patient, when released at different times, and

Compound (s) and therapeutic agent (s) of the present invention are formulated in a single dosage form to release the components in a controlled manner to administer to the patient simultaneously, continuously and / or in duplicate at the same time and / or at different times Continuous administration of the combination of the compound (s) and therapeutic agent (s) of the invention, where each part can be administered via the same or different routes.

Suitable examples of other therapeutic agents that can be used in combination with the compound (s) or pharmaceutically acceptable salts, solvates or compositions thereof of the invention include, but are not limited to

(a) a 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist,

(b) leukotriene antagonists (LTRA), including LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ antagonists,

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

(d) α ₁ -and α ₂ -adrenergic receptor agonists vasoconstrictive sympathetic agents for decongestion use,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors,

(g) theophylline,

(h) sodium chromoglycate,

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

(j) oral and inhaled glucocorticoids, such as DAGR (degraded agonist of corticosteroid receptors),

(k) mono-branched antibodies active against endogenous inflammatory monomers,

(l) β agonists, including persistent β 2 agonists,

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

(n) kinin-B ₁ -and B ₂ -receptor antagonists,

(o) immunosuppressants,

(p) inhibitors of matrix metalloprotease (MMP),

(q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,

(r) elastase inhibitors,

(s) adenosine A2a receptor agonists,

(t) urokinase inhibitors,

(u) compounds acting on dopamine receptors, such as D2 agonists,

(v) modulators of the NFκB pathway, such as IKK inhibitors,

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

(x) drugs that can be classified as mucolytic or antitussives, and

(y) antibiotics.

According to the invention, compounds of the invention and H3 antagonists, muscarinic M3 receptor antagonists, PDE4 inhibitors, glucocorticoids, adenosine A2a receptor agonists, β agonists, modulators of cytokine signaling pathways such as syk kinases, or LTB ₄ , Preferred are combinations of leukotriene antagonists (LTRA), including LTC ₄ , LTD ₄ and LTE ₄ antagonists.

According to the invention, the compounds of the invention and the glucocorticoids, in particular prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and Inhaled glucocorticosteroids with reduced systemic side effects, including mometasone furoate and mometasone furoate monohydrate; In particular muscarinic M3 receptor antagonists, including ipratropium salts, i.e., ipratropium bromide, tiotropium salts, i.e. tiotropium bromide, oxytropium salts, i.e. Anticholinergic agents; Or combinations of sustained β2 agonists, in particular salmeterol, formoterol, QAB-149 and CHF-4226, in particular.

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

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

More preferably, the compounds of the present invention are metabolized into compounds having less activity than the compounds administered.

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

Assay: TNFα Search

The anti-inflammatory properties of the compounds of the invention are demonstrated by their ability to inhibit TNFα release from human peripheral blood mononuclear cells. Venous blood was collected from healthy volunteers and monocytes were purified by centrifugation using a Histoque (Ficoll) cushion. TNFα production from these cells is stimulated by lipopolysaccharide addition. After incubating for 18 hours in the presence of LPS, the cell supernatant was removed and TNFα concentration in the supernatant was determined by ELISA. The compound of the present invention is added to reduce the amount of TNFα produced. IC ₅₀ is determined, which corresponds to a compound concentration that inhibits TNFα production by 50% when compared to LPS stimulated control wells.

Examples tested in the described assay were found to have an IC ₅₀ (TNFα screen) of less than 1000nM, when most of the tested compounds were found to have an IC ₅₀ (TNFα screen) of less than 100nM.

Testing one embodiment it has been found to have in most cases less than 100nM IC ₅₀ (p38 assay) of was found to have an IC ₅₀ (p38 assay) of less than 1000nM, the test compound.

The term "active", "effective", "efficacy" in the present invention means that the compound of formula (I) exhibits TNF activity of less than 1000 nM as measured by the TNF assay described herein.

p38 kinase assay

Cloning of Human P38a

The coding region of human p38a cDNA was obtained by PCR-amplification from RNA isolated from human monocyte line THP1. The first cDNA strand was synthesized from total RNA as follows: 2 μg of RNA was heated to 70 ° C. for 10 minutes and then annealed to 100 ng of random hexamer primer in 10 μl reaction by placing on ice for 2 minutes. RNAsin (Promega, Madison, WI), 2 μl of 50 mM dNTP, 5 μl of 4 × buffer, 2 μl of 100 mM DTT, and 1 μl of Superscript® AMV reverse transcriptase 200 U) was added to synthesize cDNA. Random primers, dNTPs, and SuperScript II® reagents were all purchased from Life-Technologies, Gathersburg, Massachusetts, USA. The reaction was incubated at 42 ° C. for 1 hour. p38 DNA amplification was performed using 5 μl of reverse transcriptase reaction, 80 μl of dH ₂ O, ₂ μl of 5 mM dNTP, 1 μl of forward and reverse primer (50 pmol / μl), 10 μl of buffer and 10 μl of expand ( Expand: Aliquot was performed in 100 μl of PCR reaction containing 1 μl of polymerase (Boehringer Mannheim). PCR primers were bound to the Bam HI site on the 5 'and 3' ends of the amplified segments and were purchased from Genosys. The sequences of the forward and reverse primers were 5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 'and 5'-GATCGAGGATTCTCAGGACTCCATCTCTTC-3', respectively. PCR amplification was performed in a DNA Thermal Cycler (Perkin Elmer) with 30 cycles of 1 minute at 94 ° C, 1 minute at 60 ° C, and 2 minutes at 68 ° C. After amplification, excess primers and unbound dNTPs are removed from the amplified segments by Wizard® PCR preparation (Promega) and digested by Bam HI (New England Biolabs). It was. Segments degraded by Bam HI are described in T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989)] was ligated to Bam HI digested pGEX 2T plasmid DNA (Pharmacia Biotech) using T4-DNA ligase (New England Biolabs). The ligation reaction was transformed into chemically competitive E. coli DH10B cells purchased from Life-Technologies according to the manufacturer's instructions. Plasmid DNA was isolated from the bacterial colonies generated using the Promega Wizard® miniprep kit. Plasmids containing the appropriate Bam HI segment were sequenced in a DNA thermal cycler (Perkin Elmer) by Prism® (Applied Biosystems Inc.) Human p38a isotype CDNA clones encoding for both were identified (see Lee et al., Nature 372, 739.) One of the clones containing cDNA for p38a-2 (CSB-2) was inserted into the gene replication site of PGEX 2T. 3 'of the GST coding site was designated as pMON 35802. The sequence obtained for this clone was exactly the same as that of the cDNA clone reported in Lee et al., GST-p38a fusion protein due to the expression plasmid Can produce

Expression of human p38a

GST / p38a fusion protein was expressed from plasmid pMON 35802 in E. coli stained with DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grown in Luria Broth (LB) containing ampicillin 100 mg / ml. The next day, 500 ml of fresh LB was inoculated into 10 ml of culture overnight, and grown at 37 ° C. in a 2-liter flask with continuous shaking until the culture reached 0.8 absorbance at 600 nm. Fusion protein expression was induced by addition of isopropyl b-D-thiogalactosidase (IPTG) to a 0.05 mM final concentration. Cultures were shaken for 3 hours at room temperature and cells harvested by centrifugation. Cell pellets were frozen and stored until protein purification.

Purification of p38 Kinase-α

Unless otherwise stated, all chemicals were purchased from Sigma Chemical Co. 20 g of E. coli pellets collected from five 1 L shake flask fermentations were resuspended in up to 200 ml volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mM Na ₂ HPO ₄ , 1.8 mM KH ₂ PO ₄ , pH 7.3). . The cell suspension was adjusted to 5 mM DTT by 2M DTT and then divided equally into five 50 ml Falcon conical tubes. Cells were sonicated on ice three times for 1 minute (pulse) with a 1 cm probe. The lysed cell material was removed by centrifugation (12,000 xg, 15 minutes) and the clear supernatant was applied to glutathione-sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography

12 ml of 50% glutathione Sepharose-PBS supernatant was added to 200 ml of clear supernatant and incubated for 30 minutes at room temperature in a batchwise manner. The resin was collected by centrifugation (600 × g, 5 min), washed twice with 150 ml PBS / 1% Triton X-100 and then 4 times with 40 ml of PBS. To partition p38 kinase from GST-p38 fusion protein, glutathione-sepharose resin was resuspended in 6 ml of PBS containing 250 units of thrombin protease (Pharmacia, inactive> 7500 units / mg) and mixed slowly at room temperature for 4 hours. It was. Glutathione-Sepharose resin was removed by centrifugation (600 × g, 5 min) and washed twice with 6 ml of PBS. PBS wash fractions, and digested supernatants containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

Thrombin-divided p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-divided samples were diluted 2-fold with A buffer (25 mM Hepes, pH 7.5, 25 mM β-glycerophosphate, 2 mM DTT, 5% glycerol) and equilibrated with A buffer to mono Q HR 10 / Injection into 10 (Pharmacia) anion exchange column. The column was eluted with 160 ml (2 ml / min flow rate) 0.1 M to 0.6 M NaCl / buffer A gradient. The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml by a Filtron 10 concentrator (Piltron Corporation).

Sephacryl S100 Gel Filtration Chromatography

Concentrated mono Q-p38 kinase purified sample was equilibrated by gel filtration chromatography (B buffer (50 mM Hepes, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol) to Pharmacia HiPrep 26/60 Sepha Krill S100 column). Protein was eluted from the column with B buffer at a flow rate of 0.5 ml / min and protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at -80 ° C. Typical purified protein yield from 5 liters of E. coli shake flask ferment was 35 mg of p38 kinase.

Reaction rate assay

Binding kinetics:

SKF-86002 (Calbiochem: KD-200 nM) increases fluorescence upon binding to p38 (observed by excitation at 340 nm and emission at 420 nm). SKF-86002 (1-2 uM) was cooled to room temperature for 5-10 minutes with p38a (20-60 nM) in a buffer consisting of 20 mM bis-tris, 2 mM EDTA, 500 mM NaCl, 0.01% NaN ₃ , 0.15% NOG and 5% DMSO. Pre-culture at. Then sample compound (20-100 nM) was added and fluorescence change was observed. When SKF was separated from the binding site on p38a, SKF was replaced by the sample compound, and a decrease in fluorescence was observed with a time scale proportional to the binding rate of the compound. The binding rate of the compound was determined by using the known binding kinetics of SKF-86002.

Decomposition reaction rate:

Sample compound (50 or 100 nM) was determined by p38a (37 nM protein or active site titration overnight at room temperature in a buffer consisting of 20 mM bis-tris, 2 mM EDTA, 0.01% NaN ₃ , 0.15% NOG, 500 mM NaCl and 5% DMSO. 21 nM). The following day, SKF 86002 was added until a final concentration of 50 uM was reached. The increase in fluorescence observed when SKF 86002 bound to p38a was observed by excitation at 340 nm and emission at 420 nm, and the degradation rate was measured.

data:

The following data was obtained using the TNF screen disclosed herein.

Examples and Preparations

Nuclear magnetic resonance (NMR) data were obtained using Varian Unity Inova-400, Varian Unity Inova-300 or Bruker AC300 spectrometer, parts per million from tetramethylsilane ) In units. Mass spectral (MS) data were obtained on Finnigan Mat. TSQ 7000 or Fisons Instruments Trio 1000. The quoted ions calculated and observed refer to the lowest mass isotropic mass. For column chromatography on silica gel, Kieselgel 60 (E. Merck, Darmstadt, Germany) was used unless otherwise stated. Kigelgel 60 F ₂₅₄ plates from E. Merck were used for TLC, and the compounds were visualized using UV light, 5% aqueous potassium permanganate or Dragendorff reagent (also included with aqueous sodium nitrite). Water content was determined on a Mitsubishi CA100 (Coulometric Karl Fisher Titrator). Other measurements were obtained using standard equipment. PdCl ₂ (dppf) .CH ₂ Cl ₂ is a 1,1-bis (diphenylphosphino) ferrocene palladium (II) chloride 1: 1 dichloromethane complex. DBU is 1,8-diazabicyclo [5.4.0] undes-7-ene.

Preparation Example 1

2,2-dimethyl-3-methylsulfanyl-propionic acid methyl ester

N, N-diisopropylethylamine (15.5 g, 0.12 mol) was added to a solution of methyl 2,2-dimethyl-3-hydroxypropionate (13.2 g, 0.1 mol) in dichloromethane (150 ml) This solution was cooled to 0 ° C. Methane sulfonyl chloride (12.6 g, 0.11 mol) was then added dropwise and the mixture was stirred at 0 ° C. for 90 minutes. The reaction mixture was then diluted with 0.5 M hydrochloric acid (100 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2 x 50 ml), the combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Methanethiol sodium salt (7.7 g, 0.11 mol) was added to the residue solution in dioxane (100 ml) and the mixture was heated at 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 column chromatography on silica gel eluting with dichloromethane: pentane 50: 50-100: afforded the title compound as pale yellow oil in 3.85 g in 24% yield.

