HK1105536B

HK1105536B - Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors

Info

Publication number: HK1105536B
Application number: HK07110750.2A
Authority: HK
Inventors: J．P．玛希亚斯; D.S.米兰; R．A．鲁斯外特; C.菲利普斯
Original assignee: 辉瑞大药厂
Priority date: 2004-08-12
Filing date: 2005-08-09
Publication date: 2011-05-06

Description

Triazolopyridinylsulfanyl derivatives as p38 MAP kinase inhibitors

Technical Field

The present invention relates to triazolopyridylsulfanyl derivatives. More particularly, the present invention relates to pyrazolyl- [ (triazolopyridinylsulfanyl) -benzyl ] -urea derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

Background

The triazolopyridylsulfanyl derivatives of the present invention are inhibitors of p38 mitogen-activated protein kinase ("p 38 MAPK", "p 38 kinase" or "p 38") (especially, p38 α kinase) and are inhibitors of tumor necrosis factor ("TNF") production, especially TNF α. They have a variety of therapeutic applications, particularly for the treatment of allergic and non-allergic airway diseases, more particularly for the treatment of obstructive or inflammatory airway diseases such as Chronic Obstructive Pulmonary Disease (COPD).

Mitogen-activated protein kinases (MAPs) constitute a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinase is activated by a wide variety of signals including nutritional and osmotic stress, ultraviolet light, growth factors, endotoxins, and inflammatory cytokines). The p38 MAP kinase group is a diverse isoform of the MAP family, including: p38 α, p38 β and p38 γ. These kinases are responsible for the phosphorylation and activation of transcription factors (e.g., ATF2, CHOP and MEF2C), as well as other kinases (e.g., MAPKAP-2 and MAPKAP-3). The p38 isoform is activated by bacterial lipopolysaccharide, physical and chemical stress, and proinflammatory cytokines including tumor necrosis factor ("TNF") and interleukin-1 ("IL-1"). The phosphorylated product of p38 mediates the production of inflammatory cytokines, including TNF.

TNF is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated production of TNF (especially TNF- α) is involved in mediating a variety of diseases, and TNF is thought to cause or contribute to the effects of general inflammation.

IL-8 is another proinflammatory cytokine, which is produced by monocytes, fibroblasts, endothelial cells and keratinocytes. This cytokine is associated with conditions including inflammation. IL-1 is produced by activated monocytes and macrophages and is involved in inflammatory reactions. IL-1 plays a role in many pathophysiological responses, including rheumatoid arthritis, fever and reduction of 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 conditions. Compounds that inhibit p38 kinase will inhibit the synthesis of IL-1, IL-8 and TNF in human monocytes.

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

International patent application PCT IB2004/000363(WO 2004/072072) (published: 8/26/2004) discloses triazolopyridines useful as anti-inflammatory compounds for the treatment of certain diseases. This application is incorporated by reference herein in its entirety.

Disclosure of Invention

The compounds of the invention are potentially useful in the treatment of a wide range of disorders. In addition to the treatment of obstructive or inflammatory airway diseases, it is believed that the compounds of the invention may also be useful in the treatment of TNF/p38 mediated diseases, such as: asthma, chronic or acute bronchoconstriction, bronchitis, acute lung injury and bronchiectasis, general inflammation (e.g., inflammatory bowel disease), arthritis, neuroinflammation, pain, fever, fibrotic diseases, lung disorders and diseases (e.g., hyperoxic alveolar injury), cardiovascular diseases, post-ischemic reperfusion injury and congestive heart failure, cardiomyopathy, stroke, ischemia, reperfusion injury, renal reperfusion injury, cerebral edema, neurotrauma trauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver diseases and nephritis, gastrointestinal conditions, ulcer diseases, ocular diseases, ophthalmic conditions, glaucoma, acute injury to ocular tissues and ocular trauma, diabetes, diabetic nephropathy, skin-related conditions, myalgia due to infection, influenza, endotoxic shock, toxin shock syndrome, inflammatory bowel disease, autoimmune diseases, transplant rejection, bone resorption diseases, multiple sclerosis, psoriasis, disorders of the female reproductive system, pathological (but not malignant) conditions (e.g., hemangiomas, angiofibromas of the nasopharynx and avascular necrosis of the bone), benign and malignant/neoplastic formations (including cancers, leukemias, lymphomas), Systemic Lupus Erythematosus (SLE), angiogenesis (including neoplastic formations), bleeding, coagulation, radiation injury and/or metastasis. Chronic release of active TNF can cause cachexia and anorexia, and TNF can be fatal.

TNF is also implicated in infectious diseases. These diseases include, for example, malaria, mycobacterial infection, and meningitis. These infectious diseases also include viral infections such as HIV, influenza virus, and herpes virus (including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (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)); pseudorabies, rhinotracheitis, etc.

Preferred uses are the treatment of obstructive or inflammatory airway diseases. Using the compounds of the invention, all types of obstructive or inflammatory airways diseases may potentially be treated, in particular those selected from the group consisting of: chronic eosinophilic pneumonia; COPD; COPD, including chronic bronchitis, emphysema or dyspnea associated or not associated with COPD; COPD, which is characterized by irreversible progressive airway obstruction; adult Respiratory Distress Syndrome (ARDS); exacerbation of airway hyperreactivity as a result of other drug treatments; and airway diseases associated with pulmonary hypertension.

There is a need to provide novel TNF inhibitors/p 38 kinase inhibitors, which are good drug candidates. Preferably, the novel TNF inhibitor/p 38 kinase inhibitors exhibit good potency, high levels of selectivity for their associated protein kinases, have properties particularly suited to provide effective treatment via the inhaled route, are suitable for the treatment of allergic and non-allergic airway diseases (especially obstructive or inflammatory airway diseases), are non-toxic and demonstrate few side effects, have physical properties suitable for administration by inhalation, exist in a stable and non-hygroscopic physical form and/or are readily formulated.

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

or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof,

wherein:

R¹is CH₃、S(O)_pCH₃、S(O)_pCH₂CH₃、CH₂CH₃H or CH₂S(O)_pCH₃；

R^1aIs CH₃Or CH₂CH₃In which CH₃And CH₂CH₃Each optionally substituted with one or more hydroxy substituents;

R²is heteroaryl, heterocyclyl, aryl or carbocyclyl;

R³is heteroaryl, heterocyclyl, aryl, carbocyclyl or R⁷；

R⁷Is (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from the group consisting of: OH, halogen, NR⁵R⁶、(C₁-C₆) Alkoxy, -S (O)_p(C₁-C₆) Alkyl, CO₂H、CONR⁵R⁶Heteroaryl, heterocyclyl, aryl, carbocyclyl, aryloxy, carbocyclyloxy, heteroaryloxy, and heterocyclyloxy;

p is 0, 1 or 2;

R⁵and R⁶Each independently selected from H and (C)₁-C₄) Alkyl radical of (C)₁-C₄) Alkyl is optionally substituted with one or more substituents independently selected from OH and halogen;

or R⁵And R⁶Together with the nitrogen to which they are attached form piperazinyl, piperidinyl, morpholinyl, or pyrrolidinyl, (said piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl each optionally substituted with one or more OH);

each "aryl group"Independently means a phenyl or naphthyl group, optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -CN, -CO ₂H、OH、CONR⁵R⁶、NR⁵R⁶、R⁸And R⁹And preferably, the phenyl or naphthyl group is optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H、OH、CONR⁵R⁶、R⁸And R⁹Substituted with the substituent(s);

each R⁸Independently selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, -CO₂(C₁-C₆) Alkyl, -S (O)_p(C₁-C₆) Alkyl, -CO (C)₁-C₆) Alkyl and (C)₃-C₇) A cycloalkyl group;

each R⁸Optionally substituted with one or more substituents independently selected from the group consisting of:

(C₁-C₆) Alkoxy (optionally substituted by one or more independently selected from OH, halogen, CO)₂H、CONR⁵R⁶And NR⁵R⁶Substituted with the substituent(s) of (a),

-S(O)_p(C₁-C₆) Alkyl (optionally substituted by one or more independently selected from OH, halogen, CO₂H、CONR⁵R⁶And NR⁵R⁶Substituted with the substituent(s) of (a),

OH，

the halogen(s) are selected from the group consisting of,

NR⁵R⁶，

CO₂H，

CONR⁵R⁶and are and

R⁹；

each R⁹Is heteroaryl²Heterocyclic group²Aryl radical²Carbocyclyl group²Aryl radical²Oxy, carbocyclic radicals²Oxy, heteroaryl²Oxy or heterocyclic radicals²An oxy group;

"aryl group²"means a phenyl or naphthyl group, optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H、OH、NR⁵R⁶And CONR⁵R⁶And preferably, the phenyl or naphthyl group is optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H. OH and CONR⁵R⁶Substituted with the substituent(s);

"carbocyclyl" means a mono-or bicyclic, saturated or partially unsaturated ring system containing 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halogen, -CN, -CO ₂H、OH、NR⁵R⁶、CONR⁵R⁶、R⁸And R⁹And preferably, it is optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H、OH、CONR⁵R⁶、R⁸And R⁹Substituted with the substituent(s);

"carbocyclyl group²"means a mono-or bicyclic, saturated or partially unsaturated ring system containing 3 to 10 ring carbon atoms, optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H、NR⁵R⁶OH and CONR⁵R⁶And preferably, it is optionally substituted with one or more substituents selected from halogen, -CN, -CO₂H. OH and CONR⁵R⁶The substituent (b) of (a) is substituted,

"carbocyclyl" and "carbocyclyl²Examples of "are groups such as: indanyl, indenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and tetrahydronaphthyl;

each of the "heterocyclic group" and "heterocyclic group²"independently means 3-to 10-membered, saturated or partially unsaturated, mono-or bicyclic, containing 1, 2, 3 or 4 independentlyA heteroatom selected from N, O and S; "Heterocyclyl" and "heterocyclyl²Examples of "are groups such as: tetrahydrofuran, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1, 4-bisAlkyl, 1, 4-oxathiacyclohexyl, morpholinyl, 1, 4-dithianyl, piperazinyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, 1, 2, 5, 6-tetrahydropyridinyl, indolinyl and dihydrobenzofuranyl;

Each "heteroaryl" and each "heteroaryl²By "independently" is meant a 5 to 10 membered, monocyclic or bicyclic, aromatic radical containing 1, 2, 3 or 4 heteroatoms (wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1) independently selected from N, O and S, and including the following groups:

pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isopyrrolylAzolyl group,Oxazolyl, isothiazolyl, thiazolyl, 1, 2, 3-triazolyl, 1, 3, 4-triazolyl, 1-oxa-2, 3-oxadiazolyl, 1-oxa-2, 4-oxadiazolyl, 1-oxa-2, 5-oxadiazolyl, 1-oxa-3, 4-oxadiazolyl, 1-thia-2, 3-oxadiazolyl, 1-thia-2, 4-oxadiazolyl, 1-thia-2, 5-oxadiazolyl, 1-thia-3, 4-oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo [2, 3-b ] pyrrole]Pyridyl, pyrrolo [2, 3-c]Pyridyl, pyrrolo [3, 2-c]Pyridyl, pyrrolo [3, 2-b]Pyridyl, imidazo [4, 5-b ]]Pyridyl, imidazo [4, 5-c)]Pyridyl, pyrazolo [4, 3-d]Pyridyl radicalPyrazolo [4, 3-c ] ]Pyridyl, pyrazolo [3, 4-c]Pyridyl, pyrazolo [3, 4-b]Pyridyl, isoindolyl, purinyl, indolinyl, imidazo [1, 2-a ] groups]Pyridyl, imidazo [1, 5-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, pyrrolo [1-2, b]Pyridazinyl, imidazo [1, 2-c ]]Pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, 1, 5-naphthyridinyl, 2, 6-naphthyridinyl, 2, 7-naphthyridinyl, pyrido [3, 2-d ] o]Pyrimidinyl, pyrido [4, 3-d ]]Pyrimidinyl, pyrido [3, 4-d ]]Pyrimidinyl, pyrido [2, 3-d ]]Pyrimidinyl, pyrido [2, 3-b ]]Pyrazinyl, pyrido [3, 4-b ]]Pyrazinyl, pyrimido [5, 4-d ]]Pyrimidinyl, pyrazino [2, 3-b ]]Pyrazinyl, pyrimido [4, 5-d ]]A pyrimidinyl group;

each "heterocyclyl" and each "heteroaryl" group is independently optionally substituted on one or more ring carbon atoms with one or more substituents selected from the group consisting of: halogen, -CN, -CO₂H、OH、NR⁵R⁶、CONR⁵R⁶、R⁸And R⁹And preferably, optionally substituted on one or more ring carbon atoms with one or more substituents independently selected from the group consisting of: halogen, -CN, -CO ₂H、OH、CONR⁵R⁶、R⁸And R⁹And optionally on one or more ring nitrogen atoms is one or more independently selected from H and (C)₁-C₆) Alkyl substituent substitution;

each "heterocyclic radical²And each heteroaryl²"the groups are independently optionally substituted on one or more ring carbon atoms with one or more substituents independently selected from the group consisting of: halogen, -CN, -CO₂H、NR⁵R⁶OH and CONR⁵R⁶And preferably, optionally substituted on one or more ring carbon atoms by one or more substituents independently selected from halogen, -CN, -CO₂H. OH and CONR⁵R⁶And optionally substituted at one or more ring nitrogen atoms with one or more substituents independently selected from H and (C)₁-C₆) Alkyl substituents.

The "alkyl" and "alkoxy" groups (including groups incorporated into the moiety) may be straight or branched chain (where the number of carbon atoms is tolerable). "(C)₁-C₄) Alkyl "or" C₁-C₆Alkyl "denotes straight or branched groups containing 1 to 4 or 1 to 6 carbon atoms respectively. This also applies when they bear substituents or are present in the form of substituents of other groups, for example, in (C)₁-C₆) Alkoxy radical, -CO₂(C₁-C₆) Alkyl radical, -CO (C)₁-C₆) Alkyl radical or-S (O)_p(C₁-C₆) In the case of alkyl groups. Suitably (C)₁-C₄) Alkyl or (C) ₁-C₆) Examples of alkyl groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. Suitably (C)₁-C₆) Examples of alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy and hexoxy.

"halogen" or "halo" refers to a halogen atom selected from fluorine, chlorine and bromine.

It is to be understood that, when all references to "treatment", "treating" or "treating" are used herein, they include curative, palliative and/or prophylactic treatment.

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

It has now been found that the compounds of formula (I) are inhibitors of p 38/TNF production, are particularly useful in the treatment of TNF mediated and/or p38 mediated diseases, disorders or conditions, and are particularly useful for administration via the inhaled route.

In another aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof, wherein:

R¹is CH₃、SCH₃、SCH₂CH₃、CH₂CH₃H or CH₂SCH₃；

R^1aIs CH₃Or CH₂CH₃；

And wherein the one or more of the one,

R²、R³、R⁷、p、R⁵、R⁶"aryl", R⁸、R⁹And an aryl group²"," carbocyclyl²"," heterocyclic group ", or" heterocyclic group ")²"," heteroaryl "and" heteroaryl²"is as defined above.

Preferably, R¹Is CH₃、SCH₃、SCH₂CH₃Or CH₂SCH₃And preferably, R¹Show CH₃Or SCH₃。

In another alternative embodiment, R is preferred¹Is CH₃、SCH₃、CH₂CH₃Or CH₂SCH₃And preferably, R¹Is CH₃、CH₂CH₃Or CH₂SCH₃。

Preferably R^1aIs CH₃。

Preferably, R²Pyridyl, tetrahydronaphthyl, or aryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

(C₁-C₆) Alkyl (of (C)₁-C₆) Alkyl is optionally substituted by one or more independently selected from OH, NR⁵R⁶Aryl radical²And halogen as a substituent),

-S(O)_p(C₁-C₆) Alkyl (the-S (O)_p(C₁-C₆) The alkyl group is optionally substituted by one or more groups independently selected from OH, aryl²And halogen as a substituent),

(C₁-C₆) Alkoxy (of (C)₁-C₆) Alkoxy is optionally substituted by one or more groups independently selected from OH, aryl²And halogen as a substituent),

-CO₂(C₁-C₆) Alkyl (the-CO)₂(C₁-C₆) The alkyl group is optionally substituted by one or more groups independently selected from OH, aryl ²And halogen as a substituent),

(C₃-C₇) Cycloalkyl (of (C)₃-C₇) Cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halogen),

pyridyl group, and

aryl radicals²。

More preferably, R²The method comprises the following steps:

3-pyridyl (optionally substituted by one or more independently selected from OH, -S (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, CF₃And halogen as a substituent),

or

Phenyl (optionally substituted by one or more substituents independently selected from (C)₁-C₆) Alkyl, OH, -S (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, CN, CF₃And halogen).

Still more preferably, R²Is phenyl (optionally substituted by one or more groups independently selected from methyl, ethyl, OH, CN, CF₃、Cl、F、-SCH₃and-OCH₃Substituted with a substituent of (a).

Even more preferably, R²Is 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl, 3, 4-dichlorophenyl, 4-tolyl, 3-methoxyphenyl, 4-hydroxy-3-tolyl, 3-tolyl or 4-hydroxy-3-chlorophenyl.

In alternative embodiments, R²Preferably a pyridyl group or an aryl group,

the pyridyl and aryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

(C₁-C₆) Alkyl (of (C)₁-C₆) Alkyl is optionally substituted by one or more groups independently selected from OH, NR⁵R⁶And halogen as a substituent),

(C₁-C₆) Alkoxy (of (C) ₁-C₆) Alkoxy is optionally substituted by one or more groups independently selected from OH, CO₂H. Aryl radicals²And halogen).

More preferably, R²The method comprises the following steps:

3-pyridyl (optionally substituted by one)Or more are independently selected from OH, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and CF₃Is substituted with a substituent), or

Phenyl (optionally substituted with one or more substituents independently selected from (C)₁-C₆) Alkyl, OH, -S (C)₁-C₆) Alkyl (wherein the-S (C)₁-C₆) Alkyl optionally substituted by OH), (C)₁-C₆) Alkoxy (wherein the (C)₁-C₆) Alkoxy optionally substituted by OH), CN, CF₃And halogen).

Even more preferably, R²Is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: (C)₁-C₄) Alkyl, OH, -S (C)₁-C₄) Alkyl (wherein the-S (C)₁-C₄) Alkyl optionally substituted by OH), (C)₁-C₄) Alkoxy (wherein the (C)₁-C₄) Alkoxy optionally substituted by OH), CN, CF₃And a halogen.

Even more preferably, R²Is phenyl (optionally substituted by one or more groups independently selected from methyl, ethyl, OH, CN, CF₃Cl, F and-OCH₂CH₂Substituent of OH).

Even more preferably still, R²Is phenyl substituted with one or two substituents independently selected from the group consisting of: OH, Cl, CN, methyl and-OCH₂CH₂OH。

Preferably, when R is²When substituted phenyl, the substitution is at the 3-and/or 4-position of the phenyl.

In another preferred embodiment, when R²When phenyl is substituted with a hydroxyethoxy substituent, the hydroxyethoxy substituent is at the 3 (meta) position of the phenyl.

In a particularly preferred embodiment of the invention, R²Is a substituted benzene according to any embodiment or preferred embodiment hereinWherein R is²The phenyl group is substituted with at least one hydroxy substituent, or at least one hydroxyethoxy substituent, more preferably, with at least one hydroxy substituent.

In a preferred embodiment of the invention, R²Is phenyl substituted with the following substituents:

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

In another embodiment, R²Preferably 3-hydroxyphenyl group, 4-hydroxyphenyl group, phenyl group, 4-tolyl group, 3-tolyl group, -OCH group₂CH₂OH or 4-hydroxy-3-chlorophenyl.

Preferably, R³Is pyridyl or aryl, wherein the pyridyl and aryl are each optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

-CO₂(C₁-C₆) Alkyl (the-CO)₂(C₁-C₆) The alkyl group is optionally substituted by one or more groups independently selected from OH, aryl²And halogen as a substituent),

pyridyl group, and

aryl radicals²，

Or, alternatively, R³Is preferably (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from OH, halogen and (C)₁-C₆) Substituent of alkoxy.

More preferably, R³Is aryl, optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

OH，

(C₁-C₆) Alkyl (of (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from OH and halogen),

(C₁-C₆) Alkoxy (of (C)₁-C₆) Alkoxy is optionally substituted with one or more substituents independently selected from OH and halogen),

or R³Is (C)₁-C₆) An alkyl group.

Even more preferably, R³Is phenyl (optionally substituted with one or more substituents independently selected from the group consisting of Cl, F, OH, methyl, ethyl, isopropyl, CF ₃Methoxy, ethoxy (the methoxy and ethoxy each being optionally OH-substituted),

or R³Is isopropyl.

In alternative embodiments, R³Preferably pyridyl or aryl, wherein the pyridyl and aryl are each optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

or, alternatively, R³Is preferably (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from OH, halogen and (C)₁-C₆) Alkoxy radicalSubstituent of the group.

The halogen(s) are selected from the group consisting of,

OH，

CN，

-S-(C₁-C₆) Alkyl (the-S- (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from OH and halogen),

or R³Is (C)₁-C₆) An alkyl group.

Even more preferably, R³Is phenyl (optionally substituted with one or more substituents independently selected from CN, Cl, F, OH, methyl, ethyl, isopropyl, CF₃、-S-(C₁-C₄) Alkyl (the-S- (C)₁-C₄) Alkyl optionally substituted by OH), methoxy, ethoxy (the ethoxy being optionally substituted by OH),

or R³Is isopropyl.

Even more preferably still, R³Is phenyl substituted with one or two substituents independently selected from the group consisting of: cl, F, CN, OH, -S-methyl, OCH₃、-SCH₂CH₂OH and-OCH₂CH₂OH。

In a particularly preferred embodiment of the invention, R³Is a warp according to any of the embodiments or preferred embodiments hereinSubstituted phenyl, wherein R³The phenyl group is substituted with at least one hydroxy substituent or with at least one hydroxyethoxy substituent, more preferably, with at least one hydroxy substituent.

In another particularly preferred embodiment of the invention, R ³Is phenyl substituted with the following substituents:

2-hydroxy and 5-chloro,

2-hydroxy and 3-chloro, and a pharmaceutically acceptable salt thereof,

3-hydroxy and 2-chloro,

5-hydroxy and 2-chloro,

a 3-cyano group and a 4-hydroxy group,

2-hydroxy, or

2-OCH₂CH₂OH。

Preferably, when R is³Is a substituted phenyl group and at least one substituent is-S- (C)₁-C₆) Alkyl, -S- (C)₁-C₄) Alkyl or-SCH₂CH₂When OH is present, the compound is-S- (C)₁-C₆) Alkyl, -S- (C)₁-C₄) Alkyl or-SCH₂CH₂OH is present in the ortho position (2-position) of the phenyl group.

Preferably, R is³Is selected from at least one of-S-methyl and-SCH₂CH₂Phenyl substituted by a substituent of OH, wherein the-S-methyl or-SCH₂CH₂OH is present in the ortho position (2-position) of the phenyl group.

Preferably, R⁵And R⁶Independently selected from H, methyl and ethyl.

Preferably "aryl" and "aryl group²"is phenyl (optionally substituted by one or more groups independently selected from halogen, -CN, OH and R⁸Substituted with a substituent of (a).

Preferably, R⁸Is (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or (C)₃-C₇) Cycloalkyl (each (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₃-C₇) Cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halogen).

More preferred R⁸The radical being CF₃Methyl, methoxy, ethyl, ethoxy, -OCH₂CH₂OH、-SCH₂CH₂OH, S-methyl and cyclopropyl.

Preferably, p is 0.

Preferably, R ⁹Is heteroaryl²Heterocyclic group²Aryl radical²Aryl radical²Oxy or heteroaryl radicals²An oxy group;

more preferably, R⁹Is heteroaryl²Or aryl radicals²。

Even more preferably, R⁹Is pyridyl or phenyl (which pyridyl or phenyl is optionally substituted with one or more OH or halogen).

Even more preferably, R⁹Is phenyl.

Another particularly preferred embodiment of the present invention are compounds of formula (I) according to any one of the embodiments or preferred embodiments herein, wherein R is²And R³Is substituted phenyl, wherein the substituted phenyl is substituted with at least one hydroxy substituent or at least one hydroxyethoxy substituent, more preferably, with at least one hydroxy substituent.

Preferably, "carbocyclyl" and "carbocyclyl²Each is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (each of which is optionally substituted by one or more OH).

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

Preferably, "heteroaryl" and "heteroaryl group²Each independently selected from pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, isoquinolyl, and pyrazinyl (each of which is optionally substituted with one or more OH).

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

According to another embodiment of the invention, preferred compounds are compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (including hydrates) thereof, wherein:

R¹is CH₃、SCH₃、CH₂CH₃Or CH₂SCH₃；

R^1aIs CH₃；

R²Is pyridyl, isoquinolinyl or phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: SCH₃Cl, F, Br, ethyl, methyl, methoxy, OH, benzyloxy, CF₃、CO₂H、CO₂Et、CN、-OCO₂H. Hydroxyethoxy and-C (O) NHCH₃(ii) a And is

R³Is isopropyl or phenyl, the phenyl being optionally substituted with one or more substituents independently selected from the group consisting of: cl, OH, F, benzyloxy, methoxy, hydroxyethoxy, isopropyl, methyl, ethyl, SCH₃、CO₂H. Hydroxyethylthio and CN.

According to another embodiment of the invention, preferred compounds are compounds of formula (I), pharmaceutically acceptable salts and/or solvates (including hydrates) thereof, wherein:

R¹is CH₃、SCH₃Or CH₂SCH₃；

R^1aIs CH₃；

R²Is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: SCH₃Cl, OH, CN and hydroxyethoxy; and is

R³Is isopropyl or phenyl, the phenyl being optionally substituted with one or more substituents independently selected from the group consisting of: cl, OH, hydroxyethoxy, SCH₃Hydroxyethylthio and CN.

In another embodiment of the invention, there are provided compounds of formula (I), wherein each R is¹、R^1a、R²And R³The substituents are independently selected from the group of substituents defined in any of the preferred or other embodiments described herein, including any combination of the preferred or other embodiments.

Preferred groups of compounds are those whose individual substituents are as detailed in the examples below.

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

Preferred groups of compounds are those in which the substituents are as listed below¹Those listed.

Preferably, the compounds of formula (I) are selected from the following list¹：

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

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

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

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

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

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

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

n- [ 3-tert-butyl-1- (4-hydroxy-3-tolyl) -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-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-phenyl-1H-pyrazol-5-yl } urea,

n- {1- (4-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,

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 } -1H-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-tolyl) -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) sulfanyl ] benzyl } -N' - [3- [ 1-methyl-1- (methylthio) ethyl ] -1- (4-tolyl) -1H-pyrazol-5-yl ] urea,

n- [ 3-tert-butyl-1- (4-tolyl) -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-tolyl) -1H-pyrazol-5-yl ] urea,

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

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

n- [ 3-tert-butyl-1- (3-tolyl) -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-tolyl) -1H-pyrazol-5-yl ] urea,

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

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

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

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

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

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

n- (2- { [3- (2-hydroxy-4-tolyl) [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-tolyl) [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] thio } benzyl) urea,

n- (2- { [3- (2-hydroxy-4-tolyl) [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-isopropyl [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) thio ] benzyl } urea,

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

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

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

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

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

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

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

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

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

n- [ 3-tert-butyl-1- (3-hydroxy-4-tolyl) -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-tolyl) -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-tolyl) -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-tolyl) -3- [ 1-methyl-1- (methylthio) ethyl ] -1H-pyrazol-5-yl } -N' - (2- { [3- (2-tolyl) [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-tolyl) [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-tolyl) -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-tolyl) -1H-pyrazol-5-yl ] urea,

n- [ 3-tert-butyl-1- (3-tolyl) -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-tolyl) -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-tolyl) -1H-pyrazol-5-yl ] urea,

N- [ 3-tert-butyl-1- (3-tolyl) -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-fluorophenyl) -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 their salts and/or solvates.

Pharmaceutically acceptable salts of the compounds of formula (I) include their acid addition and base salts.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoylphenoate, hydrochloride/chloride, hydrobromide, hydroiodic/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, glucarate, stearate, sodium salicylate, potassium salicylate, and mixtures thereof, Succinate, tartrate, p-toluenesulfonate, adipate, cyclamate, tannate, pyrrolglutamate, xinafoate (1-hydroxynaphthalene-2-formate) and trifluoroacetate.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, dibenzylethylenediamine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, N-methylglucamine salts, ethanolamine salts, potassium salts, sodium salts, tris salts, and zinc salts.

