HK1165791B - Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases - Google Patents

Description

Triazolopyridine compounds as phosphodiesterase inhibitors for the treatment of skin diseases

Technical Field

The present invention relates to novel compounds having phosphodiesterase inhibitory activity and the use of these compounds as therapeutic agents for the treatment of inflammatory diseases and conditions.

Background

Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic AMP and/or cyclic GMP to 5-AMP and 5-GMP, respectively, in cells, and thus are critical for cellular regulation of cAMP or cGMP content. Of the 11 phosphodiesterases identified to date, Phosphodiesterase (PDE)4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important regulator of cAMP expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (z.huang and j.a.mannini, Current med.chem.13, 2006, page 3253-3262). Since cAMP is a key second messenger in the regulation of inflammatory responses, PDE4 has been found to regulate the inflammatory response of inflammatory cells by modulating pro-inflammatory cytokines such as TNF α, IL-2, IFN- γ, GM-CSF, and LTB 4. Inhibition of PDE4 thus becomes an attractive target for the treatment of inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), rheumatoid arthritis, atopic dermatitis, inflammatory bowel diseases such as Crohn's disease (m.d. houselay et al, Drug Discovery Today 10(22), 2005, 1503) 1519). Since Atopic Dermatitis (AD) patients have enhanced PDE activity, PDE4 inhibitors also appear to be useful in the treatment of AD (Journal of Investigative Dermatology (1986), 87(3), 372-6).

The PDE4 gene family consists of at least four genes A, B, C and D, which have high homology (v. boswell Smith and D. spinoa, curr. opinion investig. drugs6(11), 2006, 1136-. These four PDE4 isoforms are differentially expressed in different tissues and cell types. Thus, PDE4B is predominantly expressed in monocytes and neutrophils but not in the cortex and epithelial cells, whereas PDE4D is expressed in lung, cortex, cerebellum and T-cells (c.kroegel and m.foerster, exp. opinion investig. drugs 16(1), 2007, page 109-. Inhibition of PDE4D in the brain has been speculated to be associated with adverse effects, mainly nausea and vomiting, which occur when PDE4 inhibitors are administered clinically, whereas inhibition of PDE4B is associated with anti-inflammatory effects. Lipworth, Lancet 365, 2005, page 167-. However, the PDE inhibitors developed to date are not believed to be specific for any of these four PDE4 isoforms.

The therapeutic role of various PDE4 inhibitors for inflammatory diseases, mainly asthma and COPD, has been studied.

The first of these drugs, theophylline, is a weak, non-selective phosphodiesterase inhibitor that is used in the treatment of respiratory diseases such as asthma and COPD. However, treatment with theophylline can cause mild and severe adverse effects such as cardiac arrhythmias and spasticity, limiting the clinical utility of theophylline (Kroegel and Foerster, supra). Since phosphodiesterases remain attractive targets for anti-inflammatory therapies, a number of other more selective PDE4 inhibitors have been developed and studied in the clinical setting. Many first generation PDE4 inhibitors, such as rolipram (rolipram), discontinued clinical studies due to dose-limiting side effects, primarily nausea and vomiting. Second generation PDE4 inhibitors with apparently fewer significant adverse effects are currently in clinical trials (Houslay, supra). PDE-4 inhibitors are disclosed, for example, in EP0771794 and EP 0943613.

WO2008/125111 discloses triazolopyridine compounds having potent PDE4 inhibitory activity. These compounds include a linker that includes a carbonyl between a bicyclic heterocyclic ring system and a monocyclic ring system. The linker has been shown to be important for the positioning of the single ring in relation to the related compound pyraclostrobin (piclamilast), so that it can interact with the PDE4 enzyme to obtain the desired inhibitory effect (Card G.L., England B.P., Suzuki Y., Fong D.Powell B., Lee B.L., Luu C., Tabrize M., Gillette S., Ibrahim P.N., arthritis D.R., Bollag G., Milburn M.V., Kim S.H., Schlesser J., Zhang K.Y., "Structural basis for the activity of the drugs of the group of phosphodiesterase" (Structure 2004), Struture 12-12; Struture 12-47).

Summary of The Invention

The present inventors have surprisingly found novel compounds of the invention which are similar to those disclosed in WO2008/125111, but do not include a carbonyl linker in the two ring system, but exhibit PDE4 inhibitor activity even if the linker is absent. Thus, these compounds are useful as therapeutic agents for inflammatory allergic diseases such as bronchial asthma, COPD, allergic rhinitis and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, crohn's disease, and systemic lupus erythematosus; central nervous system diseases such as depression, amnesia and dementia; ischemic reflux-related organic diseases and the like caused by heart failure, shock and cerebrovascular diseases; insulin resistant diabetes mellitus; trauma; AIDS, and the like.

The compounds of the present invention may also be useful in the prevention, treatment or amelioration of a variety of diseases such as skin diseases or conditions, such as proliferative and inflammatory skin disorders and in particular psoriasis, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin aging, photo aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

Accordingly, the present invention relates to compounds of general formula I and pharmaceutically acceptable salts, hydrates, N-oxides, or solvates thereof,

wherein R is₁Is halogen, hydroxy, cyano or thiocyano, or R₁Is alkyl, alkenyl, alkynyl, alkoxy, alkylthio, -S (O) alkyl, -S (O)₂Alkyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, amino, -C (O) alkyl, -C (O) Oalkyl, OC (O) alkyl, -NHC (O) alkyl, -N (alkyl) C (O) alkyl, -C (O) NH- (alkyl), -C (O) N- (alkyl), sulfamoyl (sulfinamoyl), -NHS (O)₂Alkyl or-N (alkyl) S (O)₂Alkyl, each of which is optionally substituted with one or more groups selected from R₃Substituted with the substituent(s);

R₂is hydrogen, cyano or halogen, or R₂Is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heterocycloalkenylalkenylAlkynyl, aralkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, -S (O) alkyl, -S (O)₂-alkyl, sulfamoyl, -C (O) OR₃、-C(O)R₃、-NR₅R₆-alkyl (NR)₅R₆) -cycloalkyl (NR)₅R₆) -cycloalkylalkyl (NR)₅R₆) -alkylcycloalkyl (NR)₅R₆)、-C(O)NR₇R₈-alkyl (C (O) NR₇R₈) -cycloalkyl (C (O) NR₇R₈) -cycloalkylalkyl (C (O) NR)₇R₈) Or-alkylcycloalkyl (C (O) NR)₇R₈) Each of which is optionally substituted by one or more groups selected from R₄Substituted with the substituent(s);

R₃is hydrogen, halogen, aryl, heteroaryl, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, oxo, cyano, amino, aminoalkyl, alkylamino, or dialkylamino;

R₄is hydrogen, halogen, hydroxy, oxo, cyano, carboxy or trihalomethyl, or R₄Is NR₅R₆、-C(O)NR₇R₈、-C(O)R₇、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-OC(O)R₃、NC(O)R₇、-OR₇、-NC(O)OR₃、-NSO₂R₇、-SO₂NR₇R₈or-SO₂R₇R₈Alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heterocycloalkenylalkenyl, heterocycloalkenylalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, cycloalkyloxy, alkylthioCycloalkylthio, sulfamoyl, alkylamino or cycloalkylamino, each of which is optionally substituted by one or more groups selected from R₉Substituted with the substituent(s);

R₅and R₆Each independently represents hydrogen, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, -C (O) alkyl, -C (O) Oalkyl, -C (O) cycloalkyl, -C (O) N-alkyl, carboxyalkyl, -C (O) alkyl-C (O) OH, -C (O) alkyl-C (O) N-alkyl, -C (O) N-aryl, -S (O)₂Alkyl, -S (O)₂Aryl, -S (O)₂N-alkyl, -S (O) aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is optionally substituted with hydroxy or one or more halogen, or R₅And R₆Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring, wherein the ring may be optionally substituted with one or more alkyl groups;

R₇and R₈Each independently represents hydrogen, alkyl, cycloalkyl, alkenyl, heteroaryl, heterocycloalkyl, carboxyalkyl, carbamoylalkyl, alkyloxyalkyl, alkenyloxyalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl or alkylheteroaryl, each of which is optionally substituted by one or more substituents selected from the group consisting of: hydroxy, halogen, oxo, cyano, alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -C (O) N-alkyl, -NC (O) O-alkyl, -OC (O) N-alkyl, -NC (O) NR₁₁R₁₂、-NR₁₁SO₂-alkyl, -S (O) -alkyl, or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring, wherein the ring may be optionally substituted with one or more alkyl groups;

R₉is hydrogen, halogen, hydroxy, alkoxy, carboxy or trihalomethyl;

x and Y are C and N respectively, or N and C;

a is aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is optionally substituted with one or more groups selected from R₁₀Substituted with the substituent(s);

R₁₀is hydrogen, cyano, halogen, hydroxy or oxo, or R₁₀Is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heterocycloalkenylalkenyl, heterocycloalkenylalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, -S (O) alkyl, -S (O)₂-alkyl, sulfamoyl, -C (O) OR₃、-C(O)R₃、-NR₅R₆-alkyl (NR)₅R₆) -cycloalkyl (NR)₅R₆) -cycloalkylalkyl (NR)₅R₆) -alkylcycloalkyl (NR)₅R₆)、-C(O)NR₇R₈-alkyl (C (O) NR₇R₈) -cycloalkyl (C (O) NR₇R₈) -cycloalkylalkyl (C (O) NR)₇R₈) Or-alkylcycloalkyl (C (O) NR)₇R₈) Each of which is optionally substituted by one or more groups selected from R₄Substituted with the substituent(s);

R₁₁and R₁₂Each independently represents hydrogen or an alkyl group.

In another aspect, the present invention relates to a compound of general formula I as defined herein for use in therapy, for example for the treatment of a skin disease or condition or an acute or chronic skin wound disorder.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of general formula I as defined above and a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier, and optionally one or more other therapeutically active compounds.

In a further aspect, the present invention relates to the use of a compound of general formula I as defined herein and a pharmaceutically acceptable and physiologically degradable ester, pharmaceutically acceptable salt, hydrate, N-oxide or solvate for the manufacture of a medicament for the prevention, treatment or amelioration of a skin disease or condition or an acute or chronic skin wound disorder.

In a further aspect, the present invention relates to a method of preventing, treating or ameliorating a skin disease or condition or an acute or chronic skin wound disorder, which method comprises administering to a person suffering from at least one of said diseases an effective amount of one or more compounds of formula I as defined above and pharmaceutically acceptable and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof; and optionally a pharmaceutically acceptable carrier or one or more excipients and optionally in combination with other therapeutically active compounds.

Detailed Description

In the present context, the term "aryl" means an aromatic carbocyclic group comprising 6 to 20 carbon atoms, such as 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, in particular a 5-or 6-membered ring, a carbocyclic ring optionally fused to at least one aromatic ring, such as phenyl, naphthyl, indenyl or indanyl.

The term "heteroaryl" means a heterocyclic aromatic ring group comprising 1-6 heteroatoms (selected from O, S and N) and 1-20 carbon atoms, such as 1-5 heteroatoms and 1-10 carbon atoms, such as 1-5 heteroatoms and 1-6 carbon atoms, such as 1-5 heteroatoms and 1-3 carbon atoms, especially a 5-or 6-membered ring having 1-4 heteroatoms selected from O, S and N, or an optionally fused bicyclic ring having 1-4 heteroatoms, and wherein at least one ring is aromatic, such as pyridyl, quinolyl, isoquinolyl, indolyl, dihydroisoindolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, pyridazinyl, isothiazolyl, benzimidazolyl, benzopyridyl, pyridinyl, and the like, Benzofuranyl or isobenzofuranyl.

The term "alkyl" means a group that results when one hydrogen atom is removed from a hydrocarbon. The alkyl group may be branched or straight chain and may contain 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, for example 1 to 6, for example 1 to 4 carbon atoms. The term includes the subclasses primary (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "cycloalkyl" means a saturated cycloalkane group, including polycyclic groups, such as bicyclic or tricyclic groups, containing 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, especially 3 to 8 carbon atoms, such as 3 to 6 carbon atoms, for example 4 to 5 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl or adamantyl.