Preparation Example 2

4,4-Dimethyl-5-methylsulfanyl-3-oxo-pentanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 1.20 g, 30 mmol) in tetrahydrofuran (20 ml) was refluxed. A solution of the product of Preparation 1 (3.84 g, 23.7 mmol) in acetonitrile (1.56 ml, 30 mmol) was added and the mixture was heated at reflux for 3 hours. The cooled reaction mixture was then diluted with water, acidified with 2M hydrochloric acid (30 ml) and extracted with dichloromethane (3 × 50 ml). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane to afford 2.70 g of the title compound as a pale yellow oil in 67% yield.

Preparation Example 3

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

The title compound was prepared in 81% yield as colorless oil from ethyl 2-methyl-2- (methylthio) propionate and acetonitrile using a method similar to Preparation Example 2.

Preparation Example 4

(3-Methylsulfanyl-phenyl) -hydrazine

Magnesium flakes (0.79 g, 33 mmol) and one iodine crystal were added to a solution of 3-bromothioanisole (6.11 g, 30 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at rt for 18 h. . The mixture was cooled to -78 ° C and di-tert-butyldiazocarboxylate (6.91 g, 30 mmol) was added. The mixture was stirred for 30 min at -78 ° C and then quenched by addition of 1M citric acid (40 ml). The reaction mixture was allowed to warm up to room temperature and 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 cooled to room temperature and concentrated in vacuo. The residue was taken up in water, made basic with saturated sodium bicarbonate solution and extracted with dichloromethane: methanol 90:10 (4 × 50 ml). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 70:30 to give the title compound as a dark orange liquid. Obtained in 36% yield.

Preparation Example 5

Di-tert-butyl 1- (4-methoxy-3-methylphenyl) hydrazine-1,2-dicarboxylate

ⁿ Butyl lithium (2.5 M in hexane, 23.9 ml, 59.75 mmol) was added to a solution of 4-bromo-2-methylanisole (10 g, 49.74 mmol) in tetrahydrofuran (150 ml) cooled to -78 ° C. The mixture was stirred at this temperature for 1 hour. Then, a solution of di-tert-butyldiazocarboxylate (13.74 g, 59.68 mmol) in tetrahydrofuran (50 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour and then at room temperature for 2 hours. The reaction was quenched with water (25 ml), concentrated to a small volume in vacuo and partitioned between diethyl ether (300 ml) and brine (300 ml). The aqueous layer was separated, re-extracted with diethyl ether (2 x 100 ml), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluting with heptane: ethyl acetate 75:25 gave 10.93 g of the title compound as a pale yellow solid in 62% yield.

Preparation Example 6

(4-methoxy-3-methylphenyl) hydrazine hydrochloride

4M hydrochloric acid (37.5 ml, 150 mmol) in 1,4-dioxane was added dropwise to a solution of the product of Preparation 5 (10.75 g, 30.50 mmol) in 1,4-dioxane (12.5 ml), and the mixture was at Stir for 48 hours. The mixture was then concentrated in vacuo and the residue was stirred for 30 min at 0 ° C. in diethyl ether. The precipitate was filtered off, washed with diethyl ether and the solid was dried under vacuum at 40 ° C. for 6 hours to give 5.43 g of the title compound in 94% yield.

Preparation Example 7

3-tert-butyl-1- [4- (methylthio) phenyl] -1H-pyrazole-5-amine

Concentrated hydrochloric acid (1 ml) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 ml), The mixture was heated at reflux for 18 h. 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 residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: to 97: 3 to afford the title compound as a yellow oil, which crystallized on standing (2.59 g, 95% yield). .

Preparation Examples 8 to 19

The following compounds having the formulas shown below were prepared by methods analogous to those described in Preparation Example 7 using appropriate hydrazine and nitrile starting materials. The reaction was observed by TLC analysis and heated at reflux for 3 to 24 hours:

In Preparation Examples 14-19, purification was carried out by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 80:20.

Preparation Example 20

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

N, N-diisopropylethylamine (1.7 ml, 7.99 mmol) was added phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g) in ethanol (15 ml). , 7.99 mmol), and the mixture was heated to 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 column chromatography on silica gel eluting with heptane: ethyl acetate 75:25 to afford the title compound as a pale orange oil, which crystallized on standing (1.21 g, 70% yield).

Preparation Examples 21 to 24

The following compounds having the following formulas were prepared in a similar manner as described in Preparation Example 20 using the appropriate hydrazine and nitrile starting materials. The reaction was observed by TLC analysis and heated at reflux for 3 to 24 hours:

Preparation Example 25

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

2-chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazine monohydrate (250 ml) and the mixture was heated at 70 ° C for 72 h. The reaction mixture is then diluted with water (750 ml) and the resulting precipitate is filtered and azeotropically distilled first with toluene (x 2) and then with dichloromethane (x 2) to give the title compound as a pale brown solid. 52 g was obtained in% yield.

Preparation Example 26

4-chloro-3-hydroxymethyl-phenol

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

Preparation Example 27

2-Chloro-5-hydroxy-benzaldehyde

Manganese dioxide (11 g, 125 mmol) was added to a suspension of the product of Preparation 26 (4 g, 25.2 mmol) in acetone (25 ml) and the mixture was heated at 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 afford 3.17 g of the title compound as a solid in 81% yield.

Preparation Example 28

2-Chloro-4-hydroxy-benzaldehyde

Diisobutylaluminum hydride (1M 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) and cooled to -78 ° C. The mixture was stirred at this temperature for 1 hour and then at room temperature for 18 hours. The mixture was then cooled to 0 ° C. and 1M hydrochloric acid (80 ml) was added dropwise. The reaction mixture was diluted with water (200 ml), filtered and washed with ethyl acetate (x 2). The filtrate layer was separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with dichloromethane to give 12.92 g of the title compound as a solid in 84% yield.

Preparation Example 29

Isobutyric acid N '-(5-bromo-pyridin-2-yl) -hydrazide

N, N-diisopropylethylamine (137 g, 1.06 mmol) was added to a suspension of the product of Preparation 25 (40 g, 213 mmol) in dichloromethane (100 ml) and the solution was cooled to 0 ° C. Isobutyryl chloride (22.7 g, 213 mmol) was then added dropwise and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was quenched with water and the resulting solid was filtered and dried for 48 hours in air. The solid was then recrystallized from methanol / N, N-diisopropylethylamine 25:75 to give 1.16 g of the title compound as a white crystalline solid in 85% yield.

Preparation Example 30

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

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

Preparation Example 31

6-bromo-3-isopropyl- [1,2,4] triazolo [4,3-a] pyridine

A suspension of the product of Preparation 29 (16 g, 62 mmol) in phosphorus oxychloride (320 ml) was heated at 75 ° C. for 18 h. The reaction mixture was then concentrated in vacuo, the residue dissolved in water, made basic with 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ethyl acetate / methanol 98: 2 to give 11.23 g of the title compound in 75% yield.

Preparation Example 32

3- (6-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -4-chloro-phenol

A mixture of the product of Preparation 27 (3.1 g, 19.7 mmol) and the product of Preparation 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 then stirred at rt for 18 h. The mixture was concentrated in vacuo, triturated with a mixture of ethyl acetate and methanol and filtered. The residue was further purified by column chromatography on silica gel eluting with dichloromethane: methanol 90:10 to afford 0.95 g of the title compound in 15% yield.

Preparation Example 33

4- (6-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -3-chloro-phenol

The title compound was prepared as a solid from the products of Preparations 28 and 25 in 78% yield using a method similar to that of Preparation Example 32.

Preparation Example 34

3- [2- (benzyloxy) phenyl] -6-bromo [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 30 using a method similar to Preparation 33. The title compound was further purified by column chromatography on silica gel eluting with ethyl acetate: dichloromethane 50:50 and then triturated with diethyl ether / ethyl acetate to give the title compound as a solid in 88% yield. .

Preparation 35

[2- (3-Isopropyl- [1,2,4] triazolo [4,3-a] pyridin-6-ylsulfanyl) -phenyl] -methanol

2-mercaptobenzyl alcohol (12.8 g, 91 mmol) in N, N-dimethylformamide (175 ml) product of Preparation 31 (19.8 g, 70 mmol), cesium carbonate (31.9 g, 98 mmol) and 1,1 To a mixture of '-bis (diphenylphosphino) ferrocenedichloropalladium (II) dichloromethane adduct (5.7 g, 7.0 mmol) was added and the reaction mixture was heated to 90 ° C. for 21 h. 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 column chromatography on silica gel eluting with ethyl acetate: methanol 98: 2 and triethylamine (1 drop per 100 ml of organic solution) to give the title compound. 7 g was obtained in 33% yield as a brown solid.

Preparation Example 36

4-chloro-3- (6-{[2- (hydroxymethyl) phenyl] thio} [1,2,4] triazolo [4,3-a] pyridin-3-yl) phenol

The title compound was prepared from the product of Preparation 32 and 2-mercaptobenzyl alcohol in a 62% yield as a pale brown solid using a method similar to the preparation of 35.

Preparation Example 37

3-chloro-4- (6-{[2- (hydroxymethyl) phenyl] thio} [1,2,4] triazolo [4,3-a] pyridin-3-yl) phenol

The title compound was prepared from the product of Preparation 33 and 2-mercaptobenzyl alcohol in a 41% yield as a pale brown foam using a method similar to the preparation of 35.

Preparation Example 38

[2-({3- [2- (benzyloxy) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) phenyl] methanol

The title compound was prepared from the product of Preparation 34 and 2-mercaptobenzyl alcohol in a 57% yield as a brown solid using a method similar to the preparation of 35.

Preparation Example 39

6- (2-azidomethyl-phenylsulfanyl) -3-isopropyl- [1,2,4] triazolo [4,3-a] pyridine

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

Preparation Example 40

3- (6-{[2- (azidomethyl) phenyl] thiol} [1,2,4] triazolo [4,3-a] pyridin-3-yl) -4-chlorophenyl diphenyl phosphate

The title compound was prepared from the product of Preparation 36 in 84% yield using a method similar to the preparation of 39.

Preparation Example 41

4- (6-{[2- (azidomethyl) phenyl] thiol} [1,2,4] triazolo [4,3-a] pyridin-3-yl) -3-chlorophenol

The title compound was prepared from the product of Preparation 37 in a 58% yield as a pale brown foam using a similar method as in Preparation 39.

Preparation Example 42

6-{[2- (azidomethyl) phenyl] thiol} -3- [2- (benzyloxy) phenyl] [1,2,4] triazolo [4,3-a] pyridine

The title compound was obtained from the product of Preparation 38 in 45% yield as a liquid using a method similar to the preparation of 39.

Preparation Example 43

{2-[(3-isopropyl [1,2,4] triazolo [4,3-a] pyridin-6-yl) thio] benzyl} amine hydrochloride

Triphenylphosphine (10.6 g, 40.3 mmol) and water (0.73 ml, 40.3 mmol) were added to a solution of the product of Preparation 39 (10.8 g, 33.6 mmol) in tetrahydrofuran (114 ml), and the mixture at room temperature. After stirring for 40 hours, it was warmed to 40 ℃ for 5 hours. The reaction mixture was then cooled to rt, 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 at rt for 18 h. The resulting precipitate was filtered and dried over phosphorus pentoxide to give 7.24 g of the title compound as a gray solid in 65% yield.

Preparation Example 44

3- (6-{[2- (aminomethyl) phenyl] thio} [1,2,4] triazolo [4,3-a] pyridin-3-yl) -4-chlorophenol hydrochloride

The title compound was prepared from the product of Preparation 40 using a method similar to that of Preparation 43. The crude product was redissolved in methanol and saturated with 1M hydrochloric acid in diethyl ether to give the desired product in quantitative yield.

Preparation Example 45

4- (6-{[2- (aminomethyl) phenyl] thio} [1,2,4] triazolo [4,3-a] pyridin-3-yl) -3-chlorophenol hydrochloride

The title compound was prepared from the product of Preparation 41 using a method similar to that of Preparation 43. The crude product was redissolved in methanol and saturated with 1M hydrochloric acid in diethyl ether to give the desired product in 60% yield.

Preparation Example 46

[2-({3- [2- (benzyloxy) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine hydrochloride

The title compound was prepared from the product of Preparation 42 using a method similar to that of Preparation 43. The crude product was redissolved in methanol and saturated with 1M hydrochloric acid in diethyl ether to afford the desired product as a white solid in 78% yield.

Preparation 47

4,4-dimethyl-3-oxohexanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 3.18 g, 79.4 mmol) in tetrahydrofuran (60 ml) 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) in tetrahydrofuran (100 ml), J. Am. Som. 1942, 64, 2964) was added and the mixture was stirred at 25 ° C. for 4 h. The mixture was then diluted with 1 M hydrochloric acid (100 ml), the aqueous layer was separated and extracted with ethyl acetate. The organic solution was then dried over magnesium sulfate and concentrated in vacuo to triturate the residue with heptane to give 2.3 g of the title compound as a pale brown solid in 27% yield.