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For a review of suitable salts, see Stahl and WermuthHandbook of Pharmaceutucal Sakts：Properties，Selection，and Use，(Wiley-VCH，Weinheim，Germany，2002)。

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of the following three methods:

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

(ii) removal of acid or base labile protecting groups from suitable precursors of compounds of formula (I) by use of a desired acid or base, or by ring opening of a suitable cyclic precursor, e.g., a lactone or lactam;

(iii) one salt of the compound of formula (I) is converted to another salt by reaction with a suitable acid or base or by means of a suitable ion exchange column.

The three aforementioned reactions are generally carried out in solution. The resulting salt precipitates out and is collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to nearly unionized.

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

Also included within the scope of the invention are complexes, e.g., clathrates, drug-host inclusion complexes (where, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts). Also included within the scope of the invention are complexes of drugs containing two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For a review of such complexes, see Haleblian J Pharm Sci,64(8)，1269-1288(August1975)。

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

The compounds of the present invention include compounds of formula (I) as defined hereinbefore, including all polymorphs and crystal habits thereof, as defined hereinafter, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labelled compounds of formula (I).

As shown, formula (II)(I) So-called 'prodrugs' of the compounds are also included within the scope of the present invention. Thus, derivatives of certain compounds of formula (I) which themselves have little or no pharmacological activity may be converted to compounds of formula (1) having the desired activity by, for example, hydrolytic cleavage reactions when administered into or onto the body. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs can be found inPro-drugs as Novel Delivery SystemsVol.14, ACS Symposium Series (T.Higuchi and W.Stella) andBioreversible Carriers in Drug Design，Pergamon Press，1987(ed.E.B.Roche，American Pharmaceutical Association)。

prodrugs according to the invention may be prepared, for example, by reacting a prodrug of the invention with certain moieties known to those skilled in the art as 'pro-moieties' (e.g., of hDesign of Prodrugs(Elsevier, 1985) instead of the appropriate functionality present in the compounds of formula (I).

Several examples of prodrugs according to the invention include:

(i) esters of compounds of formula (I) (when compounds of formula (I) contain carboxylic acid functionality (-COOH)), for example, wherein the hydrogen of the carboxylic acid functionality of compounds of formula (I) is replaced by (C)₁-C₈) An alkyl-substituted compound;

(ii) ethers of compounds of formula (I) (when compounds of formula (I) contain an alcohol functionality (-OH)), for example, wherein the hydrogen of the alcohol functionality of compounds of formula (I) is replaced by (C) ₁-C₆) Alkanoyloxymethyl-substituted compounds; and

(iii) amides of compounds of formula (I) (when compounds of formula (I) contain primary or secondary amino functionality (-NH)₂or-NHR, where R.noteq.H)), for example, where one or two hydrogens of the amino functionality of the compound of formula (I) are replaced by (C)₁-C₁₀) Alkanoyl substituted compounds.

Further examples of substituents according to the preceding examples and examples of other prodrug types can be found in the aforementioned references.

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

Metabolites of the compounds of formula (I), i.e., compounds formed in vivo after administration, are also included within the scope of the present invention. Examples of several metabolites according to the invention include:

(i) when the compound of formula (I) contains (C)₁-C₆) When it is an alkyl group, its hydroxy group (C)₁-C₆) An alkyl derivative. For example, when the compound of formula (I) contains a methyl group, the hydroxymethyl derivative (-CH) thereof₃→-CH₂OH)；

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

(iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (-NR)⁵R⁶→-NHR⁵or-NHR⁶)；

(iv) When the compound of formula (I) contains a secondary amino group, its primary derivative (-NHR)⁵→-NH₂)；

(v) When the compound of formula (I) contains a phenyl moiety, its phenolic derivative (-Ph → -PhOH);

(vi) When the compound of formula (I) contains an amide group, its carboxylic acid derivative (-CONH)₂→ COOH); and

(vii) when the compound of formula (I) contains S- (C)₁-C₆) When it is an alkyl group, its S (O) (C)₁-C₆) An alkyl derivative. For example, when the compound of formula (I) contains an S-methyl group, its S (O) methyl derivative, and when the compound of formula (I) contains an alkyl-S-alkyl group, its alkyl-S (O) -alkyl derivative.

In another aspect of the invention, active metabolites of compounds of formula (I) are provided, wherein "active" means IC₅₀(TNF. alpha. screen) less than 1000nM and in IC₅₀(TNF. alpha. screening) of less thanPreferably 100 nM. Preferably, a catalyst containing S (O) (C)₁-C₆) Alkyl groups or hydroxyl groups.

The compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Tautomerism ('tautomerism') may occur when structural isomers can interconvert via a low energy barrier. It may take the form of proton tautomerism in compounds of formula (I) containing, for example, imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. It follows that a single compound may exhibit more than one type of isomerism.

The scope of the present invention includes all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or base salts in which the counterion is optically active, for example, d-lactate or l-lysine, or in which the counterion is racemic, for example, dl-tartrate or dl-arginine.

Conventional techniques for preparing/separating individual enantiomers include: chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) may also be reacted with a suitable optically active compound, for example, an alcohol; or with an acid or base (e.g. 1-phenylethylamine or tartaric acid) in the case where the compound of formula (I) contains an acidic or basic moiety. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomeric mixtures can be converted into the corresponding pure enantiomers by means known to those skilled in the art.

Using chromatography (typically HPLC) on asymmetric resins, with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume of isopropanol (typically 2% to 20%) and 0 to 5% by volume of alkylamine (typically 0.1% by volume of diethylamine), chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form.

Stereoisomeric coacervates can be prepared by conventional techniques known to those skilled in the art (see, e.g., e.l. eliel and s.h. wilenStereochemistry of Organic Compounds(Wiley, New York, 1994)).

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for incorporation into the compounds of the invention include: an isotope of hydrogen (for example,²h and³H) an isotope of carbon (e.g.,¹¹C、¹³c and¹⁴C) an isotope of chlorine (for example,³⁶cl), isotopes of fluorine (e.g.,¹⁸F) an isotope of nitrogen (e.g.,¹³n and¹⁵n), isotopes of oxygen (e.g.,¹⁵O、¹⁷o and¹⁸o) and isotopes of sulfur (e.g., ³⁵S)。

Certain isotopically-labeled compounds of formula (I), for example, those into which a radioisotope is incorporated, are useful in drug and/or substrate tissue distribution studies. The radioactive isotope tritium (i.e.,³H) and carbon-14 (i.e.,¹⁴C) are particularly suitable for this purpose because they are easy to incorporate into the compound and easy to detect.

With heavier isotopes (e.g. deuterium: (²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus, may be desirable in some circumstancesIt is preferred.

With a positron-emitting isotope (e.g.,¹¹C、¹⁸F、¹⁵o and¹³n) can be used for Positron Emission Tomography (PET) for detecting substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying examples and preparations, by substituting the appropriate isotopically-labelled reagent for the unlabelled reagent employed hereinbefore.

Pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystallization is isotopically substituted (e.g., D) ₂O、d₆-acetone, d₆-DMSO).

The scope of the present invention also includes within its scope the novel intermediates, all salts, solvates and complexes thereof, as defined herein, and also all solvates and complexes of salts thereof, as defined herein for compounds of formula (I). The present invention includes all polymorphs of the foregoing and their crystal habits.

In the preparation of the compounds of the formula (I) according to the invention, the person skilled in the art is free to select, as is customary, the intermediate which provides the best combination of properties for this purpose. Such properties include the melting point, solubility, processability and yield of the intermediate form and whether the resulting product, when isolated, is readily purified.

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

Illustrative PXRD patterns for these compounds are shown in fig. 1-6, which contain 15% silicon internal reference standards.

FIG. 1: example 80 fig. 4: example 73

FIG. 2: example 26 fig. 5: example 63

FIG. 3: example 93 fig. 6: example 60

X-ray diffraction data were collected at room temperature using a Bruker AXS D4 powder X-ray diffractometer (Cu ka radiation) equipped with an automated sample exchanger, a theta-theta goniometer, an automated beam divergence slit, a secondary monochromator, and a scintillation counter. A sample for analysis was prepared by mixing the compound of the present invention with a silicon powder internal reference in an amount of 15 wt%. The powder was loaded on a silicon wafer sample carrier 12mm in diameter. Using copper K α 1X-ray (wavelength: 1.5406) ) While irradiating, the sample was rotated and the X-ray tube was operated at 40kV/40 mA. The analysis was performed with the goniometer operating in a 2 theta range of 2 deg. to 55 deg. in a continuous mode setting of 5 second counts per 0.02 deg. step. The resulting peaks were compared against a silicon reference standard (ICDD reference 001-.

As understood by skilled crystallographers, the relative intensities of the individual peaks reported in the tables and figures below may vary due to several factors, such as crystal orientation effects within the X-ray beam or the purity of the analyte or the degree of crystallinity of the sample. The peak position also shifts with the sample weight, but the peak position remains substantially as defined in the figure. The skilled crystallographist will also appreciate that measurements made using different wavelengths will result in different shifts according to the Bragg equation (n λ ═ 2d sin θ).

Such other PXRD patterns generated by employing alternative wavelengths are considered alternative representatives of the PXRD pattern of the crystalline material of the present invention and are themselves within the scope of the present invention.

Tables 1-6 list the corresponding major diffraction peaks (expressed in 2 θ) and intensities for the compounds, but do not include peaks that can be assigned to silicon reference standards. All 2 θ values were +/-0.1 degrees.

Table 1 lists the example 80 peaks with relative intensity greater than 33.0%.

Table 2 lists the peak of example 26 with a relative intensity greater than 36.5%.

Table 3 lists the peaks of example 93 with relative intensity greater than 15.5%.

Table 4 lists the example 73 peak with a relative intensity greater than 34.0%.

Table 5 lists the example 63 peak with a relative intensity of greater than 35.7%.

Table 6 lists the example 60 peak with a relative intensity greater than 36.4%.

Table 1: example 80 relative Strength at least 33.0%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	15.4	39.2	24.1	50.3
18.0	34.7	24.7	40.7	15.4	39.2	24.1	50.3
18.0	34.7	24.7	40.7	18.8	68.6	25.7	42.6
19.5	81.1	26.4	42.0	18.8	68.6	25.7	42.6
19.5	81.1	26.4	42.0	21.1	100.0	27.8	33.0
21.5	33.9			21.1	100.0	27.8	33.0

Table 2: example 26 relative Strength at least 36.5%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	12.5	46.9	20.5	49.9
16.9	100.0	21.3	89.9	12.5	46.9	20.5	49.9
16.9	100.0	21.3	89.9	17.2	39.6	26.3	47.5
18.5	39.2	29.2	36.5	17.2	39.6	26.3	47.5

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	19.7	45.6

Table 3: example 93 relative Strength at least 15.5%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	15.5	79.1	21.1	18.0
17.2	19.4	23.4	15.8	15.5	79.1	21.1	18.0
17.2	19.4	23.4	15.8	18.3	100.0	25.0	15.6
18.8	16.5	26.0	15.5	18.3	100.0	25.0	15.6
18.8	16.5	26.0	15.5	19.5	19.1	27.1	35.1
20.6	15.6			19.5	19.1	27.1	35.1

Table 4: example 73 relative Strength at least 34.0%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	7.6	77.1	21.8	70.7
11.0	34.7	22.1	100.0	7.6	77.1	21.8	70.7
11.0	34.7	22.1	100.0	17.3	98.9	23.0	39.2
17.8	65.4	27.7	36.9	17.3	98.9	23.0	39.2
17.8	65.4	27.7	36.9	19.1	45.5	30.3	34.0
21.1	40.3			19.1	45.5	30.3	34.0

Table 5: example 63 relative Strength at least 35.7%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	13.6	70.6	23.2	100.0
18.1	49.6	24.2	53.1	13.6	70.6	23.2	100.0
18.1	49.6	24.2	53.1	19.6	45.2	25.8	44.7
21.0	50.0	26.5	39.4	19.6	45.2	25.8	44.7
21.0	50.0	26.5	39.4	22.3	62.7
22.5	35.7			22.3	62.7

Table 6: example 60 relative Strength at least 36.4%

Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength
Angle 2-theta (degree)	Relative strength	Angle 2-theta (degree)	Relative strength	13.7	49.1	24.5	45.3
21.2	36.4	24.6	53.4	13.7	49.1	24.5	45.3
21.2	36.4	24.6	53.4	22.4	44.8	25.9	50.0
22.7	40.6	26.4	36.9	22.4	44.8	25.9	50.0
22.7	40.6	26.4	36.9	23.5	100.0

In another aspect of the invention, there is provided a compound of example No. 80, 26, 93, 73, 63 or 60 having a crystal structure as exemplified in the figures or defined in the tables herein. The present invention is not at all limited to the solid form.

The compounds of formula (I) can be prepared in a variety of ways according to known methods. The following routes illustrate such methods for preparing these compounds; those skilled in the art will appreciate that other approaches may have equal applicability. In the following schemes, unless otherwise described, the substituents are those defined above for compounds of formula (I), and

“PdCl₂(dppf)·CH₂Cl₂"is a 1: 1 dichloromethane complex of 1, 1-bis (diphenylphosphino) dicyclopentadiene iron palladium (II) chloride;

"DBU" is 1, 8-diazabicyclo [5.4.0] undec 7-ene;

"BOC" means t-butyloxycarbonyl;

"CBz" means benzyloxycarbonyl;

"Et" means ethyl;

"Me" means methyl;

"Pd" means palladium;

"eq" means molar equivalents; and is

"iPr" means isopropyl.

Scheme 1

The compounds of formula (II) are commercially available or can be prepared as shown in scheme 2.

Compounds of formula (III) are commercially available (e.g., when R is^1aIs methyl and R¹Methyl) or can be prepared as shown in scheme 3.

Compounds of general formula (IV) can be prepared from compounds of formulae (II) and (III) by step i: the compounds of formula (II) and (III) are subjected to ring condensation in a suitable solvent (e.g. methanol or ethanol) at elevated temperature, optionally in the presence of a suitable acid catalyst (e.g. hydrochloric acid), optionally in the presence of a suitable base (e.g. heni's base, triethylamine or pyridine), for 3-24 hours.Typical conditionsThe method comprises the following steps: 1.0 to 1.3 equivalents of the compound of formula (II) and 1.0 to 1.1 equivalents of the compound of formula (III) are reacted in the presence of hydrochloric acid in ethanol under heating under reflux for 3 to 24 hours.

Furthermore, the compounds of the general formula (IV) can be obtained by direct condensation of the compounds of the formula (VII) with the compounds of the formula (III) in ethanol/hydrochloric acid.

The compounds of formula (V) were prepared as shown in scheme 4.

Compounds of formula (I) may be prepared from compounds (IV) and (V) by step ii: by reacting compound (IV) in the presence of a suitable carbonyl source (e.g., N, N '-carbonyldiimidazole, phenylchloroformate or bis (trichloromethyl) carbonate) and a suitable base (e.g., heni's base or pyridine) in a suitable solvent (e.g., dichloromethane or 1, 4-bis Alkane) under ambient conditions for 48 hours, followed by addition of compound (V), the urea formation reaction can be completed.Typical conditionsComprises the following steps:

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

b)0.25 to 0.80 equivalent of compound (V), 0.25 to 1.25 equivalents of hernial base in dichloromethane or 1, 4-bisIn an alkane, under ambient conditions, for 24 hours, or

c)1 equivalent of the compound of formula (IV) and 1 equivalent of phenyl chloroformate in THF/pyridine, followed by addition of 0.8 to 1 equivalent of compound (V) in DMSO.

When R is²In the case of aryl or heteroaryl, the compounds of formula (II) can be prepared by the procedure shown in scheme 2.

Scheme 2

When R is not obtained²When Br is present, the compounds of formula (II) can be prepared from the corresponding aniline derivatives by using the conditions well known in the literaturePerforming diazotization and reduction reaction.

PG is a suitable protecting group, for example, BOC or CBz, and is preferably BOC.

When R is²When a phenol is or is included, it will be appreciated by those skilled in the art that the use of a protecting group, typically benzyloxy or methoxy, may be required.

The compounds of the general formula (VI) are commercially available.

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

Step (iii) -is accomplished by forming the appropriate organometallic reagent (e.g., arylmagnesium bromide, heteroarylmagnesium bromide, aryllithium or heteroaryllithium, optionally prepared in situ) under standard Grignard (Grignard) conditions or by reaction with the appropriate alkyllithium (e.g., n-butyllithium) in an appropriate solvent (e.g., tetrahydrofuran or diethyl ether) at a temperature between-100 ℃ and 25 ℃ for 1-18 hours. The intermediate compound (VII) is formed by the subsequent nucleophilic attack of an appropriately protected diazocarboxylate compound, preferably di-tert-butyl diazocarboxylate, in an appropriate solvent (e.g., tetrahydrofuran or diethyl ether) at-78 ℃ for 0.5 to 1.0 hour from aryl magnesium bromide/heteroaryl magnesium bromide/aryl lithium/heteroaryl lithium.

Step (iv) -deprotection of Compound (VII) is carried out using standard methods, such as those described in "Protecting Groups in Organic Synthesis" by T.W.Greene and P.Wutz. When PG is equal to the BOC, the PG,typical conditionsThe method comprises the following steps: compound (VII) in a suitable solvent (e.g., isopropanol, 1, 4-bis An alkane or an ether) under ambient conditions for 2 to 18 hours with an appropriate acid (e.g., hydrochloric acid or trifluoroacetic acid).

More preferably, the compound of formula (II) may be converted from formula (VI)A compound prepared by a combination of steps iii and iv in a one-pot synthesis.Typical conditionsComprises the following steps:

a)1.0 equivalent of the compound of formula (VI), 1.1 equivalents of magnesium band and a single crystal of iodine in tetrahydrofuran at room temperature for 18 hours, followed by addition of di-tert-butyl diazocarboxylate at-78 ℃ for 30 minutes,

b) saturation with hydrogen chloride gas in isopropanol is carried out for 0.5-1.0 hours at ambient conditions.

When R is²When a heterocyclic or carbocyclic group is represented, the compounds of formula (II) can be prepared according to scheme 2.1.

Scheme 2.1

Step (xvii) -Compounds of formula (XXVII) can be prepared from compounds of formula (VI) by reaction with an appropriately protected hydrazine (e.g., BOC-NHNH)₂) In the presence of a suitable alkali metal base (e.g., K)₂CO₃Or Na₂CO₃) In the presence of a suitable solvent (e.g. acetonitrile or N, N-dimethylformamide), at ambient temperature and 60 ℃, for up to 48 hours.

The compound of formula (II) may be prepared from the compound of formula (XXVII) using the method described in step iv above.

The compounds of the general formula (III) can be prepared according to schemes 3.1 and 3.2.

When R is¹＝-(CH₂)_nSR^bThe compounds of formula (III) may be prepared as shown in scheme 3.1.

R^bRepresents a methyl group or an ethyl group.

n represents 0 or 1.

Scheme 3.1

LG is a suitable leaving group, for example, OR 'OR Cl, and preferably OR'.

R' represents C₁-C₄Alkyl, and preferably C₁-C₂An alkyl group.

When R' is ethyl or methyl, the compounds of formula (VIII) are commercially available.

When n ═ 1, the compound of formula (IXA) can be prepared from the compound of formula (VIII) by the process step v-nucleophilic substitution reaction. The reaction is carried out by reacting compound (VIII) with methanesulfonyl chloride/anhydride or p-toluenesulfonyl chloride in the presence of a suitable base (e.g., heny's base, triethylamine or pyridine) in a suitable solvent (e.g., dichloromethane or diethyl ether) at low temperature for 1-2 hours to form an intermediate containing a suitable leaving group LG' (e.g., tosylate or p-toluenesulfonate). After concentration in vacuo, 1, 4-bis was addedAlkane or toluene and methanethiol sodium salt, and heated under reflux for 24 hours.Typical conditionsComprises the following steps:

a)1.0 equivalent of the compound (VIII), 1.0 to 1.2 equivalents of heny's base and 1.1 equivalents of methanesulfonyl chloride are reacted in dichloromethane at 0 ℃ for 1 to 2 hours,

b)1.1 equivalents of methanethiol sodium salt to 1, 4-bisIn an alkane, heated at reflux for 24 hours.

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

Compound (III) can be prepared from a compound of formula (IXA) by step vi-reacting with acetonitrile (X). Treatment of (X) with a suitable base (e.g., sodium hydride or lithium diisopropylamide) followed by quenching the intermediate anion with compound (IXA) in a suitable solvent (e.g., tetrahydrofuran) at elevated temperature for 3 hours affords compounds of formula (III).Typical conditionsComprises the following steps: 1.3 equivalents of acetonitrile, 1.3 equivalents of sodium hydride (60% dispersion in mineral oil) and 1.0 equivalent of compound (IXA) in tetrahydrofuran, heated at reflux for 3 hours.

When R is^1aRepresentation H, CH₃Or CH₂CH₃When so, the compound of formula (III) may be prepared as shown in scheme 3.2.

Scheme 3.2

LG is a suitable leaving group, for example, OR 'OR Cl, and preferably OR'.

R' represents C₁-C₄Alkyl, and preferably C₁-C₂An alkyl group.

The compound of formula (III) may be prepared from a compound of formula (IXB) by process step vi (as described hereinbefore).

The compound of formula (IXB) is commercially available or may be prepared by reaction with Julia et al, bull.soc.chim.fr.1996; 133 (1); 15-24, or Chuit et al, Tetrahedron 1980; 36(16), 2305-10 by methods similar to those disclosed.

The compound of formula (V) may be prepared as shown in scheme 4.

Scheme 4

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

The compounds of the formula (XII) can be prepared from compounds of the formula (XI) by process step vii-reaction with hydrazine monohydrate, optionally in a suitable solvent (e.g. methanol or ethanol) at elevated temperature for 18-72 hours.Typical conditionsComprises the following steps: 1.0 equivalent of compound (XI) and excess hydrazine monohydrate, heated to 70 ℃ for 72 hours.

The compound of formula (XIV) can be prepared from a compound of formula (XII) by process step viii-reaction with the appropriate alkanoyl chloride R in the presence of an appropriate base (e.g., heni's base, triethylamine or pyridine), in an appropriate solvent (e.g., dichloromethane or diethyl ether), at low temperature³C (O) Cl (XIII) for 1 to 2 hours.Typical conditionsComprises the following steps: 1.0 equivalent of Compound (XII), 1.0 equivalent of R³C (O) Cl (XIII) and 5.0 equivalents of heny's base in dichloromethane at a temperature between 0 and 5 ℃ for 1 to 2 hours.

The compound of formula (XV) can be prepared from the compound of formula (XIV) by the process step ix-cyclization reaction. The reaction is completed by using a suitable dehydrating agent (e.g., phosphorus oxychloride or phosphorus (V) oxide) in sulfuric acid at elevated temperature for 18-24 hours. Typical conditionsComprises the following steps: 1.0 equivalent of compound (XIV) is reacted in excess of phosphorus oxychloride at 75 ℃ for 18 to 24 hours.

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

A compound of formula (XVII) may be prepared from a compound of formula (XV) by process step x-in a suitable catalyst (e.g., PdCl₂(dppf)·CH₂Cl₂) In the presence ofIn the presence of a base (e.g., cesium carbonate or potassium carbonate) in a suitable solvent (e.g., N, N-dimethylformamide or 1, 4-bisAlkane) with 2-mercaptobenzyl alcohol (XVI) at elevated temperature for 2-48 hours.Typical conditionsComprises the following steps: 1.0 equivalent of compound (XV), 1.2 to 1.4 equivalents of cesium carbonate, 1.3 equivalents of 2-mercaptobenzyl alcohol (XVI) and 0.1 equivalent of PdCl₂(dPPf)·CH₂Cl₂In N, N-dimethylformamide at elevated temperature for 18 hours.

The compound of formula (XVIII) can be prepared from the compound of formula (XVII) by process step xi-azide formation reaction. The reaction is carried out by reacting compound (XVII) with a suitable base (e.g., DBU or sodium hydride) followed by reaction with a suitable azide (e.g., diphenylphosphoryl azide) in a suitable solvent (e.g., toluene or tetrahydrofuran) at a temperature of 0-25 ℃ for 18-24 hours. Typical conditionsComprises the following steps: 1.0 equivalent of compound (XVII), 1.2 equivalents of DBU and 1.2 equivalents of diphenylphosphorylazide are reacted in toluene at 0-25 ℃ for 24 hours.

Compounds of formula (V) can be prepared from compounds of formula (XVIII) by process step xii: compound (XVIII) is reduced in a suitable solvent (e.g., tetrahydrofuran or ethanol), between ambient and elevated temperature, with a suitable reducing agent (e.g., triphenylphosphine/water, tin chloride, or catalytic hydrogenation). Typical conditions include: 1.0 equivalent of compound (XVIII), 1.2 equivalents of triphenylphosphine and 1.2 equivalents of water are reacted in tetrahydrofuran at room temperature for 40 hours and at 50 ℃ for 5 hours.

Alternatively, the compounds of formula (V) may also be prepared as shown in scheme 5.

Scheme 5

The compound of formula (XII) can be prepared as shown in scheme 4.

The compounds of formula (XIX) are commercially available or can be prepared as shown in scheme 6.

Compounds of formula (XX) can be prepared from compounds of formula (XII) and formula (XIX) by process step xiii: the condensation of hydrazine (XII) with the aldehyde compound (XIX) is carried out in a suitable solvent (e.g. methanol, ethanol or toluene) at elevated temperature for 0.5-1 hour. Typical conditionsComprises the following steps: 1 equivalent of the compound (XII) and 1 equivalent of the compound (XIX) are heated in ethanol under reflux for 0.5 to 1.0 hour.

Compounds of formula (XV) can be prepared from compounds of formula (XX) by process step xiv: cyclization of compound (XX) is carried out in the presence of a suitable oxidant, for example, (diacetoxyiodo) benzene, ammonium cerium (IV) nitrate or 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, in a suitable solvent, for example ethyl acetate, dichloromethane or acetonitrile, under ambient conditions for 18-24 hours.Typical conditionsThe method comprises the following steps: 1.0 equivalent of compound (XX) and 1.2 equivalents of (diacetoxyiodo) benzene were reacted in dichloromethane at room temperature for 24 hours.

Alternatively, the compounds of formula (XV) can also be prepared from compound (XII) by process steps xiii and xiv in a one-pot synthesis.Typical conditionsComprises the following steps: 1 equivalent of the compound (XII) and 1 equivalent of the compound (XIX) are heated in ethanol under reflux for 0.5 to 1.0 hour; then, 1.2 equivalents of (diacetoxyiodo) benzene and methylene chloride were added thereto, and the reaction was carried out at room temperature for 24 hours.

The compound of formula (XVII) can be prepared from the compounds of formulae (XV) and (XVI) by process step x described in scheme 4.

The compound of formula (XVIII) can be prepared from the compound of formula (XVII) by process step xi, described in scheme 4.

The compound of formula (V) can be prepared from the compound of formula (XVIII) by the method steps xii described in scheme 4.

Alternatively, compounds of formula (V) may also be prepared from compounds of formula (XVII) by process step xviii. The reaction is carried out by reacting compound (VIII) with methanesulfonyl chloride/anhydride or p-toluenesulfonyl chloride in the presence of a suitable base (e.g., heny's base, triethylamine or pyridine) in a suitable solvent (e.g., dichloromethane or diethyl ether) at a temperature between low and ambient temperature for 1-4 hours to form an intermediate containing a suitable leaving group (e.g., methanesulfonate or p-toluenesulfonate). The resulting intermediate is then treated with an appropriate source of ammonia (typically 7M ammonia in methanol) at ambient conditions for 18-72 hours.Typical conditionsComprises the following steps: 1.0 equivalent of compound (XVII), 3.0 to 4.0 equivalents of heny's base and 2.0 to 3.0 equivalents of methanesulfonyl anhydride in dichloromethane at 25 ℃ for 1 to 4 hours. An excess of 7M ammonia in methanol was added and the reaction was stirred at ambient temperature for 18-72 hours.