The term "cycloalkenyl" means a mono-, di-, tri-or tetra-unsaturated non-aromatic cyclic hydrocarbon radical, including polycyclic radicals, containing 3 to 20 carbon atoms, typically 3 to 10 carbon atoms, such as 3 to 6 carbon atoms, for example 4 to 5 carbon atoms, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo [2.2.1] heptenyl or bicyclo [4.1.0] heptenyl.

The term "heterocycloalkyl" means a cycloalkyl group as defined above, containing 1 to 6 heteroatoms, preferably 1,2, or 3 heteroatoms selected from O, N or S, such as piperidine, [1, 3] dioxolane or [1, 3] dioxole.

The term "heterocycloalkenyl" means a cycloalkenylene radical as defined above, including polycyclic radicals, optionally fused to a carbocyclic ring, comprising 1 to 6 heteroatoms, preferably 1 to 3 heteroatoms selected from O, N or S, such as 1, 6-dihydropyridinyl, 2, 3-dihydrobenzofuranyl, 4, 5-dihydro-1H- [1,2,4] -triazolyl, 4, 5-dihydro-oxazolyl, 1H-indazolyl, 1-H-pyrazolyl or 4, 5-dihydro-isoxazolyl.

The term "alkenyl" means a mono-, di-, tri-, tetra-or pentaunsaturated hydrocarbon group comprising 2 to 10 carbon atoms, especially 2 to 6 carbon atoms, for example 2 to 4 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl.

The term "alkynyl" means a hydrocarbon group containing from 1 to 5C-C triple bonds and from 2 to 20 carbon atoms, the alkane chain of which usually comprises from 2 to 10 carbon atoms, especially from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "halogen" means a substituent from main group 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.

The term "alkoxy" means a group of the formula-OR ', wherein R' is an alkyl group as defined above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, and the like. The term "cycloalkyloxy" means a group of formula-O-Cyc, wherein Cyc is cycloalkyl as defined above.

The term "amino" means a compound of the formula-N (R)₂Wherein each R independently represents hydrogen, alkyl, alkenyl, cycloalkyl or aryl as defined above, for example-NH₂Aminophenyl, methylamino, diethylamino, cyclohexylamino, -NH-phenyl, tert-butylamino or ethylamino.

When two or more of the above-defined terms, such as arylalkyl, heteroarylalkyl, cycloalkylalkyl or the like, are used in combination, it is noted that the first-mentioned group is a substituent of the latter-mentioned group, with the point of attachment to the rest of the molecule being on the latter group.

Thus, the term "cycloalkylalkyl" means a group of formula-R '-cycloalkyl, wherein R' is an alkyl group as defined above, for example:

the term "cycloalkenylalkyl" means a group of formula-R '-cycloalkenyl, wherein R' is alkyl as defined above, for example:

the term "heterocycloalkenylalkyl" means a group of the formula-R '-cycloalkenyl, wherein R' is alkyl as defined above, for example:

the term "arylalkyl" means a group of the formula-R '-Ar, wherein R' is an alkyl group as defined above and Ar is an aryl group as defined above, for example:

the term "arylalkenyl" means a group of the formula-R "-Ar, wherein Ar is an aryl group as defined above and R" is an alkenyl group as defined above, for example:

the term "arylalkynyl" means a group of the formula-R '"-Ar, wherein Ar is an aryl group as defined above and R'" is an alkynyl group as defined above, for example:

the term "heteroarylalkyl" means a group of formula-R '-Het wherein R' is alkyl as defined above and Het is heteroaryl as defined above, for example:

the term "heteroarylalkenyl" means a group of the formula-R "-Het wherein R" is alkenyl as defined above and Het is heteroaryl as defined above, for example;

the term "heteroarylalkynyl" means a group of the formula-R '"-Het wherein R'" is alkynyl as defined above and Het is heteroaryl as defined above, for example;

the term "alkylthio" means a group of formula-SR', wherein R is alkyl as defined above. The term "cycloalkylthio" means a group of formula-S-Cyc, wherein Cyc is cycloalkyl as defined above.

The term "sulfamoyl" means a compound of the formula-S (O)₂NH₂A group of (1).

The term "aminosulfinyl" means a compound of the formula-S (O) NH₂A group of (1).

The term "pharmaceutically acceptable salt" means a salt prepared by reacting a compound of formula I with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1, 2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of the compounds of formula I may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, aqueous ammonia or the like, or a suitable non-toxic amine such as a lower alkylamine, e.g. triethylamine, a hydroxy-lower alkylamine, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine, a cycloalkylamine, e.g. dicyclohexylamine, or a benzylamine, e.g. N, N' -dibenzylethylenediamine and dibenzylamine, or L-arginine or L-lysine. Salts obtained by reaction with a suitable base include, but are not limited to, sodium, choline, 2- (dimethylamino) -ethanolate, 4- (2-hydroxyethyl) -morpholine, L-lysine, N- (2-hydroxyethyl) -pyrrolidine, ethanolamine, potassium, tetrabutylammonium, benzyltrimethylmethylammonium, hexadecyltrimethylammonium, tetramethylammonium, tetrapropylammonium, tris (hydroxymethyl) aminomethane, N-methyl-D-glucamine, silver, benzethonium chloride (benzethonium) and triethanolamine.

The term "solvate" means a species formed from the interaction of a compound, for example a compound of formula I, with a solvent, for example ethanol, glycerol or water, wherein the species is in solid form. When the solvent is water, the species is referred to as a hydrate.

Embodiments of the invention

In an embodiment of the invention, R₂Is hydrogen, cyano, halogen, or R₂Is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkylAlkenylalkenyl, heterocycloalkenylalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -C (O) OR₃、-C(O)R₃-alkyl (NR)₅R₆) -cycloalkyl (NR)₅R₆) -cycloalkylalkyl (NR)₅R₆) -alkylcycloalkyl (NR)₅R₆)、-C(O)NR₇R₈-alkyl (C (O) NR₇R₈) -cycloalkyl (C (O) NR₇R₈) -cycloalkylalkyl (C (O) NR)₇R₈) -alkylcycloalkyl (C (O) NR)₇R₈) Each of which is optionally substituted by one or more R selected from the group defined above₄Substituted with the substituent(s);

in an embodiment of the invention, A may optionally be substituted with R₁₀Is substituted in which R₁₀Is not hydrogen. For example, a may be an optionally substituted aryl group, such as an optionally substituted phenyl group or an optionally substituted indanyl group. When A is phenyl, it may suitably be substituted by cyano, halogen, aryl, alkyl, heteroaryl, sulfamoyl, -C (O) R₃、-C(O)OR₃or-NR₅R₆Is substituted in which R₃、R₅And R₆As defined above.

In alternative embodiments, a is an optionally substituted heteroaryl group, such as an optionally substituted pyridyl group, an optionally substituted benzofuranyl group, an optionally substituted 3H-isobenzofuran-1-one-yl group, or an optionally substituted 2, 3-dihydro-isoindol-1-one-yl group.

When a is pyridyl, benzofuranyl, 3H-isobenzofuran-1-one-yl or 2, 3-dihydro-isoindol-1-one-yl, it may suitably be substituted by one or more substituents selected from chloro, fluoro or bromo.

In an embodiment of the invention, a is optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, for example optionally substituted piperidinyl or optionally substituted pyridazinyl.

In an embodiment of the invention, R₁₀Is hydrogen, cyanoHalogen, oxo, alkyl, alkoxy, cycloalkyloxy, -S (O) alkyl, -S (O)₂Alkyl, -C (O) R₃、-C(O)OR₃、-C(O)NR₇R₈Wherein R is₃、R₇And R₈As defined above.

In an embodiment of the invention, R₁₀Is cyano, halogen, oxo, alkyl, alkoxy or-C (O) R₃Wherein R is₃As defined above.

In an embodiment of the invention, R₁Is halogen, hydroxy or thiocyano, or R₁Is alkyl, alkenyl, alkynyl, alkoxy, alkylthio, -S (O) alkyl, -S (O)₂Alkyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, -C (O) alkyl, -C (O) Oalkyl, -NHC (O) alkyl, -N (alkyl) C (O) alkyl, -C (O) NH- (alkyl), -C (O) N- (alkyl), sulfamoyl, -NHS (O)₂Alkyl, or-N (alkyl) S (O)₂Alkyl, each of which is optionally substituted with one or more groups selected from R₃Wherein R is₃As defined above.

More specifically, R₁Can be C_1-6Alkoxy, for example methoxy, mono-, di-or trifluoromethoxy, halogen or hydroxy.

In an embodiment of the invention, the compound of formula I is a compound of formula Ia

Wherein R is₁、R₂And A is as defined above.

In another embodiment of the invention, the compound of formula I is a compound of formula Ib

Wherein R is₁、R₂And A is as defined above.

In one embodiment of the invention, R₂Is alkyl, cycloalkyl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -cycloalkyl (C (O) NR₇R₈) Or-cycloalkylalkyl (C (O) NR)₇R₈) Each of which is optionally substituted by one or more groups selected from R₄Wherein R is₄As defined above.

In an embodiment of the invention, R₂Is alkyl, cycloalkyl, alkylcycloalkyl, or cycloalkyl (C (O) NR)₇R₈) Each of which is optionally substituted by one or more groups selected from R₄Wherein R is₄As defined above.

In one embodiment of the invention, R₂Is optionally substituted C_1-6Alkyl or optionally substituted C_3-6Cycloalkyl, such as optionally substituted cyclopropyl.

In one embodiment of the invention, R₃Is halogen, alkyl, cycloalkyl, heterocycloalkyl or oxo.

In one embodiment of the invention, R₃Is alkyl or heterocycloalkyl.

In one embodiment of the invention, R₄Is a halogen, a hydroxyl or a cyano group,

or R₄Is NR₅R₆、-C(O)NR₇R₈、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-OC(O)R₃、-NC(O)R₇、-OR₇、-NC(O)OR₃、-NSO₂R₇、-SO₂NR₇R₈、-SO₂R₇R₈Alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl each of which is optionally substituted with one or more groups selected from R₉Substituted with the substituent(s);

wherein R is₃、R₅、R₆、R₇、R₈And R₉As defined above.

In one embodiment of the invention, R₄Is a hydroxyl group or a cyano group,

or R₄is-C (O) NR₇R₈、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-NC(O)R₇、-OR₇、-NC(O)OR₃Alkyl optionally substituted by one or more groups selected from R₉Substituted with the substituent(s); wherein R is₉Is hydrogen, halogen or hydroxy, wherein R₃、R₇And R₈As defined above.

In one embodiment of the invention, R₅And R₆Each independently represents hydrogen, alkyl, alkenyl, cycloalkyl or heterocycloalkyl, or R₅And R₆Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring, wherein the ring is optionally substituted with one or more alkyl groups.

In an embodiment of the invention, R₇And R₈Each independently represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl or alkenyloxyalkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, oxo, cyano, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -C (O) N-alkyl, -NC (O) O-alkyl, -OC (O) N-alkyl, -NR₁₁SO₂-alkyl, -S (O) -alkyl, or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring,wherein the ring is optionally substituted with one or more alkyl groups; wherein R is₁₁And R₁₂Is hydrogen or C_1-4An alkyl group.

In an embodiment of the invention, R₇And R₈Each independently represents hydrogen, alkyl, cycloalkyl, alkenyloxyalkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, oxo, cyano, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -NR₁₁SO₂-alkyl or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring, wherein the ring is optionally substituted with one or more alkyl groups; wherein R is₁₁And R₁₂Is hydrogen or C_1-4An alkyl group.