Preparation Example 48

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

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

Preparation 49

Benzyl 5- (benzyloxy) -2-chlorobenzoate

The title compound was prepared from 2-chloro-5-hydroxybenzoic acid (US 2002/0037905, page 15) in quantitative yield as an oil using a method analogous to that described in Preparation 48.

Preparation 50

4- (benzyloxy) -2-chlorobenzonitrile

Potassium carbonate (66.3 g, 480 mmol) is added to a mixture of 2-chloro-4-hydroxybenzonitrile (25 g, 160 mmol) and benzyl bromide (19.3 ml, 161 mmol) in acetonitrile (300 ml) and the mixture is 18 hours. Stir at room temperature. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was triturated with heptane to afford 38.65 g of the title compound as a grayish white solid in 99% yield.

Preparation Example 51

4- (benzyloxy) -2-chlorobenzaldehyde

The title compound was prepared from the product of Preparation 50 in 97% yield using the same method as described in Preparation 28.

Preparation Example 52

4-bromo-1-ethyl-2-methoxybenzene

Methyl iodide (3 ml, 47.3 mmol) is added to a solution of 4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate (6.54 g, 47.3 mmol) in acetone (20 ml) and the mixture Was stirred at RT for 18 h. The reaction mixture was concentrated to small volume in vacuo and diluted with water. The aqueous mixture was extracted with dichloromethane (3 x 50 ml) and the combined organic solutions 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 at 150 ° C. for 60 h. The reaction mixture was then quenched with 1M hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). The combined organic solutions were dried over sodium sulphate, concentrated in vacuo and the residue was purified by Kugel Rohr fractional distillation (150 ° C./0.05 mbar) to give the title compound as a yellow oil (128 mg).

Preparation Example 53

N- (3-chloro-4-methoxyphenyl) -N '-(2,2-dimethylpropaneoil) -2,2-dimethylpropaneohydrazide

The title compound was prepared from 4-bromo-2-chloro-1-methoxy-benzene (see J. Org. Chem. 1982, 47, 5270) and di-tert-butyldiazocarboxylate. The same method was used to produce 43% yield as a white powder.

Preparation Example 54

Di-tert-butyl 1- [3- (benzyloxy) -5-methylphenyl] hydrazine-1,2-dicarboxylate

The title compound was prepared from the product of Preparation 48 and di-ter-butyldiazocarboxylate in 84% yield as a yellow liquid using the same method as described in Preparation Example 5.

Preparation Example 55

Di-tert-butyl 1- (3-ethyl-4-methoxyphenyl) hydrazine-1,2-dicarboxylate

The title compound was prepared from 4-bromo-2-ethyl-1-methoxy-benzene and di-ter-butyldiazocarboxylate in 53% yield as a solid using the same method as described in Preparation Example 53.

Preparation Example 56

Di-tert-butyl 1- (4-ethyl-3-methoxyphenyl) hydrazine-1,2-dicarboxylate

The title compound was prepared from the product of Preparation 52 and di-ter-butyldiazocarboxylate in 40% yield as a pale yellow oil using the same method as described in Preparation 53.

Preparation Example 57

(3-chloro-4-methoxyphenyl) hydrazine hydrochloride

The title compound was prepared from the product of Preparation 53 in 93% yield as a greyish white powder using the same method as described in Preparation Example 6.

Preparation 58

[3- (benzyloxy) -5-methylphenyl] hydrazine hydrochloride

The title compound was prepared from the product of Preparation 54 in 59% yield as a solid using the same method as described in Preparation 6.

Preparation Example 59

(3-ethyl-4-methoxyphenyl) hydrazine hydrochloride

The title compound was prepared from the product of Preparation 55 in quantitative yield as a solid using the same method as described in Preparation Example 6.

Preparation Example 60

(4-ethyl-3-methoxyphenyl) hydrazine hydrochloride

The title compound was prepared from the product of Preparation 56 in 85% yield as a grayish white solid using the same method as described in Preparation Example 6.

Preparation Examples 61-86, 88, and 89

The following compounds having the formulas shown below were prepared using appropriate commercial hydrazine and commercial nitrile starting materials by methods similar to those described in Preparation Example 7. If starting materials are not commercially available, the synthesis is disclosed herein. The reaction was observed by TLC analysis and heated at reflux for 3 to 24 hours.

^{The b} rough compound was purified by column chromatography on silica gel eluting with heptane: ethyl acetate 75:25.

In Preparation Example 83, the product of Preparation Example 3 and (3-ethylphenyl) -hydrazine hydrochloride (EP 177242, p31) were prepared.

In Preparation Example 84 the crude compound was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 100: 0 to 60:40.

The crude compound in Preparation 86 was purified by column chromatography on silica gel eluting with hexane: ethyl acetate 91: 9 to 83:17.

Preparation 87

(4-chloro-3-methoxyphenyl) hydrazine

A solution of sodium nitrite (1.7 g, 24.4 mmol) in concentrated hydrochloric acid (12 ml) and water (8 ml) was added to a solution of 4-chloro-3-methoxy aniline (3.86 g, 24.4 mmol) in water (8 ml) at -10 ° C. Added. The mixture was stirred for 30 minutes and then added to a solution of tin chloride (14.89 g, 66 mmol) in concentrated hydrochloric acid (24 ml) and water (24 ml). The reaction mixture was stirred for 18 hours and the temperature was raised to 25 ° C. The resulting precipitate was filtered off and the solid was recrystallized from heptane / ethyl acetate (33:66) to give 3 g of the title compound as a white solid in 72% yield.

Preparation 90

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

The title compound was obtained as an orange oil using the same method as described in Preparation 7 from 4,4-dimethyl-3-oxopentane nitrile and 3-pyridiniohydrazide (US 2002/0143176, page 22). Prepared in 50% yield.

Preparation 91

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

The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrile and 2-hydrazineopyridine in 99% yield as a solid using the same method as described in Preparation 7.

Preparation Example 92

1- [4- (benzyloxy) phenyl] -3- [1-methyl-1- (methylthio) ethyl] -1 H-pyrazol-5-amine

Concentrated hydrochloric acid (2 ml) was added dropwise to a suspension of [4- (benzyloxy) phenyl] hydrazine hydrochloride (3.19 g, 12.74 mmol) and product of Preparation 3 (2 g, 12.74 mmol) in ethanol (50 ml), and the mixture was Heated under reflux for 2 hours. Water (5 ml) was then added and the reaction mixture was heated at reflux for another 16 h. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 100: 0 to 85:15 to afford the title compound as an orange oil, which crystallized on standing (2.79 g, 62% yield). ).

Preparation Examples 93-97

The following compounds having the formulas shown below were prepared using appropriate commercial hydrazine and commercial nitrile starting materials by methods similar to those described in Preparation Example 20. If starting materials are not available, the synthesis is disclosed herein. The reaction was observed by TLC analysis and heated at reflux for 3 to 24 hours.

In Preparation Example 93 the crude compound was triturated with heptane: diethyl ether 66:33.

Preparation Example 98

[4- (5-amino-3-tert-butyl-1H-pyrazol-1-yl) phenyl] methanol

Lithium aluminum hydride (1M in tetrahydrofuran, 1.83 ml, 1.83 mmol) in 4- [5-amino-3- (1,1-dimethylethyl) -1H-pyrazole-1 in tetrahydrofuran (5 ml) -Yl] -benzoic acid methyl ester ((0.25 g, 0.92 mmol), WO 2004060306, page 134) was added to the ice-cold solution and the mixture was stirred at 0 ° C. for 1 hour. The reaction was then quenched with water (0.35 ml) and 1 M sodium hydroxide solution (0.35 ml) followed by additional water (1 ml). The mixture was then extracted with diethyl ether (10 ml) and the organic solution was dried over sodium sulfate and concentrated in vacuo to yield the title compound as red oil in 22% mg in 98% yield.

Preparation Example 99

3-tert-butyl-1- [4-({[tert-butyl (dimethyl) silyl] oxy} methyl) phenyl] -1H-pyrazol-5-amine

Of the product of Preparation 98 (0.5 g, 2.04 mmol), tert-butyldimethylsilyl chloride (0.34 g, 2.25 mmol) and imidazole (0.18 g, 2.55 mmol) in N, N-dimethylformamide (2 ml) The mixture was stirred at rt for 18 h. The reaction mixture was then diluted with methanol (1 ml) and stirred at room temperature for 15 minutes. The mixture was diluted with sodium hydrogen carbonate solution (20 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic solutions were dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with heptane: ethyl acetate 85:15, 75:25 to give the title compound as a colorless solid in 30% yield. 220.5 mg were obtained.

Preparation Example 100

3-tert-butyl-1- (3-{[tert-butyl (dimethyl) silyl] oxy} -4-methylphenyl) -1H-pyrazol-5-amine

The title compound was prepared as 5- [5-amino-3- (1,1-dimethylethyl) -1H-pyrazol-1-yl] -2-methyl-phenol hydrochloride (WO 03/005999, page 81 and P. 82) and tert-butyldimethylsilyl chloride in the 86% yield as a solid using the same method as described in Preparation Example 99.

Preparation Example 101

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

Boron tribromide (1M in dichloromethane, 12 ml, 12 mmol) was added dropwise to an ice cold solution of the product of Preparation 63 (1.28 g, 4 mmol) in dichloromethane (50 ml) and the mixture was stirred for 30 minutes Was raised to 25 ° C. The reaction mixture was then diluted with methanol (20 ml) and water, basified with 0.88 ammonia and extracted with dichloromethane (3 × 50 ml). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 100: 0 to 80:20 to give the title compound as a pale yellow foam. 825 mg were obtained in 89% yield.

Preparation Example 102

4- {5-amino-3- [1-methyl-1- (methylthio) ethyl] -1H-pyrazol-1-yl} phenol

The title compound was prepared from the product of Preparation 76 in a 40% yield as a white solid using a method similar to the method described in Preparation 101.

Preparation Example 103

N- {1- [4- (benzyloxy) phenyl] -3-tert-butyl-1H-pyrazol-5-yl} benzamide

The title compound was prepared from the product of 244 and petyl chloroformmate in quantitative yield as a brown oil using the same method as described in Preparation 116.

Preparation Example 104

1- (4-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-pyrazol-5-amine

The title compound was prepared from the product of Preparation 102 and tert-butyldimethylsilyl chloride in 48% yield as a yellow oil using the same method as described in Preparation 99.

Preparation Example 105

1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-pyrazol-5-amine

The title compound was prepared from the product of Preparation 110 and tert-butyldimethylsilyl chloride in 49% yield as a red oil using the same method as described in Preparation 99.

Preparation Example 106

3-tert-butyl-1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -1H-pyrazol-5-amine

The title compound was prepared from the product of Preparation 101 and tert-butyldimethylsilyl chloride in a 34% yield as a colorless oil using the same method as described in Preparation 99.

Preparation Example 107

3- {5-amino-3- [1,1-dimethyl-2- (methylthio) ethyl] -1H-pyrazol-1-yl} phenol

The title compound was prepared from the product of Preparation 72 in 18% yield as a yellow solid using the same method as described in Preparation 101.

Preparation Example 108

3- [5-amino-3- (1,1-dimethylpropyl) -1H-pyrazol-1-yl] phenol

A solution of boron tribromide (1.7 ml, 17.9 mmol) in dichloromethane (20 ml) was added dropwise to an ice cold solution of the product of preparation 70 (1.20 g, 3.6 mmol) in dichloromethane (15 ml) and the mixture The temperature was raised to 25 ° C. by stirring for 90 minutes. Dimethylamine (40% in water, 5 ml) was then added dropwise and the mixture was stirred at rt for 1 h. 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 column chromatography on silica gel eluting with heptane: ethyl acetate 100: 0 to 50:50 gave the title compound as a yellow foam, 390 mg in 49% yield.

Preparation Example 109

2- (6-{[2- (aminomethyl) phenyl] thio} [1,2,4] triazolo [4,3-a] pyridin-3-yl) phenol

The product of Preparation 46 (3.43 g, 7.22 ml) was suspended in bromic acid (5.7 M in glacial acetic acid, 7 ml, 40 mmol) and the mixture was stirred at rt for 18 h. 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, 400 ml). The aqueous layer of the filtrate was separated and extracted three times with dichloromethane: methanol (90:10). The extract was then combined with the dissolved residue solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 2.40 g of the title compound as a solid in 96% yield.

Preparation Example 110

3- {5-amino-3- [1-methyl-1- (methylthio) ethyl] -1H-pyrazol-1-yl} phenol

The title compound was prepared from the product of Preparation 87 in 44% yield as a white foam using the same method as described in Preparation 109.

Preparation Example 111

3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-amine

Product of Preparation 101 (750 mg, 3.25 mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (1.02 g, 4.88 mmol) and potassium carbonate in N, N-dimethylformamide (10 ml) 690 mg, 5 mmol) was stirred at 60 ° C. for 4 hours. The reaction mixture was then cooled to rt, diluted with ethyl acetate and washed with water (x 2) and brine. The organic solution is then dried over magnesium sulfate, concentrated in vacuo and the residue is purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 100: 0 to 85:15 to give the title compound as a yellow oil. Obtained in 71% yield.