Alternatively, compounds of formula (V) may also be prepared from compounds of formula (XV) and compounds of formula (XXVII) wherein PG is a protecting group, e.g., BOC.Typical conditionsComprises the following steps: 1 equivalent of the compound (XV), 1.2 equivalents of the compound (XXVII), 1.2 equivalents of cesium carbonate anhydrous, 3 equivalents of cesium fluoride, 0.1 equivalent of PdCl₂(dppf)·CH₂Cl₂Reacting in a solvent of dimethylformamide at 80-100 ℃ for 2-48 hours. The product resulting from this reaction is then subjected to acid-mediated removal of the BOC group to yield the compound of formula (V).

A compound of formula (XXVII) can be prepared from a compound of formula (XXVIII) by process step xix (scheme 5.1). The reaction proceeds by palladium catalyzed insertion of the sulfide into the aromatic bromine bond.

Typical conditionsComprises the following steps: 1 equivalent of Compound (XXVIII), 1 equivalent of SulfurPotassium tris (isopropyl) silanolate (formed from 1 equivalent of potassium tert-butoxide and 1 equivalent of triisopropylsilanethiol in toluene), 1 equivalent of Pd Cl₂(dppf)·CH₂Cl₂And in toluene as solvent at 100 ℃ for 0.5 to 2 hours.

Scheme 5.1

When R is³When a phenol is or is included, one skilled in the art will know that a protecting group, typically benzyloxy or methoxy, may be required.

Scheme 6

The compounds of formula (XXIV) are commercially available.

A compound of formula (XXV) can be prepared from a compound of formula (XXIV) by method step xv: the reduction is carried out in a suitable solvent (e.g., tetrahydrofuran or methanol) at elevated temperature with a suitable reducing agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride or sodium borohydride) for 6-18 hours.Typical conditionsComprises the following steps: 1.0 equivalent of compound (XXIV) and 1.0 to 1.2 equivalents of lithium aluminum hydride are reacted in tetrahydrofuran under reflux for 6 hours.

Compounds of formula (XIX) can be prepared from compounds of formula (XXV) by method step xvi: the oxidation is carried out in a suitable solvent (e.g. acetone, dichloromethane or dimethylsulfoxide) at a temperature between-80 and +80 c for 3-18 hours with a suitable oxidizing agent (e.g. manganese dioxide, potassium permanganate or oxalyl chloride/dimethylsulfoxide).Typical conditionsComprises the following steps: 1.0 equivalent of the compound of formula (XXV) and 0.5 equivalent of manganese dioxide,Heat in acetone at reflux for 3 hours.

Alternatively, compounds of formula (XIX) may also be prepared from commercially available compounds of formula (XXVI) by process step xvii: the nitrile is reduced by hydrogenating diisobutylaluminum in a suitable solvent (e.g., tetrahydrofuran) at low temperature. Typical conditionsComprises the following steps:

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

b) excess hydrochloric acid and water at 0 ℃.

One skilled in the art will appreciate that at any stage in the synthesis of the compounds of formula (I), it may be necessary or desirable to protect one or more sensitive groups in the molecule to avoid undesirable side reactions. More specifically, it may be necessary or desirable to protect the phenolic group. The protecting groups used in the preparation of the compounds of formula (I) may be used in a conventional manner. See, for example, "Protective Groups in Organic Synthesis" by the food of the food W.Greenand Peter G M Wuts, third edition, (John Wiley and Sons, 1999), especially Chapter 2, pages 17-245 ("Protection for the Hydroxyl Group"). Additionally, protected phenols may also be commercially available. Removal of such groups can be accomplished by conventional methods.

It will also be appreciated that compounds of formula (I) may also be converted to other compounds of formula (I) using standard chemical reactions and transformations. For example, when X (where X is a group as shown in the examples and preparations herein) is an ester, the compound of formula (I) may undergo saponification to produce a carboxylic acid derivative. When X is aryloxy, the compound of formula (I) may be dealkylated using boron tribromide or HBr/acetic acid to yield the corresponding phenol. Further, when X ═ OH, hydroxyalkoxy derivatives can be prepared by reaction with 2- (2-bromoethoxy) tetrahydro-2H-pyran, followed by deprotection of the primary alcohol using boron tribromide or p-toluenesulfonic acid.

In another embodiment of the present invention, there is provided a process for the preparation of a compound of formula (I) wherein the substituents are as defined in claim 1 and the description of the preparation process, which comprises the steps of:

i: cyclocondensing a compound of formula (II) and a compound of formula (III) to provide a compound of formula (IV):

and/or

ii: reacting a compound of formula (IV) with a compound of formula (V) in the presence of a suitable carbonyl source to form a urea.

In another embodiment of the present invention, there is provided a process for the preparation of a compound of formula (V) wherein the substituents are as defined in the description relating to the preparation process, which comprises the steps of:

xi: the compound of formula (XVIII) is formed by reacting a compound of formula (XVII) with an appropriate base, followed by reaction with an appropriate azide to form an azide

And/or

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

In another embodiment of the present invention, there is provided a novel method of preparation described herein.

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

In another embodiment of the present invention, there are provided novel intermediate compounds represented by the formulae as described herein.

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

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

1. asthma of any type, etiology or pathogenesis, in particular asthma selected from the group consisting of: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, incipient asthma, wheezy infant syndrome, and bronchiolitis,

2. Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction and emphysema,

3. obstructive or inflammatory airways diseases of any type, etiology or pathogenesis, in particular selected from the group consisting of: chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated with or not associated with COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperreactivity secondary to other drug therapy, and airway disease associated with pulmonary hypertension,

4. bronchitis of any type, etiology or pathogenesis, in particular bronchitis selected from the group consisting of: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis,

5. in the case of acute lung injury,

6. any type, etiology or pathogenesis of bronchiectasis, in particular bronchiectasis selected from the group consisting of: cylindrical bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, saccular bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

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

Another aspect of the invention is the use of a compound of formula (I) as described herein, or a salt and/or solvate thereof, in the manufacture of a medicament for the treatment of a p-38 mediated disease, disorder or condition, or a TNF mediated disease, disorder or condition.

Another aspect of the invention is a compound of formula (I) or a salt and/or solvate thereof, as described herein, for use in the treatment of a p-38 mediated disease, disorder or condition or a TNF mediated disease, disorder or condition.

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

More specifically, the present invention provides a method of treating a p-38 mediated disease, disorder or condition or a TNF mediated disease, disorder or condition, particularly those listed above, in a mammal, including a human, comprising administering to the mammal an effective amount of a compound of formula (I) or a salt and/or solvate thereof.

Preferably, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease, disorder or condition selected from: obstructive or inflammatory airways diseases of any type, etiology or pathogenesis, in particular selected from the group consisting of: chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated or unrelated to COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperreactivity secondary to other drug therapy, and airway disease associated with pulmonary hypertension; or asthma of any type, etiology or pathogenesis, in particular asthma selected from the group consisting of: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, incipient asthma, wheezy infant syndrome, and bronchiolitis.

More preferably, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD).

Preferably, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from: obstructive or inflammatory airways diseases of any type, etiology or pathogenesis, in particular selected from the group consisting of: chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated or unrelated to COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperreactivity secondary to other drug therapy, and airway disease associated with pulmonary hypertension; or asthma of any type, etiology or pathogenesis, in particular asthma selected from the group consisting of: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, incipient asthma, wheezy infant syndrome, and bronchiolitis.

More preferably, the present invention provides the use of a compound of formula (I), 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, "TNF-mediated disease" or "TNF-mediated disorder" or "TNF-mediated condition" refers to any disease, disorder or condition (particularly any pathological condition) in which TNF plays a role either through the control of TNF itself or through TNF causing the release of another monokine (e.g., IL-1, IL-6 and/or IL-8, for example). Thus, disease states in which, for example, IL-1 is a major component and its production or action is exacerbated or secreted in response to TNF may be considered TNF-mediated disorders.

As used herein, "p 38-mediated disease" or "p 38-mediated disorder" or "p 38-mediated condition" refers to any disease, disorder, or condition (particularly any pathological condition), respectively, in which p38 plays a role through the control of p38 itself or through the release of another monokine (e.g., IL-1, IL-6, and/or IL-8) caused by p 38. Thus, disease states in which, for example, IL-1 is an important component and its production or action is exacerbated or secreted in response to p38 may be considered a p 38-mediated disorder.

The compounds of the invention are useful for the treatment of TNF mediated diseases, disorders or conditions, or p38 mediated diseases, disorders or conditions, in particular allergic and non-allergic airway diseases as disclosed hereinbefore, and also for the treatment of p38 or TNF mediated conditions, such as:

(a) inflammation;

(b) arthritis, for example, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus arthritis, juvenile arthritis, osteoarthritis, and gouty arthritis;

(c) neuroinflammation;

(d) pain (i.e., the use of the compounds as analgesics), for example, neuropathic pain;

(e) heat generation (i.e., the use of the compound as a thermolytic agent);

(f) pulmonary sarcoidosis and silicosis;

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

(h) cardiomyopathy;

(i) stroke, e.g., ischemic and hemorrhagic stroke;

(j) ischemia, e.g., cerebral ischemia and ischemia due to cardiac/coronary bypass;

(k) Reperfusion injury;

(l) Renal reperfusion injury;

(m) cerebral edema;

(n) nerve and brain trauma, e.g., closed head injury;

(o) neurodegenerative disorders;

(p) central nervous system disorders (these include, for example, disorders containing an inflammatory or apoptotic component), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy;

(q) liver disease and nephritis;

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

(s) ulcerative diseases, such as gastric ulcers;

(t) ocular diseases such as retinitis, retinopathies (e.g., diabetic retinopathy), uveitis, ocular photophobia, non-glaucomatous optic atrophy, and age-related macular degeneration (ARMD) (e.g., ARMD-atrophic form);

(u) ophthalmic conditions, e.g., corneal graft rejection, ocular neovascularization, retinal neovascularization (e.g., neovascularization following injury or inflammation), and retrolental fibroplasia;

(v) glaucoma, e.g., primary wide angle glaucoma (POAG), juvenile onset primary wide angle glaucoma, angle closure glaucoma, pseudoexfoliative glaucoma, Anterior Ischemic Optic Neuropathy (AION), ocular hypertension, Reiger's syndrome, normal tension glaucoma, neovascular glaucoma, ocular inflammation and corticosteroid-induced glaucoma;

(w) acute damage to ocular tissue and ocular trauma, e.g., post-traumatic glaucoma, traumatic optic neuropathy, and Central Retinal Artery Occlusion (CRAO);

(x) Diabetes mellitus;

(y) diabetic neuropathy;

(z) skin-related conditions, such as psoriasis, eczema, scald, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders;

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

(bb) myopathy due to infection;

(cc) influenza;

(dd) endotoxic shock;

(ee) toxic shock syndrome;

(ff) autoimmune diseases, e.g., graft-versus-host reactions and allograft rejection;

(gg) bone resorption diseases, e.g., osteoporosis;

(hh) multiple sclerosis;

(ii) disorders of the female reproductive system, for example, endometriosis;

(jj) pathological but non-malignant conditions, such as hemangiomas (e.g., infantile hemangiomas), angiofibromas of the nasopharynx, and avascular osteonecrosis;

(kk) benign and malignant tumors/neoplasms (including cancers), e.g., colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasias (epithelial cancers) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancers such as lip cancer, oral cancer, esophageal cancer, small bowel cancer, and gastric, colon, liver, bladder, pancreatic, ovarian, cervical, lung, breast, skin cancers such as squamous cell and basal cell carcinomas, prostate cancer, renal cell carcinoma, and other cancers that affect epithelial cells throughout the body;

(ll) leukemia;

(mm) lymphomas, e.g., B-cell lymphomas;

(nn) Systemic Lupus Erythematosus (SLE);

(oo) angiogenesis, including neoplasia;

(pp) transfer;

(qq) fibrotic diseases;

(rr) bleeding;

(ss) blood coagulation;

(tt) acute phase reactions, as seen during infection and sepsis and shock (e.g., (uu) septic shock, hemodynamic shock, etc.);

(vv) anorexia;

(ww) mycobacterial infection;

(xx) Pseudorabies;

(yy) rhinotracheitis;

(zz)HIV；

(aaa) influenza virus;

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

(ccc) Cytomegalovirus (CMV);

(ddd) herpes zoster virus (VZV);

(eee) epstein-barr virus;

(fff) human herpesvirus type 6 (HHV-6);

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

In another embodiment of the present invention, there is provided a compound of formula (I), a salt and/or solvate thereof, for use in the treatment of a disease, disorder or condition selected from the group consisting of (a) to (ggg) as hereinbefore described.

Another embodiment of the invention is the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from the group consisting of (a) to (ggg) as described above.

Yet another embodiment of the present invention is a method of treating a disease, disorder or condition selected from the foregoing items (a) to (ggg) in a mammal, including a human, comprising administering to the mammal an effective amount of a compound of formula (I), a salt and/or solvate thereof.

The compounds of the invention may also be useful in the treatment of p38 or TNF mediated diseases (e.g., airway inflammation due to smoking, cough aggravated by inflammation), in the control of myogenesis, in the treatment of mucin overproduction, and/or in the treatment of mucus hypersecretion.

Since TNF- β has close structural homology to TNF- α (also known as cachectin) and because they each induce a similar biological response and bind to the same cellular receptor, the synthesis of both TNF- α and TNF- β tends to be inhibited by the compounds of the present invention and, therefore, are collectively referred to herein as "TNF" unless specifically indicated otherwise.

The aforementioned compounds of formula (I) or pharmaceutically acceptable salts and/or solvates thereof may be administered as medicaments to animals, preferably to mammals and especially to humans according to the present invention.

The compounds can be administered as such, in the form of a mixture with one or more other compounds of the invention or in the form of a pharmaceutical preparation which contains an effective dose of at least one compound of the invention as active ingredient and which also contains customary pharmaceutically nontoxic excipients and/or additives.

The compounds of the invention intended for pharmaceutical use may be administered in the form of crystalline or amorphous products. They can be obtained, for example, by precipitation, crystallization, freeze-drying, spray-drying or evaporation-drying, for example in the form of solid plugs (plugs), powders or films. For this purpose, microwave or radio frequency drying can be used.

They may be administered alone or in combination with one or more other compounds of the invention or with one or more other drugs (or in any combination thereof). Typically, they are administered in formulations formulated with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the invention, as well as methods for their preparation, will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example,Remington′s Pharmaceutical Sciences，19^th Edition(Mack Publishing Company，1995)。

the compounds of the invention may be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract; buccal or sublingual administration is also possible, with buccal or sublingual compounds entering the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations, for example, tablets, capsules containing microparticles, liquids or powders, lozenges (including liquid-filled), chews, multi-and nanoparticles, gels, solid solutions, liposomes, films, ovoids, sprays, and liquid formulations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as a fill in soft or hard gelatin capsules and typically comprise a carrier (for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or suitable oils), and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by reconstitution of a solid (e.g., from a sachet).

The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, for example, as described in Expert Opinion in Therapeutic Patents, 11(6), 981-.

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 the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.

Binders are commonly used to impart tack to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may comprise 0.2% to 5% by weight of the tablet and the glidant may comprise 0.2% to 1% by weight of the tablet.

Tablets also typically contain lubricants, for example, 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, coloring agents, flavoring agents, preservatives, and taste masking agents.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.

The tablet blend may be compressed into tablets either directly or by roller compaction. The tablet blend or portion of the blend may optionally be granulated, melt congealed or extruded either wet, dry or melt prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; even it can be encapsulated.

A discussion of the formulation of tablets can be found in Pharmaceutical Dosage Forms: tablets, Vol.1, by H.Lieberman and L.Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or animal use are generally flexible, water-soluble or water-swellable film dosage forms which dissolve rapidly or are viscous, and generally contain the compounds of the invention, film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Certain components of the formulation may exhibit more than one function.

The compounds of the present invention may be water soluble or water insoluble. The water soluble compound typically contains 1 wt% to 80 wt% (more typically 20 wt% to 50 wt%) solute. Less soluble compounds may contain a greater proportion of solute, typically up to 88% by weight of solute, of the composition. Alternatively, the compounds of the invention may also be in the form of multiparticulate spheres.

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

Other possible ingredients include: antioxidants, coloring, flavoring and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), lubricants, fillers, anti-foaming agents, surfactants, and taste masking agents.

The films according to the invention are generally prepared by evaporating and drying a thin aqueous film coated on a releasable substrate support or paper. This can be done in a drying oven or tunnel dryer (typically a combined coating dryer) or by freeze drying or vacuum.

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

Modified release formulations suitable for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable delivery techniques (e.g., high energy dispersions and penetration and coating of particles) can be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the bloodstream, intramuscularly or into internal organs. Suitable means for parenteral administration include: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. A device suitable for parenteral administration comprising: needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

The compounds of the invention may also be administered topically, i.e., transdermally or transdermally, to the skin or mucosa.

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either as such or in a mixture (e.g. a dry blend mixed with lactose) or as a mixed component particle, e.g. mixed with a phospholipid (e.g. lecithin), by a dry powder inhaler or by an aerosol generated by a pressurised container, pump, nebuliser or nebuliser, preferably one which uses electrohydrodynamic force to generate a fine mist, with or without the use of a suitable propellant, e.g. 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-hexafluoropropane). For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

Pressurized containers, pumps, sprayers, atomizers or sprayers contain a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or other suitable agent for dispersing, dissolving or extending the release of the active compound, a propellant as a solvent, and optionally a surfactant (e.g., sorbitan trioleate, oleic acid or oligomeric lactic acid).

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

Capsules (made, for example, from gelatin or hydroxypropylmethyl cellulose), blister packs, or cartridges for use in an inhaler or insufflator may be formulated containing a powdered mixture of a compound of the invention, a suitable powder base (for example, lactose or starch), and a performance modulator (for example, 1-leucine, mannitol, or magnesium stearate). The lactose may be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include: dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable solution formulations for nebulizers (using electro-hydraulic power to generate fine mist) may contain 1. mu.g to 20mg of a compound of the invention per actuation, and the actuation volume may vary from 1. mu.l to 100. mu.l. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol, and sodium chloride. Other solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents (e.g., menthol and levomenthol) or sweetening agents (e.g., saccharin or saccharin sodium) may be added to those formulations of the invention for inhalation/intranasal administration.

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

In the case of dry powder inhalants and aerosols, the dosage unit is determined by means of a valve delivering a metered amount. Units according to the invention are generally arranged to administer metered amounts or "puffs" containing from 0.001mg to 10mg of a compound of the invention. The total daily dose is usually in the range of 0.001mg to 40mg, which may be administered as a single dose or, more commonly, as divided doses throughout the day.

In another embodiment of the invention, the compounds of the invention are preferably administered by inhalation. More preferably, the compounds of the invention are administered by inhalation using a dry powder inhaler or a metered dose inhaler, most preferably a dry powder inhaler.

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

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

The compounds of the invention may be incorporated with soluble macromolecular entities (e.g., dextrins and suitable derivatives thereof or polyethylene glycol-containing polymers) to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for any of the foregoing modes of administration.

Drug-dextrin complexes, for example, are found to be generally applicable to most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to complexation with the drug, cyclodextrins are used as auxiliary additives, i.e. as carriers, diluents or solubilisers. For this purpose, alpha-, beta-and gamma-cyclodextrins are most commonly used, examples of which can be found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.

In another embodiment of the present 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 embodiment of the present invention, a kit is provided comprising:

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

b. instructions for treating an obstructive or inflammatory airway disease,

and

c. and a packaging container for accommodating a and b.

Preferably, the obstructive or inflammatory airway disease is COPD.

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

Since it may be desirable to administer a combination of active compounds, for example, to treat a particular disease or condition, it is also within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, may conveniently be combined in the form of a kit, which is suitable for co-administration of the compositions.

Thus, another aspect of the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention according to the invention, and means for separately containing the compositions, e.g. a container, a separate bottle or a separate tin foil packet. Examples of such kits are well known blister packs for packaging tablets, capsules and the like.

The kits of the invention are particularly suitable for administration of different dosage forms, e.g., parenterally, for administration of separate compositions at different dosage intervals, or for stepwise increasing (titrate) of the individual compositions in contrast to one another. To aid compliance, the kit typically contains instructions for medication and may provide a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention will generally be in the range of from 0.01mg to 10mg, depending, of course, on the mode of administration. For example, a daily dose of inhalation may only require 0.01mg to 5 mg. The total daily dose may be administered in a single dose or in divided doses and may fall outside the general ranges mentioned herein, at the direction of the physician.

These doses are based on a typical human subject weighing between about 65kg and 70 kg. A physician can readily determine dosages for subjects having a weight outside this range (e.g., infants and elderly).

According to another embodiment of the invention, the compounds of the invention may also be co-administered to a patient in combination with one or more other therapeutic agents to achieve certain particularly desirable end-effects of treatment, for example, pathophysiologically relevant disease processes, including (but not limited to): (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) treatment of signs and symptoms such as asthma, cough. The second and further additional 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 second and further therapeutic agents are selected from different classes of therapeutic agents.

As used herein, "co-administration," "simultaneous administration," and "in combination with" when referring to a compound of the invention and one or more other therapeutic agents is intended to mean and indeed mean and include the following:

simultaneously administering such a combination of one or more compounds of the invention and one or more therapeutic agents to a patient in need of treatment, when the ingredients are formulated together in a single dosage form that releases the ingredients into the patient at substantially the same time,

such a combination of one or more compounds of the invention and one or more therapeutic agents is administered substantially simultaneously to a patient in need of treatment, when the ingredients are formulated separately from each other into separate dosage forms which the patient takes at substantially the same time, after which the ingredients are released into the patient at substantially the same time,

continuous administration of such combinations of one or more compounds of the invention and one or more therapeutic agents to a patient in need of treatment when the ingredients are formulated separately from each other into separate dosage forms (said patient taking the dosage forms at a substantial time interval between each administration at a continuous time, after which said ingredients are released into the patient at substantially different times); and

Continuous administration of such combinations of one or more compounds of the invention and one or more therapeutic agents to a patient in need of treatment when the ingredients are formulated together in a single dosage form (which dosage form releases the ingredients in a controlled manner, after which the ingredients are administered to the patient at the same and/or different times, simultaneously, continuously and/or overlapping); wherein each moiety may be administered by the same or different route.

Suitable examples of other therapeutic agents that may be used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, solvate or composition thereof, include (but are not limited to):

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

(b) leukotriene antagonists (LTRAs) including LTB₄、LTC₄、LTD₄And LTE₄The antagonist of (a) or (b),

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

(d)α₁-and a₂-an adrenoceptor agonist, a vasoconstrictor, a sympathomimetic agent for decongestant use,

(e) a muscarinic M3 receptor antagonist or an anticholinergic agent,

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

(g) the content of the theophylline is determined,

(h) the content of the sodium cromoglycate is as follows,

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

(j) Oral and inhaled glucocorticosteroids, e.g., DAGR (dissociative agonist of the corticoid receptor),

(k) monoclonal antibodies active against endogenous inflammatory entities,

(l) Beta 2 agonists, including long-acting beta 2 agonists,

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

(n) kinin-B₁-and B₂-an antagonist of a receptor,

(o) an immunosuppressive agent, wherein,

(p) inhibitors of Matrix Metalloproteinases (MMPs),

(q) tachykinin NK₁、NK₂And NK₃(ii) an antagonist of a receptor,

(r) an inhibitor of an elastase,

(s) adenosine A2a receptor agonists,

(t) an inhibitor of urokinase,

(u) compounds acting at dopamine receptors, e.g., D2 agonists,

(v) modulators of the NF κ β pathway, e.g., IKK inhibitors,

(w) modulators of cytokine signaling pathways, e.g., syk kinase or JAK kinase inhibitors,

(x) An agent which can be classified as a mucolytic or an antitussive, and

(y) an antibiotic.

According to the invention, the combination of a compound of the invention with the following therapeutic agents is preferred:

-an antagonist of H3, and,

-a muscarinic M3 receptor antagonist,

-a PDE4 inhibitor which is,

-a glucocorticosteroid which is a compound of formula (I),

-an adenosine A2a receptor agonist,

-a beta 2 agonist, which is a beta-agonist,

modulators of cytokine signaling pathways, e.g. syk kinase, or

-leukotrienesAntagonists (LTRAs), including LTB₄、LTC₄、LTD₄And LTE₄An antagonist of (1).

According to the invention, further preferred is the combination of a compound of the invention with the following therapeutic agents:

glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, comprising: prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, mometasone furoate and mometasone furoate monohydrate,

-muscarinic M3 receptor antagonists or anticholinergics, including in particular: ipratropium salts, i.e., ipratropium bromide; tiotropium salts, i.e. tiotropium bromide; oxitropium (oxitropium) salts, i.e. oxitropium bromide; poricipine (perenzapine) and telenzapine,

-or a β 2 agonist, in particular a long acting β 2 agonist, comprising: salmeterol, formoterol, QAB-149, and CHF-4226.

Preferably, the compounds of the present invention exhibit slow-offset (slow-offset) binding kinetics to p 38.

In another preferred embodiment, when the compounds of the invention are administered via the inhalation route, they are rapidly metabolized as they leave the lungs.

More preferably, the compounds of the present invention are metabolized to compounds that are less active than the administered compound.

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

And (3) analysis: TNF alpha screening

The anti-inflammatory properties of the compounds of the present invention are demonstrated by their ability to inhibit TNF α release from human peripheral blood mononuclear cells. From healthy volunteersVenous blood was collected and mononuclear cells were purified by centrifugation using histopaque (ficoll) pads. The cells were stimulated to produce TNF α by addition of lipopolysaccharide, after incubation for 18 hours in the presence of LPS, cell supernatants were removed and TNF α concentrations in the supernatants were determined by ELISA. The addition of the compounds of the invention reduces the amount of TNF α produced. Determination of IC₅₀The IC₅₀Equal to the concentration at which the compound inhibited 50% of the TNF α production compared to LPS-stimulated control wells.

In the above analysis, the compounds of the examples were tested and their IC's were found₅₀(TNF. alpha. screen) less than 1000nM and for most of the compounds tested, we found IC₅₀(TNF. alpha. screen) less than 100 nM.

The tested compounds were found to have an IC of less than 1000nM₅₀(p38 analysis), and for most of the compounds tested, we found IC₅₀(p38 assay) was less than 100 nM.

In the present invention, the terms "active", "potent" or "potency" refer to compounds of formula (I) that exhibit TNF activity of less than 1000nM, as measured according to the TNF assay described herein.

p38 kinase assay：

Cloning of human p38a：

The coding region of human p38a cDNA was obtained from RNA isolated from the human monocytic cell line THP.1 by PCR-amplification. First strand cDNA was synthesized from whole RNA as follows: mu.g of RNA was annealed to 100ng of random hexamer primer in 10. mu.l reaction by heating to 70 ℃ for 10 min followed by cooling on ice for 2 min. Then, by adding 1. mu.l of RNAsin (Promega, Madison Wis.), 2. mu.l of 50mM dNTP's, 4. mu.l of 5 Xbuffer, 2. mu.l of 100mM DTT, and 1. mu.l (200U) of Superscript II^TMAMV reverse transcriptase, synthesizing eDNA. Random primers, dNTP's and Superscript II^TMReagents were purchased from Life-Technologies, Gaithersburg, Mass. The reaction solution was incubated at 42 ℃ for 1 hour. By aliquoting 5. mu.l of the reverse transcriptase reaction solution into 100. mu.l of the PCR reaction solution containing: 80 μ l dH ₂O, 2. mu.l of 50mM dNTP's, 1. mu.l each of the forward and reverse primers (50 pmol/. mu.l), 10. mu.l of 10 Xbuffer, and 1. mu.l of Expand^TMThe amplification of the p38cDNA was performed with polymerase (Boehringer Mannheim). PCR primers incorporated Bam HI occupy the 5 'and 3' ends of the amplified fragment and were purchased from Genosys. The sequences of the forward and reverse primers were: 5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3', and 5'-GATCGAGGATTCTCAGGACTCCATCTCTTC-3'. PCR amplification was performed in DNAThermal Cycler (Perkin Elmer) by repeating 30 cycles of 1 minute at 94 ℃, 1 minute at 60 ℃ and 2 minutes at 68 ℃. After amplification, Wizard was used^TMPCR preparations (Promega) and digestion with Bam HI (New England Biolabs) removed excess primers and unbound dNTP's from the amplified fragments. T-4 DNA ligase (New England Biolabs) was used, as described in T.Maniatis, Molecular Cloning: a Laboratory Manual, 2^nded. (1989) ligation of the BamHI digested fragment to BamHI digested pGEX 2T plasmid DNA (pharmacia Biotech). The ligation reaction was transferred to chemically appropriate E.coli DH10B cells (purchased from Life-Technologies) according to the manufacturer's instructions. Using Promega Wizard ^TMMini preparative kits, plasmid DNA was isolated from the bacterial colonies generated. In a device equipped with Prism^TM(AppliedBiosystems Inc.) in a DNA Thermal Cycler (Perkin Elmer), the plasmid containing the appropriate BamHI fragment was sequenced. eDNA clones encoding both human p38a isoforms were identified (Lee et al, Nature 372, 739). One of the clones containing the cDNA for p38a-2(CSB-2) (at the cloning site for PGEX 2T, 3' inserted into the GST coding region) was named pMON 35802. The sequence of the clone obtained matched precisely with the cDNA clone reported by Lee et al. This expression plasmid allows the production of a GST-p38a fusion protein.