Examples of compounds of formula I may be selected from:

2-cyclopropyl-8-methoxy-5- (3-acetyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-phenyl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (4-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (4-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3, 4-dimethoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-thiophen-2-yl- [1,2,4] triazolo [1,5-a ] pyridine,

n- [3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -acetamide,

2-cyclopropyl-8-methoxy-5- (3-trifluoromethoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (3-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine, 1- [5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -thiophen-2-yl ] -ethanone,

2-cyclopropyl-8-methoxy-5-pyrimidin-5-yl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3-methanesulfonyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

n- [3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -methanesulfonamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N-methyl-benzamide,

2-cyclopropyl-8-methoxy-5- (4-acetyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -acetamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid methyl ester,

2-cyclopropyl-8-methoxy-5-pyridin-3-yl- [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid methyl ester,

2-cyclopropyl-5- (4-methanesulfonyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (2-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- [4- (2-methoxy-ethoxy) -phenyl ] - [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzamide,

5- (3-butoxy-phenyl) -2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-pyridin-4-yl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (2, 4-dichloro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- [4- (morpholine-4-sulfonyl) -phenyl ] - [1,2,4] triazolo [1,5-a ] pyridine,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzyl ] -acetamide,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzyl ] -methanesulfonamide,

2-cyclopropyl-5- (4-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzonitrile,

3- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -propionic acid methyl ester,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N- (2-hydroxy-ethyl) -benzenesulfonamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzonitrile,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid,

[3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -methanol,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N, N-dimethyl-benzamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzamide,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N, N-dimethyl-benzamide,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N-methyl-benzamide,

2-cyclopropyl-8-methoxy-5-piperidin-1-yl- [1,2,4] triazolo [1,5-a ] pyridine,

1- [3- (2-cyclopropyl-8-hydroxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -ethanone,

2- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -isonicotinonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

3- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -benzonitrile,

pyrrolidine-1-carboxylic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

3- [2- (1-benzyloxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -benzonitrile,

n- {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } -isobutyramide,

{1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } -carbamic acid cyclopentyl ester,

pyrrolidine-1-carboxylic acid {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } amide,

6- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-methyl-4, 5-dihydro-2H-pyridazin-3-one,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -nicotinonitrile,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -indan-1-one,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-methyl-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -indan-1-one,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-fluoro-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-fluoro-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-methoxy-benzonitrile,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -3H-isobenzofuran-1-one,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-hydroxymethyl-benzonitrile,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-methoxy-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -3H-isobenzofuran-1-one,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2, 3-dihydro-isoindol-1-one,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethyl-amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethyl-amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo- [1,5-a ] pyridin-5-yl } -benzonitrile,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

3- { 8-methoxy-2- [1- (pyrrolidine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

2-methyl-acrylic acid 2- ({1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylcarbonyl } -amino) -ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methoxy-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

4- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

4- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid methylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid propylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclopropylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyanomethylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-acetylamino-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonylamino-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (3-morpholin-4-yl-3-oxo-propyl) amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid [2- (methanesulfonyl-methyl-amino) -ethyl ] -amide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

1- (3- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -phenyl) -ethanone,

1- (3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -phenyl) -ethanone,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

2-methyl-acrylic acid 2- ({1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylcarbonyl } -amino) -ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-hydroxy-ethyl) -amide,

cyclohexyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

5- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -nicotinonitrile,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2-methoxy-benzonitrile,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2-methyl-benzonitrile,

3- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -benzonitrile,

5- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -indan-1-one,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -indan-1-one,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-hydroxy-8- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [8- (5-cyano-pyridin-3-yl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [ 5-hydroxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

diethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

4- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -2-methoxy-benzonitrile,

4- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -2-methoxy-benzonitrile,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonylamino-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclopropylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

5- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -nicotinonitrile,

5- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -nicotinonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid [2- (methanesulfonyl-methyl-amino) -ethyl ] -amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide.

In one or more embodiments of the invention, the compounds of general formula I have a molecular weight of less than 800 daltons, such as less than 750 daltons, for example less than 700 daltons or less than 650, 600, 550 or 500 daltons.

In one or more embodiments of the invention, the compounds of general formula I as defined hereinbefore may be used in therapy, for example for the treatment of skin diseases or conditions or acute or chronic skin wound disorders.

In one or more embodiments of the invention, the skin disease or condition is selected from the group consisting of proliferative and inflammatory skin disorders, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin aging, skin photoaging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis, and eczema.

The compounds of formula I can be obtained directly in crystalline form by concentration from an organic solvent or by crystallization or recrystallization from an organic solvent or from a mixture of such a solvent and a co-solvent, which can be organic or inorganic, for example water. The crystals may be isolated in a form substantially free of solvent or in the form of a solvate, such as a hydrate. The present invention covers all crystalline modifications and forms as well as mixtures thereof.

The compounds of formula I may or may not include asymmetrically substituted (chiral) carbon atoms, which may contribute to isomeric forms such as enantiomers and possibly diastereomers. The present invention relates to isomers in all pure forms or in mixtures thereof (e.g., racemates). Pure stereoisomeric forms of the compounds of the invention and intermediates thereof may be obtained by applying methods known in the art. The various isomeric forms can be separated by the application of physical separation methods such as selective crystallization and chromatographic techniques, e.g., liquid chromatography using a chiral stationary phase. Enantiomers can be separated from each other by selective crystallization of their diastereoisomeric salts with optically active amines such as 1-ephedrine. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. The pure stereoisomeric forms may also be obtained from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that a stereoselective or stereospecific reaction occurs. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereoselective or stereospecific methods of preparation. These processes will advantageously use chirally pure starting materials.

The compounds according to the invention, optionally in combination with other active compounds, can be used for the treatment of skin diseases or conditions or acute or chronic skin wound disorders, in particular for the treatment of proliferative and inflammatory skin diseases, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid-induced skin atrophy, skin ageing, skin photoaging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis and eczema.

In addition to being useful for the treatment of humans, the compounds of the present invention are also useful for the veterinary treatment of animals, including mammals, such as horses, cattle, sheep, pigs, dogs, and cats.

For use in therapy, the compounds of the invention are typically in the form of pharmaceutical compositions. Accordingly, the present invention is directed to pharmaceutical compositions comprising a compound of formula I and optionally one or more other therapeutically active compounds, together with a pharmaceutically acceptable excipient or vehicle. An excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Suitably, the active ingredient comprises from 0.05 to 99.9% by weight of the formulation.

In dosage unit form, the compound may be administered one or more times daily at appropriate intervals, but always on a patient basis, following the prescription made by a medical practitioner. Suitably, the dosage unit of the formulation contains between 0.1mg and 1000mg, preferably between 1mg and 100mg, for example 5mg-50mg, of a compound of formula I.

Suitable dosages for the compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the condition to be treated and other factors well known to the attending physician. The compounds may be administered orally, parenterally or topically according to different dosing schedules, for example daily or at weekly intervals. In general, a single dose will be in the range of 0.01mg/kg body weight to 400mg/kg body weight. The present compounds may be administered in a bolus form (i.e., one administration of the entire daily dose) or in divided doses administered twice or more daily.

In the case of topical treatment, the expression "use unit" may be more appropriate, which means a single dose capable of being administered to a patient and being easily handled and packaged, in a physically and chemically stable unit dosage form comprising the active substance or a mixture of this substance with a solid or liquid pharmaceutical diluent or carrier.

The term "use unit" in connection with topical treatment means a unit, i.e. a single dose capable of topical administration to a patient of 0.1 to 10mg and preferably 0.2 to 1mg of the active ingredient per square centimeter of affected area.

It is also contemplated that in certain treatment regimens, administration at long intervals, such as every other day, week, or longer interval, may be beneficial.

If treatment involves administration of another active compound, a suitable dosage of The compound is recommended by reference to The Pharmacological Basis of Therapeutics, 9 th edition, J.G.Hardman and L.E.Limbird (eds.), McGraw-Hill 1995, by Goodman & Gilman.

The compounds of the invention may be administered simultaneously or sequentially with one or more other active compounds.

Formulations include, for example, those suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular, and intravenous), transdermal, ophthalmic, topical, dermal, nasal, or buccal administration. Topical application of the claimed formulations is particularly suitable.

The formulations are suitably presented in dosage unit form and may be prepared by any method well known in The art of Pharmacy, for example as disclosed in Remington, The Science and Practice of Pharmacy, 20 th edition, 2000. All methods include the step of bringing into association the active ingredient with the carrier constituted by one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, caplets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oil may be an edible oil, such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginates, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers, and polyvinylpyrrolidone. The active ingredient may also be administered in the form of a bolus (bolus), electuary or paste.

Tablets may be prepared by compressing or molding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with: binders such as lactose, glucose, starch, gelatin, acacia, tragacanth, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes, and the like; lubricants, such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like; disintegrating agents such as starch, methyl cellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone and the like; or a dispersing agent such as polysorbate 80. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent with a suitable carrier.

Formulations for rectal administration may be in the form of suppositories in which the compounds of the invention are combined with low melting water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycols or fatty acid esters of polyethylene glycols, although elixirs may be prepared using tetradecyl palmitate.

Formulations suitable for parenteral administration suitably comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient, for example isotonic physiological saline, isotonic glucose solution or buffer solutions. The formulation may conveniently be sterilised, for example by filtration through a bacteria-retaining filter, addition of a sterilising agent to the formulation, irradiation of the formulation or heating of the formulation. Liposome formulations as disclosed, for example, in Encyclopedia of pharmaceutical Technology, volume 9, 1994 are also suitable for parenteral administration.

Alternatively, the compounds of formula I may be provided in the form of a sterile solid formulation, for example a lyophilized powder, which is readily soluble in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of plasters or patches.

Formulations suitable for ophthalmic administration may be in the form of sterile aqueous preparations of the active ingredient, which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposome formulations or biodegradable polymer systems, such as those disclosed in Encyclopedia of pharmaceutical technology, Vol.2, 1989, may also be used to provide the active ingredient for ophthalmic administration.

Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid formulations, such as liniments, lotions, gels, paints, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or solutions or suspensions, e.g. drops. The composition for ophthalmic treatment may preferably additionally contain cyclodextrin.

For topical administration, the compounds of formula I may generally be present in an amount of from 0.01% to 20%, for example from 0.1% to about 10%, by weight of the composition, and may also be present in an amount up to about 50% of the composition.

Formulations suitable for nasal or buccal administration include powder, self-propelled and spray formulations, such as aerosols and nebulizers. Such formulations are disclosed in more detail, for example, in Modern pharmaceuticals, 2 nd edition, g.s.banker and c.t.rhodes (eds.), pages 427-432, Marcel Dekker, new york; modern pharmaceuticals, 3 rd edition, G.S.Bank and C.T.Rhodes (eds.), pages 618-619 and 718-721, Marcel Dekker, New York; and encyclopedia of Pharmaceutical Technology, volume 10, J.Swarbrich and J.C.Boylan (eds.), pp.191-221, Marcel Dekker, New York.

In addition to the above ingredients, the formulation of the compounds of formula I may also include one or more additional ingredients such as diluents, buffers, fragrances, colorants, surfactants, thickeners, preservatives such as methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

When the active ingredient is administered in the form of a salt with a pharmaceutically acceptable non-toxic acid or base, the preferred salt is, for example, one that is readily or sparingly soluble in water in order to obtain a specific and suitable absorption ratio.

The pharmaceutical composition may additionally comprise one or more other active ingredients conventionally used in the treatment of skin diseases or conditions, for example selected from glucocorticoids, vitamin D and vitamin D analogues, antihistamines, Platelet Activating Factor (PAF) antagonists, anticholinergics, methylxanthines, β -adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamate (flufenamate), naproxen, timegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts, sulfasalazine (salicylsulfapyridine) and calcineurin (calcein) inhibitors.

The term "compound of formula I" as used herein is meant to include compounds of formula Ia.