Preparation Example 112

3- [1-methyl-1- (methylthio) ethyl] -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazole-5- Amine

The title compound was prepared from the product of Preparation Example 110 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in 94% yield as an orange oil using the same method as described in Preparation Example 111.

Preparation Example 113

3- [1,1-dimethyl-2- (methylthio) ethyl] -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazole -5-amine

The title compound was prepared from the product of Preparation Example 107 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in the same manner as described in Preparation Example 111 in a 71% yield as a yellow oil.

Preparation Example 114

3- (1,1-dimethylpropyl) -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-amine

The title compound was prepared from the product of Preparation Example 108 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in the yield of 71% as a yellow oil using the same method as described in Preparation Example 111.

Preparation Example 115

3- [1-methyl-1- (methylthio) ethyl] -1- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazole-5- Amine

The title compound was prepared from the product of Preparation 102 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in the 82% yield as a yellow oil using the same method as described in Preparation 111.

Preparation Example 116

Phenyl (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) carbamate

Phenylchloroformate (1.94 g, 12.4 mmol) was added to an ice cold solution of the product of Preparation 111 (4.05 g, 11.3 mmol) and pyridine (1.09 ml, 13.5 mmol) in tetrahydrofuran (50 ml), and the mixture was 0 ° C. Stirred for 5 minutes at room temperature and 20 minutes at room temperature. The reaction mixture was then 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 yield 5.22 g of the title compound as a yellow oil in 86% yield.

Preparation Example 117

Phenyl (3- [1-methyl-1- (methylthio) ethyl] -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazole- 5-day) carbamate

The title compound was prepared from the product of Preparation 112 and phenylchloroformate in quantitative yield as an orange oil using the same method as described in Preparation 116.

Preparation Example 118

Phenyl {1- [3- (benzyloxy) phenyl] -3-tert-butyl-1H-pyrazol-5-yl} carbamate

The title compound was prepared from the product of Preparation 63 and phenylchloroformate in 94% yield as a brown solid using the same method as described in Preparation 116.

Preparation Example 119

Phenyl [3-tert-butyl-1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -1H-pyrazol-5-yl] carbamate

The title compound was prepared from the product of Preparation 106 and phenylchloroformate in quantitative yield as a clear oil using the same method as described in Preparation 116.

Preparation Example 120

Phenyl {1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- [1-methyl-1- (methylthio) ethyl] -1H-pyrazol-5-yl} carbamate

The title compound was prepared from the product of Preparation 105 and phenylchloroformate in quantitative yield as a red oil using the same method as described in Preparation 116.

Preparation Example 121

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

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

Preparation Example 122

N- [2-({3-2- (benzyloxy) phenyl [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] -N '-[3-tert -Butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl} urea

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

Preparation Examples 123 to 166

The following compounds having the formulas shown below were prepared using appropriate amines, N, N′-carbonyldiimidazole and suitable aminopyrazole starting materials by methods analogous to those described in Preparation Example 121, wherein the starting materials May be available or commercially available from the synthetic methods disclosed herein. The reaction was observed by TLC analysis and heated at room temperature for 20-72 hours.

In Preparation Examples 124, 132 and 133, the crude compound was purified by column chromatography on silica gel eluting with dichloromethane: 7M methanolic ammonia 100: 0 to 97.5: 2.5. Further purification using reverse phase column chromatography on C18 silica gel eluting with water / 7M methanolic ammonia (98: 2): acetonitrile / 7M methanolic ammonia (98: 2) 75:25 to 25:75. It was.

In Preparation Example 134, the crude compound was purified by column chromatography on silica gel eluting with dichloromethane: 7M methanolic ammonia / dichloromethane (10:90) 100: 0 to 50:50. It was further purified by trituration with dichloromethane: methanol: diethanol ether.

Prepared from the products of Preparations 17 and 206 in Preparation Example 160.

Prepared from product of Preparations 104 and 214 in Preparation 163.

Prepared from the suitable aminopyrazoles in preparations 165 and 166 and the product of preparation 208. The crude compound is eluted with hexane: ethyl acetate 90:10 followed by column chromatography on silica gel eluting with pentane: ethyl acetate 80:20 to 20:80, and then ethyl acetate: methanol 100: 0 to 50:50. Purification by chromatography.

Preparation Example 167

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

The title compound was prepared from the products of Preparation 46 and 90 in 15% yield using the same method as described in Preparation 121.

Preparation 168

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

The title compound was prepared from the products of Preparation 46 and 91 in 63% yield using the same method as described in Preparation 121.

Preparation Example 169

N- [2-({3-2- (benzyloxy) phenyl [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] -N '-(3- [ 1,1-dimethyl-2- (methylthio) ethyl] -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazole-5- Urea

Pyridine (64 μl, 0.8 mmol) and phenylchloroformmate (110 mg, 0.70 mmol) were added successively to an ice cold solution of the product of Preparation 113 (250 mg, 0.62 mmol) in tetrahydrofuran (10 ml), and the mixture was 0 ° C. Stir for 10 min at 40 min at room temperature. 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 (5 ml), the product of Preparation 46 (332 mg, 0.70 mmol) and N, N-ethyldiisopropylamine (0.17 ml, 1 mmol) were added and the mixture was stirred at 50 ° C. Stir for 90 minutes. The reaction mixture was then cooled to rt, diluted with water and washed with 0.1M citric acid, saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and concentrated in vacuo to yield 614 mg of the title compound as a yellow foam in quantitative yield.

Preparation 170

N- [2-({3-2- (benzyloxy) phenyl [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] -N '-(3- ( 1,1-dimethylpropyl) -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) urea

The title compound was prepared from the products of Preparation Examples 114 and 46 using the same method as described in Preparation Example 169. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 100: 0 to 30:70 to afford the desired product in 59% yield as a white foam.

Preparation Example 171

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

The title compound was prepared from the products of Preparations 63 and 206 using the same methods as described in Preparation 169. The crude compound was purified by column chromatography using 12 g ISCO silica cartridges eluting with ethyl acetate to afford the desired product in 43% yield.

Preparation Example 172

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

The title compound was prepared from the products of Preparations 85 and 109 using the same method as described in Preparation 169. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to afford the desired product in 33% yield.

Preparation Example 173

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- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) urea

Example 26 product (89 mg, 0.15 mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (36 mg, 0.17 mmol) and potassium carbonate (28 mg) in N, N-dimethylformamide (2 ml) , 0.2 mmol) was stirred at room temperature for 18 hours and heated at 60 ° C. for 12 hours. The reaction mixture was then cooled to rt, diluted with ethyl acetate and washed with water and brine. The organic solution is then dried over magnesium sulfate, concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia 100: 0: 0 to 94: 6: 1. This gave the title compound as a glass in 67% yield.

Preparation Example 174

N- {1- [3- (benzyloxy) phenyl] -3-tert-butyl-1H-pyrazol-5-yl} -N '-{2-[(3- {2- [2- (tetrahydro -2H-pyran-2-yloxy) ethoxy] phenyl} [1,2,4] triazolo [4,3-a] pyridin-6-yl) thio] benzyl} urea

The title compound was prepared from the product of Preparation 123 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in 75% yield as a white foam using the same method as described in Preparation Example 111.

Preparation Example 175

N- (3-tert-butyl-1- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) -N '-( 2-{[3- (2-chlorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the product of Preparation 257 and 2- (2-bromoethoxy) tetrahydro-2H-pyran in 45% yield as pale yellow foam using the same method as described in Preparation Example 111.

Preparation Example 176

[5- (benzyloxy) -2-chlorophenyl] methanol

The title compound was prepared from the product of Preparation 49 using the same method as described in Preparation 26. The crude compound was triturated with diethyl ether to afford the desired product in 91% yield as a white solid.

Preparation Example 177

5- (benzyloxy) -2-chlorobenzaldehyde

The title compound was prepared from the product of Preparation 176 using a method similar to the method described in Preparation 27. The crude compound was recrystallized from isopropyl ether to give the desired product in 67% yield as a solid.

Preparation Examples 178 to 183

The following compounds having the formulas shown below were prepared using the product of Preparation 25 and an appropriate commercial aldehyde in a manner similar to that described in Preparation 30. For Preparation 182, the starting material 4-benzyloxy-2-chloro benzaldehyde is described in J. Pat. Chem. Soc. Perkin Trans 1990, (2), 253].

Preparation Example 184

6-bromo-3- (2-ethylphenyl) [1,2,4] triazolo [4,3-a] pyridine

(Diacetoxyurodo) benzene (6.95 g, 22 mmol) was added to a solution of the product of Preparation 178 (5.46 g, 18 mmol) in dichloromethane (200 ml), 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 column chromatography on silica gel eluting with ethyl acetate: dichloromethane 50:50 to afford the title compound as a solid in quantitative yield.

Preparation 185

6-bromo-3- (2-chlorophenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 181 using the same method as described in Preparation 184. The crude compound was triturated with ethyl acetate for further purification to afford the desired product in 73% yield.

Preparation Example 186

6-bromo-3- [2- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridine

(Diacetoxy urido) benzene (500 mg, 1.55 mmol) was added to an ice-cold solution of the product of Preparation Example 180 (500 mg, 1.55 mmol), and the mixture was stirred for 6 hours to raise the temperature to 25 ° C. Additional (diacetoxyurido) benzene (500 mg, 1.55 mmol) 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 column chromatography on silica gel eluting with ethyl acetate to afford the title compound as a white solid in 68% yield.

Preparation Example 187

6-bromo-3- (2-methylphenyl) [1,2,4] triazolo [4,3-a] pyridine

To a solution of the product of Preparation 179 (9.25 g, 31.88 mmol) in ethanol (190 ml) and dichloromethane (60 ml) was added ammonium cerium nitrate (35 g, 63.76 mmol). The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic solution was separated, washed with water (4 x 100 ml), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluting with pentane: ethyl acetate 75:25 and then dichloromethane: ethanol 50:50 gave 1.94 g of the title compound in 21% yield.

Preparation Example 188

6-bromo-3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from 2-fluorobenzaldehyde and the product of Preparation 25 in the 54% yield as a white powder using the same method as described in Preparation 32.

Preparation Example 189

6-bromo-3- (2-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridine

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

Preparation 190

6-bromo-3- (2-chloro-3-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridine

A mixture of 2-chloro-3-methoxybenzaldehyde ((10 g, 58.6 mmol), WO 2005/007165, page 47) and the product of Preparation 25 (11.13 g, 58.6 mmol) in ethanol (70 ml) was prepared. Heated to < RTI ID = 0.0 > Udobenzene diacetate (24.5 g, 76 mmol) was added and the reaction mixture was diluted with ethanol (40 mL) and stirred at rt for 18 h. The resulting precipitate was filtered, washed with ethanol and dried in vacuo to give 12.70 g of the title compound as a solid in 64% yield.

Preparation Example 191

3- [5- (benzyloxy) -2-chlorophenyl] -6-bromo [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 177 in 60% yield as a solid using a method similar to that described in Preparation 190.

Preparation Example 192

3- [4- (benzyloxy) -2-chlorophenyl] -6-bromo [1,2,4] triazolo [4,3-a] pyridine

A mixture of the product of Preparation 182 (53.4 g, 128 mmol) and iodobenzene diacetate (41.3 g, 128 mmol) in dichloromethane (50 ml) and ethyl acetate (50 ml) was stirred at room temperature for 18 hours. The resulting yellow precipitate was filtered off and provided the first fraction of the title compound. The filtrate was then treated with dichloromethane (50 ml) and diethyl ether (100 ml) and the resulting yellow precipitate was filtered to give additional title compound, with a total yield of 37.1 g (70%).

Preparation Example 193

3- [2- (benzyloxy) -5-chlorophenyl] -6-bromo [1,2,4] triazolo [4,3-a] pyridine

A suspension of the product of Preparation 183 (6.2 g, 14.8 mmol) in dichloromethane (300 ml) and ethanol (100 ml) was warmed to 40 ° C. Udobenzene diacetate (6.39 g, 19.24 mmol) was added and the mixture was stirred at 40 ° C. for 10 minutes and then cooled to room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (400 ml) and 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 5.7 g of the title compound as a white solid in 92% yield.

Preparation Examples 194-203

The following compounds having the formulas shown below were prepared using the appropriate starting materials and 2-mercaptobenzyl alcohol by methods analogous to those described in Preparation Example 35.

The crude compound in Preparation Example 195 was purified by column chromatography on silica gel eluting with ethyl acetate: dichloromethane 50:50 and then dichloromethane: methanol 95: 5.

The crude compound in Preparation Example 196 was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 40:60 to 0: 100.

In Preparation Examples 197, 198 and 202, the compound of roughness was triturated with diethyl ether.