Expression of human p38a

The GST/p38a fusion protein was expressed from plasmid pMON 35802 in E.coli strain DH10B (Life Technologies, Gibco-BRL). The overnight cultures were grown in Luria Broth (LB) containing 100mg/ml ampicillin. The following day, 500mL of fresh LB was inoculated with 10mL of this overnight culture and cultured in a 2L flask at 37 ℃ with constant shaking until the absorbance of the culture at 600nm reached 0.8. Expression of the fusion protein was induced by addition of isopropyl b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The culture was shaken for 3 hours at room temperature, and centrifuged to harvest the cells. The cell pellets were stored frozen until protein purification was performed.

purification of p38 kinase-alpha

All chemicals used were purchased from Sigma Chemical co unless otherwise noted. The E.coli cell pellets collected from 5 1L shake flask fermentations were resuspended in a volume up to 200ml of PBS (140mM sodium chloride, 2.7mM potassium chloride, 10mM Na. multidot. MNa)₂HPO₄，1.8mM KH₂PO₄pH 7.3). The cell suspension was adjusted to 5mM DTT using 2M DTT and then aliquoted into 5 50mL Falcon conical tubes. Cells were sonicated (Ultrasonics model W375) for 3x 1 min (pulsatile) on ice with a 1 cm probe. Using centrifugation (12,000Xg, 15 min), the lysed cellular material was removed and the clarified supernatant was applied to glutathione-agarose resin (Pharmacia).

Glutathione-agarose affinity chromatography

12ml of a 50% glutathione-agarose-PBS suspension was added to 200ml of the clear supernatant and incubated batch-wise at room temperature for 30 minutes. The resin was collected by centrifugation (600Xg, 5 min) and washed with 150ml PBS/1% Triton X-100 (twice) and 40ml PBS (four times). Glutathione-agarose resin was resuspended in 6mL PBS containing 250 units of thrombin protease (Pharmacia, specific activity > 7500 units/mg) and gently mixed for 4 hours at room temperature to cleave p38 kinase from GST-p38 fusion protein. By centrifugation (600xg, 5 min), the glutathione-agarose resin was removed and washed twice with 6mL PBS. The PBS wash fraction and the digestion supernatant containing p38 kinase protein were pooled together and adjusted to 0.3mM PMSF.

Mono Q anion exchange chromatography

The thrombin-cleaved p38 kinase was further purified using FPLC-anion exchange chromatography. The thrombin cleavage sample was double diluted with buffer A (25mM HEPES, pH 7.5; 25mM beta-glycerophosphate; 2mM DTT; 5% glycerol) and injected onto a Mono Q HR 10/10(Pharmacia) anion exchange column equilibrated with buffer A. The column was eluted with 160mL of a 0.1M-0.6M sodium chloride/buffer A gradient (flow rate: 2 mL/min). The p38 kinase peak eluted with 200mM sodium chloride was collected and concentrated to a volume of 3-4mL using a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 gel filtration chromatography

The concentrated Mono Q-p38 kinase was purified by gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 column equilibrated with buffer B (50mM HEPES, pH 7.5; 50mM sodium chloride; 2mM DTT; 5% glycerol). The protein was eluted from the column with buffer B at a flow rate of 0.5 mL/min and detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and refrigerated at-80 ℃. A typical purified protein produced by a 5 liter E.coli shake flask fermentation is 35mg of p38 kinase.

Kinetic analysis

Binding kinetics：

SKF-86002 (available from Calbiochem; KD-200 nM) increases fluorescence when bound to p38a(as monitored by excitation at 340nm and emission at 420 nm). At room temperature, in a medium consisting of 20mM Bis-Tris, 2mM EDTA, 500mM NaCl, 0.01% NaN₃SKF-86002 (1-2. mu.M) was pre-incubated with p38a (20-60nM) in a buffer consisting of 0.15% NOG and 5% DMSO for 5-10 min. Then, a sample compound (20-100nM) was added and the change in fluorescence was monitored. When SKF is pulled away from its binding site on p38a, it is replaced by the test compound and a decrease in fluorescence is observed on a time scale proportional to the rate of binding of the compound. The binding rate of the compounds was measured using the known binding kinetics of SKF-86002.

Kinetics of dissociation：

At room temperature, in a medium consisting of 20mM Bis-Tris, 2mM EDTA, 0.01% NaN₃Test compounds (50 or 100nM) were preincubated overnight with p38a (37nM protein or 21nM as determined by active site titration) in a buffer consisting of 0.15% NOG, 500mM NaCl, and 5% DMSO. The following day, SKF-86002 was added to a final concentration of 50. mu.M. The increase in fluorescence observed upon binding of SKF-86002 to p38a was monitored by excitation at 340nm and emission at 420nm, and the off-rate was measured.

Data of：

The following data were generated using the TNF screening methods disclosed herein.

Examples	TNFICnM	Examples	TNFICnM	Examples	TNFICnM
Examples	TNFICnM	Examples	TNFICnM	Examples	TNFICnM	26	1.6	73	0.9	116	3.2

Examples	TNFICnM	Examples	TNFICnM	Examples	TNFICnM
Examples	TNFICnM	Examples	TNFICnM	Examples	TNFICnM	33	2.0	74	4.0	118	15.7
34	1.3	76	0.8	124	4.6	33	2.0	74	4.0	118	15.7
34	1.3	76	0.8	124	4.6	36	4.8	77	2.7	125	80.0
37	2.8	78	0.8	128	3.7	36	4.8	77	2.7	125	80.0
37	2.8	78	0.8	128	3.7	44	1.1	80	1.1	132	4.5
45	1.4	81	1.8	136	1.0	44	1.1	80	1.1	132	4.5
45	1.4	81	1.8	136	1.0	46	0.8	86	0.8	139	3.2
51	0.7	87	0.6	140	1.8	46	0.8	86	0.8	139	3.2
51	0.7	87	0.6	140	1.8	54	0.7	93	1.1	141	1.4
55	0.9	94	0.9	142	2.2	54	0.7	93	1.1	141	1.4
55	0.9	94	0.9	142	2.2	57	1.2	95	0.6	143	1.2
58	1.6	97	0.6	144	1.2	57	1.2	95	0.6	143	1.2
58	1.6	97	0.6	144	1.2	59	1.3	98	0.4	145	0.9
60	1.4	100	1.1	151	1.4	59	1.3	98	0.4	145	0.9
60	1.4	100	1.1	151	1.4	63	1.4	102	1.7	152	4.9
64	0.9	104	1.0	153	4.8	63	1.4	102	1.7	152	4.9
64	0.9	104	1.0	153	4.8	68	2.3	105	0.6	179	1.5
70	0.9	109	1.2	180	21.0	68	2.3	105	0.6	179	1.5
70	0.9	109	1.2	180	21.0	71	3.0	114	3.6	181	2.7
				182	0.7	71	3.0	114	3.6	181	2.7

Examples and preparation examples

Nuclear Magnetic Resonance (NMR) data were measured using a Varian Unity Inova-400, Varian Unity Inova-300 or Bruker AC300 spectrometer and are expressed in ppm relative to tetramethylsilane. Mass Spectral (MS) data were obtained on Finnigan mat.tsq 7000 or Fisons Instruments Trio 1000. The cited theoretical and measured ions refer to the lowest mass isotope composition. For silica gel column chromatography, Kieselgel 60, 230- "400 mesh from e.merck, Darmstadt was used unless otherwise stated. Kireselgel 60F from merck₂₅₄The plates were used for TLC and the compounds were applied using UV light, 5% aqueous potassium permanganate or Dragendorff's reagent (spray-on solution containing)Sodium nitrite in water) to be observed by naked eyes. The water content was determined as Mitsubishi CA100 (Coulometric Karl Fisher titror). Other measurements are taken by standard means.

PdCl₂(dppf)·CH₂Cl₂Is a 1: 1 dichloromethane complex of 1, 1-bis (diphenylphosphino) ferrocene palladium (II) chloride.

DBU is 1, 8-diazabicyclo [5.4.0] undec-7-ene.

Preparation example 1

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

N, N-diisopropylethylamine (15.5g, 0.12mol) was added to a solution of methyl 2, 2-dimethyl-3-hydroxypropionate (13.2g, 0.1mol) in dichloromethane (150mL, 30mmol) and the solution was cooled to 0 ℃. Then, methanesulfonyl chloride (12.6g, 0.11mol) was added dropwise and the mixture was stirred at 0 ℃ for 90 minutes. The reaction mixture was then diluted with 0.5M hydrochloric acid (100mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 50mL) and the combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Methanethiol sodium salt (7.7g, 0.11mol) was added to the resulting residue in dioxaneTo the resulting solution in alkane (100mL) and the mixture was heated at reflux for 24 hours. The mixture was then diluted with ethyl acetate (250mL), 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 to 100: 0) gave 3.85g of the title compound as a pale yellow oil in 24% yield.

Preparation example 2

4, 4-dimethyl5-methylsulfanyl-3-oxo-valeronitrile

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

Preparation example 3

4-methyl-4-methylsulfanyl-3-oxo-valeronitrile

The title compound was prepared in a colorless oil in 81% yield from ethyl 2-methyl-2- (methylthio) propionate and acetonitrile in a similar manner to preparation example 2.

Preparation example 4

(3-methylsulfanyl-phenyl) -hydrazine

Magnesium ribbons (turnings) (0.79g, 33mmol) and a single crystal of iodine were added to a solution of 3-bromophenylthiomethane (6.11g, 30mmol) in tetrahydrofuran (50mL) and the mixture was stirred at room temperature for 18 hours. The mixture was cooled to-78 ℃ and di-tert-butyl diazocarboxylate (6.91g, 30mmol) was added. The mixture was stirred at-78 ℃ for 30 minutes and then quenched by the addition of 1M citric acid (40 mL). The reaction mixture was warmed 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 resulting residue was redissolved in isopropanol (200mL) and the solution was saturated with hydrogen chloride gas. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was taken up in water, basified with saturated sodium bicarbonate solution and extracted with dichloromethane: methanol, 90: 10 (4X 50 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo; and the resulting residue was purified by silica gel column chromatography (eluting with methylene chloride: methanol, 100: 0 to 70: 30) to give the title compound as a dark orange liquid in 36% yield.

Preparation example 5

1- (4-methoxy-3-tolyl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester

Butyllithium (2.5M in hexanes, 23.9mL, 59.75mmol) was added to a solution of 4-bromo-2-methylmethoxybenzene (10g, 49.74mmol) in tetrahydrofuran (150mL) that had been cooled to-78 deg.C, and the mixture was stirred at this temperature for 1 hour. Then, a solution of di-tert-butyl diazocarboxylate (13.74g, 59.68mmol) in tetrahydrofuran (50mL) was added dropwise, and the mixture was stirred at-78 ℃ for 1 hour and then at room temperature for 2 hours. The reaction was quenched with water (25mL), concentrated to low volume in vacuo and partitioned between ether (300mL) and brine (300 mL). The aqueous layer was separated and re-extracted with ether (2 × 100mL), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with heptane: ethyl acetate, 75: 25) to give 10.93g of the title compound as a pale yellow solid in 62% yield.

Preparation example 6

(4-methoxy-3-tolyl) hydrazine hydrochloride

Will be in 1, 4-two4M hydrochloric acid in an alkane (37.5mL, 150mmol) was added dropwise to the product of preparation 5 (10.75g, 30.50mmol) in 1, 4-bis To the resulting solution in alkane (12.5mL) and the mixture was stirred at room temperature for 48 hours. Then, the mixture was concentrated in vacuo and the resulting residue was stirred in ether at 0 ℃ for 30 minutes. The precipitate was filtered off and washed with ether, and the solid was dried under vacuum at 40 ℃ for 6 hours to give 5.43g of the title compound in 94% yield.

Preparation example 7

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

Concentrated hydrochloric acid (1mL) was added dropwise to a mixture of 4-methylthiophenylhydrazine (2g, 10.5mmol) and 4, 4-dimethyl-3-oxopentanenitrile (1.44g, 11.5mmol) in ethanol (30mL), and the mixture was heated at reflux for 18 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol, 100: 0 to 97: 3) to give the title compound as a yellow oil which crystallized upon standing (2.59g, yield 95%).

Preparation examples 8 to 19

The compounds of the following general formula were prepared using the appropriate hydrazine and nitrile starting materials in a similar manner to that described in preparation example 7. The reaction was monitored by TLC analysis and heated at reflux for 3-24 hours.

Preparation examples 14 to 19: purification was accomplished by silica gel column chromatography (using dichloromethane: ethyl acetate, 80: 20).

Preparation example 20

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

N, N-diisopropylethylamine (1.7mL, 7.99mmol) was added to a mixture of phenylhydrazine hydrochloride (1.5g, 10.39mmol) and 4, 4-dimethyl-3-oxopentanenitrile (1.0g, 7.99mmol) in ethanol (15mL), and the mixture was heated at reflux for 18 h. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with heptane: ethyl acetate, 75: 25) to give the title compound as a light orange-colored product which crystallized upon standing (1.21g, yield 70%).

Preparation examples 21 to 24

The compounds represented by the following general formula were prepared by a similar method to that described in preparation example 20, using the appropriate hydrazine and nitrile starting materials. The reaction was monitored by TLC analysis and heated at reflux for 3-24 hours.

Numbering	X	Y	Data of	Yield of
Numbering	X	Y	Data of	Yield of	21	H	CH	LRMS：m/z API-ES 230.7[MH]	79％
22	H	O-CH	LRMS：m/z API-ES 246.6[MH]	58％	21	H	CH	LRMS：m/z API-ES 230.7[MH]	79％
22	H	O-CH	LRMS：m/z API-ES 246.6[MH]	58％	23	CH	OCH	LRMS：m/z API-ES 260[MH]	84％
24	O-CH	H	LRMS：m/z API-ES 246.7[MH]	99％	23	CH	OCH	LRMS：m/z API-ES 260[MH]	84％

Preparation example 25

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

2-chloro-5-bromopyridine (64g, 333mmol) was suspended in hydrazine monohydrate (250mL) and the mixture was heated at 70 ℃ for 72 hours. The reaction mixture was then diluted with water (750mL) and the resulting precipitate was filtered off and azeotroped with toluene (x2) followed by dichloromethane (x2) to give 52g of the title compound as a light brown solid in 83% yield.

Preparation example 26

4-chloro-3-hydroxymethyl-phenol

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

Preparation example 27

2-chloro-5-hydroxy-benzaldehyde

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

Preparation example 28

2-chloro-4-hydroxy-benzaldehyde

Diisobutylaluminum hydride (1M in hexane, 240mL, 240mmol) was added to a cooled-78 ℃ solution of 2-chloro-4-hydroxybenzonitrile (15g, 97.7mmol) in tetrahydrofuran (200mL), and the mixture was stirred at this temperature for 1 hour, then at room temperature for 18 hours. Then, the mixture was cooled to 0 ℃, and 1M hydrochloric acid (80mL) was added dropwise. The reaction mixture was diluted with water (200mL) and filtered, washed with ethyl acetate (x 2). The layers of the filtrate were separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was triturated with dichloromethane to give 12.92g 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 (137g, 1.06mol) was added to a suspension of the product of preparation 25 (40g, 213mmol) in dichloromethane (100mL) and the solution so obtained was cooled to 0 ℃. Isobutyryl chloride (22.7g, 213mmol) was then added dropwise and the mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with water and the resulting solid was filtered off and air dried for 48 hours. The solid was then recrystallized from methanol/N, N-diisopropylethylamine, 25: 75 to give 1.16g 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 (10g, 53.2mmol) in ethanol (350mL) was heated at 80 ℃ for 15 minutes. The resulting precipitate was filtered, washed with ethanol and dried in vacuo for 18 h 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 compound

A suspension of the product of preparation 29 (16g, 62mmol) in phosphorus oxychloride (320mL) was heated at 75 ℃ for 18 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was dissolved in water, basified with 2M sodium hydroxide solution, and extracted with ethyl acetate. The resulting organic solution was dried over sodium sulfate and concentrated in vacuo. The resulting residue was triturated in ethyl acetate/methanol (98: 2) to give 11.23g 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 preparation 27 (3.1g, 19.7mmol) and preparation 25 (3.7g, 19.7mmol) in ethanol (75mL) was heated at reflux for 1 h. The mixture was then cooled to room temperature, diluted with ethanol (75mL) and iodobenzene diacetate (6.30g, 19.7mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, triturated with a mixture of ethyl acetate and methanol, and filtered. The resulting residue was further purified by silica gel column chromatography (eluting with methylene chloride: methanol, 90: 10) to give 0.95g 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-phenols

The title compound was prepared in 78% yield as a solid from the products of preparation 28 and 25 using a method analogous to preparation 32.

Preparation example 34

3- [2- (benzyloxy) phenyl]6-bromo [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

The title compound was prepared from the product of preparation 30 by a similar method to that of preparation 33. The title compound was further purified by silica gel column chromatography (eluting with ethyl acetate: dichloromethane, 50: 50) followed by trituration with ether/ethyl acetate to give the title compound as a solid in 88% yield.

Preparation example 35

[2- (3-isopropyl- [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-ylsulfanyl) -phenyl]-methanol

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

Preparation example 36

4-chloro-3- (6- { [2- (hydroxymethyl) phenyl]Thio } [1, 2, 4]Triazolo [4, 3-a]Pyridin-3-yl) phenols

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

Preparation example 37

3-chloro-4- (6- { [2- (hydroxymethyl) phenyl]Thio } [1, 2, 4]Triazolo [4, 3-a]Pyridin-3-yl) phenols

The title compound was prepared in 41% yield as a light brown foam from the product of preparation 33 and 2-mercaptobenzyl alcohol in analogy to preparation 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 in 57% yield as a brown solid in analogy to preparation 35 from the product of preparation 34 and 2-mercaptobenzyl alcohol.

Preparation example 39

6- (2-azidomethyl-phenylthio)Alkyl) -3-isopropyl- [1, 2, 4]Triazolo [4, 3-a]Pyridine compound

1, 8-diazabicyclo [5.4.0] undec-7-ene (6.4g, 42.1mmol) was added to an ice-cooled suspension of the product of preparation 35 (10.5g, 35.1mmol) and diphenylphosphoryl azide (11.6g, 42.1mmol) in toluene (60mL), and the mixture was stirred at 0 ℃ for 3 hours and at room temperature for 18 hours. Then, the reaction solution was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification was carried out by silica gel column chromatography (eluting with ethyl acetate: methanol, 98: 2 and triethylamine (1 drop per 100mL of organic solution)), followed by obtaining 9g of the title compound as a brown oil in 79% yield.

Preparation example 40

Phosphoric acid 3- (6- { [2- (azidomethyl) phenyl]Thio } [1, 2, 4]Triazolo [4, 3-a]Pyridine-3- Phenyl) -4-chlorophenyl ester

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

Preparation example 41

4- (6- { [2- (azidomethyl) phenyl]Thio } [1, 2, 4]Triazolo [4, 3-a]Pyridine- 3-yl) -3-chlorophenol

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

Preparation example 42

6- { [2- (azidomethyl) phenyl]Thio } -3- [2- (benzyloxy) phenyl][1，2，4]- Triazolo [4, 3-a]Pyridine compound

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

Preparation example 43

{2- [ (3-isopropyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl amine hydrochloride

Triphenylphosphine (10.6g, 40.3mmol) and water (0.73mL, 40.3mmol) were added to a solution of the product of preparation 39 (10.8g, 33.6mmol) in tetrahydrofuran (114mL) and the mixture was stirred at room temperature for 40 h, then warmed to 40 ℃ for 5 h. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in dichloromethane and cooled in an ice bath. 1M hydrochloric acid in ether (35mL) was added dropwise, and the mixture was stirred at room temperature for 18 hours. The resulting precipitate was filtered off and dried over phosphorus pentoxide to give 7.24g of the title compound as a brown 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 analogous to preparation 43. The crude product obtained was redissolved in methanol and saturated with 1M hydrochloric acid (in 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-chloro Phenolate salts

The title compound was prepared from the product of preparation 41 by a similar method to that of preparation 43. The crude product obtained was redissolved in methanol and saturated with 1M hydrochloric acid (in 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 similar method to preparation 43. The crude product obtained was redissolved in methanol and saturated with 1M hydrochloric acid (in diethyl ether) to give the desired product as a white solid in 78% yield.

Preparation example 47

4, 4-dimethyl-3-oxohexanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 3.18g, 79.4mmol) in tetrahydrofuran (60mL) was heated at 60 ℃ for 1 hour. Then, the reaction mixture was cooled to room temperature, acetonitrile (4.2mL, 79.4mmol) and ethyl 2, 2-dimethylbutyrate [ (7.95g, 61mmol), j.am.chem.soc., 1942, 64, 2964] in tetrahydrofuran (100mL) were added, and the mixture was stirred at 25 ℃ for 4 hours. Then, the mixture was diluted with 1M hydrochloric acid (100mL), and the aqueous layer was separated and extracted with ethyl acetate. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the resulting residue triturated with heptane to give 2.3g of the title compound as a light brown solid in 27% yield.

Preparation example 48

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

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

Preparation example 49

5- (benzyloxy) -2-chlorobenzoic acid benzyl ester

The title compound was prepared as an oil in quantitative yield from 2-chloro-5-hydroxybenzoic acid (US2002/0037905, p15) using a similar method to that described for preparation 48.

Preparation example 50

4- (benzyloxy) -2-chlorobenzonitrile

Potassium carbonate (66.3g, 480mmol) was added to a mixture of 2-chloro-4-hydroxybenzonitrile (25g, 160mmol) and benzyl bromide (19.3mL, 161mmol) in acetonitrile (300mL) and the mixture was stirred at room temperature for 18 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was triturated with heptanes to give 38.65g of the title compound as an off-white solid in 99% yield.

Preparation example 51

4- (benzyloxy) -2-chlorobenzaldehyde

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

Preparation example 52

4-bromo-1-ethyl-2-methoxybenzene

Methyl iodide (3mL, 47.3mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25g, 43mmol) and potassium carbonate (6.54g, 47.3mmol) in acetone (20mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to low volume in vacuo and diluted with water. The aqueous mixture was extracted with dichloromethane (3 × 50mL) and the combined organic solutions were washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 1, 2-ethanediol (10mL), hydrazine (19.47mL, 400mmol) and potassium hydroxide (7.86g, 140mmol) were added, and the reaction mixture was heated at 150 ℃ for 60 h. Then, the reaction mixture was quenched with 1M hydrochloric acid and extracted with ethyl acetate (3X 20 mL). The combined organic solutions were dried over sodium sulfate, concentrated in vacuo and the resulting residue was purified by Kugel Rohr fractionation (150 ℃/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-dimethylpropionyl) -2, 2-dimethylpropionylhydrazine

The title compound was prepared as a white powder in 43% yield from 4-bromo-2-chloro-1-methoxy-benzene (j. org. chem.1982, 47, 5270) and di-tert-butyl diazocarboxylate using the same procedure as preparation 5.

Preparation example 54

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

The title compound was prepared in 84% yield as a yellow liquid from the product of preparation 48 and di-tert-butyl diazocarboxylate using the same procedure as described in preparation 5.

Preparation example 55

1- (3-Ethyl-4-methoxyphenyl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester

The title compound was prepared as a solid in 53% yield from 4-bromo-2-ethyl-1-methoxy-benzene and di-tert-butyl diazocarboxylate using the same procedure as described for preparation 53.

Preparation example 56

1- (4-Ethyl-3-methoxyphenyl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester

The title compound was prepared in 40% yield as a pale yellow oil from the product of preparation 52 and di-tert-butyl diazocarboxylate by the same procedure 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 an off-white powder by the same method as preparation 6.

Preparation example 58

[3- (benzyloxy) -5-tolyl radical]Hydrazine hydrochloride

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

Preparation example 59

(3-ethyl-4-methoxyphenyl) hydrazine hydrochloride

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

Preparation example 60

(4-Ethyl-3-methoxyphenyl) hydrazine hydrochloride

The title compound was prepared in 85% yield as an off-white solid from the product of preparation 56 using a similar method to that described for preparation 6.

Preparation examples 61 to 86, 88 and 89

The compounds of the following general formula were prepared by a similar method to that described in preparation example 7, using the appropriate commercially available hydrazine and commercially available nitrile starting materials. When the starting materials are not commercially available, the synthesis is disclosed herein. The reaction was monitored by TLC analysis and heated at reflux for 3-24 hours.

^bThe crude compound was purified by column chromatography on silica gel (eluting with heptane: ethyl acetate, 75: 25).

Preparation example 83: from the product of preparation 3 and (3-ethylphenyl) -hydrazine hydrochloride (EP 177242, p 31).

Preparation example 84: the crude product is chromatographed on silica gel (eluting with pentane: ethyl acetate, 100: 0 to 60: 40)) To be purified.

Preparation example 86: the crude product was purified by column chromatography on silica gel (eluting with hexane: ethyl acetate, 91: 9 to 83: 17).

Preparation example 87

(4-chloro-3-methoxyphenyl) hydrazine

A solution of concentrated hydrochloric acid (12mL) and sodium nitrite (1.7g, 24.4mmol) in water (8mL) was added to a solution of 4-chloro-3-methoxyaniline (3.86g, 24.4mmol) in water (8mL) at-10 ℃. The mixture was stirred for 30 minutes, then added to a solution of tin chloride (14.89g, 66mmol) in concentrated hydrochloric acid (24mL) and water (24mL) that had cooled to 0 ℃. The reaction mixture was stirred for 18 hours and the temperature was allowed to rise to 25 ℃. The resulting precipitate was filtered off and the solid was recrystallized from heptane/ethyl acetate (33: 66) to yield 3g of the title compound as a white solid in 72% yield.

Preparation example 90

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

The title compound was prepared in 50% yield as an orange oil in the same manner as described in preparation 7 from 4, 4-dimethyl-3-oxopentanenitrile and 3-pyridohydrazide (U.S. Pat. No. 2002/0143176, p 22).

Preparation example 91

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

The title compound was prepared as a solid in 99% yield from 4, 4-dimethyl-3-oxopentanenitrile and 2-hydrazinopyridine using the same procedure as described for preparation 7.

Preparation example 92

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

Concentrated hydrochloric acid (2mL) was added dropwise to a suspension of [4- (benzyloxy) phenyl ] hydrazine hydrochloride (3.19g, 12.74mmol) and the product of preparation 3 (2g, 12.74mmol) in ethanol (50mL) and the mixture was heated at reflux for 2 hours. Then, water (5mL) was added and the reaction mixture was heated under reflux for an additional 16 hours. 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 obtained was purified by silica gel column chromatography (eluting with dichloromethane: ethyl acetate, 100: 0 to 85: 15) to give the title compound as an orange oil which crystallized upon standing (2.79g, yield 62%).

Preparation examples 93 to 97

The compounds of the following general formula were prepared by a similar method to that described in preparation example 20, using the appropriate commercially available hydrazine and commercially available nitrile starting materials. When the starting materials are not commercially available, the synthesis is disclosed herein. The reaction was monitored by TLC analysis and heated at reflux for 3-24 hours.

Preparation example 93: the crude compound was triturated with heptane to ether 66: 33.