Preparation method

The compounds of the present invention can be prepared using a variety of methods well known to those skilled in the art of synthesis. For example, the compounds of formula I may be prepared using the reactions and techniques outlined below, as well as methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reaction is carried out in a solvent appropriate to the reagents and materials used and to the conversion being effected. Also, in the synthetic methods described below, it is understood that the selection of all proposed reaction conditions, including solvent, reaction pressure, reaction temperature, test duration, and work-up procedures, are selected as standard conditions for the reaction, which should be readily recognized by one skilled in the art of organic synthesis. In some such methods, not all compounds belonging to a given class may be compatible with some of the required reaction conditions. Limitations on substituents that are compatible with these reaction conditions will be apparent to those skilled in the art and alternative methods may be used.

The starting materials should be known or commercially available compounds or can be prepared by conventional synthetic methods well known to those skilled in the art.

General procedure, preparation examples and examples

¹An H Nuclear Magnetic Resonance (NMR) spectrum is recorded at 300MHz, and¹³c NMR spectra were recorded at 75.6MHz or 151 MHz. Tetramethylsilane (δ ═ 0.00) or chloroform (δ ═ 7.25) or deuterated chloroform (for the internal standard) in the indicated solvents¹³CNMR, δ 76.81) quotes chemical shift values (δ, in ppm). Unless ranges are quoted, values for defined (doublet (d), triplet (t), quartet (q)) or undefined (m) multiplets at about the midpoint are given. (bs) represents a broad singlet. The organic solvent used is generally anhydrous. Chromatography was carried out on Merck silica gel (0.040-0.063 mm). Unless otherwise specified, the indicated solvent ratios refer to v: v.

The following abbreviations are used throughout

Preparative HPLC/MS

Preparative HPLC/MS was performed on a Dionex APS-system with two Shimadzu PP150 prep pumps and a ThermoMSQ Plus mass spectrometer. A chromatographic column: waters XTerraC-18, 150mm × 19mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 18 mL/min; method (10 min): the linear gradient method was from 10% B to 100% B in 6 minutes, with a dwell of 100% B for 2 minutes. Fractions were collected based on the ion trace of the relevant ion and the PDA signal (240-400 nm).

Analytical HPLC/MS (A)

Analytical HPLC/MS was performed on a system consisting of Waters 2795HPLC, Micromass ZQ mass spectrometer, Waters 996 PDA. A chromatographic column: waters XTerra C-18, 50mm x 3.0mm, 5 μm; solvent system: water acetonitrile 95: 5 (0.05% formic acid) and B acetonitrile (0.05% formic acid); the flow rate is 1.0 mL/min; method (8 min): the linear gradient method was from 10% B to 100% B in 6.0 min and held at 100% B for 1 min.

Analytical HPLC/MS (B)

Analytical HPLC/MS was performed on a Dionex APS-system with P680A analytical pump and Thermo MSQ Plus mass spectrometer. A chromatographic column: waters XTerra C-18, 150mm × 4.6mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 1.0 mL/min; method (10 min): the linear gradient method ranged from 10% B to 100% B in 6.6 minutes and stayed at 100% B for 1.5 minutes.

General preparation procedure:

the compounds of the invention can be prepared, for example, by the following general methods:

a) reacting a compound of the formula II

Wherein Hal is halogen; r₁、R₂X and Y are as defined herein,

with boronic acid (A-B (OH)₂) Or a boronic acid ester (A-B (OR)₂) (wherein A is defined herein) under Suzuki conditionsReaction using a suitable catalyst (e.g., tetrakis (triphenylphosphine) palladium) and a suitable base (e.g., potassium carbonate, sodium hydroxide, triethylamine, K)₃PO₄) In a suitable solvent such as but not limited to DMF, NMP, 1, 2-dimethoxyethane, THF, 1, 4-bisAlkane, water or a mixture of two or more solvents of these) at a temperature of, for example, -78 ℃ to reflux.

b) Reacting a compound of the formula II

Wherein Hal is halogen; r₁、R₂X and Y are as defined herein,

with a nucleophilic heterocycloalkyl system (e.g., piperidine; A-H), potentially in the presence or absence of a suitable catalyst (e.g., tetrakis (triphenylphosphine) palladium) and a suitable base (e.g., triethylamine), in the presence or absence of a suitable solvent such as 2-propanol, ethylene glycol, DMF, NMP, 1, 2-dimethoxyethane, THF, 1, 4-bis-dimethoxyethaneThe reaction is carried out in an alkane or a mixture of two or more solvents of these at a temperature of, for example, -78 ℃ to reflux.

The starting materials for compound II were prepared according to standard procedures known to chemists skilled in the art of organic synthesis. According to the known procedures described in scheme 1 and scheme 2, O-N-amination of 2-aminopyridines at the pyridine nitrogen with phenylsulfonylhydroxylamines followed by treatment with aldehydes to form the desired 1,2, 4-triazolo- [1,5, a]Pyridine heterocycles (Tet. Lett. (2003), 44, 1675-78).

Scheme 1

Scheme 2

c) Reacting a compound of the formula III

Wherein R' is hydrogen or alkyl; r₁、R₂X and Y are as defined herein,

with a halide (A-Hal, wherein A is as defined herein) under Suzuki conditions using a suitable catalyst (e.g. tetrakis (triphenylphosphine) palladium) and a suitable base such as potassium carbonate, sodium hydroxide, triethylamine, K₃PO₄In a suitable solvent such as but not limited to DMF, NMP, 1, 2-dimethoxyethane, THF, 1, 4-bisIn an alkane, water or a mixture of two or more solvents of these, at a temperature of, for example, -78 ℃ to reflux.

d) Reacting a compound of formula IV

Wherein R is alkyl; r₁、R₂X and Y are as defined herein,

with a halide (A-Hal, wherein A is as defined herein) under Stille conditions using a suitable catalyst (e.g., tetrakis (triphenylphosphine) palladium or Pd₂(dba)₃And P (furyl)₃) In a suitable solvent such as, but not limited to, toluene, benzene, 1, 2-dimethoxyethane, THF, 1, 4-bisAlkane, acetonitrile, DMF or a mixture of two or more solvents of these, at temperatures of, for example, -78 ℃ to reflux.

Preparation example 1 (Compound 301)

2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine

Adding O-Ethyl alkylsulfonylacetylhydroxamate (22.7g, 77.1mmol, 97% pure) with bisThe alkanes (14.8mL) were mixed under argon. The suspension was cooled on ice and washed with 70% HClO₄(8.68 mL). After 10min, ice-cooled water (130mL) was added at 0 deg.C and the white precipitate was filtered and washed with additional ice-cooled water. The precipitate was redissolved in DCM (140 mL). Excess water was decanted and DCM was washed with Na₂SO₄And (5) drying. The DCM solution was used directly in the next step after filtration. The solution was added slowly (20min) to a cold (5 ℃) solution of 2-amino-3-methoxy-pyridine (7.97g, 64.2mmol) in DCM (100 mL). The brownish yellow suspension was stirred at room temperature for 120 minutes and then treated with tert-butyl methyl ether (120 mL). The white precipitate that formed was filtered and washed with DCM: t-butyl methyl ether (1: 1) to give 19.2g of an off-white solid. Redissolving 12.2g of the product in two under argonIn an alkane (120mL), treated with cyclopropanecarboxaldehyde (3.34mL) and heated to 90 ℃ for 2.5 hours. Additional cyclopropanecarboxaldehyde (1.11mL) was added. Heating was continued for 4 hours. The reaction mixture was cooled to 0 ℃, then treated with 1N KOH in MeOH (36mL) and allowed to stand at room temperature for 17 hours. The solvent was evaporated in vacuo and NaCl solution was added to the product. The product was extracted with DCM and the combined organic phases were taken up with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by flash silica gel chromatography using DCM-EtOA as eluent. The obtained 2-cyclopropyl-8-methoxy- [1,2,4] is a light yellow solid]Triazolo [1,5-a]Pyridine (5.15g, 76%).

¹H NMR(300MHz，CDCl₃)δ8.10(dd，1H)，6.81(bt，1H)，6.71(bd，1H)，4.01(s，3H)，2.22(m，1H)，1.18(m，2H)，1.04(m，2H)

LC/MS (System A): (m/z)190.3(MH +); rt 2.01 min; purity (UV) ═ 100%

Preparation example 2 (Compound 302)

2-cyclopropyl-5-iodo-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridines

To compound 301(5.54g, 29.3mmol) and N-iodosuccinimide (6.94g, 29.3mmol) was added BF under argon and cooling (0 ℃ C.)₃×2H₂O (14.9mL, 234 mmol). The suspension was stirred at room temperature for 20 hours, then N-iodosuccinimide (3.48g, 17.4mmol) was added. After a further 30 hours, the suspension was slowly added to saturated NaHCO₃(400mL) solution and DCM (250 mL). Na for organic phase₂S₂O₃The solution was washed and the aqueous phase was extracted with DCM (2X 250 mL). The combined organic phases were washed with Na₂SO₄Drying, filtering and vacuum concentrating. By fast siliconThe product was purified by gel chromatography using DCM-EtOA as eluent. Obtaining the 2-cyclopropyl-5-iodo-8-methoxy- [1,2,4] as a yellow-green solid]Triazolo [1,5-a]Pyridine (7.75g, 84%).

¹H NMR(300MHz，CDCl₃)δ7.26(d，1H)，6.58(d，1H)，4.01(s，3H)，2.29(m，1H)，1.22(m，2H)，1.04(m，2H)

LC/MS (System A): (m/z)316.4(MH +), Rt 2.87min, purity (UV) -80%

Example 1

Parallel Synthesis procedure for Compounds 101-142

To the solution of 2-cyclopropyl-5-iodo-8-methoxy- [1,2,4] under argon]Triazolo [1,5-a]A solution of pyridine (15.8mg, 0.05mmol) in 300. mu.L of 1, 2-dimethoxyethane was added with K₂CO₃(100. mu.L, 1N H)₂O solution, 0.1mmol or alternatively 150 μ L in case the boronic acid building block contains an acidic proton). To this mixture was added boronic acid (0.0625mmol) and tetrakis (triphenylphosphine) palladium (2.9mg, 0.0025mmol) and then heated to 80 ℃ in a closed reaction vessel for 3 days.

Brine (2mL) was added to the reaction mixture. 4N HCl (75 μ L) was added to 150 μ LK solution₂CO₃In the reaction of (1). The reaction mixture was extracted with 3mL of dichloromethane and the phases were separated using a phase separation cartridge (Chromabond, PTS). The organic phase was concentrated in vacuo and the residue was dissolved in 350 μ LN, N-dimethylformamide and purified by preparative HPLC/MS.

Example 2

2-cyclopropyl-8-methoxy-5-piperidin-1-yl- [1,2,4]Triazolo [1,5-a]Pyridine (Compound 143)

2-propanol (200. mu.L), ethylene glycol (12.4mg, 0.200mmol), piperidine (10.1mg, 0.12mmol) and 2-cyclopropyl-5-iodo-8-methoxy- [1,2, 4%]Triazolo [1,5-a]Pyridine (31.5mg, 0.100mmol) was added to cuprous iodide (1.0mg, 0.005mmol) and potassium phosphate (42.5mg, 0.200mmol), which were kept under argon. The resulting suspension was heated to 80 ℃ for 4 days. The reaction mixture was cooled to room temperature and then extracted with dichloromethane (3 mL). The organic phase was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo. By flash chromatography (SiO)₂20% to 40% EtOAc in toluene) to obtain 2-cyclopropyl-8-methoxy-5-piperidin-1-yl- [1,2,4]Triazolo [1,5-a]Pyridine (2.2 mg).

¹H NMR(300MHz，CDCl₃)δ6.97(d，1H)，6.32(d，1H)，3.87(s，3H)，3.18(m，4H)，2.16(m，1H)，1.75-1.55(m，6H)，1.05-0.90(m，4H)

LC/MS (System A): (m/z)273.5(MH +); rt 3.59min.