Preparation Example 204

(2-{[3- (2-ethylphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

Methanesulfonic anhydride (5 g, 29 mmol) was added to a solution of the product of Preparation Example 194 (3.5 g, 9.7 mmol) and N, N-ethyldiisopropylamine (6.8 ml, 38.8 mmol) in dichloromethane (100 ml). Was added and the mixture was stirred at rt for 90 min. Then 7M methanolic ammonia (140 ml) was added and the mixture was stirred at rt for 72 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (200 ml) and washed with sodium hydrogen carbonate solution (2 × 200 ml) and 2M hydrochloric acid (4 × 50 ml). The acidic washes were combined, made basic to pH 8 with 2M sodium hydroxide and extracted with dichloromethane (3 × 100 ml). The combined organic solutions were dried over sodium sulfate, concentrated in vacuo and the residue was redissolved with dichloromethane. The resulting solution was cooled in an ice bath and then bubbled with hydrogen chloride gas until saturation occurred. The reaction mixture was then concentrated in vacuo and the residue was azeotropic distilled with diethyl ether followed by dichloromethane to afford 1.66 g of the title compound as an orange foam in 43% yield.

Preparation Example 205

(2-{[3- (2-chlorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

Methanesulfonic anhydride (4.99 g, 28.66 mmol) of the product of Preparation 199 (5.27 g, 14.33 mmol) and N, N-ethyldiisopropylamine (7.4 ml, 42.99 mmol) in dichloromethane (150 ml) To the ice cold solution was added and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 4 hours. Then 7M methanolic ammonia (143 ml) was added and the mixture was stirred at rt for 18 h. 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 (3 × 70 ml). The acidic washes were combined, made basic with 2M sodium hydroxide (250 ml) and extracted with dichloromethane (4 × 125 ml). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia 95: 5: 0.5 to give an orange foam. . The foam was then dissolved in dichloromethane (15 ml) and acidified with hydrochloric acid (4M in dioxane, 3.1 ml). The mixture was azeotropic distilled with methanol and dichloromethane and the residue was triturated with diethyl ether to give 2.82 g of the title compound as a white solid in 48% yield.

Preparation Example 206

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

Methanesulfonic anhydride (2.7 g, 15.49 mmol) was prepared from the product of Preparation 195 (1.8 g, 5.18 mmol) and N, N-ethyldiisopropylamine (3.6 ml, 20.72 mmol) in dichloromethane (50 ml). The solution was added and the mixture was stirred at rt for 1 h. Then 7M methanolic ammonia (140 ml) was added and the mixture was stirred at rt for 72 h. The reaction mixture was then washed with sodium bicarbonate solution, brine and 2M hydrochloric acid (3 × 100 ml). The acidic washes were combined, made basic to pH 8 with 2M sodium hydroxide and extracted with dichloromethane (5 x 150 ml). The combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give 982 mg of the title compound as an orange rubber in 55% yield.

Preparation Example 207

[2-({3- [2- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine

The title compound was prepared from the product of Preparation 196 in 49% yield as a pale orange foam using the same method as described in Preparation 206.

Preparation Example 208

[2-({3- [2- (benzyloxy) -5-chlorophenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine

The title compound was prepared from the product of Preparation 203 using the same method as described in Preparation 206. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia 97: 3: 0.2 to 95: 5: 0.5 to give the desired compound as a pale brown rubber in 52% yield.

Preparation Example 209

6-{[2- (azidomethyl) phenyl] thio} -3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 197 and diphenylphosphoryl azide in 95% yield using a method similar to Preparation 39.

Preparation Example 210

6-{[2- (azidomethyl) phenyl] thio} -3- (2-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 198 and diphenylphosphoryl azide in 86% yield using a method similar to Preparation 39.

Preparation Example 211

6-{[2- (azidomethyl) phenyl] thio} -3- (2-chloro-3-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 200 and diphenylphosphoryl azide using a method similar to Preparation 39. The crude compound was triturated with dichloromethane / diethyl ether to give the desired product in 59% yield.

Preparation Example 212

6-{[2- (azidomethyl) phenyl] thio} -3- [4- (benzyloxy) -2-chlorophenyl] [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 201 and diphenylphosphoryl azide in quantitative yield as a brown foam using a method similar to Preparation 39.

Preparation Example 213

6-{[2- (azidomethyl) phenyl] thio} -3- [5- (benzyloxy) -2-chlorophenyl] [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 202 and diphenylphosphoryl azide in quantitative yield using a method similar to Preparation 39.

Preparation Example 214

(2-{[3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

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

Preparation Example 215

(2-{[3- (2-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

The title compound was prepared from the product of Preparation 210 in 52% yield as a solid using the same method as described in Preparation 214.

Preparation Example 216

(2-{[3- (2-chloro-3-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

The title compound was prepared from the product of Preparation Example 211 in 72% yield as a solid using the same method as described in Preparation Example 214.

Preparation Example 217

[2-({3- [4- (benzyloxy) -2-chlorophenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine hydrochloride

The title compound was prepared from the product of Preparation 212 in 64% yield as a solid using a method similar to the method described in Preparation 214.

Preparation Example 218

[2-({3- [5- (benzyloxy) -2-chlorophenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine

The title compound was prepared from the product of Preparation 213 in 85% yield as a solid using a method similar to the method described in Preparation 214.

Preparation Example 219

N- (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) -N- (2 -{[3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

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

Preparation Example 220

N- (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) -N '-( 2-{[3- (2-chlorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the products of Preparations 205 and 116 in 45% yield as a white foam using the same method as described in Preparation 219.

Preparation Example 221

N- (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} -1H-pyrazol-5-yl) -N '-( 2-{[3- (2-isopropylphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the products of Preparation Examples 237 and 116 using the same method as described in Preparation Example 219 in 37% yield as a white foam.

Preparation Example 222

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

The title compound was prepared from the products of Preparations 215 and 116 in the 46% yield as a white foam using the same method as described in Preparation 219.

Preparation Example 223

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

The title compound was prepared from the products of Preparation 118 and 205 in 59% yield as pale yellow foam using the same method as described in Preparation 219.

Preparation Example 224

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

The title compound was prepared from the products of Preparation Examples 118 and 46 in 58% yield as a white solid using the same method as described in Preparation Example 219.

Preparation Example 225

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

The title compound was prepared from the products of Preparation Examples 120 and 43 in a 69% yield as a white foam using the same method as described in Preparation Example 219.

Preparation Example 226

N- {1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-pyrazol-5-yl}- N '-(2-{[3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the products of Preparation Examples 120 and 214 in a 48% yield as a greyish white foam using the same method as described in Preparation Example 219.

Preparation Example 227

N- {1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- [1-methyl-1- (methylthio) ethyl] -1 H-pyrazol-5-yl}- N '-(2-{[3- (2-methoxyphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the products of Preparation Examples 120 and 215 in 53% yield as a white foam using the same method as described in Preparation Example 219.

Preparation Example 228

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

The title compound was prepared from the products of Preparation 204 and Preparation 17 in 41% yield using the same method as described in Preparation Example 121.

Preparation Example 229

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

The title compound was prepared from the products of Preparation Examples 207 and 63 in a 52% yield as a white solid using the same method as described in Preparation Example 121.

Preparation Example 230

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

The title compound was prepared from the products of Preparation 92 and 206 in 19% yield using the same method as described in Preparation 121.

Preparation Example 231

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

The title compound was prepared from the products of Preparations 95 and 217 in 59% yield as a brown powder using the same method as described in Preparation Example 121.

Preparation Example 232

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

The title compound was prepared from the products of Preparation Examples 218 and 95 in a 40% yield as a white powder using the same method as described in Preparation Example 121.

Preparation Example 234

6-bromo-3- (2-isopropylphenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 25 and 2-isopropylbenzaldehyde using the same method as described in Preparation 189. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to give the desired product as a yellow liquid in 35% yield.

Preparation Example 235

[3- (2-isopropylphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] methanol

The title compound was prepared from the product of Preparation Example 234 and 2-mercaptobenzyl alcohol using the same method as described in Preparation Example 35. The crude compound was purified by column chromatography eluting with dichloromethane: methanol 95: 5 to give the desired product in 45% yield as dark brown oil.

Preparation Example 236

6-{[2- (azidomethyl) phenyl] thio} -3- (2-isopropylphenyl) [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation Example 235 and diphenylphosphoryl azide in 66% yield as a brown oil using the same method as described in Preparation Example 39.

Preparation Example 237

(2-{[3- (2-isopropylphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) amine hydrochloride

The title compound was prepared from the product of Preparation 236 in 80% yield as a white solid using the same method as described in Preparation 214.

Preparation Example 238

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

A mixture of the product of Preparation 117 (399 mg, 0.78 mmol), the product of Preparation 214 (307 mg, 0.78 mmol) and N, N-ethyldiisopropylamine (0.30 ml, 1.70 mmol) in dimethyl sulfoxide (2 ml). Was stirred at RT for 18 h. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic solution is dried over sodium sulfate, concentrated in vacuo and the residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 95: 5 to give the title compound as a white foam in 40% yield. 266 mg were obtained.

Preparation Example 239

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

The title compound was prepared from the products of Preparations 117 and 215 in 45% yield as a white foam using the same method as described in Preparation Example 238.

Preparation Example 240

1- [3- (benzyloxy) phenyl] -3- (1,1-dimethylpropyl) -1H-pyrazol-5-amine

The title compound was prepared from the product of Preparation 47 and 3-benzyloxyphenylhydrazine hydrochloride using the same method as described in Preparation 7. The crude compound was triturated with diethyl ether to afford the desired product in 91% yield as a pink solid.

Preparation Example 241

3- [5-amino-3- (1,1-dimethylpropyl) -1H-pyrazol-1-yl] phenol

The title compound was prepared from the product of Preparation 240 in 49% yield as a yellow foam using the same method as described in Example 99.

Preparation Example 242

1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- (1,1-dimethylpropyl) -1H-pyrazole-5-amine

The title compound was prepared from the product of Preparation 241 and tert-butyldimethylsilyl chloride in 69% yield as a solid using the same method as described in Preparation 99.

Preparation Example 243

N- [1- (3-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- (1,1-dimethylpropyl) -1H-pyrazol-5-yl] -N '-[ 2-({3- [2- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] urea

The title compound was prepared from the products of Preparation Examples 242 and 207 in 47% yield using the same method as described in Preparation Example 169.

Preparation Example 244

1- [4- (benzyloxy) phenyl] -3-tert-butyl-1H-pyrazol-5-amine

The title compound was prepared as a pale pink powder from 4,4-dimethyl-3-oxopentane nitrile and 4-benzyloxyphenylhydrazine hydrochloride as pale pink powder using the same method as described in Preparation Example 7.

Preparation Example 245

4- (5-amino-3-tert-butyl-1H-pyrazol-1-yl) phenol

The title compound was prepared from the product of Preparation 244 in 72% yield as a brown powder using the same method as described in Example 99.

Preparation Example 246

3-tert-butyl-1- (4-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -1H-pyrazol-5-amine

The title compound was prepared from the product of Preparation 245 and tert-butyldimethylsilyl chloride in 18% yield as a white solid using the same method as described in Preparation 99.

Preparation Example 247

Phenyl [3-tert-butyl-1- (4-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -1H-pyrazol-5-yl] carbamate

The title compound was prepared from the product of Preparation 246 and phenylchloroformate in quantitative yield using the same method as described in Preparation 116.

Preparation Example 248

N- [3-tert-butyl-1- (4-{[tert-butyl (dimethyl) silyl] oxy} phenyl) -1H-pyrazol-5-yl] -N '-(2-{[3- (2-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea

The title compound was prepared from the products of Preparations 214 and 247 using the same method as described in Preparation 219 in 93% yield as colorless glass.

Preparation Example 249

4- (methylthio) benzaldehyde (5-bromopyridin-2-yl) hydrazone

The title compound was prepared from the product of Preparation 25 and 4- (methylthio) benzaldehyde in 92% yield as a pale yellow solid using the same method as described in Preparation 30.

Preparation 250

6-bromo-3- [4- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridine

The title compound was prepared from the product of Preparation 249 in a 72% yield as a white solid using the same method as described in Preparation 184.

Preparation Example 251

[2-({3- [4- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) phenyl] methanol

The title compound was prepared from the product of Preparation 250 and 2-mercaptobenzyl alcohol in 58% yield as a white solid using the same method as described in Preparation 35.

Preparation Example 252

[2-({3- [4- (methylthio) phenyl] [1,2,4] triazolo [4,3-a] pyridin-6-yl} thio) benzyl] amine hydrobromide

Thionyl bromide (235 μl, 3.03 mmol) was added to an ice cold solution of the product of Preparation 251 (384 mg, 1.01 mmol) in dichloromethane (10 ml) and the mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was redissolved in dichloromethane. The solution was cooled to 0 ° C., 7M methanolic ammonia (15 ml) was added dropwise and the mixture was stirred at rt for 18 h. 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. The residue was purified by column chromatography on silica gel eluting with methanol: ethyl acetate 20:80 to 50:50 to give 154 mg of the title compound as a pale yellow solid in 40% yield.

Preparation Example 253

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

The title compound was prepared from the products of Preparation 252 and 63 in 65% yield as a white solid using the same method as described for the product of Preparation Example 121.