Preparation example 98

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

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

Preparation example 99

3-tert-butyl-1- [4- ({ [ tert-butyl (dimethyl) silyl) group]Oxy } methyl) phenyl]- 1H-pyrazol-5-amines

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

Preparation example 100

3-tert-butyl-1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } -4-tolyl) -1H-pyrazol-5-amine

The title compound was prepared as a solid in 86% yield from 5- [ 5-amino-3- (1, 1-dimethylethyl) -1H-pyrazol-1-yl ] -2-methyl-phenolate (WO 03/005999, p81-82) and tert-butyldimethylsilyl chloride using the same method as described in preparation 99.

Preparation example 101

3- [ 5-amino-3-tert-butyl-1H-pyrazol-1-yl]Phenol and its salts

Boron tribromide (1M in dichloromethane, 12mL, 12mmol) was added dropwise to an ice-cooled solution of the product of preparation 63 (1.28g, 4mmol) in dichloromethane (50mL), and the mixture was stirred for 30 minutes, raising its temperature to 25 ℃. The reaction mixture was then diluted with methanol (20mL) and water, basified with 0.88 ammonia and extracted with dichloromethane (3X 50 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: ethyl acetate, 100: 0 to 80: 20) to give 825mg of the title compound as a pale yellow foam 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 in 40% yield as a white solid from the product of preparation 76 using a similar method to that described for preparation 101.

Preparation example 103

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

The title compound was prepared in quantitative yield as a brown oil from the product of preparation 244 and phenyl chloroformate in the same manner as described in preparation 116.

Preparation example 104

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

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

Preparation example 105

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

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

Preparation example 106

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

The title compound was prepared in 34% yield as a colorless oil from the product of preparation 101 and tert-butyldimethylsilyl chloride using the same procedure as described for 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 as a yellow solid in 18% yield from the product of preparation 72 using the same procedure as described for preparation 101.

Preparation example 108

3- [ 5-amino-3- (1, 1-dimethylpropyl) -1H-pyrazol-1-yl]Phenol and its salts

A solution of boron tribromide (1.7mL, 17.9mmol) in dichloromethane (20mL) was added dropwise to an ice-cooled solution of the product of preparation 70 (1.20g, 3.6mmol) in dichloromethane (15mL) and the mixture was stirred for 90 minutes, raising its temperature to 25 ℃. Dimethylamine (40% in water, 5mL) was then added dropwise and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated, extracted with ethyl acetate and the organic solution was dried over magnesium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with heptanes: ethyl acetate, 100: 0 to 50: 50) to give 390mg of the title compound as a yellow foam in 49% yield.

Preparation example 109

2- (6- { [2- (aminomethyl) phenyl]Thio } [1, 2, 4]Triazolo [4, 3-a]Pyridin-3-yl) phenols

The product of preparation 46 (3.43g, 7.22mmol) was suspended in hydrobromic acid (5.7M in glacial acetic acid, 7mL, 40mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ether (150mL), stirred at room temperature for 15 minutes, and then filtered. The resulting residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, the resulting precipitate was filtered off 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 combined with a solution of the dissolved residue and concentrated in vacuo. The resulting residue was triturated with ether to give 2.40g 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 as a white foam in 44% yield from the product of preparation 87 using the same method as described for preparation 109.

Preparation example 111

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

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

Preparation example 112

3- [ 1-methyl-1- (methylthio) ethyl]-1- {3- [2- (tetrahydro-2H-pyran-2- Aryloxy) ethoxy]Phenyl } -1H-pyrazol-5-amines

The title compound was prepared in 94% yield as an orange oil in the same manner as described for preparation 111, starting from the product of preparation 110 and 2- (2-bromoethoxy) tetrahydro-2H-pyran.

Preparation example 113

3- [1, 1-dimethyl-2- (methylthio) ethyl]-1- {3- [2- (tetrahydro-2H-pyran-2- Aryloxy) ethoxy ]Phenyl } -1H-pyrazol-5-amines

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

Preparation example 114

3- (1, 1-dimethylpropyl) -1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Benzene and its derivatives 1H-pyrazol-5-amines

The title compound was prepared in 71% yield as a yellow oil in the same manner as described for preparation 111, starting from the product of preparation 108 and 2- (2-bromoethoxy) tetrahydro-2H-pyran.

Preparation example 115

3- [ 1-methyl-1- (methylthio) ethyl]-1- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Benzene and its derivatives 1H-pyrazol-5-amines

The title compound was prepared in 82% yield as a yellow oil in the same manner as described for preparation 111, starting from the product of preparation 102 and 2- (2-bromoethoxy) tetrahydro-2H-pyran.

Preparation example 116

(3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] ethoxy]Phenyl } -1H-pyrazole-5- Yl) carbamic acid phenyl ester

Phenyl chloroformate (1.94g, 12.4mmol) was added to an ice-cooled solution of the product of preparation 111 (4.05g, 11.3mmol) and pyridine (1.09mL, 13.5mmol) in tetrahydrofuran (50mL), and the mixture was stirred at 0 ℃ for 5 minutes and at room temperature for another 20 minutes. The reaction mixture was then extracted with ethyl acetate, washed with water, 5% citric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 5.22g of the title compound as a yellow oil in 86% yield.

Preparation example 117

(3- [ 1-methyl-1- (methylthio) ethyl)]-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] Phenyl } -1H-pyrazol-5-yl) carbamic acid phenyl ester

The title compound was prepared in quantitative yield as an orange oil from the product of preparation 112 and phenyl chloroformate in the same manner as described in preparation 116.

Preparation example 118

{1- [3- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } carbamic acid phenyl ester

The title compound was prepared in 94% yield as a brown solid from the product of preparation 63 and phenyl chloroformate by the same method as described in preparation 116.

Preparation example 119

[ 3-tert-butyl-1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } phenyl) -1H-pyrazole- 5-radical]Carbamic acid phenyl ester

The title compound was prepared in quantitative yield as a clear oil from the product of preparation 106 and phenyl chloroformate in the same manner as described for preparation 116.

Preparation example 120

{1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } phenyl) -3- [ 1-methyl-1- (methylthio) ethyl ester Base of]-1H-pyrazol-5-yl } carbamic acid phenyl ester

The title compound was prepared in quantitative yield as a red oil in analogy to the procedure described for preparation 116 from the product of preparation 105 and phenyl chloroformate.

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

Preparation example 122

N- [2- ({3-2- (benzyloxy) phenyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]-N' - (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) - Ethoxy radical]Phenyl } -1H-pyrazol-5-yl) urea

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

Preparation examples 123 to 166

The compounds of the general formula below were prepared by a similar procedure as described in preparation 121, using the appropriate amine, N' -carbonyldiimidazole and the appropriate aminopyrazole starting materials, which can be prepared by the syntheses disclosed herein or are commercially available products. The reaction was monitored by TLC analysis and heated at reflux for 20-72 hours.

^aThe crude compound was purified by trituration with diethyl ether.

Preparation examples 124, 132 and 133: the crude compound was purified by column chromatography on silica gel (eluting with dichloromethane: 7M ammonia in methanol, 100: 0 to 97.5: 2.5). This was followed by reverse phase column chromatography (on C18 silica gel, with water/7M ammonia in methanol (98: 2) and acetonitrile/7M ammoniaMethanol solution (98: 2), 75: 25 to 25: 75 for elution) for further purification.

Preparation example 134: the crude compound was purified by column chromatography on silica gel (eluting with dichloromethane: 7M ammonia in methanol/dichloromethane (10: 90), 100: 0 to 50: 50). After this time, further purification was carried out by trituration with dichloromethane: methanol: ether.

Preparation example 160: from the products of preparations 17 and 206.

Preparation example 163: from the products of preparations 104 and 214.

Preparation examples 165 and 166: from the appropriate aminopyrazoles and the product of preparation 208. The crude product was purified by column chromatography on silica gel eluting with hexane: ethyl acetate 90: 10, pentane: ethyl acetate 80: 20 to 20: 80, and ethyl acetate: methanol 100: 0 to 50: 50, respectively.

Preparation example 167

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

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

Preparation example 168

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

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

Preparation example 169

N- [2- ({3-2- (benzyloxy) phenyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]-N' - (3- [1, 1-dimethyl-2- (methylthio) ethyl)]-1- (3- [2- (tetrahydro- 2H-pyran-2-yloxy) ethoxy]Phenyl) -1H-pyrazol-5-yl) urea

Pyridine (64. mu.L, 0.8mmol) and phenyl chloroformate (110mg, 0.70mmol) were sequentially added to an ice-cooled solution of the product of preparation 113 (250mg, 0.62mmol) in tetrahydrofuran (10mL), and the mixture was stirred at 0 ℃ for 10 minutes and at room temperature for 40 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (5mL), then the product of preparation 46 (332mg, 0.70mmoL) and N, N-ethyldiisopropylamine (0.17mL, 1mmoL) were added and the mixture was stirred at 50 ℃ for 90 minutes. The reaction mixture was then cooled to room temperature, 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 give 614mg of the title compound as a yellow foam in quantitative yield.

Preparation example 170

N- [2- ({3-2- (benzyloxy) phenyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]-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 preparations 114 and 46 by the same method as described for preparation 169. The crude product obtained was purified by column chromatography on silica gel (eluting with dichloromethane: ethyl acetate, 100: 0 to 30: 70) to give the title compound as a white foam in 59% yield.

Preparation example 171

N- {1- [3- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } -N' - (2- { [3- (2-toluene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared from the products of preparation 63 and 206 using the same method as described for preparation 169. The crude compound obtained was subjected to column chromatography (eluting with ethyl acetate) using a cartridge containing 12g of silica to give 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 ] methyl ester]-1- (4-tolyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared from the products of preparation 85 and 109 using the same method as described for preparation 169. The crude compound obtained was purified by silica gel column chromatography (eluting with dichloromethane: methanol, 95: 5) to give the desired product in 33% yield.

Preparation example 173

N- {2- [ (3-isopropyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl } -N' - (3- [ 1-methyl) 1- (methylthio) ethyl radical]-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Benzene and its derivatives Radical } -1H-pyrazol-5-yl) urea

A mixture of the product from example 26 (89mg, 0.15mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (36mg, 0.17mmol) and potassium carbonate (28mg, 0.2mmol) in N, N-dimethylformamide (2mL) was stirred at room temperature for 18H and at 60 ℃ for 12H. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0 to 94: 6: 1) to give 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-l-ydrogen) -2H-pyran-2-yloxy) ethoxy]Phenyl } [1, 2, 4 ] group]Triazolo [4, 3-a]Pyridine compound -6-yl) thio]Benzyl urea

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

Preparation 175

N- (3-tert-butyl-1- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Phenyl } -1H-pyrazoles -5-yl) -N' - (2- { [3- (2-chlorophenyl) [1, 2, 4]Triazolo [4, 3-a]Pyridine- 6-yl]Thio } benzyl) urea

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

Preparation example 176

[5- (benzyloxy) -2-chlorophenyl group]Methanol

The title compound was prepared from the product of preparation 49 by the same method as described for preparation 26. The crude compound was triturated with ether to give the desired product as a white solid in 91% yield.

Preparation example 177

5- (benzyloxy) -2-chlorobenzaldehyde

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

Preparation examples 178 to 183

The following compounds of the formulae shown below were prepared by analogous methods to those described for preparation 30, using the product of preparation 25 and the appropriate commercially available aldehyde. For preparation 182, 4-benzyloxy-2-chlorobenzaldehyde starting material was prepared as described in j.chem.soc.perkin Trans 1990, (2), 253.

Numbering	Data of	Yield of
Numbering	Data of	Yield of	178	Z-2-ethyl	84％
179	Z-2-methyl	Quantification of	178	Z-2-ethyl	84％
179	Z-2-methyl	Quantification of	180	Z is 2- (methylthio)	89％
181	Z-2-chloro	98％	180	Z is 2- (methylthio)	89％
181	Z-2-chloro	98％	182	Z-2-chloro, 4-benzyloxy	89％
183	Z-2-benzyloxy, 5-chloro	94％	182	Z-2-chloro, 4-benzyloxy	89％

Preparation example 184

6-bromo-3- (2-ethylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 185

6-bromo-3- (2-chlorophenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

The title compound was prepared from the product of preparation 181 using the same method as described for preparation 184. The crude compound obtained was further purified by trituration with ethyl acetate to give the desired product in 73% yield.

Preparation example 186

6-bromo-3- [2- (methylthio) phenyl][11，2，4]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 187

6-bromo-3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

Cerium ammonium nitrate (35g, 63.76mmol) was added to a solution of the product of preparation 179 (9.25g, 31.88mmol) in ethanol (190mL) and dichloromethane (60mL), and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate (200mL) and water (100 mL). The organic solution was separated, washed with water (4 × 100mL) and dried over sodium sulfate, then concentrated in vacuo. The residue obtained was purified by column chromatography on silica gel (elution with pentane: ethyl acetate, 75: 25 and dichloromethane: ethanol, 50: 50 respectively) to yield 1.94g of the title compound in 21% yield.

Preparation example 188

6-bromo-3- (2-fluorophenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation 189

6-bromo-3- (2-methoxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 190

6-bromo-3- (2-chloro-3-methoxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation 191

3- [5- (benzyloxy) -2-chlorophenyl]6-bromo [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 192

3- [4- (benzyloxy) -2-chlorophenyl]6-bromo [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

A mixture of the product of preparation 182 (53.4g, 128mmol) and iodobenzene diacetate (41.3g, 128mmol) in dichloromethane (50mL) and ethyl acetate (50mL) was stirred at room temperature for 18 h. The resulting yellow precipitate was filtered off to give the first portion of the title compound. The resulting filtrate was then treated with dichloromethane (50mL) and ether (100mL) and the yellow precipitate formed was filtered off to give another portion of the title compound in 37.1g (70%) total yield.

Preparation example 193

3- [2- (benzyloxy) -5-chlorophenyl]6-bromo [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 194-

The following compounds of the general formula shown below were prepared from the appropriate starting materials and 2-mercaptobenzyl alcohol by a similar procedure as described in preparation 35.

Numbering	Data of	Yield of
Numbering	Data of	Yield of	194	R2-ethyl phenyl	75％
195	R2-tolyl radical	77％	194	R2-ethyl phenyl	75％
195	R2-tolyl radical	77％	196	R2- (methylthio) phenyl	48％
197	R2-fluorophenyl	67％	196	R2- (methylthio) phenyl	48％
197	R2-fluorophenyl	67％	198	R2-methoxyphenyl radical	61％
199	R2-chlorophenyl group	93％	198	R2-methoxyphenyl radical	61％
199	R2-chlorophenyl group	93％	200	R2-chloro-3-methoxyphenyl	91％

Numbering	Data of	Yield of
Numbering	Data of	Yield of	201	R2-chloro-4-benzyloxyphenyl	87％
202	R2-chloro-5-benzyloxyphenyl	71％	201	R2-chloro-4-benzyloxyphenyl	87％
202	R2-chloro-5-benzyloxyphenyl	71％	203	R2-benzyloxy-5-chlorophenyl	37％

Preparation example 195: the crude compound was purified by silica gel column chromatography eluting with ethyl acetate: dichloromethane, 50: 50, and dichloromethane: methanol, 95: 5, respectively.

Preparation example 196: the crude compound was purified by column chromatography on silica gel (eluting with dichloromethane: ethyl acetate, 40: 60 to 0: 100).

Preparation examples 197, 198 and 202: the crude compound was purified by trituration 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 (5g, 29mmol) was added to a solution of the product of preparation 194 (3.5g, 9.7mmol) and N, N-ethyldiisopropylamine (6.8mL, 38.8mmol) in dichloromethane (100mL) and the mixture was stirred at room temperature for 90 min. Then, 7M ammonia in methanol (140mL) was added, and the mixture was stirred at room temperature for 72 hours. Then, the reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in dichloromethane (200mL), then washed with sodium bicarbonate solution (2 × 200mL) and 2M hydrochloric acid (4 × 50 mL). The acidic washings were combined, basified to pH8 with 2M sodium hydroxide, and extracted with dichloromethane (3X 100 mL). The combined organic solutions were dried over sodium sulfate, concentrated in vacuo and the resulting residue redissolved in dichloromethane. The solution thus obtained was cooled in an ice bath and charged with hydrogen chloride gas until saturation occurred. The reaction mixture was concentrated in vacuo and the resulting residue was azeotroped with diethyl ether and dichloromethane to yield 1.66g 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

Methane sulfonic anhydride (4.99)g, 28.66mmol) were added to an ice-cooled solution of the product from preparation 199 (5.27g, 14.33mmol) and N, N-ethyldiisopropylamine (7.4mL, 42.99mmol) in dichloromethane (150mL) and the mixture was stirred at 0 ℃ for 10 min and at room temperature for 4 h. Then, 7M ammonia in methanol (143mL) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in dichloromethane (150mL) and washed with sodium bicarbonate solution (150mL) and 2M hydrochloric acid (3 × 70 mL). The acidic washes were combined, basified with 2M sodium hydroxide (250mL) and extracted with dichloromethane (4X 125 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.5) to give an orange foam. The foam was then dissolved in dichloromethane (15mL) and washed with hydrochloric acid (4M in dichloromethane @ 3.1mL in alkane). The mixture was azeotroped with methanol and dichloromethane and the resulting residue was triturated with ether to give 2.82g of the title compound as a white solid in 48% yield.

Preparation example 206

(2- { [3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) amines

Methanesulfonic anhydride (2.7g, 15.49mmol) was added to a solution of the product of preparation 195 (1.8g, 5.18mmol) and N, N-ethyldiisopropylamine (3.6mL, 20.72mmol) in dichloromethane (50mL) and the mixture was stirred at room temperature for 1 h. Then, 7M ammonia in methanol (140mL) was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then washed with sodium bicarbonate solution, brine and 2M hydrochloric acid (3 × 100 mL). The acidic washes were combined, basified with 2M sodium hydroxide to pH8, and extracted with dichloromethane (5 × 150 mL). The combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give 982mg of the title compound as an orange gum in 55% yield.

Preparation example 207

[2- ({3- [2- (methylthio) phenyl)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl ]Amines as pesticides

The title compound was prepared in 49% yield as a light orange foam from the product of preparation 196 using the same procedure as described for preparation 206.

Preparation example 208

[2- ({3- [2- (benzyloxy) -5-chlorophenyl)][1，2，4]Triazolo [4, 3-a]Pyridine-6- Thio) benzyl radical]Amines as pesticides

The title compound was prepared from the product of preparation 203 using the same method as described for preparation 206. The crude compound obtained 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 product as a pale brown gum in 52% yield.

Preparation example 209

6- { [2- (azidomethyl) phenyl]Thio } -3- (2-fluorophenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

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

Preparation example 210

6- { [2- (azidomethyl) phenyl]Thio } -3- (2-methoxyphenyl) [1, 2, 4 ]]- Triazolo [4, 3-a]Pyridine compound

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

Preparation example 211

6- { [2- (azidomethyl) phenyl]Thio } -3- (2-chloro-3-methoxyphenyl) [1, 2, 4 ]]Triazolo compounds [4，3-a]Pyridine compound

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

Preparation 212

6- { [2- (azidomethyl) phenyl]Thio } -3- [4- (benzyloxy) -2-chlorophenyl][1，2，4]Triazolo compounds [4，3-a]Pyridine compound

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

Preparation example 213

6- { [2- (azidomethyl) phenyl]Thio } -3- [5- (benzyloxy) -2-chlorophenyl][1，2，4]Triazolo compounds [4，3-a]Pyridine compound

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

Preparation example 214

(2- { [3- [ 2-fluorophenyl ] group][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) amine hydrochloride

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

Preparation 215

(2- { [3- (2-methoxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]- Thio } benzyl) amine hydrochloride

The title compound was prepared as a solid in 52% yield from the product of preparation 210 using the same method as described for 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 as a solid in 72% yield from the product of preparation 211 using the same method as described for preparation 214.

Preparation 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 as a solid in 64% yield from the product of preparation 212 using a similar method to that described for preparation 214.

Preparation 218

[2- ({3- [5- (benzyloxy) -2-chlorophenyl)][1，2，4]Triazolo [4, 3-a]Pyridine- 6-yl } thio) benzyl]Amines as pesticides

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

Preparation example 219

N- (3-tert-butyl-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Phenyl } -1H-pyrazoles -5-yl) -N' - (2- { [3- (2-fluorophenyl) [1, 2, 4]Triazolo [4, 3-a]Pyridine- 6-yl]Thio } benzyl) Urea

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

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]Pyridine- 6-yl]Thio } benzyl) urea

The title compound was prepared in 45% yield as a white foam from the products of preparation 205 and 116 using the same method as described for 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]Pyridine- 6-yl]Thio } benzyl) urea

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

Preparation 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 in 46% yield as a white foam from the products of preparation 215 and 116 using the same procedure as described for preparation 219.

Preparation example 223

N- {1- [3- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } -N' - (2- { [3- (2-chlorobenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

Preparation 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 as a white solid in 58% yield from the products of preparation 118 and 46 using the same method as described for preparation 219.

Preparation example 225

N- {1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } 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 groups]Benzyl urea

The title compound was prepared in 69% yield as a white foam from the products of preparation 120 and 43 using the same procedure as described for preparation 219.

Preparation example 226

N- {1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } phenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-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 48% yield as an off-white foam from the products of preparation 120 and 214 using the same procedure as described for preparation 219.

Preparation example 227

N- {1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } phenyl) -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 in 53% yield as a white foam from the products of preparation 120 and 215 using the same procedure as described for preparation 219.

Preparation example 228

N- {1- [3- (benzyloxy) phenyl]-3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Radical } -N' - (2- { [3- (2-ethylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared in 41% yield from the products of preparation 204 and 17 using the same procedure as described for preparation 121.

Preparation example 229

N- {1- [3- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } -N' - [2- ({3- [2- (methylthio) Phenyl radical][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl]Urea

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

Preparation example 230

N- {1- [4- (benzyloxy) phenyl]-3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Phenyl } -N' - (2- { [3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

Preparation example 231

N- [2- ({3- [4- (benzyloxy) -2-chlorophenyl)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]-N′- [ 3-tert-butyl-1- (3, 4-difluorophenyl) -1H-pyrazol-5-yl]Urea

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

Preparation example 232

N- [2- ({3- [5- (benzyloxy) -2-chlorophenyl)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]-N' - [ 3-tert-butyl-1- (3, 4-difluorophenyl) -1H-pyrazol-5-yl]Urea

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

Preparation example 234

6-bromo-3- (2-isopropylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine compound

The title compound was prepared from the product of preparation 25 and 2-isopropylbenzaldehyde by the same method as described in preparation 189. The crude compound obtained was purified by silica gel column chromatography (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]Pyridine-6-]Methanol

The title compound was prepared from the product of preparation 234 and 2-mercaptobenzyl alcohol by the same method as described for preparation 35. The crude compound obtained was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 95: 5) to give the desired product as a dark brown oil in 45% yield.

Preparation example 236

6- { [2- (azidomethyl) phenyl]Thio } -3- (2-isopropylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridine (II) Pyridine (I)

The title compound was prepared in 66% yield as a brown oil from the product of preparation 235 and diphenylphosphoryl azide using the same method as described in preparation 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 as a white solid in 80% yield from the product of preparation 236 using the same procedure as described for preparation 214.

Preparation 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 group]-1- {3- [2- (tetrahydro-2H-pyran-2-yloxy) - Ethoxy radical]Phenyl } -1H-pyrazol-5-yl) urea

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

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 in 45% yield as a white foam from the products of preparation 117 and 215 using the same procedure as described for preparation 238.

Preparation example 240

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

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

Preparation example 241

3- [ 5-amino-3- (1, 1-dimethylpropyl) -1H-pyrazol-1-yl]Phenol and its salts

The title compound was prepared in 49% yield as a yellow foam from the product of preparation 240 using the same procedure as described in example 99.

Preparation example 242

1- (3- { [ tert-butyl (dimethyl) silyl group]Oxy } phenyl) -3- (1, 1-dimethylpropyl) -1H- Pyrazole-5-amines

The title compound was prepared as a solid in 69% yield from the product of preparation 241 and tert-butyldimethylsilyl chloride using the same method as described in example 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]Pyridine- 6-yl } thio) benzyl]Urea

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

Preparation example 244

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

The title compound was prepared in pink powder in quantitative yield from 4, 4-dimethyl-3-oxopentanenitrile and 4-benzyloxyphenylhydrazine hydrochloride using the same procedure as described for preparation 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 the same manner as described in example 99 in a yield of 72% as a brown powder.

Preparation example 246

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

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

Preparation 247

[ 3-tert-butyl-1- (4- { [ tert-butyl (dimethyl) silyl) group ]Oxy } phenyl) -1H-pyrazol-5-yl]Ammonia Phenyl formate ester

The title compound was prepared in quantitative yield from the product of preparation 246 and phenyl chloroformate in the same manner as described in preparation 116.

Preparation example 248

N- [ 3-tert-butyl-1- (4- { [ tert-butyl (dimethyl) silyl)]Oxy } phenyl) -1H-pyrazole-5- Base of]-N' - (2- { [3- (2-fluorophenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) Urea

The title compound was prepared as a colorless glass in 93% yield from the products of preparation 214 and 247 by the same method as described for preparation 219.

Preparation example 249

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

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

Preparation example 250

6-bromo-3- [4- (methylthio) phenyl][1，2，4]Triazolo [4, 3-a]Pyridine compound

The title compound was prepared as a white solid in 72% yield from the product of preparation 249 using the same procedure as described for 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 in 58% yield as a white solid from the product of preparation 250 and 2-mercaptobenzyl alcohol using the same procedure as described for preparation 35.

Preparation example 252

[2- ({3- [ 4-methylthio ] methyl group]Phenyl } [1, 2, 4 ] group]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]- Benzyl radical]Amine hydrobromide salt

Thionyl bromide (235 μ L, 3.03mmol) was added to an ice-cooled solution of the product of preparation 251 (384mg, 1.01mmol) in dichloromethane (10mL) and the mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo, and the resulting residue was redissolved in dichloromethane. The solution was cooled to 0 ℃, 7M ammonia in methanol (15mL) was added dropwise, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with methanol: ethyl acetate, 20: 80 to 50: 50) to give 154mg of the title compound as a pale yellow solid in a yield of 40%.

Preparation example 253

N- {1- [3- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } -N' - [2- ({3- [4- (methylthio) Phenyl radical][1，2，4]Triazolo [4, 3-a ]Pyridin-6-yl } thio) benzyl]Urea

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

Preparation example 254

N- [2- ({3- [2- (benzyloxy) phenyl)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio group) Benzyl Base of]-N' - [ 3-tert-butyl-1- (3-fluorophenyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared from the products of preparation 62 and 46 using the same method as described for preparation 121. The crude compound obtained was triturated with ether to give the desired product as a solid in 85% yield.

Preparation example 255

N- (2- { [3- (2-isopropylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } - Benzyl Base) -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 in 48% yield as a white foam from the products of preparation 237 and 117 using the same method as described for preparation 219.

Preparation 256

N- {1- [4- (benzyloxy) phenyl]-3-tert-butyl-1H-pyrazol-5-yl } -N' - (2- { [3- (2-chlorobenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared as a foam in 74% yield from the products of preparation 103 and 205 using the same method as described for 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 256 using the same method as described for preparation 101. The crude compound obtained was further purified by trituration with diethyl ether 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) methyl ester [1，2，4]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl radical]Urea

The product of preparation 7 (0.13g, 0.50mmol) was added to a solution of N, N' -carbonyldiimidazole (0.49g, 3.00mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then diluted with brine and stirred vigorously for 15 minutes. The aqueous layer was separated and extracted with dichloromethane (3 × 15mL), the combined organics were dried over sodium sulfate and concentrated in vacuo. The product of preparation 43 (0.15g, 0.49mmol) was added to the residue obtained and N-ethyldiisopropylamine (65mg, 0.50mmol) in 1, 4-bis To the resulting solution in alkane (10mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with water (25mL) and brine (25mL), dried over sodium sulfate and concentrated in vacuo. The residue obtained is purified by chromatography on silica gel (dichloromethane: 7M ammonia in methanol, 100: 0 to 97.5: 2.5). The appropriate fractions were concentrated in vacuo and used a FlashmasterSilica column (eluted with dichloromethane: 7M ammonia in methanol, 100: 0 to 97.5: 2.5), the residue obtained being purerAnd converted twice to give the title compound.