Example 3

1- [3- (2-cyclopropyl-8-hydroxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -phenyl]-ethanones (chemical combination) Thing 144)

Compound 101(30.7mg, 0.10mmol) was dissolved in DMF (0.70mL) in a screw vessel under argon. Tert-dodecyl mercaptan (0.41g, 2.0mmol) and K were added₂CO₃(0.138g, 1.0 mmol). The suspension was shaken at 140 ℃ for 16 hours, the suspension was poured into water, the pH was adjusted to 6 with 2N HCl, CH was added₂Cl₂The reaction mixture was extracted. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering, and concentrating. By flash Chromatography (CH)₂Cl₂Methanol 99.5: 0.5 → 97.5: 2.5). The title compound was obtained as a light-colored solid.

1H NMR(600MHz，DMSO-SPE)δ8.51(t，J＝1.7Hz，1H)，8.20-8.17(m，1H)，8.10-8.06(m，1H)，7.69(dd，J＝9.7，5.9Hz，1H)，7.36(d，J＝8.2Hz，1H)，7.22-7.19(m，1H)，4.02(s，3H)，3.49(s，2H)，3.41-3.36(m，2H)，2.65(s，3H)，2.20(s，2H)，2.07(s，2H)，2.01(s，3H)，1.47(dd，J＝7.1，4.2Hz，2H)，1.39(dd，J＝7.1，4.1Hz，2H).

Preparation example 3

(2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) boronic acids (Compound 303)

In a two-necked flask, compound 302(0.16g, 0.50mmol) was dissolved in dry THF (2mL) under argon. The solution was cooled to-78 ℃. iPrMgCl (0.5mL, 0.5mmol 1.0M in THF) was added dropwise over 5 min. Stirring at-70 deg.C for 20 min. Trimethyl borate (0.070mL, 0.63mmol) was added and the solution was stirred at room temperature for 1 h. 4N HCl in dioxin (0.5mL) was added. The suspension was concentrated, resuspended in toluene and concentrated again. The crude product was dissolved in 2N NaOH (10mL) and washed with EtOAc. To the aqueous phase was added 4N HCl (6mL) to bring the pH to 1. Using CH as the aqueous phase₂Cl₂+ 5% EtOH (. times.3) extraction and drying (Na)₂SO₄) Filtering, and concentrating. Compound 303 was obtained as a solid.

Example 4

2- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -isonicotinic acid nitrile (compound 145)

(2-cyclopropyl-8-methoxy- [1,2,4] in a screw vial under argon]Triazolo [1,5-a]Pyridin-5-yl) boronic acid Compound 303(26mg, 0.1mmol) was dissolved in DME (0.6mL) and 1MK₂CO₃(0.2 mL). 2-bromo-isonicotinic acid nitrile (18mg, 0.1mmol) and Pd (PPh) were added₃)₄(6mg, 0.005 mmol). The suspension was shaken at 80 ℃ for 17h, then brine was added and the aqueous phase was extracted with DCM (. times.3)And (6) taking. The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography (eluent, TBME: heptane 4: 1 → 9: 1). The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ9.23-9.09(m，1H)，9.00(dd，J＝4.9，0.8Hz，1H)，7.95(dd，J＝4.9，1.5Hz，1H)，7.90(d，J＝8.3Hz，1H)，7.24(d，J＝8.4Hz，1H)，4.03(s，3H)，2.29(tt，J＝8.1，5.0Hz，1H)，1.18-0.87(m，4H).

Preparation example 4

1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-cyclopropanecarboxylic acid ethyl ester (Compound) 304)

Ethyl 1-hydroxymethyl-cyclopropanecarboxylate (5.0g, 34.7mmol) was dissolved in DCM (200mL) under argon. Adding NaHCO₃(11.7g, 139mmol) and dess-martin oxidant (DessMartin periodinane) (29.4g, 69.4 mmol). The suspension was stirred at room temperature for 30 min. The temperature was maintained at 20 ℃ and saturated Na was added₂S₂O₃Solution and saturated NaHCO₃1: 1 solution of the solution (200 mL). The mixture was stirred for 20min and extracted with DCM (× 2). The combined organic phases were dried (Na)₂SO₄) Filtration and concentration gave the crude product of ethyl 1-formyl-cyclopropanecarboxylate (5.1g), which was used directly in the next step.

Under argon, the mixture is subjected toEthyl alkylsulfonyl acetylhydroxamate (22.7g, 77.1mmol, 97% pure) and dioxane (14.8mL) were combined. The suspension was ice-cooled and 70% HClO was added₄(8.68 mL). After 10min, ice cold water (130mL) was added at 0 deg.C, the white precipitate was filtered and reusedAdditional ice cold water wash. The precipitate was redissolved in DCM (140 mL). The excess water was decanted and DCM was washed with Na₂SO₄And (5) drying. After filtration, the DCM solution was used directly in the next step. The resulting solution was slowly (20min) added to a cold (5 ℃) solution of 2-amino-3-methoxy-pyridine (7.97g, 64.2mmol) in DCM (100mL) and the tan suspension was stirred at RT for 120 min before treatment with tert-butyl methyl ether (120 mL). The white precipitate formed was filtered and washed with DCM: tert-butyl methyl ether (1: 1) to give 19.2g (2,4, 6-trimethyl-benzenesulfonate-1, 2-diamino-3-methoxy-pyridinium salt) as an off-white solid.

6.11g (18mmol) of the product was redissolved in dioxane (60mL) under argon, treated with 1-formyl-cyclopropanecarboxylic acid ethyl ester (5.1g, 27mmol) and heated to 90 ℃ for 17 h. The reaction mixture was cooled to room temperature, treated with 1N KOH in MeOH (18mL), and allowed to stand at room temperature for 24 h. The solvent was evaporated in vacuo and NaCl solution was added to the product. The product was extracted with DCM and the combined organic phases were taken up with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by flash chromatography on silica gel using DCM-EtOA as eluent. The title compound (4.15g) was obtained as a pale yellow solid.

1H NMR(300MHz，CDCl3)δ8.17(dd，J＝6.8，0.8Hz，1H)，6.89(dd，J＝7.8，6.8Hz，1H)，6.79-6.70(m，1H)，4.18(q，J＝7.1，2H)，4.03(s，3H)，1.72(dt，J＝6.7，3.5Hz，2H)，1.62-1.52(m，2H)，1.20(t，J＝7.1Hz，3H).

Preparation example 5

1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-cyclopropanecarboxylic acid ethyl ester (Compound No.) Thing 305)

In an argon atmosphereThen, 1- (8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid ethyl ester (4.1g, 13.7mmol) was combined with N-iodosuccinimide (4.9g, 21.9 mmol). Addition of BF at 20 DEG C₃＊2H₂O (7.0mL, 110 mmol). The dark suspension was stirred at room temperature for 24 h. NIS (2.5g) and BF were added₃＊2H₂O (2.0mL), the suspension was stirred for 24 h. NIS (2.5g) and BF were added₃＊2H₂O (2.0mL), the suspension was stirred for another 24h and then poured into saturated Na₂S₂O₃Solution and saturated NaHCO₃1: 1 solution (300 mL). The aqueous phase was extracted with DCM and the combined organic phases were washed with brine, Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM-EtOA as eluent. The title compound (4.1g) was obtained as a colorless solid.

1H NMR(300MHz，CDCl3)δ7.33(d，J＝8.1Hz，1H)，6.62(d，J＝8.1Hz，1H)，4.16(q，J＝7.1Hz，2H)，4.02(s，3H)，1.73(dd，J＝7.5，4.3Hz，2H)，1.63-1.54(m，2H)，1.20(t，J＝7.1Hz，3H).

Example 5

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Ethyl acid ester (Compound 146)

1- (5-iodo-8-methoxy- [1,2,4] under argon atmosphere]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid ethyl ester (0.50g, 1.3mmol) was dissolved in DME (7.8 mL). Add 1M K₂CO₃Aqueous solution (2.6mL), followed by 4-CN-phenylboronic acid (0.38g, 2.6mmol) and Pd (PPh)₃)₄(75.1mg, 0.065 mmol). The reaction mixture is added inStirred at 80 ℃ for 17h and then cooled to room temperature. The resulting suspension was poured into brine and the aqueous phase was extracted with DCM. The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: EtOAc 20: 1 → 10: 1 as eluent. The title compound was obtained as a pale solid.

1H NMR(300MHz，CDCl3)δ8.12-8.05(m，2H)，7.82-7.75(m，2H)，7.07(d，J＝8.1Hz，1H)，6.89(t，J＝6.3Hz，1H)，4.17(q，J＝7.2Hz，2H)，4.09(s，3H)，1.72(dt，J＝6.8，3.6Hz，2H)，1.62-1.54(m，2H)，1.22(t，J＝7.1Hz，3H).

Example 6

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (Compound 147)

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropanecarboxylic acid ethyl ester (0.39g, 1.08mmol) was suspended in 1, 4-dioxane (10mL) and aqueous LiOH solution (68mg, 1.6mmol in 1.6mL water) and stirred at room temperature for 17 h. The reaction mixture was concentrated in vacuo. The crude product was suspended in water (3mL) and 4N HCl (0.6mL) was added. The aqueous phase was extracted with DCM (. times.3), and the combined organic phases were extracted with Na₂SO₄Drying, filtering and vacuum concentrating. The title compound was obtained as a pale solid.

1H NMR(300MHz，CDCl3)δ8.02-7.92(m，2H)，7.87-7.77(m，2H)，7.14(d，J＝8.3Hz，1H)，7.01(d，J＝8.2Hz，1H)，4.12(s，3H)，1.99(dd，J＝7.8，3.5Hz，2H)，1.78(dd，J＝7.6，3.8Hz，2H).

Example 7

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid amides (Compound 148)

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]Cyclopropanecarboxylic acid (27mg, 0.08mmol) was dissolved in DCM (0.3 mL). Oxalyl chloride (0.008mL, 0.09mmol) and one drop of DMF were added. Stirring for 5 min. Oxalyl chloride (0.003mL) was added. After 20min, the suspension was concentrated and resuspended in dioxane (0.3 mL). Addition of NH₃Aqueous solution (25%, 0.1 mL). The suspension was stirred at room temperature for 2h and then concentrated in vacuo. Mixing the crude product with Na₂CO₃The aqueous solutions were mixed and the aqueous phase was extracted with DCM (. times.3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The title compound was obtained as a pale solid.

1H NMR(300MHz，DMSO)δ8.21-8.12(m，2H)，8.04-7.98(m，2H)，7.95(s，1H)，7.41(d，J＝8.2Hz，1H)，7.35(s，1H)，7.24(d，J＝8.3Hz，1H)，4.04(s，3H)，1.50(dd，J＝6.9，3.5Hz，2H)，1.37(dd，J＝7.0，3.5Hz，2H).

Preparation example 6

1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-cyclopropanecarboxylic acid (compound) 306)

1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid ethyl ester (compound 305) (0.06g, 0.16mmol) was suspended in 1, 4-dioxane (1.4mL) and LiOH (0.01g, 0.23mmol) in H was added₂O solution (0.23 mL). The suspension was stirred for 15 h. The mixture was concentrated in vacuo. Addition of H₂O and 4N HCl (0.085 mL). Brine was added and the aqueous phase was extracted with DCM (× 3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The title compound was obtained as a pale solid.

Preparation example 7

1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid isopropyl acyl Amine (Compound 307)

Under argon, 1- (5-iodo-8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -Cyclopropanecarboxylic acid (Compound 306) (0.05g, 0.14mmol) was dissolved in DMF (0.5mL) and Et₃N (0.058mL, 0.42 mmol). HATU (0.082g, 0.21mmol) and isopropylamine (0.018mL, 0.21mmol) were added. The solution was stirred at room temperature for 2 h. Addition of H₂O, aqueous phase extracted with EtOAc (× 3). Combined organic phases with H₂O and brine, Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: EtOAc 9: 1 → 3: 1 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，CDCl3)δ9.00(bs，1H)，7.34(d，J＝8.1Hz，1H)，6.66(d，J＝8.1Hz，1H)，4.25-4.10(m，1H)，4.04(s，3H)，1.88-1.81(m，2H)，1.71-1.64(m，2H)，1.29(d，J＝6.9Hz，3H)，1.26(d，J＝6.9Hz，3H).