Preparation Example 254

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

The title compound was prepared from the products of Preparation Examples 62 and 46 using the same method as described in Preparation Example 121. The crude compound was triturated with diethyl ether to afford the desired product in 85% yield as a solid.

Preparation Example 255

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

The title compound was prepared from the products of Preparation Examples 237 and 117 using the same method as described in Preparation Example 219 in 48% yield as a white foam.

Preparation Example 256

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

The title compound was prepared from the products of Preparations 103 and 205 in the 74% yield as foam using the same method as described in Preparation 219.

Preparation Example 257

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

The title compound was prepared from the product of Preparation Example 256 using the same method as described in Preparation Example 101. The crude compound was triturated with diethyl ether to further purify to give the title compound as a white solid in 47% yield.

Example 1

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

The product of Preparation Example 7 (0.13 g, 0.50 mmol) was added to a solution of N, N'-carbonyldiimidazole (0.49 g, 3.00 mmol) in dichloromethane (10 ml), and the mixture was kept at room temperature for 20 hours. Stirred. The reaction mixture was then washed with brine and stirred vigorously for 15 minutes. The aqueous layer was separated, extracted with dichloromethane (3 x 15 ml), the combined organics were dried over sodium sulfate and concentrated in vacuo. The product of Preparation 43 (0.15 g, 0.49 mmol) was added to the residue in 1,4-dioxane (10 ml) and a solution of N-ethyldiisopropylamine (65 mg, 0.50 mmol) and the mixture was stirred for 18 hours. Stir at room temperature. The reaction mixture was then diluted with ethyl acetate, washed with water (25 ml) and brine (25 ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 7M ammonia 100: 0 to 97.5: 2.5 in dichloromethane: methanol. The appropriate fractions are concentrated in vacuo and the residue is re-purified twice using eluting with 7M ammonia 100: 0 to 97.5: 2.5 in dichloromethane: methanol using a Flashmaster® silica column to provide the title compound. Obtained.

Examples 2-12

The following compounds having the following formulas were prepared using the product of Preparation 43, N, N'-carbonyldiimidazole and appropriate pyrazole starting materials by a method analogous to that described in Example 1. The reaction was observed by TLC analysis and stirred at room temperature for 20-48 hours.

In Example 3 the reaction was carried out in dichloromethane alone. Purification was performed using a Biotage® silica column eluting with ethyl acetate.

In Example 4 the reaction was carried out in dichloromethane alone. Purification by ISCO companion® silica column eluting with pentane: ethyl acetate 100: 0, 50:50, 20:80.

Purification was carried out by ISCO Companion® silica column eluting with ethyl acetate in Example 5.

The crude product in Example 9 was further purified by recrystallization from dichloromethane / diethyl ether to give the final compound.

The compound of roughness in Example 11 was further purified eluting with ethyl acetate using a Flashmaster® silica column.

Example 13

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

The title compound was prepared from the products of Preparations 21 and 45 in a 54% yield using a method similar to Example 1.

Example 14

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

The title compound was prepared from the products of Preparations 21 and 44 in 51% yield using a method similar to Example 1.

Example 15

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

The product of Preparation Example 15 (209 mg, 0.80 mmol) was added to a solution of N, N'-carbonyldiimidazole (810 mg, 5.00 mmol) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 24 hours. It was. The reaction mixture was then diluted with water and extracted with dichloromethane (3 x 15 ml). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. The product of Preparation 43 (215 mg, 0.64 mmol) was added to a residue in dichloromethane (10 ml) and a solution of N-ethyldiisopropylamine (129 mg, 1 mmol), and the mixture was stirred at room temperature for 24 hours. . The reaction mixture was then diluted with 0.1 M hydrochloric acid (25 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: methanol 100: 0 to 85:15. The appropriate fractions were concentrated in vacuo and the residue was crystallized from ethyl acetate to give 206 mg of the title compound in 55% yield.

Examples 16-20

The following compound having the following formula was prepared by a method similar to the method described in Example 15 using the product of Preparation Example 43, N, N'-carbonyldiimidazole, and an appropriate pyrazole starting material. The reaction was observed by TLC analysis and stirred at room temperature for 0.5-18 hours.

Examples 21-23

The following compounds having the following formulas were prepared using the product of Preparation 46, N, N'-carbonyldiimidazole and appropriate pyrazole starting materials by a method analogous to that described in Example 15. The reaction was observed by TLC analysis and stirred at room temperature for 0.5-18 hours.

Example 24

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

The solution of the product of Example 12 (0.26 g, 0.45 mmol) in dichloromethane (5.5 ml) was cooled to 10 ° C. and boron tribromide (1M in dichloromethane, 5.5 ml, 5.50 mmol) was added The mixture was stirred at rt for 18 h. Ethylenediamine solution (15% in water, 25 ml) was added dropwise, then the mixture was acidified to pH 1 with 6M hydrochloric acid. The aqueous layer was separated, extracted with ethyl acetate (3 x 20 ml), then the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluting with dichloromethane: methanol 96: 4 to 92: 8 and trituration with dichloromethane / diethyl ether gave 88 mg of the title compound in 35% yield. It was.

Example 25

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

The title compound was prepared from the product of Example 11 using a method similar to Example 24. The crude compound was purified using a Flashmaster® silica column eluting with 7M ammonia 100: 0 to 95: 5 in dichloromethane: methanol to afford the desired product in 84% yield.

Example 26

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

The title compound was prepared from the product of Example 18 using a method similar to Example 24. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate: methanol 100: 0 to 90:10. The appropriate fractions were concentrated in vacuo and the residue was recrystallized from ethyl acetate to give the title compound as a solid in 55% yield.

Examples 27-29

The following compounds having the following formulas were prepared using appropriate urea starting materials by methods analogous to those described in Example 24. The reaction was observed by TLC analysis and stirred at room temperature for 0.5-1.0 h.

Example 30

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

A mixture of the product of Example 5 (68.5 mg, 0.11 mmol) and 2M sodium hydroxide solution (1 ml) in dioxane (2 ml) was heated at 90 ° C. for 18 h. The solvent was then evaporated under reduced pressure, the aqueous residue diluted with water (10 ml), acidified to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate (2 × 10 ml). The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: acetic acid 95: 5: 0.5. The relevant fractions were concentrated in vacuo and the residue was dried in vacuo at 50 ° C. to give 16.8 mg of the title compound in 27% yield.

Example 31

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

The mixture of the product of Example 4 (130 mg, 0.21 mmol) and 2M sodium hydroxide solution (1.5 ml) in dioxane (3 ml) was heated at 90 ° C. for 16 h. The mixture was then diluted with ethyl acetate (10 ml) and extracted with sodium hydroxide solution (2 x 5 ml). The aqueous solution was acidified to pH 5 with 1M hydrochloric acid and extracted with ethyl acetate (2 × 5 ml). The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: acetic acid 95: 5: 0.5 to 90: 10: 1. The relevant fractions were concentrated in vacuo and the residue was azeotropic distilled with toluene and dried under vacuum at 50 ° C. to give 7 mg of the title compound in 6% yield.

Example 32

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

The title compound was prepared from the product of Example 10 in 46% yield as a white powder using a method similar to the method described in Example 24.

Example 33

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

The title compound was prepared from the products of Preparation Examples 94 and 43, using the same method as described in Preparation Example 121. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: 7M methanolic ammonia 100: 0 to 97.5: 2.5. This was further purified using reverse phase column chromatography on C18 silica gel eluting with water / 7M methanolic ammonia (98: 2): acetonitrile / 7M methanolic ammonia (98: 2) 75:25 to 25:75. The desired product was obtained in 22% yield as a white solid.

Example 34

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

The title compound was prepared from the products of Preparations 90 and 43 using a method similar to the method described in Preparation Example 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 to 95: 5: 0.5. The residue was further purified by column chromatography on silica gel eluting with ethyl acetate: methanol 90:10 to give the desired product in 5% yield.

Example 35

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

The title compound was prepared from the products of Preparations 21 and 216 using the same method as described in Preparation Example 121. The crude compound was triturated with diethyl ether to afford the desired product as a solid in 56% yield.

Example 36

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

The title compound was prepared from the product of Example 36 using a method similar to the method described in Example 72. The crude compound was recrystallized from dichloromethane / methanol: diethyl ether to give 23% yield as a solid.

Example 37

N- {1- [3- (2-hydroxyethoxy) 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

Para-toluenesulfonic acid (20 mg) was added to a solution of the product of Preparation 173 (72 mg, 0.1 mmol) in methanol (10 ml) and the mixture was stirred at rt for 18 h. The reaction mixture was then diluted with ethyl acetate, washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: methanol 100: 0 to 90:10 to give 62 mg of the title compound as a white solid in 98% yield.

Examples 38-42

The following compounds having the following formulas were prepared in a similar manner to the method described in Example 37 using appropriate starting materials and para-toluenesulfonic acid.

Example 43

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

A solution of the product of 219 mg (215 mg, 0.29 mmol) was dissolved in a mixture of acetic acid (4 ml), tetrahydrofuran (2 ml) and water (1 ml), and the resulting solution was heated to 60 ° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 99: 1 to 92: 8. The appropriate fractions were evaporated under reduced pressure and the residue was triturated with dichloromethane / diethyl ether to give 50.2 mg of the title compound as a white powder in 26% yield.

Example 44

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

The title compound was prepared from the product of Preparation 221 in a 66% yield as a white powder using the same method as described in Example 43.

Example 45

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

The title compound was prepared from the product of Preparation 222 in a 45% yield as a white powder using the same method as described in Example 43.

Example 46

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

Boron tribromide (1M in dichloromethane, 1 ml, 1 mmol) was added dropwise to an ice-cold solution of the product of Preparation 121 (186 mg, 0.27 mmol) in dichloromethane (10 ml) and the mixture was kept at 0 ° C. for 10 minutes. Stirred. The reaction mixture was then diluted with dichloromethane (25 ml) and water (25 ml) and stirring continued at 0 ° C. for a further 10 minutes. 0.88 ammonia (5 ml) was added, the aqueous layer was separated and extracted with dichloromethane (2 × 25 ml). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel 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 to give 78 mg of the title compound as a pale yellow solid in 48% yield.

Examples 47-69

The following compounds having the following formulas were prepared using appropriate starting materials and 4 to 6 equivalents of boron tribromide by a similar method as described in Example 46.

^A roughness of the compound was triturated with diethyl ether rather than recrystallized from ethyl acetate.

The crude compound in Example 48 was further purified by column chromatography on silica gel eluting with ethyl acetate: methanol 100: 0 to 95: 5 and then the residue was triturated with diethyl ether.

In Example 66 the crude compound was recrystallized from ethyl acetate / methanol.

Example 70

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

The title compound was prepared from the product of Preparation 167 in 75% yield using the same method as described in Example 46.

Example 71

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

The title compound was prepared from the product of Preparation 168 in 18% yield as a brown solid using the same method as described in Example 46.

Example 72

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

Boron tribromide (1M in dichloromethane, 5.05 ml, 5.05 mmol) was added dropwise to a solution of the product of Preparation 124 (0.18 g, 0.25 mmol) in dichloromethane (2 ml) and the mixture was allowed to stand at room temperature for 18 hours. Stirred at. The reaction mixture was then diluted with water (1.5 ml) and stirring continued for an additional 10 minutes before 1,2-diaminoethane (1.5 ml) was added. The mixture was then vigorously stirred and acidified to pH 1 with 6M hydrochloric acid. The aqueous layer was separated, reextracted with dichloromethane (5 ml), the combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the residue from dichloromethane: methanol 50:50 gave the title compound as a white solid in 36% yield.

Examples 73-79

The following compounds having the following formula were prepared by appropriate methods similar to those described in Example 72 and 4-6 equivalents of boron tribromide.

In Example 73 the crude compound was further purified by recrystallization from dichloromethane / methanol: diethyl ether.

In Example 74 the crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol 98: 2 to 92: 8.

In Example 75 the crude compound was recrystallized from dichloromethane / methanol: diethyl ether.

The crude compound in Example 78 was purified by column chromatography on silica gel eluting with dichloromethane: methanol 97: 3 to 94: 6 and then triturated with dichloromethane / methanol: diethyl ether (x3). It was.

In Example 79 the crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 95: 5 and then triturated with dichloromethane.

Example 80

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

Boron tribromide (1M in dichloromethane, 1.6 ml, 1.6 mmol) was added dropwise to a solution of the product of Preparation Example 122 (270 mg, 0.33 mmol) in dichloromethane (10 ml), cooled to -78 ° C, The mixture was stirred at this temperature for 90 minutes. The reaction mixture was stirred for an additional 30 minutes and the temperature was raised to 25 ° C. and then quenched with methanol (10 ml) and 0.88 ammonia (3 ml). The mixture was acidified with 2M hydrochloric acid and extracted with dichloromethane (3 × 50 ml). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 90:10. The appropriate fractions were evaporated under reduced pressure to recrystallize the residue from ethyl acetate / methanol to give 120 mg of the title compound as a solid in 56% yield.