¹H NMR(300MHz，CDCl₃)δ：1.20(d，6H)，1.40(s，9H)，2.29(s，3H)，3.15(m，1H)，4.50(d，2H)，6.30(s，1H)，6.72(d，1H)，6.80(d，2H)，7.05(d，2H)，7.21(m，5H)，7.48(d，1H)，7.65(s，1H)，8.15(s，1H)；LRMS：m/z API-ES 586.7[MH]⁺。

Examples 2 to 12

The compound represented by the following general formula was prepared from the product of preparation 43, N' -carbonyldiimidazole and appropriate pyrazole starting materials by a similar method to that described in example 1. The reaction was monitored by tlc analysis and stirred at room temperature for 20-48 hours.

Numbering	X	Y	Data of	Yield of
Numbering	X	Y	Data of	Yield of	2	SCH	H	¹H NMR (300MHz，CDCl)δ：1.30(m，15H)，2.25(s，3H)，3.15(m，1H)，4.55(d，2H)，6.32(s，1H)，6.75-7.30(m，8H)，7.45(d，1H)7.72(s，1H)，8.40(brs，1H)LRMS：m/z API-ES 586.7 [MH]	55％

3	Cl	Cl	¹H NMR (400MHz，CDCl)δ：1.28(m，15H)，3.14(m，1H)，4.55(d，2H)，6.33(s，1H)，6.87(d，1H)，6.99(d，1H)，7.09(d，1H)，7.23(m，1H)，7.28(m，3H)，7.40(m，1H)，7.45(d，1H)，7.54(s，1H)，7.68(s，1H)，8.79(bs，1H)LRMS：m/z APCI608[MH]	27％
3	Cl	Cl		27％	4	H	COCHCH	¹H NMR(400MHz，CDCl)δ：1.24-1.33(m，18H)，3.14(m，1H)，4.26(q，2H)，4.54(d，2H)，6.33(s，1H)，6.85(d，1H)，7.03(d，1H)，7.19(m，1H)，7.26(m，3H)，7.43(d，1H)，7.49(d，2H)，7.71(m，3H)，8.56(s，1H)LRMS：m/z APCI 612[MH]Micro-analysis: cHNOS.0.1dcm theoretical value (%): c64.10; h6.05; n15.81; found (%) C63.85; h6.14. N15.43.	46％
5	COCHCH	H	¹H NMR(400MHz，CDCl)δ：1.28(m，18H)，3.15(m，1H)，4.21(q，2H)，4.52(d，2H)，6.33(s，1H)，6.86(d，1H)，7.03(bs，1H)，7.12(d，1H)，7.16-7.27(m，4H)，7.40(d，1H)，7.59(d，1H)，7.66(d，1H)，7.71(s，1H)，8.08(s，1H)，8.31(s，1H)LRMS：m/zAPCI 612[MH]	24％	4	H	COCHCH		46％
5	COCHCH	H		24％	6	H	CN	¹H NMR (400MHz，CDCl)δ：1.29(m，15H)，3.17(m，1H)，4.55(d，2H)，6.30(s，1H)，6.94(d，1H)，7.13(d，1H)，7.24-7.33(m，4H)，7.40(m，2H)，7.45(d，1H)，7.65(d，2H)，7.74(s，1H)，8.64(s，1H)：LRMS：m/z APCI 565[MH]	52％

7	CN	H	¹H NMR (400MHz，CDOD)δ：1.31(s，9H)，1.41(d，6H)，3.46(m，1H)，4.50(d，2H)，6.27(s，1H)，7.20(d，1H)，7.25-7.39(m，4H)，7.58-7.64(m，2H)，7.71(d，1H)，7.81(d，1H)，7.87(s，1H)，8.31(s，1H)LRMS：m/z APCI 565[MH]	58％
7	CN	H		58％	8	H	H	¹H NMR(300MHz，DMSO-d)δ：1.21(s，9H)，1.35(d，6H)，3.55(m，1H)，4.40(d，2H)，6.25(s，1H)，7.10(d，1H)，7.20-7.30(m，4H)，7.35(m，1H)，7.50(m，4H)，7.65(s，1H)，7.70(d，1H)，8.30(s，1H)，8.60(s，1H)LRMS：m/z API-ES540.8[MH]	In quantitative terms
9	H	CH	¹H NMR(300MHz，DMSO-d)δ：1.25(s，9H)，1.40(d，6H)，2.27(s，3H)，3.55(m，1H)，4.40(d，2H)，6.20(s，1H)，7.00(m，1H)，7.10(d，1H)，7.20-7.40(m，8H)，7.65(d，1H)，8.20(s，1H)，8.56(s，1H)LRMS：m/zAPI-ES 554.8[MH]	71％	8	H	H		In quantitative terms

10	H	O-CH	¹H NMR(300MHz，CDCl)δ：1.30(s，9H)，1.36(d，6H)，3.16(m，1H)，3.68(s，3H)，4.54(d，2H)，6.27(s，1H)，6.42(m，1H)，6.66(d，2H)，6.85(d，1H)，7.17-7.31(m，7H)，7.38(d，1H)，7.70(s，1H)，LRMS：m/zAPI-ES 570.8[MH]	80％
10	H	O-CH		80％	11	CH	O-CH	¹H NMR(300MHz，CDCl)δ：1.30(s，9H)，1.38(d，6H)，2.05(s，3H)，3.20(m，1 H)，3.71(s，3H)，4.60(d，2H)，6.27(m，2H)，6.60(d，1H)，6.88(d，1H)，7.10(d，1H)，7.16(m，2H)，7.20-7.34(m，4H)，7.40(d，1H)，7.75(s，1H)，LRMS：m/zAPl-ES 584.6[MH]	49％

10	H	O-CH	¹H NMR(300MHz，CDCl)δ：1.30(s，9H)，1.36(d，6H)，3.16(m，1H)，3.68(s，3H)，4.54(d，2H)，6.27(s，1H)，6.42(m，1H)，6.66(d，2H)，6.85(d，1H)，7.17-7.31(m，7H)，7.38(d，1H)，7.70(s，1H)，LRMS：m/zAPI-ES 570.8[MH]	80％
10	H	O-CH		80％	12	O-CH	H	¹H NMR(300MHz，CDCl)δ：1.30(m，15H)，3.15(m，1H)，3.62(s，3H)，4.55(d，2H)，6.32(s，1H)，6.55(d，1H)，6.85-7.10(m，5H)，7.20-7.40(m，5H)，7.72(s，1H)，8.40(brs，1H)LRMS：m/z API-ES 570.8[MH]	88％

Example 3: the reaction was carried out in dichloromethane only. The purification was carried out by Biotage Silica column (elution with ethyl acetate).

Example 4: the reaction was carried out in dichloromethane. Purification by ISCO compensationSilica column (elution with pentane: ethyl acetate, 100: 0, 50: 50, 20: 80).

Example 5: purification is by ISCO companySilica column (elution with ethyl acetate).

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

Example 11: using a FlashmasterSilica column (eluting with ethyl acetate) and the crude product was further purified.

Example 13

N- [ 3-tert-butyl-1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-chloro-4-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared in 54% yield as a white foam from the products of preparation 21 and 45 using a similar method to example 1.

¹H NMR(300MHz，CDCl₃)δ：1.30(s，9H)，2.40(s，3H)，4.45(d，2H)，6.30(s，1H)，6.85(dd，1H)，7.00(d，1H)，7.15(d，1H)，7.20-7.32(m，10H)，7.40(d，1H)，7.65(s，1H)，7.70(d，1H)；LRMS：m/z API-ES 638.5[MH]⁺。

Example 14

N- [ 3-tert-butyl-1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-chloro-5-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(300MHz，DMSO-d₆)δ：1.25(s，9H)，2.30(s，3H)，4.35(d，2H)，6.20(s，1H)，6.95-7.10(m，3H)，7.20-7.40(m，9H)，7.45(d，1H)，7.85(d，1H)，7.99(s，1H)，8.20(s，1H)；LRMS：m/z API-ES 638.5[MH]⁺。

Example 15

N- {3- [1, 1-dimethyl-2- (methylthio) ethyl-1-phenyl-1H-pyrazol-5-yl]-N' - {2- [ (3-iso-methyl-) Propyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.29(s，6H)，1.34(d，6H)，1.97(s，3H)，2.77(s，2H)，3.55(m，1H)，4.40(d，2H)，6.29(s，1H)，7.02(t，1H)，7.10(d，1H)，7.26(m，4H)，7.38(t，1H)，7.46(m，4H)，7.70(d，1H)，8.35(s，1H)，8.60(s，1H)；LRMS：m/z APCI 586[MH]⁺(ii) a Micro-analysis: c₃₃H₃₅N₇OS₂·0.2H₂O, theoretical value (%): c63.17, H6.05, N16.63; found (%): c63.03, H6.00, N16.42.

Examples 16 to 20

The compound represented by the following general formula was prepared from the product of production example 43, N' -carbonyldiimidazole and an appropriate pyrazole starting material by a similar method to that described in example 15. The reaction was monitored by tlc analysis and stirred at room temperature for 0.5 to 18 hours.

Numbering	X	Y	n	Data of	Yield of
Numbering	X	Y	n	Data of	Yield of	16	H	CH	1：	¹H NMR(400MHz，DMSO-d)δ：1.28(s，6H)，1.34(d，6H)，1.96(s，3H)，2.34(s，3H)，2.76(s，2H)，3.55(m，1H)，4.39(d，2H)，6.26(s，1H)，7.00(t，1H)，7.10(d，1H)，7.23-7.33(m，8H)，7.69(d，1H)，8.27(s，1H)，8.60(s，1H)LRMS：m/z APCI 600[MH]Micro-analysis: cHNOSTheoretical value (%): c64.08; h6.22; n16.35; found (%) C63.79; h6.20, N16.14.	67％
17	H	H	0	¹H NMR(400MHz，DMSO-d)δ：1.33(d，6H)，1.57(s，6H)，1.89(s，3H)，3.55(m，1H)，4.40(d，2H)，6.36(s.1H)，7.06(m，1H)，7.10(d，1H)，7.26(d，4H)，7.40(m，1H)，7.48(m，4H)，7.70(d，1H)，8.38(s，1H)，8.60(s，1H)LRMS：m/z APCI 572[MH]Micro-analysis: cHNOSTheoretical value (%): c63.02; h5.82; n17.15; found (%) C62.75; h5.80, N17.09.	76％	16	H	CH	1：		67％

Numbering	X	Y	n	Data of	Yield of
Numbering	X	Y	n	Data of	Yield of	18	-OCHPh	H	0	¹H NMR(400MHz，CDCl)δ：1.37(d，6H)，1.68(s，6H)，1.95(s，3H)，3.17(m，1H)，4.58(d，2H)，4.98(s，2H)，6.15(bs，1H)，6.46(s，1H)，6.80(d，1H)，6.95(d，1H)，7.00(d，1H)，7.06(bs，1H)，7.09(t，1H)，7.17(t，1H)，7.23-7.37(m，9H)，7.46(s，1H)，7.72(s，1H)LRMS：m/zAPCI 678[MH]Micro-analysis: cHNOS.0.2HTheoretical value of O (%): c63.17; h6.05; n16.63; found (%) C63.03; h6.00, N16.42.	77％
19	H	Cl	0	¹H NMR(400MHz，CDCl)δ：1.38(d，6H)，1.65(s，6H)，1.98(s，3H)，3.18(m，1H)，4.61(d，2H)，6.48(s，1H)，7.00-7.65(m，13H)，m/zES 606[MH]CHClNOSTheoretical value (%): c59.44; h5.32; n16.17; found (%) C59.29; h5.19. N16.07.	58％	18	-OCHPh	H	0		77％

20

H

CF

0

¹H NMR(400MHz，CDCl)δ：1.35(d，6H)，1.65(s，6H)，1.98(s，3H)，3.15(m，1H)，4.62(d，2H)，6.49(s，1H)，7.20-7.65(m，13H)，m/z ES 640[MH]CHFNOS 0.4 HTheoretical value of O (%): c57.19; h4.86; n15.00; found (%) C57.55; h5.11, N15.15.

87％

Examples 21 to 23

The compound represented by the following general formula was prepared from the product of production example 46, N' -carbonyldiimidazole and an appropriate pyrazole starting material by a similar method to that described in example 15. The reaction was monitored by tlc analysis and stirred at room temperature for 0.5 to 18 hours.

Numbering	X	Y	Data of	Yield of
Numbering	X	Y	Data of	Yield of	21	H	H	¹H NMR(400MHz，CDCl)δ：1.66(d，6H)，1.34(s，3H)，4.51(d，2H)，5.02(s，2H)，6.20(bs.1H)，6.45(s，1H)，6.86(d，1H)，6.99(d，1H)，7.05(t，1H)，7.10-7.15(m，5H)，7.17-7.28(m，7H)，7.35-7.40(m，3H)，7.51-7.59(m，2H)，7.81(s，1H)，LRMS：m/z APCI712[MH]	82％

22	H	Cl	¹H NMR(400MHz，CDCl)δ：1.65(d，6H)，1.95(s，3H)，4.55(d，2H)，5.01(s，2H)，6.42(s，1H)，6.43(brs，1H)，6.90(brs，1H)，7.05-7.35(m，15H)，7.42-7.60(m，4H)，7.72(brs，1H)LRMS：m/z ESI 746[MH]	75％
22	H	Cl		75％	23	H	CF	¹H NMR(400MHz，CDCl)δ：1.65(d，6H)，1.95(s，3H)，4.55(d，2H)，4.97(s，2H)，6.49(s，1H)，6.71(d，1H)，6.82(d，1H)，6.91(brs，1H)，7.00(brs，1H)，7.01-7.32(m，10H)，7.40-7.58(m，4H)，7.68(s，1H)8.38(brs，1H)LRMS：m/z ESI 780[MH]	52％

Example 24

N- [ 3-tert-butyl-1- (3-hydroxyphenyl) -1H-pyrazol-5-yl]-N' - {2- [ (3-isopropyl [1, 2, 4 ]]III Azolo [4, 3-a ] s]Pyridin-6-yl) thio groups]Benzyl urea

A solution of the product of example 12 (0.26g, 0.45mmol) in dichloromethane (5.5mL) was cooled to 10 ℃, boron tribromide (1M in dichloromethane, 5.5mL, 5.50mmol) was added, and the mixture was stirred at room temperature for 18 hours. A solution of ethylenediamine (15% in water, 25mL) was added dropwise and the mixture was then acidified to pH1 with 6M hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate (3 × 20mL), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 96: 4 to 92: 8) followed by trituration with dichloromethane/ether to give 88mg of the title compound in 35% yield.

¹H NMR(300MHz，CDCl₃)δ：1.20(s，9H)，1.40(d，6H)，3.60(m，1H)，4.40(d，2H)，6.20(s，1H)，6.75(d，1H)，6.85(m，2H)，7.20(m，2H)，7.30(m，5H)，7.72(d，1H)，8.30(s，1H)，8.60(s，1H)，9.70(s，1H)；LRMS：m/z API-ES 556.8[MH]⁺。

Example 25

N- [ 3-tert-butyl-1- (4-hydroxy-3-methylphenyl) -1H-pyrazol-5-yl]-N' - {2- [ (3-isopropyl) methyl ester [1，2，4]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

The title compound was prepared from the product of example 11 using a similar method to example 24. Using a Flashmaster The crude compound obtained was purified on a silica column (eluted with dichloromethane: 7M ammonia in methanol, 100: 0 to 95: 5) to give the desired product in 84% yield.

¹H NMR(300MHz，DMSO-d₆)δ：1.20(s，9H)，1.35(d，6H)，2.14(s，3H)，3.55(m，1H)，4.60(d，2H)，6.20(s，1H)，6.80(d，1H)，6.95-7.05(m，2H)，7.10(m，2H)，7.20-7.34(m，4H)，7.70(d，1H)，8.10(s，1H)，8.60(s，1H)，9.60(bs，1H)；LRMS：m/z API-ES 570.6[MH]⁺。

Example 26

N- {1- (3-hydroxyphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Radical } -N' - {2- [ (3-isopropyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.34(d，6H)，1.57(s，6H)，1.88(s，3H)，3.56(m，1H)，4.41(d，2H)，6.34(s，1H)，6.79(d，1H)，6.88(m，2H)，7.10(m，2H)，7.23-7.30(m，5H)，7.70(d，1H)，8.35(s，1H)，8.60(s，1H)，9.79(s，1H)；LRMS：m/z APCI 588[MH]⁺。

Examples 27 to 29

The compounds represented by the following general formula were prepared by a similar method to that described in example 24, using the appropriate urea starting material. The reaction was monitored by tlc analysis and stirred at room temperature for 0.5 to 1.0 hours.

Numbering	X	Y	Data of
Numbering	X	Y	Data of	27	H	H	HRMS: m/z found: 622.2072, respectively; cHNOSTheoretical value 622.2053
28	H	Cl	HRMS: m/z found 656.1669; cHClNOSTheoretical value 656.1664	27	H	H
28	H	Cl	HRMS: m/z found 656.1669; cHClNOSTheoretical value 656.1664	29	H	CF	HRMS: m/z found 690.1927; cHFNOSTheoretical value 690.1927

Example 30

3- (3-tert-butyl-5- {3- [2- (3-isopropyl- [1, 2, 4)]Triazolo [4, 3-a]Pyridin-6-ylsulfanyl) - Benzyl radical]-ureido } -pyrazol-1-yl) -benzoic acid

The product of example 5 (68.5mg, 0.11mmol) and 2M sodium hydroxide solution (1mL) were added to sodium hydroxide solution (1mL) at 90 deg.CThe resulting mixture of alkane (2mL) was heated for 18 hours. Then, under reduced pressure, the solvent was evaporated and the resulting aqueous residue was diluted with water (10mL), acidified to pH3 with 1M hydrochloric acid and extracted with ethyl acetate (2 × 10 mL). The organic solution was dried over sodium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: acetic acid, 95: 5: 0.5). The relevant fractions were concentrated in vacuo and the resulting residue was dried in vacuo at 50 ℃ to give 16.8mg of the title compound in 27% yield.

¹H NMR(400MHz，CD₃OD)δ：1.31(s，9H)，1.41(d，6H)，3.48(m，1H)，4.49(s，2H)，6.28(s，1H)，7.19(d，1H)，7.23-7.31(m，3H)，7.37(d，1H)，7.52-7.65(m，3H)，8.02(d，1H)，8.11(s，1H)，8.27(s，1H)；LRMS：m/z APCI 582[MH]⁺(ii) a Micro-analysis: c₃₁H₃₃N₇O₃S · 0.55DCM, theoretical (%): c60.11, H5.45, N15.55; theoretical value (%): c59.76, H5.57, N15.42.

Example 31

4- (3-tert-butyl-5- { [ ({2- [ (3-isopropyl [1, 2, 4))]Triazolo [4, 3-a ]Pyridin-6-yl) thio groups] Benzyl Group } amino) carbonyl]Amino } -1H-pyrazol-1-yl) benzoic acid

The product of example 4 (130mg, 0.21mmol) was dissolved in 2M sodium hydroxide solution (1.5mL) at 90 ℃ in dichloromethaneThe resulting mixture of alkane (3mL) was heated for 16 hours. The mixture was then diluted with ethyl acetate (10mL) and extracted with sodium hydroxide solution (2X 5 mL). The aqueous solution was acidified to pH5 with 1M hydrochloric acid and extracted with ethyl acetate (2X 5 mL). The organic solution was dried over sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: acetic acid, 95: 5: 0.5 to 90: 10: 1). The relevant fractions were concentrated in vacuo and the resulting residue was azeotroped with toluene and dried under vacuum at 50 ℃ to give 7mg of the title compound in 6% yield.

¹H NMR(400MHz，CD₃OD)δ：1.31(s，9H)，1.41(d，6H)，3.47(m，1H)，4.50(s，2H)，6.28(s，1H)，7.20(d，1H)，7.24-7.39(m，4H)，7.53(d，2H)，7.59(d，1H)，8.09(d，2H)，8.27(s，1H)；LRMS：m/z ES 607[MNa]⁺。

Example 32

N- [ 3-tert-butyl-1- (4-hydroxyphenyl) -1H-pyrazol-5-yl]-N' - {2- [ (3-isopropyl [1, 2, 4 ]]III Azolo [4, 3-a ] s]Pyridin-6-yl) thio groups]Benzyl urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.24(s，9H)，1.35(d，6H)，3.56(m，1H)，4.41(d，2H)，6.22(s，1H)，6.85(d，2H)，7.03(m，1H)，7.12(dd，1H)，7.19-7.34(m，6H)，7.71(d，1H)，8.15(s，1H)，8.60(s，1H)，9.74(s，1H)；LRMS：m/z API-ES 556.4[MH]⁺。

Example 33

N- [ 3-tert-butyl-1- (3-chloro-4-methoxyphenyl) -1H-pyrazol-5-yl]-N' - {2- [ (3-isopropyl) methyl ester [1，2，4]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

The title compound was prepared from the products of preparations 94 and 43 using the same procedures as described for preparation 121. The crude compound obtained was purified by column chromatography on silica gel (eluted with dichloromethane: 7M ammonia in methanol, 100: 0 to 97.5: 2.5). Further purification was then carried out by reverse phase column chromatography (on C18 silica gel eluting with water/7M ammonia in methanol (98: 2) to acetonitrile/7M ammonia in methanol (98: 2) at 75: 25 to 25: 75) to give the title compound as a white solid in 22% yield.

¹H NMR(300MHz，CDCl₃)δ：1.25-1.47(m，15H)，3.15(m，1H)，3.79(s，3H)，4.55(d，2H)，6.30(s，1H)，6.67(d，1H)，6.81(m，2H)，7.07(m，1H)，7.17-7.31(m，4H)，7.36(m，1H)，7.42(m，1H)，7.66(s，1H)，7.94(m，1H)；LCMS m/z 604/606[M+H]⁺。

Example 34

N- (3-tert-butyl-1-pyridin-3-yl-1H-pyrazol-5-yl) -N' - {2- [ (3-isopropyl [1, 2, 4 ]]Triazole compounds And [4, 3-a ]]Pyridin-6-yl) thio groups]Benzyl urea

The title compound was prepared from the products of preparations 90 and 43 using a method analogous to that described for preparation 121. Column chromatography (using Biotage)Silica gel cartridge eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0 to 95: 5: 0.5) to purify the crude compound obtained. The residue obtained was further purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 90: 10) to give the desired product in 5% yield.

¹H NMR(400MHz，CD₃OD)δ：1.32(s，9H)，1.42(d，6H)，3.49(m，1H)，4.50(s，2H)，6.29(s，1H)，7.21(d，1H)，7.26-7.40(m，4H)，7.54(m，1H)，7.61(d，1H)，7.96(d，1H)，8.31(s，1H)，8.55(d，1H)，8.74(s，1H)；LRMS APCI m/z 541[M+H]⁺。

Example 35

N- [ 3-tert-butyl-1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-chloro-3-methoxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared from the products of preparation 21 and 216 using the same method as described for preparation 121. The crude compound obtained was triturated with ether to give the desired product as a solid in 56% yield.

¹H NMR(300MHz，CDCl₃)δ：1.29(s，9H)，2.27(s，3H)，3.96(s，3H)，4.51(d，2H)，5.79(s，1H)，6.24(s，1H)，6.58(s，1H)，6.97(m，1H)，7.07-7.38(m，10H)，7.41-7.49(m，1H)，7.52(m，1H)，7.70(s，1H)；LCMSm/z 652.6[M+H]⁺。

Example 36

N- [ 3-tert-butyl-1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-chloro-3-hydroxybenzene) Radical) [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 similar method to that described for example 72. The crude compound obtained was recrystallized from dichloromethane/methanol/ether to yield a solid in 23% yield.

¹H NMR(300MHz，DMSO-d₆)δ：1.29(s，9H)，2.34(s，3H)，4.35(d，2H)，6.21(m，1H)，6.95(m，1H)，7.11(m，1H)，7.20-7.36(m，11H)，7.88(m，1H)，8.01(m，1H)，8.22(m，1H)，10.67(s，1H)；LCMS m/z 638.6[M+H]⁺。

Example 37

N- {1- [3- (2-hydroxyethoxy) phenyl]-3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyridine Oxazole-5- Radical } -N' - {2- [ (3-isopropyl [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

P-toluenesulfonic acid (20mg) was added to a solution of preparation 173(72mg, 0.1mmol) in methanol (10mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 100: 0 to 90: 10) to give 62mg of the title compound as a white solid in 98% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.34(d，6H)，1.57(s，6H)，1.89(s，3H)，3.56(m，1H)，3.71(m，2H)，4.02(m，2H)，4.41(d，2H)，4.88(t，1H)，6.36(s，1H)，6.97(d，1H)，7.03(m，2H)，7.09(m，2H)，7.24(m，2H)，7.29(m，2H)，7.39(m，1H)，7.69(d，1H)，8.06(s，1H)，8.38(s，1H)；LRMS APCIm/z 632[M+H]⁺。

Examples 38 to 42

The compounds represented by the general formula shown below were prepared by a similar method to that described in example 37, using the appropriate starting materials and p-toluenesulfonic acid.

Example 43

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-fluorobenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹HNMR(400MHz，DMSO-d₆)δ：1.24(s，9H)，3.68(m，2H)，3.98(m，2H)，4.37(m，2H)，4.85(t，1H)，6.22(s，1H)，6.92(m，1H)，7.00-7.11(m，3H)，7.21-7.44(m，8H)，7.65(m，1H)，7.78(m，1H)，7.87(m，1H)，8.19(m，1H)，8.35(s，1H)；LCMS m/z 652.6[M+H]⁺。

Example 44

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazol-5-yl } -N' - (2- { [3- (2-iso) Propyl phenyl group)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl) urea

The title compound was prepared as a white solid in 66% yield from the product of preparation 221 using the same method as described for example 43.

¹HNMR(400MHz，DMSO-d₆)δ：1.07(d，6H)，1.24(s，9H)，2.75(m，1H)，3.68(m，2H)，4.00(m，2H)，4.35(m，2H)，4.86(t，1H)，6.21(s，1H)，6.90(m，1H)，7.01(m，3H)，7.16-7.36(m，7H)，7.47(m，1H)，7.58(m，2H)，7.86(m，2H)，8.31(s，1H)；LCMS m/z 676.2[M+H]⁺。

Example 45

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazol-5-yl } -N' - (2- { [3- (2-methyl) amide Oxyphenyl) [1, 2, 4]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.25(s，9H)，2.75(m，1H)，3.68-3.70(m，5H)，4.01(m，2H)，4.35(m，2H)，4.86(t，1H)，6.22(s，1H)，6.94(m，1H)，7.01(m，3H)，7.13-7.34(m，8H)，7.57(m，2H)，7.85(m，2H)，8.31(s，1H)；LCMS m/z 664.6[M+H]⁺。

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, 1mL, 1mmol) was added dropwise to an ice-cooled solution of the product of preparation 121 (186mg, 0.27mmol) in dichloromethane (10mL) and the mixture was stirred at 0 ℃ for 10 minutes. The reaction mixture was then diluted with dichloromethane (25mL) and water (25mL) and stirred for an additional 10 minutes at 0 ℃. 0.88 ammonia (5mL) was added and the aqueous layer was separated and extracted with dichloromethane (2X 25 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 100: 0 to 95: 5). The appropriate fractions were evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to yield 78mg of the title compound as a pale yellow solid in 48% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.23(s，9H)，4.35(d，2H)，6.23(s，1H)，6.96(m，1H)，7.00(t，1H)，7.05(d，1H)，7.04-7.55(m，7H)，7.43(m，1H)，7.48(dd，2H)，7.54(dd，1H)，7.83(d，1H)，8.05(s，1H)，8.28(s，1H)，10.44(s，1H)；LRMS APCI m/z 608[M+H]⁺。

Examples 47 to 69

The compounds represented by the general formulae below were prepared by a similar method to that described in example 46, using the appropriate starting materials and 4-6 equivalents of boron tribromide.