Example 8

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid isopropylamide (Compound 149)

Under argon, 1- (5-iodo-8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -Cyclopropanecarboxylic acid isopropylamide (Compound 307) (0.022g, 0.055mmol) was dissolved in DME (0.33mL) and 1M K₂CO₃(0.11 mL). 5-CN-3-pyridylboronic acid (0.016g, 0.11mmol) was added followed by Pd (PPh)₃)₄(0.003g, 0.003 mmol). The mixture was shaken at 80 ℃ for 20 h. Brine was added and the aqueous phase was extracted with DCM (× 3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: EtOAc 3: 7 → 15: 85 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ9.42(d，J＝2.2Hz，1H)，9.14(d，J＝2.0Hz，1H)，8.90(t，J＝2.1Hz，1H)，8.29(d，J＝7.5Hz，1H)，7.54-7.48(m，1H)，7.28(d，J＝8.3Hz，1H)，4.05(s，3H)，3.96(td，J＝13.2，6.5Hz，1H)，1.52(dd，J＝6.9，3.5Hz，2H)，1.41(dd，J＝7.0，3.4Hz，2H)，1.10(d，J＝6.6Hz，6H).

Preparation example 8

[1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]-methanol (compound) 308)

In N₂To a solution of 1- (tert-butyl-diphenyl-silanyloxymethyl) -cyclopropanecarboxaldehyde (7.0g, 20.71mmol) in dioxane (175mL) was added 2,4, 6-trimethyl-benzenesulfonate 1, 2-diamino-3-methoxy-pyridinium salt (6.9g, 20.71mmol, prepared as described for preparation of compound (304)) under gas and the reaction mixture was heated to reflux. After 24h, the reaction mixture was cooled to room temperature and the N was removed₂After the atmosphere, 1M KOH (20.71mmol, 20ml) was added slowly. The reaction mixture was stirred further. After 1h, the reaction mixture was concentrated and the residue was dissolved in EtOAc. The organic phase was washed with water and anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 2- (1- ((tert-butyldiphenylsilyloxy) methyl) cyclopropyl) -8-methoxy- [1,2,4 as a solid]Triazolo [1,5-a]Pyridine (4.5g, 47%).

To 2- (1- ((tert-butyldiphenylsilyloxy) methyl) cyclopropyl) -8-methoxy- [1,2,4 at room temperature]Triazolo [1,5-a]A solution of pyridine (4.5g, 9.84mmol) in dry THF (40mL) was added TBAF (38.38mmol, 1M in THF), and the mixture was stirred further. After 16h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The obtained residue was purified by column chromatography to give (1- (8-methoxy- [1,2, 4) as a solid]Triazolo [1,5-a]Pyridin-2-yl) cyclopropyl) methanol (1.7g, 79%).

Reacting (1- (8-methoxy- [1,2,4 ]) at room temperature]Triazolo [1,5-a]Pyridin-2-yl) cyclopropyl) methanol (1.7g, 7.76mmol) and N-iodosuccinimide (1.7g, 7.76mmol) mixtures were BF treated with BF₃.2H₂O (8.5g, 77.6mmol, 5.3 ml). After 24h, the reaction mixture was poured into NaHCO₃(1M) and Na₂S₂O₃(1M) in a 1: 1 mixture of aqueous solutions, then extracted with DCM. Combined organic phases with H₂Washing with O, and passing through anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatographyTo obtain (1- (5-iodo-8-methoxy- [1,2, 4) as a solid]Triazolo [1,5-a]Pyridin-2-yl) cyclopropyl) methanol.

1H NMR(300MHz，dmso)δ7.47(d，J＝8.2Hz，1H)，6.89(d，J＝8.2Hz，1H)，4.63(t，J＝5.8Hz，1H)，3.93(s，3H)，3.90(m，2H)，1.09(t，J＝5.0Hz，2H)，1.03(t，J＝5.0Hz，2H).

Example 9

3- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-5-yl]-benzyl Nitrile (Compound 150)

Mixing [1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methanol (Compound 308) (0.24g, 0.07mmol) dissolved in DME (4.5mL) and 1M K₂CO₃(1.4 mL). 5-CN-3-pyridylboronic acid (0.21g, 1.4mmol) was added followed by Pd (PPh)₃)₄(0.04g, 0.035 mmol). The reaction mixture was shaken at 80 ℃ for 18 h. Brine was added and the aqueous phase was extracted with DCM (× 3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: MeOH 99: 1 as eluent. The impure product was suspended in 2-propanol and filtered to give the title compound as a solid.

1H NMR(300MHz，DMSO)δ8.45(t，J＝1.5Hz，1H)，8.38-8.31(m，1H)，7.95(dt，J＝7.7，1.2Hz，1H)，7.75(t，J＝8.0Hz，1H)，7.36(d，J＝8.1Hz，1H)，7.16(d，J＝8.3Hz，1H)，4.61(t，J＝5.7Hz，1H)，4.01(s，3H)，3.89(d，J＝5.4Hz，2H)，1.10(dd，J＝6.3，3.9Hz，2H)，1.03(dd，J＝6.3，3.8Hz，2H).

Example 10

Pyrrolidine-1-carboxylic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine compound -2-yl]-cyclopropylmethyl ester (Compound 151)

Under argon, 3- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl]-benzonitrile (compound 150) (0.03g, 0.08mmol) was dissolved in DMF (0.5 mL). NaH (0.02g, 0.48mmol) was added, the suspension was heated to 65 ℃ for 1h, then 1-pyrrolidinecarbonyl chloride (0.088mL, 0.8mmol) was added. Stir at 65 ℃ for 1 h. The reaction mixture was cooled and NaHCO was added₃Aqueous solution and H₂And O. The aqueous phase was extracted with EtOAc (. times.2). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: MeOH 99: 1 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ8.43(d，J＝1.4Hz，1H)，8.33(d，J＝8.1Hz，1H)，7.95(d，J＝7.8Hz，1H)，7.73(t，J＝7.9Hz，1H)，7.37(d，J＝8.2Hz，1H)，7.18(d，J＝8.2Hz，1H)，4.41(s，2H)，4.01(s，3H)，3.19(d，J＝18.8Hz，4H)，1.72(t，J＝6.5Hz，4H)，1.26(dd，J＝6.4，4.1Hz，2H)，1.15(dd，J＝6.5，4.1Hz，2H).

Example 11

Isopropyl-carbamic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine (II) Pyridin-2-yl]-cyclopropylmethyl ester (compound 152)

Under argon, 3- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl]-benzonitrile (compound 150) (0.03g, 0.08mmol) in CH₃CN (1 mL). Et was added₃N (0.005mL) and isopropyl isocyanate (0.04mL) and the reaction mixture was shaken at 65 ℃ for 20 h. Then Et is added₃N (0.005mL) and isopropyl isocyanate (0.04mL) and the reaction mixture was shaken at 65 ℃ for an additional 24 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel with DCM: MeOH 99: 1 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ8.41(s，1H)，8.37(d，J＝8.1Hz，1H)，7.95(d，J＝7.8Hz，1H)，7.72(t，J＝7.9Hz，1H)，7.39(d，J＝8.2Hz，1H)，7.18(d，J＝8.3Hz，1H)，6.93(d，J＝7.6Hz，1H)，4.40(s，2H)，4.01(s，3H)，3.65-3.48(m，1H)，1.25(dd，J＝6.3，4.1Hz，2H)，1.12(dd，J＝6.4，4.O Hz，2H)，0.98(d，J＝6.5Hz，6H).

Example 12

3- [2- (1-benzyloxymethyl-cyclopropyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine-5- Base of]-benzonitrile (compound 153)

Under argon atmosphere, [1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methanol (compound 150) (0.033g, 0.06mmol) was dissolved in DMF (0.5 mL). NaH (0.014g, 0.36mmol) was added and the suspension was added at 65 deg.CHeat for 1h, then add benzyl bromide (0.071mL, 0.6 mmol). The reaction mixture was stirred at 65 ℃ for 30min and then cooled to room temperature. Adding NaHCO₃Aqueous solution and H₂And O. The aqueous phase was extracted with EtOAc (. times.2). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: MeOH 99: 1 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ8.47(t，J＝1.5Hz，1H)，8.37-8.28(m，1H)，8.00-7.90(m，1H)，7.72(t，J＝7.9Hz，1H)，7.37(d，J＝8.2Hz，1H)，7.29-7.22(m，5H)，7.17(d，J＝8.3Hz，1H)，4.55(s，2H)，4.01(s，3H)，3.97-3.80(m，2H)，1.27-1.15(m，2H)，1.07(dd，J＝6.4，3.9Hz，2H).

Preparation example 9

C- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]-methylamine (compound) 309)

1- (tert-Butoxycarbonylamino-methyl) -cyclopropanecarboxylic acid (3.23g, 15.0mmol) was dissolved in THF (50mL) under argon and cooled to-70 ℃. Tetrahydrofuran borane complex (1M in THF, 22.5mL, 22.5mmol) was added at-70 ℃. The mixture was stirred at 0 ℃ for 2.5h, then tetrahydrofuran borane complex (1M in THF, 7.5mL, 7.5mmol) was added at 0 ℃. The mixture was stirred at room temperature for 1.5 h. NH was added at 20 deg.C₄Aqueous Cl (50mL) and aqueous phase extracted with EtOAc (. times.3). The combined organic phases are washed with Na₂SO₄Drying, filtration and concentration in vacuo gave (1-hydroxymethyl-cyclopropylmethyl) -carbamic acid tert-butyl ester (2.6g) as an oil.

Oxalyl chloride (1.17mL, 13.8mmol) was dissolved in DCM (30mL) under argon and cooled to-At 70 ℃. A solution of DMSO (1.95mL, 27.6mmol) in DCM (2.5mL) was added over 5min and stirred for 10 min. A solution of (1-hydroxymethyl-cyclopropylmethyl) -carbamic acid tert-butyl ester (2.6g, 12mmol) in DCM (8.5mL) was added at-70 ℃ over 5min and the mixture was stirred for 30 min. Et was added over 5min₃N (6.4mL, 45.6mmol), the temperature was brought to room temperature over 1 h. Addition of H₂O, aqueous phase extracted with DCM (. times.2). The combined organic phases were washed with brine, over Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using heptane: EtOAc 1: 15 as eluent. This gave tert-butyl (1-formyl-cyclopropylmethyl) -carbamate (0.65g) as an oil.

(1-formyl-cyclopropylmethyl) -carbamic acid tert-butyl ester (0.63g, 3.19mmol) was dissolved in dioxane (8.2mL) under argon and 2,4, 6-trimethyl-benzenesulfonate 1, 2-diamino-3-methoxy-pyridinium salt (0.73g, 2.13mmol, prepared as described for compound 304) was added. The suspension was heated to 90 ℃ for 4 days. The reaction mixture was cooled to room temperature, treated with 1N KOH in MeOH (2.13mL), and stirred at room temperature for 24 h. The solvent was evaporated in vacuo and NaCl solution was added to the product. The product was extracted with DCM and the combined organic phases were taken up with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by flash chromatography on silica gel using toluene/EtOAc 85: 15 → 70: 30 as eluent to give [1- (8-methoxy- [1,2,4] as a solid]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]-carbamic acid tert-butyl ester (0.37 g).

Under argon atmosphere, [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Tert-butyl carbamate (0.37g, 1.16mmol) was mixed with N-iodosuccinimide (0.42g, 1.9 mmol). Addition of BF at 20 DEG C₃＊2H₂O (0.6mL, 9.3mmol), the dark suspension was stirred at room temperature for 24h, then it was poured into 1: 1 saturated Na₂S₂O₃Solution and saturated NaHCO₃In solution (30 mL). The aqueous phase was extracted with DCM and the combined organic phases were washed with brine and Na₂SO₄Drying, filtering and vacuum-pumpingAnd (5) concentrating. By using DCM: MeOH: NH₃The crude product was purified by flash chromatography on silica gel using 95: 5: 0.5 as eluent. To obtain boc-deprotected compound C- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]-methylamine.