Example 81

N- [3- tert -Butyl-1- (3- Hydroxyphenyl ) -1H- Pyrazole -5-yl] -N '-[2-({3- [2- (2- Hydroxyethoxy ) Phenyl ] [1,2,4] Triazolo [4,3-a] pyridin-6-yl} Thio )benzyl] Urea

Boron tribromide (1M in dichloromethane, 1.3 ml, 1.3 mmol) was added dropwise to a solution of the product of Preparation 174 (214 mg, 0.26 mmol) in dichloromethane (10 ml) at −78 ° C., and the mixture was 5 Stir at that temperature for minutes. The reaction mixture was then stirred for an additional 5 minutes to warm the temperature to 0 ° C. The mixture was recooled to -78 ° C, quenched with methanol (5 ml) and the temperature was raised to 25 ° C. The reaction mixture was then diluted with water and extracted with dichloromethane (3 x 40 ml). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel 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 was recrystallized from ethyl acetate / methanol to give 79 mg of the title compound as a solid in 47% yield.

Example 82

N- {1- (4-ethylphenyl) -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

The title compound was prepared from the product of Preparation 157 in 60% yield as a solid using the same method as described in Example 81.

Example 83

N- {1- (3-ethylphenyl) -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

The title compound was prepared from the product of Preparation 158 using the same method as described in Example 81. The crude compound was triturated with ethyl acetate / dichloromethane to afford the desired product in 52% yield as a solid.

Example 84

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

The title compound was prepared from the product of Preparation 159 using the same method as described in Example 81. The crude compound was triturated with ethyl acetate to afford the desired product in 43% yield as a solid.

Example 85

N- {1- (3-chlorophenyl) -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

The title compound was prepared from the product of Preparation Example 154 using the same method as described in Example 81. The crude compound was triturated with ethyl acetate to afford the desired product in 44% yield as a solid.

Example 86

N- (2-{[3- (5-chloro-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

The title compound was prepared from the product of Preparation 165 using a method similar to the method described in Example 81. The crude compound was triturated with methanol to afford the desired product in 26% yield as a solid.

Example 87

N- (2-{[3- (5-chloro-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

The title compound was prepared from the product of Preparation 166 using a method similar to the method described in Example 81. The crude compound was triturated with ethyl acetate / methanol to afford the desired product in 24% yield as a solid.

Example 88

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-methylphenyl) -1H-pyrazol-5-yl] urea

The title compound was prepared from the product of Preparation 149 using a method similar to the method described in Example 81. The crude compound was triturated with ethyl acetate / methanol to afford the desired product in 52% yield as a solid.

Example 89

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

A solution of the product of Preparation 228 (280 mg, 0.38 mmol) in dichloromethane (6 ml) was cooled to -78 ° C. Boron tribromide (1M in dichloromethane, 1.9 ml, 1.9 mmol) was added dropwise and the mixture was stirred for 20 minutes. The reaction mixture was then diluted with methanol (10 ml) and the temperature was raised to 25 ° C. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with 0.88 ammonia (2 × 10 ml). The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 99.75: 0.25 to 95: 5 to give 146 mg of the title compound in 59% yield. Obtained.

Example 90

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

The title compound was prepared from the product of Preparation 230 in a 10% yield as a solid using a method similar to the method described in Example 89.

Example 91

N- {1- (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

The title compound was prepared from the product of Preparation 160 in 66% yield as a solid using a method similar to the method described in Example 89.

Example 92

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

The title compound was prepared from the product of Preparation 164 using a method similar to the method described in Example 89. The crude compound was triturated with ethyl acetate / methanol to give the title compound as a solid in 59% yield.

Example 93

N- [3-tert-butyl-1- (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

Boron tribromide (1M in dichloromethane, 0.74 ml, 0.74 mmol) was added dropwise to a solution of the product of Preparation 229 (107 mg, 0.15 mmol) in dichloromethane (5 ml) at −78 ° C. Stir at this temperature for a time. The reaction mixture was then quenched with methanolic ammonia (7M, 5 ml) and warmed to room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: methanol 100: 0 to 90:10 to give 64 mg of the title compound as a pale yellow solid in 68% yield.

Example 94

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

The title compound was prepared from the product of Preparation 152 in 41% yield as a solid using the same method as described in Example 93.

Example 95

N- {1- (3,4-Difluorophenyl) -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

The title compound was prepared from the product of Preparation 156 using the same method as described in Example 93. The crude compound is further purified by HPLC using a Phenomenex Luna C18 system eluting with acetonitrile: water / trifluoroacetic acid (5.95: 0.1): acetonitrile 100: 0 to 0: 100. To give the desired product in 3% yield.

Example 96

N- {1- (3-fluorophenyl) -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

Boron tribromide (1M in dichloromethane, 0.85 ml, 0.85 mmol) was added dropwise to a solution of the product of Preparation 153 (150 mg, 0.21 mmol) in dichloromethane (10 ml) and cooled to -40 ° C. The mixture was stirred at this temperature for 20 minutes. The reaction mixture was then quenched with methanol (5 ml), diluted with water (30 ml) and dichloromethane (30 ml) and allowed to warm to room temperature. The mixture was made basic with 0.88 ammonia (5 ml) and extracted with dichloromethane (3 × 30 ml), the combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was dichloromethane: methanol 100: Purification by column chromatography on silica gel eluting from 0 to 95: 5 gave 61 mg of the title compound as a white solid in 45% yield.

Example 97

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

Boron tribromide (2M in dichloromethane, 0.63 ml, 1.26 mmol) was added dropwise to a solution of the product of Preparation 138 (300 mg, 0.42 mmol) in dichloromethane (2.5 ml) and cooled to -45 ° C. The mixture was then stirred at this temperature for 45 minutes. Then additional boron tribromide (2M in dichloromethane, 0.63 ml, 1.26 mmol) was added and the mixture was stirred at -45 ° C for 30 minutes. The reaction mixture was then quenched with dimethylamine (40% in water, 2 ml) and warmed to room temperature. The mixture was diluted with water (10 ml) and dichloromethane (10 ml) and the biphasic system made acidic with 4M hydrochloric acid. The aqueous layer was separated, extracted with dichloromethane (3 x 10 ml), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 90:10 and then triturated with dichloromethane / diethyl ether to give the title compound as a white solid in 29% yield. 76.9 mg was obtained.

Example 98

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

The title compound was prepared from the product of 139, using the same method as described in Example 97. The crude compound was further purified by reverse phase column chromatography on C18 silica gel eluting with water: acetonitrile 67:33 to 33:67, then triturated with dichloromethane / diethyl ether to give the desired product in 11% yield. It was.

Example 99

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

The product of Preparation 141 (203 mg, 0.29 mmol) was suspended in bromic acid (5.7 M in glacial acetic acid, 4 ml, 22.8 mmol) and the mixture was stirred at rt for 18 h. 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. The residue was triturated with diethyl ether to give 144 mg of the title compound as a white solid in 81% yield.

Example 100

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

The title compound was prepared from the product of Preparation 170 in a 21% yield as a solid using a method similar to the method described in Example 99.

Example 101

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

Example 47 product (100 mg, 0.17 mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (30 μl, 0.20 mmol) and potassium carbonate in N, N-dimethylformamide (3 ml) 32 mg, 0.25 mmol) was heated at 60 ° C. for 18 hours. Additional 2- (2-bromoethoxy) tetrahydro-2H-pyran (15 μl, 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 (3 ml), para-toluenesulfonic acid (20 mg) was added and the mixture was stirred at rt for 48 h. The reaction mixture was then diluted with ethyl acetate (20 ml), washed with water (3 x 10 ml), then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to 92: 8. The residue was further purified by column chromatography on silica gel eluting with ethyl acetate: methanol 97.5: 2.5 to 95: 5 to give 24.5 mg of the title compound as a solid in 23% yield.

Example 102

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

The title compound was prepared from the product of Example 89 in 52% yield using the same method as described in Example 101.

Example 103

N- [2-({3- [2- (2-hydroxyethoxy) phenyl] [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

The title compound was prepared from the product of Preparation 172 in 34% yield using a method similar to the method described in Example 101.

Example 104

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

A solution of the product of Preparation 204 (360 mg, 1 mmol) in dimethylsulfoxide (5 ml) was added to a solution of the product of Preparation Example 116 (490 mg, 1 mmol), and the mixture was stirred at room temperature for 18 hours and 3 at 50 ° C. Stir for hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (10 ml) and washed with 1M 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 (5 ml), para-toluenesulfonic acid (100 mg) was added and the mixture was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane (30 ml) and washed with water (2 × 10 ml). The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: methanol 95: 5 to give 208.3 mg of the title compound in 31% yield.

Example 105

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

The title compound was prepared from the products of Preparations 116 and 206 in 36% yield as a solid using the same method as described in Example 104.

Example 106

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

Tetraethylammonium fluoride dihydrate (60 mg, 0.40 mmol) was added to a solution of the product of Preparation 136 (200 mg, 0.29 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred at rt for 6 h. Further tetraethylammonium fluoride dihydrate (60 mg, 0.32 mmol) was added and the mixture was stirred at rt for 48 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 1M hydrochloric acid (20ml) and dichloromethane (20ml). The aqueous layer was separated, extracted with dichloromethane (5 x 20 ml), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel eluting with dichloromethane: methanol 99: 1 to 92.5: 7.5 and trituration with dichloromethane / diethyl ether to give the title compound as a solid in 68.8 mg 41% yield. Obtained.

Example 107

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

The title compound was prepared from the product of Preparation 227 in 65% yield as a white solid using a method similar to the method described in Example 106.

Example 108

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

Tetraethylammonium fluoride dihydrate (2.78 g, 15.0 mmol) was added to a solution of the product of Preparation 137 (951 mg, 1.39 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was then concentrated in vacuo and the residue was partitioned between 1M hydrochloric acid (25 ml) and dichloromethane (25 ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. Purify the residue by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to 90:10 and then triturate with dichloromethane / methanol: diethyl ether to give the title compound as a 11% yield. 83.7 mg was obtained.

Example 109

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

The title compound was prepared from the product of Preparation 163 in a 26% yield as a white solid using a method similar to the method described in Example 108.

Example 110

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

The title compound was prepared from the product of Preparation 225 in 53% yield as a white solid using a method similar to the method described in Example 108.

Example 111

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

The title compound was prepared from the product of Preparation 226 in a 53% yield as a white solid using a method similar to the method described in Example 108.

Example 112

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

The title compound was prepared from the product of Preparation 243 in a 31% yield as a white solid using a method similar to the method described in Example 108.

Example 113

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

The title compound was prepared in 95% yield as a white solid using the same method as described in the preparation of Example 108 from the product of Preparation Example 248.

Example 114

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

The title compound was prepared from the product of Preparation 253 in 78% yield as a pale yellow solid using the same method as described in the preparation of Example 97.

Example 115

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

Para-toluenesulfonic acid (63 mg, 3.3 mmol) was added to a solution of the product of Preparation 255 (262 mg, 3.3 mmol) in methanol (15 ml) and the mixture was stirred at rt for 72 h. The reaction mixture was then diluted with water, made basic with sodium bicarbonate solution and the resulting precipitate was filtered to give the title compound as a white solid in 76% yield.

The following compounds were prepared analogously to the process described above.