59	X ═ 3- (2-hydroxyethoxy), R2- (hydroxyphenyl)¹HNMR(400MHz，DMSO-d)δ：1.28(s，6H)，1.96(s，3H)，2.76(s，2H)，3.70(m，2H)，4.00(t，2H)，4.37(d，2H)，4.88(brs，1H)，6.28(s，1H)，6.94(d，1H)，7.02(m，5H)，7.19(m，3H)，7.27(m，2H)，7.37(m，1H)，7.43(m，1H)，7.54(d，1H)，7.84(d，1H)，8.06(s，1H)，8.37(s，1H)，10.47(brs，1H)；LRMSESI m/z696[M+H]	63％
59		63％	60	X＝H，R2- (hydroxyphenyl)¹HNMR(400MHz，DMSO-d)δ：1.39(s，6H)，2.00(s，3H)，2.83(s，2H)，4.56(d，2H)，6.35(s，1H)，6.85(brm，1H)，6.92(m，1H)，7.00(d，1H)，7.12-7.52(m，14H)，7.74(brm，1H)；LRMS ESI m/z636[M+H]	47％
61	X＝4-CH，R2- (hydroxyphenyl)¹HNMR(400MHz，DMSO-d)δ：1.39(s，6H)，2.00(s，3H)，2.18(s，3H)，2.84(s，2H)，4.56(d，2H)，6.35(s，1H)，6.87(brm，1H)，6.93(m，1H)，7.01-7.05(m，3H)，7.15(d，1H)，7.20-7.52(m，10H)，7.72(brm，1H)；LRMS ESIm/z 650[M+H]	49％	60		47％
61		49％	62	X＝4-F；R2- (hydroxyphenyl)¹HNMR(400MHz，CDOD)δ：1.37(s，6H)，1.99(s，3H)，2.82(s，2H)，4.49(s，2H)，6.31(s，1H)，7.01(m，2H)，7.15-7.49(m，10H)，7.55(d，1H)，7.71(d，1H)，7.82(s，1H)；LRMS APCI m/z654[M+H]	32％
63	X＝3-F；R2- (hydroxyphenyl)¹HNMR(400MHz，CDOD)δ：1.38(s，6H)，1.99(s，3H)，2.83(s，2H)，4.50(s，2H)，6.31(s，1H)，6.98(d，1H)，7.03(m，1H)，7.14(m，1H)，7.23-7.33(m，6H)，7.37(d，1H)，7.41-7.50(m，2H)，7.55(d，1H)，7.71(d，1H)，7.80(s，1H)；LRMSAPCI m/z 654[M+H]	34％	62		32％
63		34％	64	X＝3-F，4-F；R2- (hydroxyphenyl)¹HNMR(400MHz，CDCl)δ：1.38(s，6H)，1.99(s，3H)，2.79(s，2H)，4.50(s，2H)，6.22(s，1H)，6.97(m，2H)，7.15-7.28(m，6H)，7.30-7.41(m，5H)，7.45(d，1H)，7.55(m，1H)，7.78(m，1H)；LRMS APCI m/z 672[M+H]	19％
65	X＝3-OH；R＝CH(CH)¹HNMR(400MHz，DMSO-d)δ：1.28(s，6H)，1.34(d，6H)，1.96(s，3H)，2.76(s，2H)，3.56(m，1H)，4.40(d，2H)，6.26(s，1H)，6.77(d，1H)，6.87(m，2H)，7.04(m，1H)，7.11(d，1H)，7.24(m，2H)，7.30(m，3H)，7.70(d，1H)，8.32(s，1H)，8.60(s，1H)，9.76(s，1H)；LRMS APCI m/z 602[M+H]	53％	64		19％

59	X ═ 3- (2-hydroxyethoxy), R2- (hydroxyphenyl)¹HNMR(400MHz，DMSO-d)δ：1.28(s，6H)，1.96(s，3H)，2.76(s，2H)，3.70(m，2H)，4.00(t，2H)，4.37(d，2H)，4.88(brs，1H)，6.28(s，1H)，6.94(d，1H)，7.02(m，5H)，7.19(m，3H)，7.27(m，2H)，7.37(m，1H)，7.43(m，1H)，7.54(d，1H)，7.84(d，1H)，8.06(s，1H)，8.37(s，1H)，10.47(brs，1H)；LRMSESI m/z696[M+H]	63％
59		63％	66	X＝4-OH；R＝CH(CH)¹HNMR(400MHz，DMSO-d)δ：1.27(s，6H)，1.34(d，6H)，1.95(s，3H)，2.74(s，2H)，3.55(m，1H)，4.39(d，2H)，6.23(s，1H)，6.84(d，2H)，7.00(m，1H)，7.11(d，1H)，7.18(d，2H)，7.24(m，2H)，7.28(m，2H)，7.69(d，1H)，8.15(s，1H)，8.59(s，1H)，9.73(s，1H)；LRMS APCI m/z 602[M+H]	58％

^aThe crude compound was triturated with diethyl ether rather than recrystallised from ethyl acetate.

Example 48: the crude compound was further purified by trituration of the residue obtained by silica gel column chromatography (eluting with ethyl acetate: methanol, 100: 0 to 95: 5) followed by diethyl ether.

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-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The title compound was prepared in 75% yield from the product of preparation 167 using the same procedure as described for example 46.

¹H NMR(400MHz，CD₃OD)δ：1.32(s，9H)，4.48(s，2H)，6.30(s，1H)，7.01(m，2H)，7.24-7.37(m，5H)，7.44(m，1H)，7.54(m，2H)，7.71(d，1H)，7.84(s，1H)，7.97(d，1H)，8.52(d，1H)，8.73(s，1H)；LRMS APCI m/z591[M+H]⁺。

Example 71

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

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

¹H NMR(400MHz，DMSO-d₆)δ：1.25(s，9H)，4.46(s，2H)，6.49(s，1H)，7.00(m，1H)，7.23-7.30(m，5H)，7.40-7.45(m，2H)，7.54(d，1H)，7.83-7.86(m，2H)，7.94-8.00(m，1H)，8.05(m，1H)，8.11(s，1H)，8.35(m，1H)，10.45(s，1H)，10.99(s，1H)；LRMS APCI m/z 591[M+H]⁺。

Example 72

N- [ 3-tert-butyl-1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

Boron tribromide (1M in dichloromethane, 5.05mL, 5.05mmol) was added dropwise to a solution of the product of preparation 124 (0.18g, 0.25mmol) in dichloromethane (2mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with water (1.5mL) and stirring continued for an additional 10 minutes, followed by the addition of 1, 2-diaminoethane (1.5 mL). The mixture was then stirred vigorously and acidified to pH1 with 6M hydrochloric acid. The aqueous layer was separated and re-extracted with dichloromethane (5mL) and the combined organic solutions were dried over magnesium sulfate and then concentrated in vacuo. The resulting residue was recrystallized from dichloromethane: methanol (50: 50) to give the title compound as a white solid in 36% yield.

¹H NMR(300MHz，DMSO-d₆)δ：1.29(s，9H)，2.34(s，3H)，4.39(d，2H)，6.25(s，1H)，7.02-7.59(m，14H)，7.81-7.91(m，1H)，8.08(s，1H)，8.28(s，1H)，10.53(s，1H)；LCMS m/z 604.6[M+H]⁺。

Examples 73 to 79

The compounds represented by the general formulae below were prepared by a similar method to that described in example 72, using the appropriate starting materials and 4-6 equivalents of boron tribromide.

Example 73: the crude product was isolated by recrystallization from dichloromethane/methanol/diethyl ether and further purified.

Example 74: the crude product was purified by column chromatography on silica gel (eluting with methylene chloride: methanol, 98: 2 to 92: 8).

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

Example 78: the crude compound was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 97: 3 to 94: 6) followed by trituration with dichloromethane/methanol: ether (x 3).

Example 79: the crude compound was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 100: 0 to 95: 5).

Example 80

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.24(s，9H)，3.70(m，2H)，4.00(t，2H)，4.37(d，2H)，4.86(m，1H)，6.25(s，1H)，6.94(dd，1H)，7.03(m，5H)，7.19(m，3H)，7.26(d，2H)，7.36(t，1H)，7.54(d，1H)，7.83(d，1H)，8.06(s，1H)，8.32(s，1H)，10.45(s，1H)；LRMS APCI m/z 650[M+H]⁺。

Example 81

N- [ 3-tert-butyl-1- (3-hydroxyphenyl) -1H-pyrazol-5-yl]-N' - [2- ({3- [2- (2-Hydroxyethyl) ethyl ester Oxy) phenyl][1.2.4]Triazolo [4.3-a]Pyridin-6-yl } thio) benzyl]Urea

Boron tribromide (1M in dichloromethane, 1.3mL, 1.3mmol) was added to a solution of the product of preparation 174 (214mg, 0.26mmol) in dichloromethane (10mL) at-78 ℃ and the mixture was stirred at this temperature for 5 minutes. The reaction mixture was then stirred for a further 5 minutes, the temperature of which was raised to 0 ℃. The mixture was cooled again to-78 ℃, quenched with methanol (5mL) and allowed to warm to 25 ℃. The reaction mixture was then diluted with water and extracted with dichloromethane (3 × 40 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0 to 93: 7: 1). The appropriate fractions were evaporated under reduced pressure and the resulting residue recrystallized from ethyl acetate/methanol to give 79mg of the title compound as a solid in 47% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.23(s，9H)，3.52(m，2H)，4.06(t，2H)，4.36(d，2H)，4.72(t，1H)，6.22(s，1H)，6.76(d，1H)，6.88(m，2H)，7.01(t，1H)，7.14(t，1H)，7.17-7.28(m，7H)，7.58(m，2H)，7.82(d，1H)，8.12(s，1H)，8.28(s，1H)，9.73(s，1H)；LRMS APCI m/z 650[M+H]⁺。

Example 82

N- {1- (4-Ethylphenyl) -3- [ 1-methyl-1- (methylthio) ethyl ]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，CDCl₃)δ：1.19(t，3H)，1.57(s，6H)，1.88(s，3H)，2.64(q，2H)，4.37(d，2H)，6.34(s，1H)，7.03(m，3H)，7.18-7.37(m，9H)，7.43(m，1H)，7.54(d，1H)，8.06(s，1H)，8.32(s，1H)，10.46(s，1H)；LRMSAPCI m/z 650[M+H]⁺。

Example 83

N- {1- (3-Ethylphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -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 procedures as described for example 81. The crude compound obtained was recrystallized from ethyl acetate/dichloromethane to give the desired product as a solid in 52% yield.

¹H NMR(400MHz，CDCl₃)δ：1.17(t，3H)，1.57(s，6H)，1.89(s，3H)，2.64(q，2H)，4.37(d，2H)，6.35(s，1H)，7.01(m，3H)，7.05(d，1H)，7.19-7.29(m，8H)，7.39(m，1H)，7.44(d，1H)，7.54(d，1H)，8.06(s，1H)，8.33(s，1H)，10.45(s，1H)；LRMS APCI m/z 650 [M+H]⁺。

Example 84

N- (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl -N' - {1- (4-methoxy-3-tolyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Radical urea

The title compound was prepared from the product of preparation 159 using the same method as described for example 81. The crude compound obtained was triturated with ethyl acetate to give the desired product as a solid in 43% yield.

¹H NMR(400MHz，CDCl₃)δ：1.56(s，6H)，1.88(s，3H)，2.17(s，3H)，3.81(s，3H)，4.36(d，2H)，6.32(s，1H)，6.99-7.06(m，4H)，7.18-7.26(m，7H)，7.43(m，1H)，7.54(d，1H)，7.83(d，1H)，8.06(s，1H)，8.21(s，1H)，10.45(s，1H)；LRMS APCI m/z 666[M+H]⁺。

Example 85

N- {1- (3-chlorophenyl) -3- [ 1-methyl-1- (methylthio) ethyl ]-1H-pyrazole-5- Base } -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 154 using the same procedures as described for example 81. The crude compound obtained was triturated with ethyl acetate to give the desired product as a solid in 44% yield.

¹H NMR(400MHz，CDCl₃)δ：1.55(s，6H)，1.88(s，3H)，4.35(d，2H)，6.35(s，1H)，6.87-7.32(m，8H)，7.34-7.62(m，6H)，7.82(d，1H)，8.05(s，1H)，8.50(s，1H)，10.50(s，1H)；LRMS APCI m/z 608/610[M+H]⁺。

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 ] methyl ester]-1- (3-tolyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared from the product of preparation 165 using the same method as described for example 81. The crude compound obtained was triturated with methanol to give the desired product as a solid in 26% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.56(s，6H)，1.87(s，3H)，2.34(s，3H)，4.36(d，2H)，6.35(s，1H)，7.02(m，1H)，7.05(d，1H)，7.22(m，8H)，7.36(m，1H)，7.47(m，1H)，7.55(s，1H)，7.83(d，1H)，8.10(s，1H)，8.31(s，1H)，10.75(s，1H)；LRMS APCI m/z 60％10[M+H]⁺。

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 ] methyl ester]-1- (4-tolyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared from the product of preparation 166 using a similar method to that described for example 81. The crude compound obtained was triturated with ethyl acetate/methanol to give the desired product as a solid in 24% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.56(s，6H)，1.87(s，3H)，2.34(s，3H)，4.36(d，2H)，6.33(s，1H)，7.01(m，1H)，7.05(d，1H)，7.25(m，9H)，7.47(m，1H)，7.54(s，1H)，7.83(d，1H)，8.11(s，1H)，8.27(s，1H)，10.75(s，1H)；LRMS APCI m/z 60％10[M+H]⁺。

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 ] methyl ester]-1- (4-tolyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared from the product of preparation 149 using a similar method to that described for example 81. The crude compound obtained was triturated with ethyl acetate/methanol to give the desired product as a solid in 52% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.26(s，6H)，1.95(s，3H)，2.33(s，3H)，2.77(s，2H)，4.36(d，2H)，6.27(s，1H)，6.98(m，1H)，7.06(d，1H)，7.16-7.35(m，9H)，7.47(d，1H)，7.55(s，1H)，7.84(d，1H)，8.12(s，1H)，8.27(s，1H)，10.78(s，1H)；LRMS APCI m/z 684/686[M+H]⁺。

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

¹H NMR(400MHz，CDCl₃)δ：0.96(t，3H)，1.59(s，6H)，1.88(s，3H)，2.38(q，2H)，4.43(s，2H)，6.42-6.45(m，2H)，6.76(m，2H)，6.85(m，1H)，6.95(d，1H)，7.10-7.37(m，8H)，7.37(m，1H)，7.45(m，1H)，7.54(s，1H)，8.28(s，1H)；LRMS APCI m/z 650[M+H]⁺。

Example 90

N- {1- (4-hydroxyphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Phenyl } -N' - (2- { [3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，CD₃OD)δ：1.61(s，6H)，1.90(s，3H)，2.17(s，3H)，4.45(s，2H)，6.36(s，1H)，6.87(d，2H)，7.19-7.52(m，11H)，7.66(s，1H)，7.73(d，1H)；LRMS APCI m/z 636[M+H]⁺。

Example 91

N- {1- (3-hydroxyphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Phenyl } -N' - (2- { [3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，CDCl₃)δ：1.62(s，6H)，1.91(s，3H)，2.15(s，3H)，4.47(s，2H)，6.44(m，1H)，6.48(s，1H)，6.76(s，1H)，6.82(d，1H)，6.93(m，2H)，7.04(d，1H)，7.18(m，1H)，7.24-7.45(m，9H)，7.58(s，1H)，7.98(s，1H)；LRMS APCI m/z 636[M+H]⁺。

Example 92

N- {1- (3, 5-dimethylphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -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 similar method to that described for example 89. The crude compound obtained was triturated with ethyl acetate/methanol to give the title compound as a solid in 59% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.37(s，6H)，1.89(s，3H)，2.30(s，6H)，4.37(d，2H)，6.44(s，1H)，7.02(m，6H)，7.10(m，5H)，7.42(m，1H)，7.54(d，1H)，7.81(d，1H)，8.05(s，1H)，8.30(s，1H)，10.45(s，1H)；LRMSAPCI m/z 650[M+H]⁺。

Example 93

N- [ 3-tert-butyl-1- (3-hydroxyphenyl) -1H-pyrazol-5-yl ]-N' - [2- ({3- [2- (methylthio) Phenyl radical][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl]Urea

Boron tribromide (1M in dichloromethane, 0.74mL, 0.74mmol) was added dropwise to a solution of the product of preparation 229 (107mg, 0.15mmol) in dichloromethane (5mL) at-78 ℃, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was then quenched with a solution of ammonia in methanol (7M, 5mL) and allowed to warm to room temperature. The mixture was diluted with water and extracted with ethyl acetate, the organic solution was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 100: 0 to 90: 10) to give 64mg of the title compound as a yellow solid in 68% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.22(s，9H)，2.38(s，3H)，4.36(d，2H)，6.21(s，1H)，6.76(d，1H)，6.86(d，1H)，6.87(s，1H)，7.00(m，1H)，7.23-7.34(m，7H)，7.49-7.65(m，3H)，7.83(s，1H)，7.88(d，1H)，9.26(s，1H)，9.73(s，1H)；LRMS APCI m/z 636[M+H]⁺。

Example 94

N- {1- (4-fluorophenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.57(s，6H)，1.88(s，3H)，4.36(d，2H)，6.34(s，1H)，7.01(m，2H)，7.05(d，1H)，7.17-7.27(m，5H)，7.32(m，2H)，7.43(m，1H)，7.48-7.55(m，3H)，7.84(d，1H)，8.06(s，1H)，8.33(s，1H)，10.44(s，1H)；LRMS APCI m/z 640[M+H]⁺。

Example 95

N- {1- (3, 4-difluorophenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -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 by the same method as described in example 93. The crude compound obtained was further purified by HPLC (elution with acetonitrile: water/trifluoroacetic acid (5.95: 0.1) to acetonitrile, 100: 0 to 0: 100, using a Phenomenex Luna C18 system) to give the desired product in 3% yield.

¹H NMR(400MHz，CDCl₃)δ：1.65(s，6H)，1.94(s，3H)，4.52(d，2H)，6.40(s，1H)，6.80(d，1H)，6.91(m，1H)，7.00(s，1H)，7.12(m，1H)，7.19(m，1H)，7.25-7.42(m，9H)，7.61(m，2H)，8.71(s，1H)。

Example 96

N- {1- (3-fluorophenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

Boron tribromide (1M in dichloromethane, 0.85mL, 0.85mmol) was added dropwise to a solution of the product of preparation 153 (150mg, 0.21mmol) in dichloromethane (10mL) that had been cooled to-40 ℃, and at that temperature, the mixture was stirred for 20 minutes. The reaction mixture was then quenched with methanol (5mL), washed with water (30mL) and dichloromethane (30mL), and allowed to warm to room temperature. The mixture was basified with 0.88 ammonia (5mL) and extracted with dichloromethane (3X 30 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol, 100: 0 to 95: 5) to give 61mg of the title compound as a white solid in 45% yield.

¹H NMR(400MHz，DMSO-d₆)δ：1.58(s，6H)，1.89(s，3H)，4.36(d，2H)，6.37(s，1H)，7.00(m，1H)，7.04(m，2H)，7.18-7.27(m，6H)，7.36(m，2H)，7.43(m，1H)，7.53(m，2H)，7.83(d，1H)，8.06(s，1H)，8.44(s，1H)，10.44(s，1H)；LRMS APCI m/z 640[M+H]⁺。

Example 97

N- [ 3-tert-butyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

Boron tribromide (2M in dichloromethane, 0.63mL, 1.26mmol) was added dropwise to a solution of the product of preparation 138 (300mg, 0.42mmol) in dichloromethane (2.5mL) that had been cooled to-45 ℃ and at that temperature the mixture was stirred for 45 minutes. Then, boron tribromide (2M in dichloromethane, 0.63mL, 1.26mmol) was added again, and the mixture was stirred at-45 ℃ for 30 minutes. The reaction mixture was then quenched with dimethylamine (40% in water, 2mL) and allowed to warm to room temperature. The mixture was diluted with water (10mL) and dichloromethane (10mL) and the resulting biphasic system was acidified with 4M hydrochloric acid. The aqueous layer was separated and extracted with dichloromethane (3 × 10mL), and the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 100: 0 to 90: 10) followed by trituration with dichloromethane/ether to give 76.9mg of the title compound as a white solid in 29% yield.

¹H NMR(300MHz，DMSO-d₆)δ：1.24(s，9H)，3.77(s，3H)，4.37(d，2H)，6.21(s，1H)，6.91-7.04(m，5H)，7.17-7.41(m，8H)，7.51(dd，1H)，7.81(d，1H)，7.92(s，1H)，8.03(s，1H)，10.60(brs，1H)；LCMS APCI m/z620[M+H]⁺。

Example 98

N- [ 3-tert-butyl-1- (3-methoxyphenyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-hydroxybenzene) Radical) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(300MHz，DMSO-d₆)δ：1.25(s，9H)，3.76(s，3H)，4.37(d，2H)，6.24(s，1H)，6.90-7.06(m，6H)，7.18-7.25(m，5H)，7.32-7.45(m，2H)，7.53(d，1H)，7.82(s，1H)，8.04(s，1H)，8.33(s，1H)，10.40(brs，1H)；LCMS APCI m/z 620[M+H]⁺。

Example 99

N- [3- (1, 1-dimethylpropyl) -1- (4-tolyl) -1H-pyrazol-5-yl]-N' - (2- { [3- (2-hydroxy) Phenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

The product of preparation 141 (203mg, 0.29mmol) was suspended in hydrobromic acid (5.7M in glacial acetic acid, 4mL, 22.8mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was triturated with ether to give 144mg of the title compound as a white solid in 81% yield.

¹H NMR(400MHz，DMSO-d₆)δ：0.73(t，3H)，1.17(s，6H)，1.54(q，2H)，2.32(s，3H)，4.36(d，2H)，6.19(s，1H)，6.98-7.06(m，2H)，7.15-7.33(m，10H)，7.45(m，1H)，7.55(d，1H)，7.85(d，1H)，8.06(s，1H)，8.24(s，1H)，10.47(s，1H)；LRMS ESI m/z 618 [M+H]⁺。

Example 100

N- {3- (1, 1-dimethylpropyl) -1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-hydroxyphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(300MHz，DMSO-d₆)δ：0.76(t，3H)，1.20(s，6H)，1.56(q，2H)，3.70(s，2H)，4.01(t，2H)，4.37(d，2H)，4.86(s，1H)，6.21(s，1H)，6.94(m，1H)，7.05(m，5H)，7.23(m，5H)，7.38(m，2H)，7.53(dd，1H)，7.82(d，1H)，8.05(s，1H)，8.32(s，1H)，10.43(s，1H)；LCMS m/z 665[M+H]⁺。

Example 101

N- [ 3-tert-butyl-1- (3-fluorophenyl) -1H-pyrazol-5-yl]-N' - [2- ({3- [2- (2-hydroxyethoxy) ethoxy Radical) phenyl][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl]Urea

A mixture of the product from example 47 (100mg, 0.17mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (30. mu.L, 0.20mmol) and potassium carbonate (32mg, 0.25mmol) in N, N-dimethylformamide (3mL) was heated at 60 ℃ for 18H. An additional portion of 2- (2-bromoethoxy) tetrahydro-2H-pyran (15. mu.L, 0.10mmol) was added and the mixture was heated at 60 ℃ for 6 hours. The cooled reaction mixture was then diluted with ethyl acetate (20mL), washed with water (10mL) and brine (10mL), dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dissolved in methanol (3mL), p-toluenesulfonic acid (20mg) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate (20mL), washed with water (3 × 10mL), dried over magnesium sulfate, and concentrated in vacuo. The residue obtained is purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 95: 5 to 92: 8). The resulting residue was further purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 97.5: 2.5 to 95: 5) to give 24.5mg of the title compound as a solid in 23% yield.

¹H NMR(400MHz，CDCl₃)δ：1.24(s，9H)，3.70(m，2H)，4.01(m，2H)，4.37(d，2H)，6.25(s，1H)，6.68(m，1H)，6.92(m，2H)，7.00-7.07(m，5H)，7.15(m，1H)，7.20-7.39(m，4H)，7.53(m，2H)，7.71(m，1H)，7.79(s，1H)。

Example 102

N- (2- { [3- (2-ethylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl Radical) -N' - {1- [3- (2-hydroxyethoxy) phenyl]-3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazoles -5-yl } urea

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

¹H NMR(400MHz，CDCl₃)δ：1.01(t，3H)，1.63(s，6H)，1.92(s，3H)，2.44(q，2H)，3.72(m，2H)，3.86(m，2H)，4.46(d，2H)，6.47(s，1H)，6.58(d，1H)，6.90-7.36(m，13H)，7.41(d，1H)，7.49(d，1H)，7.49(t，1H)，7.64(s，1H)，8.03(s，1H)；LRMS APCI m/z 695[M+H]⁺。

Example 103

N- [2- ({3- [2- (2-hydroxyethoxy) phenyl][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl sulfur Radical) benzyl radical]-N' - [3- [ 1-methyl-1- (methylthio) ethyl group]-1- (4-tolyl) -1H-pyrazol-5-yl]Urea

The title compound was prepared in 34% yield from the product of preparation 172 using a similar method to that described for example 101.

¹H NMR(400MHz，CDCl₃)δ：1.57(s，6H)，1.89(s，3H)，2.34(q，2H)，3.52(m，2H)，4.06(m，2H)，4.36(d，2H)，4.70(m，1H)，6.33(s，1H)，6.99(m，1H)，7.10-7.34(m，11H)，7.58(m，2H)，7.81(d，1H)，8.10(s，1H)，8.25(s，1H)；LRMS APCI m/z 681[M+H]⁺。

Example 104

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazole-5- Radical } -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 (360mg, 1mmol) in dimethylsulfoxide (5mL) was added to a solution of the product of preparation 116 (490mg, 1mmol) and the mixture was stirred at room temperature for 18 hours and further at 50 ℃ for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (10mL) and washed with 1M hydrochloric acid (1mL), water (10mL), 1M sodium hydroxide (10mL) and brine (10 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in methanol (5mL), p-toluenesulfonic acid (100mg) was added, and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in dichloromethane (30mL) and washed with water (2 × 10 mL). The resulting organic solution was dried over magnesium sulfate, concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with ethyl acetate: methanol, 95: 5) to give 208.3mg of the title compound in 31% yield.

¹H NMR(400MHz，CDCl₃)δ：1.07(t，3H)，1.31(s，9H)，2.52(q，2H)，3.84(t，2H)，4.01(t，2H)，4.53(d，2H)，6.13(brs，1H)，6.33(s，1H)，6.75(d，1H)，7.01(m，3H)，7.21(m，3H)，7.26(m，3H)，7.36(m，3H)，7.45(d，1H)，7.52(m，1H)，7.57(d，1H)，7.71(s，1H)；LRMS APCI m/z 662 [M+H]⁺。

Example 105

N- { 3-tert-butyl-1- [3- (2-hydroxyethoxy) phenyl]-1H-pyrazole-5- Phenyl } -N' - (2- { [3- (2-tolyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) urea

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

¹H NMR(400MHz，CDCl₃)δ：1.31(s，9H)，2.21(s，3H)，3.83(m，2H)，3.98(m，2H)，4.53(d，2H)，6.18(brs，1H)，6.33(s，1H)，6.72(d，1H)，7.00(m，3H)，7.09(brs，1H)，7.20(m，3H)，7.35(m，6H)，7.45(d，1H)，7.52(d，1H)，7.71(s，1H)；LRMS APCI m/z 648[M+H]⁺。

Example 106

N- { 3-tert-butyl-1- [4- (hydroxymethyl) phenyl]-1H-pyrazol-5-yl } -N' - {2- [ (3-isopropyl) methyl ester [1，2，4]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

Tetraethylammonium fluoride dihydrate (60mg, 0.40mmol) was added to a solution of the product of preparation 136 (200mg, 0.29mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 6 hours. Then, another portion of tetraethylammonium fluoride dihydrate (60mg, 0.32mmol) was added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between 1M hydrochloric acid (20mL) and dichloromethane (20 mL). The aqueous layer was separated and extracted with dichloromethane (5 × 20mL), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by column chromatography on silica gel (eluting with dichloromethane: methanol, 99: 1 to 92.5: 7.5) followed by trituration with dichloromethane/ether to give 68.8 mg of the title compound as a solid in 41% yield.