1H NMR(300MHz，DMSO)δ8.47-8.36(m，1H)，7.04-6.93(m，2H)，3.95(s，3H)，2.96(s，2H)，1.11(dd，J＝6.4，3.8Hz，2H)，0.98(dd，J＝6.4，3.8Hz，2H).

Example 13

N- {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4 [ ]]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl group Methyl } -isobutyramide (Compound 154)

Under argon, adding C- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methylamine (0.05g, 0.23mmol) dissolved in THF (1mL) and Et₃N (0.048mL, 0.35 mmol). Isobutyryl chloride (0.03mL, 0.29mmol) was added. Stirring for 30 min. Adding NaHCO₃Aqueous solution and H₂And O. The aqueous phase was extracted with DCM (. times.3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating to obtain solid N- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]-isobutyramide.

Under argon, N- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Isobutyramide (0.063g, 0.22mmol) was combined with N-iodosuccinimide (0.15g, 0.65 mmol). Addition of BF at 0 DEG C₃＊2H₂O (0.47mL, 7.4 mmol). The dark suspension was stirred at room temperature for 3h and then poured into 1: 1 saturated Na₂S₂O₃Solution and saturated NaHCO₃In solution (20 mL). The aqueous phase was extracted with DCM (. times.2), the combined organic phases were washed with brine, and Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using EtOAc: toluene 3: 1 → 7: 1 as eluent. The solid N- [1- (5-iodo-8-methoxy- [1,2,4] is obtained]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]-isobutyramide.

In a screw vial, N- [1- (5-iodo-8-methoxy- [1,2,4] is placed under argon]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Isobutyramide (0.03g, 0.07mmol) was dissolved in DME (0.45mL) and 1M K₂CO₃(0.14 mL). 3-cyanophenylboronic acid (0.021g, 0.15mmol) and Pd (PPh) were added₃)₄(4mg, 0.004 mmol). The suspension was shaken at 80 ℃ for 17h, then brine was added and the aqueous phase was extracted with DCM (. times.3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography using toluene/EtOAc 1: 7 → 0: 100 as eluent. The title compound was obtained as an oil.

1H NMR(300MHz，DMSO)δ8.45(t，J＝1.6Hz，1H)，8.37(ddd，J＝8.0，1.8，1.2Hz，1H)，7.98-7.91(m，1H)，7.74(t，J＝8.1Hz，1H)，7.67-7.60(m，2H)，7.37(d，J＝8.3Hz，1H)，7.18(d，J＝8.3Hz，1H)，4.01(s，3H)，3.66(d，J＝5.8Hz，2H)，2.43-2.32(m，1H)，1.12(t，J＝3.0Hz，2H)，0.99(dd，J＝6.7，4.2Hz，2H)，0.95(d，J＝6.9Hz，6H).

Example 14

{1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl methyl Yl } -carbamic acid cyclopentyl ester (compound 155)

Under argon, adding C- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methylamine (0.063g, 0.29mmol) dissolved in THF (1mL) and Et₃N (0.06mL, 0.43 mmol). Cyclopentyl chloroformate (0.053g, 036mmol) was added. Stir at rt for 24 h. Adding NaHCO₃Aqueous solution and H₂And O. The aqueous phase was extracted with DCM (. times.3). The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. Purification of the crude product by flash chromatography using toluene/EtOAc 2: 1 → 1: 1 as eluent gave [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Cyclopentyl carbamate.

Under argon atmosphere, [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Cyclopentyl-carbamate is mixed with N-iodosuccinimide. Addition of BF at 0 DEG C₃＊2H₂And O. The dark suspension was stirred at room temperature for 3h and then poured into 1: 1 saturated Na₂S₂O₃Solution and saturated NaHCO₃In solution (20 mL). The aqueous phase was extracted with DCM (. times.2), the combined organic phases were washed with brine, and Na₂SO₄Drying, filtering and vacuum concentrating. Purifying the crude product by flash silica gel chromatography to obtain [1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Cyclopentyl carbamate.

In a screw-top vial under argon, [1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Cyclopentyl carbamate in DME (0.45mL) and 1MK₂CO₃(0.14 mL). 3-cyanophenylboronic acid (0.021g, 0.15mmol) and Pd (PPh) were added₃)₄(4mg, 0.004 mmol). The suspension was shaken at 80 ℃ for 17h, then brine was added and the aqueous phase was extracted with DCM (. times.3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography using EtOAc: toluene 1: 1 → 2: 1 as eluent to give the title compound as an oil.

1H NMR(300MHz，DMSO)δ8.41(d，J＝1.5Hz，1H)，8.36-8.27(m，1H)，8.01-7.90(m，1H)，7.75(t，J＝7.9Hz，1H)，7.34(d，J＝8.1Hz，1H)，7.18(d，J＝8.3Hz，1H)，5.92(t，J＝5.9Hz，1H)，4.01(s，3H)，3.61(d，J＝5.9Hz，2H)，3.21-3.08(m，4H)，1.76(dd，J＝8.0，5.2Hz，4H)，1.15-0.97(m，4H).

Example 15

Pyrrolidine-1-carboxylic acid {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine compound -2-yl]-cyclopropylmethyl } amide (compound 156)

Under argon, adding C- [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methylamine (0.050g, 0.23mmol) dissolved in THF (1mL) and Et₃N (0.048mL, 0.35 mmol). 1-Pyrrolidinecarbonyl chloride (0.032mL, 0.29mmol) was added. Stir at rt for 24 h. Adding NaHCO₃Aqueous solution and H₂And O. The aqueous phase was extracted with DCM (. times.3). The combined organic phases were washed with Na₂SO₄Drying, filtering and vacuum concentrating to obtain pyrrolidine-1-carboxylic acid [1- (8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]And (3) amide crude product.

Pyrrolidine-1-carboxylic acid [1- (8-methoxy- [1,2,4] under argon]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Amide (0.085g, 0.23mmol) was combined with N-iodosuccinimide (0.16g, 0.69 mmol). Addition of BF at 0 DEG C₃＊2H₂O (0.5mL, 7.8 mmol). The dark suspension was stirred at room temperature for 4h, then N-iodosuccinimide (0.08gl) and BF were added₃＊2H₂O (0.25 mL). The suspension was stirred for 24h and then poured into 1: 1 saturated Na₂S₂O₃Solution and saturated NaHCO₃Solutions of(30 mL). The aqueous phase was extracted with DCM (. times.2), the combined organic phases were washed with brine, and Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using DCM: MeOH 97: 3 as eluent. To obtain the pyrrolidine-1-carboxylic acid [1- (5-iodine-8-methoxyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]An amide.

Pyrrolidine-1-carboxylic acid [1- (5-iodo-8-methoxy- [1,2,4] was reacted in a screw vial under argon]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropylmethyl]Amide dissolution in DME (0.45mL) and 1MK₂CO₃(0.14 mL). 3-cyanophenylboronic acid (0.021g, 0.15mmol) and Pd (PPh) were added₃)₄(4mg, 0.004 mmol). The suspension was shaken at 80 ℃ for 17h, then brine was added and the aqueous phase was extracted with DCM (. times.3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using DCM: MeOH 97: 3 as eluent. The title compound is obtained in amorphous form.

1H NMR(300MHz，DMSO)δ8.41(t，J＝1.4Hz，1H)，8.32(ddd，J＝8.0，1.7，1.2Hz，1H)，8.00-7.92(m，1H)，7.74(t，J＝8.0Hz，1H)，7.34(d，J＝8.2Hz，1H)，7.18(d，J＝8.2Hz，1H)，5.91(t，J＝5.9Hz，1H)，4.01(s，3H)，3.61(d，J＝6.0Hz，2H)，3.20-3.10(m，4H)，1.79-1.71(m，4H)，1.14-0.99(m，4H).

Preparation example 10

2-cyclopropyl-8-methoxy-5-trimethylstannanyl- [1,2,4]]Triazolo [1,5-a]Pyridine (Compound) 310)

Hexamethyldisilazane (0.63g, 1.9mmol) was dissolved in toluene (9mL) under argon. Adding 2-cyclopropyl-5-iodo-8-methoxy- [1,2, 4%]Triazolo [1,5-a]Pyridine (0.49g,1.5mmol) and then (PPh) is added₃)₂Pd(OAc)₂(0.041g, 0.055 mmol). The dark suspension was stirred at 100 ℃ for 1 h. KF (10% in H) was added at room temperature₂O, 4.2mL), the mixture was stirred at room temperature for 2 h. The mixture was filtered through celite and washed with toluene. The filtrate was extracted with toluene (. times.2). The combined organic phases were washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using toluene/EtOAc 10: 1 as eluent. The title compound was obtained as an oil.

Example 17

6- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -5-methyl-4, 5-dihydro -2H-pyridazin-3-one (Compound 158)

Under argon, 2-cyclopropyl-8-methoxy-5-trimethylstannyl- [1,2,4] is reacted]Triazolo [1,5-a]Pyridine (compound 310) (1.33g, 3.8mmol) was dissolved in toluene (20 mL). Propionyl chloride (0.39g, 4.2mmol) and Pd were added₂(dba)₃(0.087g, 0.095 mmol). The solution was heated at 70 ℃ for 2.5h, then NaHCO was added₃An aqueous solution. For aqueous phaseAnd (4) extracting. The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography using toluene/EtOAc 8: 2 → 7: 3 as eluent to give 1- (2-cyclopropyl-8-methoxy- [1,2,4] as a solid]Triazolo [1,5-]Pyridin-5-yl) -propyl-1-one.

1- (2-cyclopropyl-8-methoxy- [1,2,4] under argon]Triazolo [1,5-]Pyridine compound-5-yl) -propan-1-one (0.42g, 1.7mmol) was dissolved in THF (5.0 mL). The solution was cooled to-70 ℃ and lithium bis (trimethylsilyl) amide (1M in THF, 1.96mL, 1.96mmol) was added over 3 minutes. The cooling bath was removed and the suspension was stirred at room temperature for 40 min. The suspension was cooled to-70 ℃ and tert-butyl bromoacetate (0.29mL, 1.96mmol) was added. The solution was stirred at room temperature for 22h, then NH was added₄Aqueous Cl solution. For aqueous phaseAnd (4) extracting. The combined organic phases were washed with brine, Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography on silica gel using toluene: EtOAc 85: 15 as eluent. To obtain 4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -3-methyl-4-oxo-butyric acid tert-butyl ester.

Under argon, 4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -3-methyl-4-oxo-butyric acid tert-butyl ester (0.29g) was dissolved in trifluoroacetic acid (0.6mL), stirred at room temperature for 2h, and the mixture was concentrated in vacuo. The crude product was suspended in 1N NaOH (5mL) and treated with Et₂O (. times.2) washing. The aqueous phase was adjusted to pH1 with 4N HCl (1.5 mL). The aqueous phase was extracted with DCM (. times.2), and the combined organic phases were extracted with Na₂SO₄Drying, filtering and vacuum concentrating to obtain 4- (2-cyclopropyl-8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-5-yl) -3-methyl-4-oxo-butyric acid crude product.

Under argon, 4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -3-methyl-4-oxo-butyric acid (0.1g, ca. 0.33mmol) was dissolved in EtOH (1.5 mL). AcOH (0.11mL, 1.98mmol) and NH were added₂NH₂＊H₂O (0.048mL, 0.99 mmol). The solution was heated to reflux for 17h, then concentrated in vacuo and co-concentrated with toluene. Adding NaHCO₃Aqueous solutions, for aqueous phasesAnd (4) extracting. The combined organic phases are washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography with EtOAc as eluent to give the title compound as a solid.