The following compounds described in Listing ² below can be prepared analogously to the methods described above. In another embodiment of the invention, the preferred group of compounds is such that each substituent is specified in Listing ² :

Preferably, the compound of formula I is selected from the following list ² :

N- [3-tert-butyl-1- (3-chloro-4-hydroxyphenyl) -1H-pyrazol-5-yl] -N '-[2-({3- [2- (2-hydroxy Oxyethoxy) 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-hydroxy Oxyethoxy) 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-hydroxy Oxyethoxy) 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- [2- (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-yl) thio] benzyl} urea,

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

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

N- {1- (4-Chloro-3-hydroxyphenyl) -3- [1,1-dimethyl-2- (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-chloro-4-hydroxyphenyl) -3- (1,1-dimethylpropyl) -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- (1,1-dimethylpropyl) -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- (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-yl} 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] triazolo [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-iso Propyl [1,2,4] triazolo [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- { 2-[(2-hydroxyethyl) thio] phenyl} [1,2,4] triazolo [4,3-a] pyridin-6-yl) thio] benzyl} urea,

N- [1- (4-chloro-3-hydroxyphenyl) -3- (1,1-dimethylpropyl) -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- (1,1-dimethylpropyl) -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- (1,1-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-hydroxyphenyl) -3- (1,1-dimethylpropyl) -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- (1,1-dimethylpropyl) -1H-pyrazol-5-yl] -N '-{2-[(3-iso Propyl [1,2,4] triazolo [4,3-a] pyridin-6-yl) thio] benzyl} urea,

N- [1- (4-chloro-3-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-cyano-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-cyano-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-cyano-4-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- (3-cyano-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-cyano-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-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-hydroxyethoxy) 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- [3- (2-hydroxyethoxy) 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- [4- (2-hydroxyethoxy) 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- (methylthio) 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-isopropyl [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-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] -1 H-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-cyano-4-hydroxyphenyl) -3- [1,1-dimethyl-2- (methylthio) ethyl] -1 H-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- (3-cyano-4-hydroxyphenyl) -3- [1,1-dimethyl-2- (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- (3-cyano-4-hydroxyphenyl) -3- [1,1-dimethyl-2- (methylthio) ethyl] -1 H-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-cyano-4-hydroxyphenyl) -3- [1,1-dimethyl-2- (methylthio) ethyl] -1 H-pyrazol-5-yl} -N'- {2-[(3-isopropyl [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] -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-dimethylpropyl) -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-cyano-4-hydroxyphenyl) -3- (1,1-dimethylpropyl) -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- (3-cyano-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-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] triazolo [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- Isopropyl [1,2,4] triazolo [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-chloro-5-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- (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) 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- [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) 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- [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-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- (3-cyano -4-hydroxyphenyl) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) urea,

N- (2-{[3- (3-cyano-4-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- (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,

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) [1,2,4] triazolo [4,3-a] pyridin-6-yl] thio} benzyl) -N ' -{3- (1,1-dimethylpropyl) -1- [4- (2-hydroxyethoxy) phenyl] -1H-pyrazol-5-yl} urea, and

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 (28)

A compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, including hydrates: Formula I

Where R ¹ is CH ₃ , S (O) _p CH ₃ , S (O) _p CH ₂ CH ₃ , CH ₂ CH ₃ , H or CH ₂ S (O) _p CH ₃ ; R ^1a is CH ₃ or CH ₂ CH ₃ , wherein CH ₃ and CH ₂ CH ₃ are each unsubstituted or substituted with one or more hydroxy substituents; R ² is heteroaryl, heterocyclyl, aryl or carbocyclyl; R ³ is heteroaryl, heterocyclyl, aryl, carbocyclyl or R ⁷ ; R ⁷ is 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, heterocycle (C ₁ -C ₆ ) alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of aryl, aryl, carbocyclyl, aryloxy, carbocyclyloxy, heteroaryloxy and heterocyclyloxy ; p is 0, 1 or 2; R ⁵ and R ⁶ are each independently selected from the group consisting of H and (C ₁ -C ₄ ) alkyl, wherein (C ₁ -C ₄ ) alkyl is one or more substituents independently selected from the group consisting of OH and halo Substituted or unsubstituted with, or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a piperazinyl, piperidinyl, morpholinyl or pyrrolidinyl group (the piperazinyl, piperidinyl, morpholinyl and pyrrolidinyl are each 1). Or unsubstituted with one or more OH); "Aryl" each independently means phenyl or naphthyl, said phenyl or naphthyl consisting of halo, -CN, -CO ₂ H, OH, CONR ⁵ R ⁶ , NR ⁵ R ⁶ , R ⁸ and R ⁹ Or is unsubstituted with one or more substituents independently selected from the group; R ⁸ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -CO ₂ (C ₁ -C ₆ ) alkyl, -S (O) _p (C ₁ -C ₆ ) alkyl, -CO Each independently selected from the group consisting of (C ₁ -C ₆ ) alkyl and (C ₃ -C ₇ ) cycloalkyl; R ⁸ is (C ₁ -C ₆ ) alkoxy (unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH, halo, CO ₂ H, CONR ⁵ R ⁶ and NR ⁵ R ⁶ ), -S _{(O) p (C 1 -C} 6) Al keel (OH, halo, CO ₂ H, CONR ⁵ R ⁶ and NR ⁵ R ⁶ is not substituted with one or more substituents independently selected from the group consisting of substituted), Or is not substituted with one or more substituents independently selected from the group consisting of OH, halo, NR ⁵ R ⁶ , CO ₂ H, CONR ⁵ R ⁶ , and R ⁹ ; R ⁹ is heteroaryl ² , heterocyclyl ² , aryl ² , carbocyclyl ² , aryl ² oxy, carbocyclyl ² oxy, heteroaryl ² oxy or heterocyclyl ² oxy; "Aryl ² " means phenyl or naphthyl, said phenyl or naphthyl being one or more independently selected from the group consisting of halo, -CN, -CO ₂ H, OH, NR ⁵ R ⁶ and CONR ⁵ R ⁶ Substituted or unsubstituted with a substituent; "Carbocyclyl" is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, OH, NR ⁵ R ⁶ , CONR ⁵ R ⁶ , R ⁸ and R ⁹ Monocyclic or bicyclic saturated or partially unsaturated ring systems containing 3 to 10 ring carbon atoms; "Carbocyclyl ² " is 3- to 10, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, -CN, -CO ₂ H, NR ⁵ R ⁶ , OH and CONR ⁵ R ⁶ Monocyclic or bicyclic saturated or partially unsaturated ring systems containing two ring carbon atoms; “Heterocyclyl” and “Heterocyclyl ² ” each independently represent a 3-10 membered saturated or partially unsaturated including 1-4 ring heteroatoms independently selected from the group consisting of N, O and S. A monocyclic or bicyclic group; “Heteroaryl” and “heteroaryl ² ” each independently mean a 5-10 membered monocyclic or bicyclic aromatic group containing 1-4 ring heteroatoms independently selected from the group consisting of N, O and S (Wherein the total number of ring S atoms does not exceed 1 and the total number of ring O ring atoms does not exceed 1); “Heterocyclyl” and “heteroaryl” groups each independently represent halo, —CN, —CO ₂ H, OH, NR ⁵ R ⁶ , CONR ⁵ R ⁶ , R ^8, and R ⁹ on one or more ring carbon atoms Unsubstituted or substituted with one or more substituents independently selected from the group consisting of and unsubstituted or substituted with one or more substituents independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl on one or more ring nitrogen atoms No; "Heterocyclyl ² " and "heteroaryl ² " groups are each independently independent from the group consisting of halo, -CN, -CO ₂ H, NR ⁵ R ⁶ , OH and CONR ⁵ R ⁶ on one or more ring carbon atoms And is not substituted or substituted with one or more substituents selected from, and one or more substituents independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl on one or more ring nitrogen atoms. The method of claim 1, A compound, salt and / or solvate wherein R ¹ is CH ₃ , SCH ₃ , CH ₂ CH ₃ or CH ₂ SCH ₃ . The method according to claim 1 or 2, Compounds, salts and / or solvates wherein R ^1a is CH ₃ . The method according to any one of claims 1 to 3, R ² is optionally substituted with one or more substituents independently selected from the group consisting of 3-pyridyl (OH, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and CF ₃ ), or Phenyl ((C ₁ -C ₆ ) alkyl, OH, -S (C ₁ -C ₆ ) alkyl, optionally substituted with OH, (C ₁ -C ₆ ) alkoxy, optionally substituted with OH, CN, CF Unsubstituted or substituted with one or more substituents independently selected from the group consisting of ₃ and halo. The method of claim 4, wherein R ² is phenyl ((C ₁ -C ₄ ) alkyl, OH, —S (C ₁ -C ₄ ) alkyl optionally substituted with OH, (C ₁ -C ₄ ) alkoxy optionally substituted with OH, Unsubstituted or substituted with one or more substituents independently selected from the group consisting of CN, CF ₃ and halo. The method of claim 5, R ² is phenyl (substituted or unsubstituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, CN, CF ₃ , Cl, F and OCH ₂ CH ₂ OH), and / or Solvates. The method according to any one of claims 1 to 6, When R ² is phenyl substituted with one or two substituents, the compound, salt and / or solvate wherein the substitution is at the 3 and / or 4 position of the phenyl. The method according to any one of claims 1 to 7, When R ² is substituted phenyl, said phenyl is substituted with one or more hydroxy substituents, salts and / or solvates. The method according to any one of claims 1 to 7, R ² is 3-chloro and 4-hydroxy, 3-cyano and 4-hydroxy, 3-hydroxy, 4-hydroxy, 3-hydroxyethoxy, 3-hydroxy and 4-chloro, or 3 Compounds, salts and / or solvates which are phenyl substituted by hydroxy and 4-cyano. The method according to any one of claims 1 to 9, R ³ is halo, OH, CN, (C ₁ -C ₆ ) alkyl (unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and halo), (C ₁ -C ₆ ) alkoxy (OH and halo-substituted or not substituted with one or more substituents independently selected from the group consisting of _{a), -S- (C 1 -C 6} ) alkyl (optionally substituted with one or more substituents independently selected from the group consisting of OH and halo, or Unsubstituted or substituted with one or more substituents independently selected from the group consisting of: or a compound, salt and / or solvate wherein R ³ is (C ₁ -C ₆ ) alkyl. The method of claim 10, R ³ is CN, Cl, F, OH, methyl, ethyl, isopropyl, CF ₃ , -S- (C ₁ -C ₄ ) alkyl (with or without OH), methoxy and ethoxy (with OH Substituted or unsubstituted), phenyl unsubstituted or substituted with one or more substituents, or wherein R ³ is isopropyl; salts and / or solvates. The method of claim 11, R ³ is a phenyl substituted with Cl, F, CN, OH, -S- methyl, methoxy, -SCH ₂ CH ₂ OH and -OCH ₂ CH 1 or 2 substituents independently selected from the group consisting of ₂ OH Compounds, salts and / or solvates. The method according to any one of claims 1 to 12, When R ³ is substituted phenyl, said phenyl is substituted with one or more hydroxy substituents; salts and / or solvates. The method of claim 12, R ³ is 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 -A compound, salt and / or solvate that is hydroxy, or phenyl substituted with 2-OCH ₂ CH ₂ OH. The method according to any one of claims 1 to 12, When R ³ is phenyl substituted with one or more substituents independently selected from the group consisting of -S-methyl and -SCH ₂ CH ₂ OH, the -S-methyl or -SCH ₂ CH ₂ OH is substituted at the ortho position of phenyl. Compounds, salts and / or solvates present. The method according to any one of claims 1 to 15, R ⁵ and R ⁶ are each independently selected from the group consisting of H, methyl and ethyl; salts and / or solvates. The method according to any one of claims 1 to 16, compounds, salts and / or solvates where p is zero. The method according to any one of claims 1 to 17, At least one of R ² and R ³ is substituted phenyl, wherein the substituted phenyl is substituted with one or more hydroxy substituents. The method according to any one of claims 1 to 18, Compounds, salts and / or solvates for use in medicine. The method according to any one of claims 1 to 18, Asthma of any type, etiology or pathogenesis, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorders Endogenous asthma caused by external factors, exogenous asthma caused by external factors, unexplained or unclear essential asthma, non-atopic asthma, bronchitis asthma, emphysema, exercise-induced asthma, allergen-induced asthma, cold Asthma selected from the group consisting of air-induced asthma, occupational asthma, infectious asthma, non-allergic asthma, early asthma, whiskey infant syndrome and bronchiolitis caused by bacterial, fungal, antigenic or viral infections ; Chronic or acute bronchial contraction, chronic bronchitis, small airway obstruction and emphysema; COPD, irreversible with obstructive or inflammatory airway disease of any type, etiology or pathogenesis, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or dyspnea associated with or not associated with COPD Obstructive or inflammatory airway disease selected from the group consisting of COPD characterized by advanced airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness as a result of other medications, and airway disease associated with pulmonary hypertension; Bronchitis of any type, etiology or pathogenesis, especially acute bronchitis, acute laryngeal bronchitis, arachidous bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthma bronchitis, wet bronchitis, staphylococcus or streptococcal bronchitis, and alveolar bronchitis Bronchitis selected from the group consisting of; Acute lung injury; And Bronchiectasis of any type, etiology or pathogenesis, especially cylindrical bronchiectasis, saculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular Bronchiectasis selected from the group consisting of bronchiectasis Compounds, salts and / or solvates for use in treating a disease, disorder or condition selected from the group consisting of: The method according to any one of claims 1 to 18, Obstructive or inflammatory respiratory tract disorders of any type, etiology or pathogenesis, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or COPD Obstructive or selected from the group consisting of COPD accompanying, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), airway hyperresponsiveness resulting from other medications and airway disease associated with pulmonary hypertension Compounds, salts and / or solvates for use according to claim 20 which are inflammatory airway diseases. The method according to any one of claims 1 to 18, A compound, salt and / or solvate for use according to claim 21 wherein the disease, disorder or condition is chronic obstructive pulmonary disease (COPD). Use of a compound, salt and / or solvate according to any one of claims 1 to 18 in the manufacture of a medicament for treating a disease, disorder or condition as defined in any of claims 20 to 22. . The method according to any one of claims 1 to 18, Compounds, salts and / or solvates for use in treating a TNF-mediated disease, disorder or condition, or p38-mediated disease, disorder or condition. Use of a compound, salt and / or solvate according to any one of claims 1 to 18 in the manufacture of a medicament for treating a TNF-mediated disease, disorder or condition, or p38-mediated disease, disorder or condition. . A pharmaceutical composition comprising a compound, salt and / or solvate according to any one of claims 1 to 18 and a pharmaceutically acceptable diluent, carrier or adjuvant. A method of treating a disease, disorder or condition as defined in claim 20 comprising administering to a mammal an effective amount of a compound as defined in claim 1. Compounds, salts and / or solvates disclosed herein.

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