¹H NMR(300MHz，CDCl₃)δ：1.27(s，9H)，1.29(d，6H)，3.18(m，1H)，4.33(s，2H)，4.46(d，2H)，4.69(brs，1H)，6.30(s，1H)，6.87(d，1H)，6.95(d，2H)，7.07-7.25(m，7H)，7.36(d，1H)，7.74(s，1H)，8.04(s，1H)；LCMR m/z 570[M+H]⁺。

Example 107

N- {1- (3-hydroxyphenyl) -3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazole-5- Base } -N' - (2- { [3- (2-methoxyphenyl) [1.2.4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl) Urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.58(s，6H)，1.89(s，3H)，3.69(s，3H)，4.38(d，2H)，6.32(s，1H)，6.77(dd，1H)，6.86(m，2H)，7.05(m，1H)，7.22(m，8H)，7.56(m，2H)，7.84(m，2H)，8.32(s，1H)，9.77(s，1H)；LCMSm/z 652 [M+H]⁺。

Example 108

N- [ 3-tert-butyl-1- (3-hydroxy-4-methylphenyl) -1H-pyrazol-5-yl]-N' - {2- [ (3-isopropyl) methyl ester [1，2，4]Triazolo [4, 3-a]Pyridin-6-yl) thio groups]Benzyl urea

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

¹H NMR(300MHz，DMSO-d₆)δ：1.24(s，9H)，1.37(d，6H)，2.15(s，3H)，3.38(m，1H)，4.42(d，2H)，6.19(s，1H)，6.74(d，1H)，6.89(s，1H)，7.10-7.13(m，2H)，7.25-7.33(m，4H)，7.47(m，1H)，7.88(m，2H)，8.30(s，1H)，8.80(s，1H)；LCMS m/z 570.6[M+H]⁺。

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 ester]-1H-pyrazol-5-yl } urea

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

¹H NMR(300 MHz，DMSO-d₆)δ：1.56(s，6H)，1.88(s，3H)，4.36(d，2H)，6.30(s，1H)，6.83(d，2H)，7.00(m，1H)，7.23(m，7H)，7.44(m，2H)，7.66(m，1H)，7.77(m，1H)，7.86(d，1H)，8.16(d，2H)，9.72(s，1H)；LCMSm/z 640 [M+H]⁺。

Example 110

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

¹H NMR(300MHz，DMSO-d₆)δ：1.24(s，9H)，1.38(d，6H)，3.58(m，1H)，4.41(d，2H)，6.23(s，1H)，6.74(m，1H)，6.87(m，2H)，7.01-7.17(m，2H)，7.20-7.29(m，5H)，7.67(m，1H)，8.28(m，1H)，8.58(m，1H)，9.72(s，1H)；LCMS m/z 632.6[M+H]⁺。

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 in 53% yield as a white solid from the product of preparation 226 using a similar method to that described for example 108.

¹H NMR(300MHz，DMSO-d₆)δ：1.57(s，6H)，1.89(s，3H)，4.38(d，2H)，6.32(s，1H)，6.78(dd，1H)，6.86(m，2H)，7.05(m，1H)，7.28(m，6H)，7.44(m，2H)，7.67(m，1H)，7.77(m，1H)，7.87(d，1H)，8.20(m，1H)，8.31(s，1H)，9.77(s，1H)；LCMS m/z 640[M+H]⁺。

Example 112

N- [3- (1, 1-dimethylpropyl) -1- (3-hydroxyphenyl) -1H-pyrazole-5- Base of]-N' - [2- ({3- [2- (methylthio) phenyl)][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl Base of]Urea

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

¹H NMR(300MHz，DMSO-d₆)δ：0.75(t，3H)，1.19(s，6H)，1.57(q，2H)，2.40(s，3H)，4.38(d，2H)，6.20(s，1H)，6.76(d，1H)，6.87(m，2H)，7.03(m，1H)，7.24-7.37(m，6H)，7.55(m，2H)，7.61(m，1H)，7.85-7.92(m，2H)，8.30(m，2H)，9.77(s，1H)；LCMS m/z 650[M+H]⁺。

Example 113

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

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

¹H NMR(300MHz，DMSO-d₆)δ：1.23(s，9H)，4.37(d，2H)，6.14(s，1H)，6.85(d，2H)，7.18-7.30(m，8H)，7.39-7.49(m，2H)，7.68(m，1H)，7.76-7.87(m，2H)，8.19(s，1H)，8.38(s，1H)，9.87(s，1H)；LCMS m/z 608[M+H]⁺。

Example 114

N- [ 3-tert-butyl-1- (3-hydroxyphenyl) -1H-pyrazol-5-yl]-N' - [2- ({3- [4- (methylthio) Phenyl radical][1，2，4]Triazolo [4, 3-a]Pyridin-6-yl } thio) benzyl]Urea

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

¹H NMR(400MHz，DMSO-d₆)δ：1.21(s，9H)，2.53(s，3H)，4.40(d，2H)，6.21(s，1H)，6.75(d，1H)，6.85(d，1H)，6.88(s，1H)，7.02(m，1H)，7.20(d，1H)，7.25(m，2H)，7.31(m，3H)，7.43(d，2H)，7.81(d，2H)，7.83(d，1H)，8.27(s，1H)，8.37(s，1H)，9.73(s，1H)；LRMS APCI m/z 636[M+H]⁺。

Example 115

N- {1- [3- (2-hydroxyethoxy) phenyl]-3- [ 1-methyl-1- (methylthio) ethyl]-1H-pyrazoles -5-yl } -N' - (2- { [3- (2-isopropylphenyl) [1, 2, 4 ]]Triazolo [4, 3-a]Pyridin-6-yl]Thio } benzyl Yl) urea

P-toluenesulfonic acid (63mg, 3.3mmol) was added to a solution of the product of preparation 255 (262mg, 3.3mmol) in methanol (15mL), and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted with water, basified with sodium bicarbonate solution, and the precipitate so produced was filtered off to give the title compound as a white solid in 76% yield.

¹H NMR(300MHz，DMSO-d₆)δ：1.09(d，6H)，1.57(s，6H)，1.89(s，3H)，2.75(m，1H)，3.69(s，2H)，4.40(d，2H)，4.34(d，2H)，4.88(brs，1H)，6.31(s，1H)，6.93(dd，1H)，7.03(m，2H)，7.26(m，8H)，7.46(d，1H)，7.56(d，2H)，7.83(d，2H)，8.63(s，1H)；LCMS m/z 708[M+H]⁺。

The following compounds were prepared by methods analogous to those described above.

Example numbering	Definition of	LCMS m/z[M+H]
Example numbering	Definition of	LCMS m/z[M+H]	116	A＝C(CH)；X＝4-CH；R2-benzyloxyphenyl	694.6
117	A＝(CHS)C(CH)；X＝3-CF；R＝CH(CH)	640	116	A＝C(CH)；X＝4-CH；R2-benzyloxyphenyl	694.6
117	A＝(CHS)C(CH)；X＝3-CF；R＝CH(CH)	640	118	A＝C(CH)；X＝4-C(O)NHCH；R＝CH(CH)	597.2747

Practice ofExample number	Definition of	LCMS m/z[M+H]
Practice ofExample number	Definition of	LCMS m/z[M+H]	119	A＝C(CH)；X＝3-F，4-F；R2-chloro-3-methoxyphenyl	674.6
120	A＝C(CH)；X＝3-Cl，4-Cl；R2-benzyloxyphenyl	748	119	A＝C(CH)；X＝3-F，4-F；R2-chloro-3-methoxyphenyl	674.6
120	A＝C(CH)；X＝3-Cl，4-Cl；R2-benzyloxyphenyl	748	121	A＝C(CH)；X＝3-CN；R2-benzyloxyphenyl	705
122	A＝C(CH)；X＝4-CN；R2-benzyloxyphenyl	705	121	A＝C(CH)；X＝3-CN；R2-benzyloxyphenyl	705
122	A＝C(CH)；X＝4-CN；R2-benzyloxyphenyl	705	123	A＝C(CH)；X＝3-F；R2-benzyloxyphenyl	698
124	A＝C(CH)(ii) a X is 3-benzyloxy, 5-CH；R＝CH(CH)	660.6	123	A＝C(CH)；X＝3-F；R2-benzyloxyphenyl	698
124	A＝C(CH)(ii) a X is 3-benzyloxy, 5-CH；R＝CH(CH)	660.6	125	A＝(CHS)C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r＝CH(CH)	632
126	A＝(CHS)C(CH)；X＝4-Br；R＝CH(CH)	652	125	A＝(CHS)C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r＝CH(CH)	632
126	A＝(CHS)C(CH)；X＝4-Br；R＝CH(CH)	652	127	A＝(CHS)C(CH)；X＝3-Br；R＝	652

	CH(CH)
	CH(CH)		128	A＝C(CH)；X＝3-F，4-F；R2-chloro-3-hydroxyphenyl;	660.5
129	A＝C(CH)；X＝3-CHCH，4-OCH；R＝CH(CH)	598.6	128	A＝C(CH)；X＝3-F，4-F；R2-chloro-3-hydroxyphenyl;	660.5

	CH(CH)
	CH(CH)		130	A＝C(CH)；X＝3-OCH，4-CHCH；R＝CH(CH)	598.6
131	A＝C(CH)；X＝3-OH，5-CHCH；R＝CH(CH)	584.6	130	A＝C(CH)；X＝3-OCH，4-CHCH；R＝CH(CH)	598.6
131	A＝C(CH)；X＝3-OH，5-CHCH；R＝CH(CH)	584.6	132	A＝(CHS)C(CH)；X＝4-OH；R2-ethylphenyl;	650.2364
133	A＝(CHS)C(CH)；X＝4-OH；R＝CH(CH)	588	132	A＝(CHS)C(CH)；X＝4-OH；R2-ethylphenyl;	650.2364
133	A＝(CHS)C(CH)；X＝4-OH；R＝CH(CH)	588	134	A＝(CHS)C(CH)；X＝4-Br；R2-hydroxyphenyl group	700
135	A＝C(CH)；X＝3-OCH，4-Cl；R＝CH(CH)	604.6	134	A＝(CHS)C(CH)；X＝4-Br；R2-hydroxyphenyl group	700
135	A＝C(CH)；X＝3-OCH，4-Cl；R＝CH(CH)	604.6	136	A＝(CHS)C(CH)；X＝3-CH，5-CH；R＝CH(CH)	600
137	A＝(CHS)C(CH)；X＝4-CHCH；R＝CH(CH)	600	136	A＝(CHS)C(CH)；X＝3-CH，5-CH；R＝CH(CH)	600
137	A＝(CHS)C(CH)；X＝4-CHCH；R＝CH(CH)	600	138	A＝C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-methoxyphenyl group	664.5
139	A＝C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-isopropylphenyl	676.6	138		664.5
139	A＝C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-isopropylphenyl	676.6	140	A＝(CHS)C(CH)；X＝4-OH；R2-methoxyphenyl group	652.6
141	A＝C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-fluorophenyl	652.6	140	A＝(CHS)C(CH)；X＝4-OH；R2-methoxyphenyl group	652.6

	CH(CH)
	CH(CH)		142	A＝(CHS)C(CH)；X＝4-OH；R2-isopropylphenyl	664.6
143	A＝C(CH)；X＝4-OH：R2-methoxyphenyl group	620.6	142	A＝(CHS)C(CH)；X＝4-OH；R2-isopropylphenyl	664.6
143	A＝C(CH)；X＝4-OH：R2-methoxyphenyl group	620.6	144	A＝C(CH)；X＝4-OH；R2-isopropylphenyl	632.6

145	A＝C(CH)；X＝3-OH；R2-methoxyphenyl group	620.6
145	A＝C(CH)；X＝3-OH；R2-methoxyphenyl group	620.6	146	A＝(CHS)C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-fluorophenyl	684.4
147	A＝(CHS)C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-methoxyphenyl group	696.5	146		684.4
147		696.5	148	A＝C(CH)；X＝3-OH；R2-fluorophenyl	608.6
149	A＝(CHS)C(CH)(ii) a X ═ 4- (2-hydroxyethoxy); r2-isopropylphenyl	708.6	148	A＝C(CH)；X＝3-OH；R2-fluorophenyl	608.6
149		708.6	150	A＝(CHS)C(CH)；X＝3-OH；R2-isopropylphenyl	664.6
151	A＝(CHS)C(CH)；X＝3-CH；R2-hydroxy-4-tolyl radical	650	150	A＝(CHS)C(CH)；X＝3-OH；R2-isopropylphenyl	664.6
151	A＝(CHS)C(CH)；X＝3-CH；R2-hydroxy-4-tolyl radical	650	152	A＝(CHS)C(CH)；X＝3-CH；R2-hydroxy-3-chlorophenyl	669
153	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-3-chlorophenyl	Micro-analysis found: c, 60.69; h, 4.82; n, 14.27.CHClNOSTheoretical value C, 60.93; h, 4.81; n, 14.63 percent.	152	A＝(CHS)C(CH)；X＝3-CH；R2-hydroxy-3-chlorophenyl	669
153	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-3-chlorophenyl		154	A＝(CHCH)C(CH)；X＝H；R2-hydroxyphenyl group	604.6

145	A＝C(CH)；X＝3-OH；R2-methoxyphenyl group	620.6
145	A＝C(CH)；X＝3-OH；R2-methoxyphenyl group	620.6	155	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-4-tolyl radical	650
156	A＝C(CH)；X＝4-F；R2-hydroxy-4-tolyl radical	622	155	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-4-tolyl radical	650
156	A＝C(CH)；X＝4-F；R2-hydroxy-4-tolyl radical	622	157	A＝C(CH)；X＝3-F；R2-hydroxy-4-tolyl radical	622
158	A＝(CHCH)C(CH)；X＝3-Cl；R＝CH(CH)	570.6	157	A＝C(CH)；X＝3-F；R2-hydroxy-4-tolyl radical	622
158	A＝(CHCH)C(CH)；X＝3-Cl；R＝CH(CH)	570.6	159	A＝C(CH)；X＝4-OH；R2-chlorophenyl group	624
160	A＝C(CH)(ii) a X ═ 3- (2-hydroxyethoxy); r＝CH(CH)	600	159	A＝C(CH)；X＝4-OH；R2-chlorophenyl group	624
160	A＝C(CH)(ii) a X ═ 3- (2-hydroxyethoxy); r＝CH(CH)	600	161	A＝C(CH)；X＝3-CH；R2-hydroxy-3-chloro-phenyl	638,640
162	A＝(CHCH)C(CH)；X＝3-Cl，4-OH；R＝CH(CH)	604.6	161	A＝C(CH)；X＝3-CH；R2-hydroxy-3-chloro-phenyl	638,640

163	A＝(CHCH)C(CH)；X＝3-F；R2-hydroxyphenyl group	622.6
163	A＝(CHCH)C(CH)；X＝3-F；R2-hydroxyphenyl group	622.6	164	A＝(CHS)C(CH)；X＝4-OH；R2-chlorophenyl group	656
165	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxyphenyl group	637	164	A＝(CHS)C(CH)；X＝4-OH；R2-chlorophenyl group	656
165	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxyphenyl group	637	166	A＝(CHSCH)C(CH)；X＝3-CH；R2-hydroxyphenyl group	650
167	A＝C(CH)；X＝3-CH；R2-hydroxyphenyl group	604	166	A＝(CHSCH)C(CH)；X＝3-CH；R2-hydroxyphenyl group	650

163	A＝(CHCH)C(CH)；X＝3-F；R2-hydroxyphenyl group	622.6
163	A＝(CHCH)C(CH)；X＝3-F；R2-hydroxyphenyl group	622.6	168	A＝C(CH)；X＝4-OH；R2-hydroxyphenyl group	606
169	A＝C(CH)；X＝H；R4-carboxyphenyl radical	616	168	A＝C(CH)；X＝4-OH；R2-hydroxyphenyl group	606
169	A＝C(CH)；X＝H；R4-carboxyphenyl radical	616	170	A＝C(CH)；X＝4-CH；R3-chloro-5-fluoro-2-hydroxyphenyl	656.1997
171	A＝(CHSCH)C(CH)；X＝3-CN；R2-hydroxyphenyl group	661	170	A＝C(CH)；X＝4-CH；R3-chloro-5-fluoro-2-hydroxyphenyl	656.1997
171	A＝(CHSCH)C(CH)；X＝3-CN；R2-hydroxyphenyl group	661	172	A＝(CHSCH)C(CH)；X＝4-CN；R2-hydroxyphenyl group	661
173	A＝C(CH)；X＝4-OH；R3- (2-hydroxyethoxy) phenyl	650	172	A＝(CHSCH)C(CH)；X＝4-CN；R2-hydroxyphenyl group	661
173	A＝C(CH)；X＝4-OH；R3- (2-hydroxyethoxy) phenyl	650	174	A＝C(CH)；X＝4-CH；R3-chloro-5-fluoro-4-hydroxyphenyl	656
175	A＝C(CH)(ii) a X ═ 3-carboxymethoxy; (ii) a R＝CH(CH)	614	174	A＝C(CH)；X＝4-CH；R3-chloro-5-fluoro-4-hydroxyphenyl	656
175	A＝C(CH)(ii) a X ═ 3-carboxymethoxy; (ii) a R＝CH(CH)	614	176	A＝(CHS)C(CH)(ii) a X ═ 3- (2-hydroxyethoxy); r2-hydroxyphenyl group	634
177	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-6-tolyl radical	650	176		634
177	A＝(CHS)C(CH)；X＝4-CH；R2-hydroxy-6-tolyl radical	650	178	A＝(CHS)C(CH)；X＝4-OH；R3- (2-hydroxyethoxy) phenyl	682.2252
179	A＝C(CH)；X＝3-OH；R2- [ (2-hydroxyethyl) thio]Phenyl radical	666	178	A＝(CHS)C(CH)；X＝4-OH；R3- (2-hydroxyethoxy) phenyl	682.2252

A＝HRMS：m/z

B＝LRMS：m/z[M-H]^-

Example numbering	Definition of	LCMS m/z[M+H]
Example numbering	Definition of	LCMS m/z[M+H]	180	A＝C(CH)；RPyridin-2-yl; r＝CH(CH)	541
181	A＝C(CH)；R-isoquinolin-5-yl; r＝CH(CH)	591.6	180	A＝C(CH)；RPyridin-2-yl; r＝CH(CH)	541
181	A＝C(CH)；R-isoquinolin-5-yl; r＝CH(CH)	591.6	182	A＝(CHCH)C(CH)；RPyridin-3-yl; r2-hydroxyphenyl group	605.6
183	A＝C(CH)；R1-isoquinolin-7-yl; r＝CH(CH)	591.2	182	A＝(CHCH)C(CH)；RPyridin-3-yl; r2-hydroxyphenyl group	605.6

In the following list²The compounds of (1) are prepared by methods analogous to those described above. In another embodiment of the invention, a preferred group of compounds is that in which the substituents are as in the following list²As particularly described herein.

Preferably, the compounds of formula (I) are selected from the list²：

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

n- {1- (4-chloro-3-hydroxyphenyl) -3- [1, 1-dimethyl-2- (methylthio) ethyl ] -1H-pyrazol-5-yl } -N' - {2- [ (3- {2- [ (2-hydroxyethyl) thio ] phenyl } [1, 2, 4] triazolo [4, 3-a ] 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-isopropyl [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-isopropyl [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 ] -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-dimethyl-2- (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, 1-dimethyl-2- (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, 1-dimethyl-2- (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, 1-dimethyl-2- (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, 1-dimethyl-2- (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-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;

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

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R¹Is CH₃、SCH₃、SCH₂CH₃、CH₂CH₃H or CH₂SCH₃；

R^1aIs CH₃Or CH₂CH₃；

R²Is heteroaryl or aryl;

R³is aryl or R⁷；

R⁷Is (C)₁-C₆) An alkyl group;

p is 0, 1 or 2;

R⁵and R⁶Each independently selected from H and (C)₁-C₄) Alkyl radical of (C)₁-C₄) Alkyl is optionally substituted with one or more substituents independently selected from OH and halogen, or R⁵And R⁶Together with the nitrogen to which they are attached form piperazinyl, piperidinyl, morpholinyl, or pyrrolidinyl, each of which is optionally substituted with one or more OH;

"aryl" means a phenyl or naphthyl group, optionally substituted with one or more substituents independently selected from halogen, -CN, -CO₂H、OH、CONR⁵R⁶、R⁸And R⁹Substituted with the substituent(s);

R⁸is selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, -CO₂(C₁-C₆) Alkyl, -S (O)_p(C₁-C₆) Alkyl, -CO (C)₁-C₆) Alkyl and (C)₃-C₇) A cycloalkyl group;

(C₁-C₆) Alkoxy, optionally substituted by one or more groups independently selected from OH, halogen, CO₂H、CONR⁵R⁶And NR⁵R⁶The substituent (b) of (a) is substituted,

-S(O)_p(C₁-C₆) Alkyl is selected from one or more of OH, halogen, CO₂H、CONR⁵R⁶And NR⁵R⁶The substituent (b) of (a) is substituted,

OH，

the halogen(s) are selected from the group consisting of,

NR⁵R⁶，

CO₂H，

CONR⁵R⁶and

R⁹；

R⁹is aryl radical²；

"aryl group²"refers to phenyl or naphthyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -CO ₂H. OH and CONR⁵R⁶Substituted with the substituent(s);

"heteroaryl" refers to a 5 to 10 membered, mono-or bicyclic, aromatic radical containing 1 to 4 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1; and

"heteroaryl" is optionally substituted on one or more ring carbon atoms by one or more substituents independently selected from halogen, -CN, -CO₂H、OH、CONR⁵R⁶、R⁸And R⁹And optionally substituted on one or more ring nitrogen atoms with one or more substituents independently selected from H and (C)₁-C₆) Alkyl substituents.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is CH₃、SCH₃、CH₂CH₃Or CH₂SCH₃。

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹Is CH₃Or SCH₃。

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R^1aIs CH₃。

5. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereofAn acceptable salt, wherein R²Selected from the group consisting of pyridyl, tetrahydronaphthyl, and aryl, each pyridyl, tetrahydronaphthyl, and aryl optionally substituted with one or more substituents independently selected from the group consisting of:

The halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

(C₁-C₆) Alkyl radical of (C)₁-C₆) Alkyl is optionally substituted by one or more independently selected from OH, NR⁵R⁶Aryl radical²And a substituent of a halogen,

-S(O)_p(C₁-C₆) Alkyl, the-S (O)_p(C₁-C₆) The alkyl group is optionally substituted by one or more groups independently selected from OH, aryl²And a substituent of a halogen,

(C₁-C₆) Alkoxy group of the (C)₁-C₆) Alkoxy is optionally substituted by one or more groups independently selected from OH, aryl²And a substituent of a halogen,

-CO₂(C₁-C₆) Alkyl radical, the-CO₂(C₁-C₆) The alkyl group is selected from one or more of OH, aryl independently²And a substituent of a halogen,

(C₃-C₇) Cycloalkyl group of (C)₃-C₇) Cycloalkyl is optionally substituted with one or more substituents independently selected from OH and halogen,

pyridyl group, and

aryl radicals²。

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R²The method comprises the following steps:

3-pyridyl optionally substituted with one or more substituents independently selected from OH, -S (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, CF₃And a substituent of a halogen,

or

Phenyl optionally substituted by one or more substituents independently selected from (C)₁-C₆) Alkyl, OH, -S (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, CN, CF₃And halogen substituents.

7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R²Is phenyl, optionally substituted by one or more groups independently selected from methyl, ethyl, OH, CN, CF ₃、Cl、F、-SCH₃and-OCH₃Is substituted with the substituent(s).

8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R²Is 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl, 3, 4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl or 4-hydroxy-3-chlorophenyl.

9. A compound according to any one of claims 1 to 3 and 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R³Is pyridyl or aryl, each pyridyl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

-CN，

-CO₂H，

OH，

CONR⁵R⁶，

Pyridyl group, and

aryl radicals²

Or R³Is (C)₁-C₆) Alkyl optionally substituted with one or more substituents independently selected from OH, halogen and (C)₁-C₆) Substituent of alkoxy.

10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R³Is aryl, optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

OH，

CONR⁵R⁶，

(C₁-C₆) Alkyl radical of (C)₁-C₆) Alkyl is optionally substituted with one or more substituents independently selected from OH and halogen,

(C₁-C₆) Alkoxy group of the (C)₁-C₆) Alkoxy is optionally substituted with one or more substituents independently selected from OH and halogen,

or R³Is (C)₁-C₆) An alkyl group.

11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R³Is phenyl, optionally substituted by one or more groups independently selected fromSubstituent substitutions of the following: cl, F, OH, methyl, ethyl, isopropyl, CF₃Methoxy, ethoxy, the methoxy and ethoxy being optionally substituted by OH,

or R³Is isopropyl.

12. A compound according to any one of claims 1 to 3, 6 to 8 and 10 to 11, or a pharmaceutically acceptable salt thereof, wherein R⁵And R⁶Each independently selected from H, methyl and ethyl.

13. A compound according to any one of claims 1 to 3 and 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R ³Is aryl, optionally substituted with one or more substituents independently selected from the group consisting of:

the halogen(s) are selected from the group consisting of,

OH，

CN，

-S(C₁-C₆) Alkyl group, -S (C)₁-C₆) Alkyl is optionally substituted with one or more substituents independently selected from OH and halogen,

or R³Is (C)₁-C₆) An alkyl group.

14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R³Is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: CN, Cl, F, OH, methyl, ethyl, isopropyl, -S (C) optionally substituted with OH₁-C₄) Alkyl, methoxy, optionally substituted OHA substituted ethoxy group which is a substituent of a substituted ethoxy group,

or R³Is isopropyl.

15. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R³Is selected from one or two of Cl, F, CN, OH, -S-methyl, methoxy and-SCH₂CH₂OH and-OCH₂CH₂A phenyl group substituted with a substituent of OH.

16. A compound according to any one of claims 1 to 3, 6 to 8, 10 to 11 and 14 to 15, or a pharmaceutically acceptable salt thereof, wherein R ³Is selected from at least one of-S-methyl and-SCH₂CH₂Phenyl substituted by a substituent of OH, the-S-methyl or-SCH₂CH₂OH is present in the ortho position to the phenyl group.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:

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

n- [ 3-tert-butyl-1- (4-chlorophenyl) -1H-pyrazol-5-yl ] -N' - (2- { [3- (2-hydroxy-4-tolyl) [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, and

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- (methylthiophenyl) -1H-pyrazol-5-yl ] -N' - {2- [ (3-isopropyl } [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] thio } benzyl) urea, or a pharmaceutically acceptable salt thereof.

N- [ 3-tert-butyl-1- (4-methylphenyl) -1H-pyrazol-5-yl ] -N' - (2- { [ (3- (2-chlorophenyl) [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] thio } benzyl) urea, or a pharmaceutically acceptable salt thereof.

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

N- [ 3-tert-butyl-1- (3-chloro-4-hydroxyphenyl) -1H-pyrazol-5-yl ] -N' - {2- [ (3- {2- [ (2-hydroxyethyl) [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] thio } benzyl) urea, or a pharmaceutically acceptable salt thereof.

22. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from:

asthma of any type, etiology or pathogenesis,

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

obstructive or inflammatory airways diseases of any type, etiology or pathogenesis,

Bronchitis of any type, etiology or pathogenesis,

acute lung injury, and

bronchiectasis of any type, etiology or pathogenesis.

23. The use of claim 22, wherein the medicament is for treating a disease, disorder or condition selected from the group consisting of:

asthma selected from the group consisting of: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolitis

An obstructive or inflammatory airway disease selected from the group consisting of: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease including chronic bronchitis, emphysema or dyspnea associated with or not associated with chronic obstructive pulmonary disease, chronic obstructive pulmonary disease characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome, exacerbation of airway hyperresponsiveness secondary to other drug therapy, and airway diseases associated with pulmonary hypertension,

Bronchitis selected from the group consisting of: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis and alveolar bronchitis, and

a bronchodilator selected from the group consisting of: cylindrical bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

24. The use of claim 22 or 23, wherein the disease, disorder or condition is an obstructive or inflammatory airway disease selected from any type, cause or pathogenesis.

25. The use of claim 24, wherein the disease, disorder or condition is an obstructive or inflammatory airway disease selected from the group consisting of: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease, adult respiratory distress syndrome, exacerbation of airway hyperreactivity secondary to other drug therapies, and airway diseases associated with pulmonary hypertension.

26. The use of claim 24, wherein the disease, disorder or condition is chronic obstructive pulmonary disease of chronic bronchitis, emphysema or dyspnea associated with or not associated with chronic obstructive pulmonary disease, or chronic obstructive pulmonary disease characterized by irreversible progressive airway obstruction.

27. The use of claim 22 or 23, wherein the disease, disorder or condition is chronic obstructive pulmonary disease.

28. Use of a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a TNF-mediated disease, disorder or condition, or a p 38-mediated disease, disorder or condition.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent, carrier or adjuvant.