1H NMR(300MHz，DMSO)δ11.17(s，1H)，7.16(d，J＝8.1Hz，1H)，7.09(d，J＝8.2Hz，1H)，3.98(s，3H)，3.66-3.50(m，1H)，2.72(dd，J＝16.7，6.7Hz，1H)，2.34(dd，J＝16.8，5.1Hz，1H)，2.22-2.10(m，1H)，1.10-1.00(m，5H)，0.99-0.92(m，2H).

General procedure 1

Compound 310(25mg, 0.07mmol) was dissolved in toluene (0.8mL) under argon. Aryl bromide or heteroaryl bromide (0.085mmol) was added followed by Pd (PPh)₃)₄(3mg, 0.003 mmol). The mixture was shaken at 100 ℃ for 24 h. The mixture was cooled, filtered through celite, and the filter was then washed with 0.5mL of toluene. The filtrate was purified by preparative HPLC/MS to give the title compound.

Example 18:

compound 159-171 was prepared according to general procedure 1.

5- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -nicotinonitrile (Compound 159)

1H NMR(300MHz，DMSO)δ9.41(d，J＝2.2Hz，1H)，9.11(d，J＝1.9Hz，1H)，8.89(t，J＝2.1Hz，1H)，7.44(d，J＝8.2Hz，1H)，7.19(d，J＝8.3Hz，1H)，4.01(s，3H)，2.29-2.10(m，1H)，1.12-0.89(m，4H).

5- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl-indan-1-ones Thing 160)

1H NMR(300MHz，DMSO)δ8.13(s，1H)，7.96(d，J＝8.1Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.28(d，J＝8.1Hz，1H)，7.15(d，J＝8.3Hz，1H)，4.00(s，3H)，3.25-3.10(m，2H)，2.78-2.62(m，2H)，2.16(tt，J＝8.1，5.0Hz，1H)，1.11-0.88(m，4H).

4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -2-methyl-benzonitrile Compound 161)

1H NMR(300MHz，DMSO)δ8.01(s，1H)，8.01-7.96(m，1H)，7.92(d，J＝8.1Hz，1H)，7.29(d，J＝8.3Hz，1H)，7.19-7.09(m，1H)，3.99(d，J＝4.4Hz，3H)，2.57(s，3H)，2.16(tt，J＝8.1，5.0Hz，1H)，1.09-0.91(m，4H).

4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl-indan-1-ones Thing 162)

1H NMR(300MHz，CDCl3)δ7.91(dd，J＝7.6，0.9Hz，1H)，7.75(dd，J＝7.4，1.1Hz，1H)，7.53(t，J＝7.6Hz，1H)，6.84(s，2H)，4.08(s，3H)，3.08-2.98(m，2H)，2.76-2.65(m，2H)，2.19(tt，J＝8.4，4.9Hz，1H)，1.22-1.13(m，2H)，1.05-0.98(m，2H).

3- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -5-fluoro-benzonitrile (Compound) Thing 164)

1HNMR(300MHz，DMSO)δ8.32(t，J＝1.4Hz，1H)，8.27(ddd，J＝10.2，2.3，1.6Hz，1H)，7.98(ddd，J＝8.4，2.5，1.3Hz，1H)，7.41(d，J＝8.1Hz，1H)，7.16(d，J＝8.3Hz，1H)，4.01(s，3H)，2.20(tt，J＝8.2，4.9Hz，1H)，1.10-0.90(m，4H).

4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -2-fluoro-benzonitrile (Compound) Thing 165)

1H NMR(300MHz，DMSO)δ8.26-8.17(m，1H)，8.13-8.06(m，2H)，7.44(d，J＝8.3Hz，1H)，7.17(d，J＝8.3Hz，1H)，4.01(s，3H)，2.24-2.14(tt，J＝8.1，5.0Hz，1H)，1.11-0.90(m，4H).

4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -2-methoxy-benzonitrile (Compound 166)

1H NMR(300MHz，DMSO)δ7.88(d，J＝8.1Hz，1H)，7.83(d，J＝1.2Hz，1H)，7.73-7.68(m，1H)，7.39(d，J＝8.1Hz，1H)，7.16(d，J＝8.3Hz，1H)，4.01(d，J＝0.9Hz，6H)，2.18(tt，J＝8.2，5.0Hz，1H)，1.09-0.91(m，4H).

5- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -3H-isobenzofuran -1-one (Compound 167)

1H NMR(300MHz，DMSO)δ8.24(s，1H)，8.15-8.09(m，1H)，7.99(d，J＝8.1Hz，1H)，7.30(d，J＝8.2Hz，1H)，7.17(d，J＝8.2Hz，1H)，5.51(s，2H)，4.01(s，3H)，2.26-2.05(m，1H)，1.14-0.85(m，4H).

3- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -5-hydroxymethyl-benzonitrile (Compound 168)

1H NMR(300MHz，DMSO)δ8.53(s，1H)，8.28(s，1H)，8.19(s，1H)，7.85(s，1H)，7.29(d，J＝8.1Hz，1H)，7.18(d，J＝6.9Hz，1H)，4.65(s，2H)，4.00(s，3H)，2.25-2.10(m，1H)，1.07-0.93(m，4H).

3- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -5-methoxy-benzonitrile (Compound 169)

1H NMR(300MHz，DMSO)δ7.97(t，J＝1.3Hz，1H)，7.88(dd，J＝2.5，1.6Hz，1H)，7.56(dd，J＝2.5，1.3Hz，1H)，7.34(d，J＝8.2Hz，1H)，7.14(d，J＝8.2Hz，1H)，4.00(s，3H)，3.90(s，3H)，2.18(dq，J＝8.2，4.9Hz，1H)，1.02(dt，J＝7.7，2.5Hz，2H)，0.99-0.95(m，2H).

4- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -3H-isobenzofuran -1-one (Compound 170)

And (3) purification: a solid precipitated during the reaction. The solid was filtered and purified by preparative HPLC/MS.

1H NMR(300MHz，DMSO)δ8.12(dd，J＝7.6，0.8Hz，1H)，8.02(d，J＝7.0Hz，1H)，7.79(t，J＝7.6Hz，1H)，7.25(d，J＝8.1Hz，1H)，7.15(d，J＝8.1Hz，1H)，5.47(s，2H)，4.01(s，3H)，2.25-2.10(m，1H)，1.08-0.85(m，4H).

5- (2-cyclopropyl-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-5-yl) -2, 3-dihydro-isoindoles -1-one (Compound 171)

And (3) purification: a solid precipitated during the reaction. The solid was filtered and purified by preparative HPLC/MS.

1H NMR(300MHz，DMSO)δ8.67(s，1H)，8.12(s，1H)，8.05-7.97(m，1H)，7.81(d，J＝8.0Hz，1H)，7.24(d，J＝8.2Hz，1H)，7.15(d，J＝8.2Hz，1H)，4.47(s，2H)，4.00(s，3H)，2.22-2.09(m，1H)，1.08-0.89(m，4H).

General procedure 2

Under argon, 1- (5-iodo-8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid, compound 306(0.075g, 0.20mmol), was dissolved in DMF (0.7 mL). Et was added₃N (0.086mL, 0.6mmol) and HATU (0.12g, 0.3 mmol). Amine (0.3mmol) was added and the mixture was shaken at room temperature for 2 h. The solvent was concentrated in vacuo and NaHCO was added₃Aqueous solution (1 mL). The aqueous phase was shaken with DCM (1.5mL) and the phases were separated using a phase separation cartridge (Chromabond, PTS). The organic phase was concentrated and the crude product was used directly in the next step.

The crude iodide (ca. 0.03mmol) was dissolved in 1, 4-dioxane (0.5mL) and H under argon₂O (0.25 mL). Argon was bubbled through the mixture. Adding boronic acid or boronic ester and K₃PO₄(3.5eq) followed by addition of Pd₂(dba)₃(0.01eq) and PCy₃(0.02 eq). The mixture was heated in a microwave oven at 100 ℃ for 5 min. The reaction mixture was filtered and the filtrate was purified by preparative HPLC/MS.

Example 19:

compounds 172-178 and 180-186 were prepared according to general procedure 2.

General procedure 3

Under argon, 1- (5-iodo-8-methoxy)Radical- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid, compound 306(0.075g, 0.20mmol), was dissolved in DMF (0.7 mL). Et was added₃N (0.086mL, 0.6mmol) and HATU (0.12g, 0.3 mmol). Amine (0.3mmol) was added and the mixture was shaken 2H at room temperature. The solvent was concentrated in vacuo and NaHCO was added₃Aqueous solution (1 mL). The aqueous phase and DCM (1.5mL) were shaken together and the phases were separated using a phase separation cartridge (Chromabond, PTS). The organic phase was concentrated and the crude product was used directly in the next step.

The crude iodide (ca. 0.03mmol) was dissolved in DME (0.8mL) and K under argon₂CO₃In aqueous solution (1M, 0.1mL, 0.1 mmol). Argon is passed into the mixture, boronic acid or boronic ester is added, followed by the addition of Pd (PPh)₃)₄(0.002g, 0.002 mmol). The mixture was heated at 80 ℃ overnight. The reaction mixture was filtered and the filtrate was purified by preparative HPLC/MS.

Example 20:

compounds 179 and 187 were prepared according to general procedure 3.

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid benzylamide (Compound 172)

1H NMR(300MHz，DMSO)δ8.72(s，1H)，7.93(d，J＝7.5Hz，1H)，7.78(d，J＝7.7Hz，1H)，7.53(t，J＝7.5Hz，1H)，7.27-7.15(m，6H)，4.32(d，J＝6.0Hz，2H)，4.04(s，3H)，3.05-2.95(s，2H)，2.61-2.54(m，2H)，1.50(dd，J＝7.0，3.5Hz，2H)，1.36(dd，J＝7.1，3.6Hz，2H).

1- [5- (5-cyano-pyridin-3-yl) -8-methoxyRadical- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid benzylamide (Compound 173)

1H NMR(300MHz，DMSO)δ9.43(d，J＝2.2Hz，1H)，9.12(d，J＝1.9Hz，1H)，8.90(t，J＝2.0Hz，1H)，8.67(t，J＝5.8Hz，1H)，7.52(d，J＝8.2Hz，1H)，7.38-7.14(m，6H)，4.36(d，J＝5.9Hz，2H)，4.04(s，3H)，1.53(dd，J＝6.9，3.5Hz，2H)，1.40(dd，J＝7.0，3.5Hz，2H).

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid cyclohexylmethylamide (Compound 174)

1H NMR(300MHz，DMSO)δ8.64(s，1H)，7.88(d，J＝8.1Hz，1H)，7.80(s，1H)，7.67(dd，J＝8.1，1.4Hz，1H)，7.44(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.04(s，3H)，3.99(s，3H)，3.01(t，J＝6.2Hz，2H)，1.9-0.7(m，15H).

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid isopropylamide (Compound 175)

1H NMR(300MHz，DMSO)δ8.49(d，J＝7.3Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.79-7.66(m，2H)，7.46(d，J＝8.3Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.05(s，3H)，4.00(s，3H)，4.00-3.85(m，1H)，1.52(d，J＝3.5Hz，2H)，1.41(d，J＝3.6Hz，2H)，1.06(d，J＝6.6Hz，6H).

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid cyclohexyl methyl amide (Compound 176)

1H NMR(300MHz，DMSO)δ8.57(s，1H)，7.94(d，J＝7.8Hz，1H)，7.82(d，J＝7.4Hz，1H)，7.61(t，J＝7.5Hz，1H)，7.25(s，2H)，4.05(s，3H)，2.96(dd，J＝13.6，6.9Hz，4H)，2.69-2.60(m，2H)，1.52(d，J＝19.2Hz，8H)，1.38(d，J＝3.6Hz，2H)，1.26(s，1H)，1.13-0.92(m，4H)，0.75(d，J＝10.9Hz，2H).

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide (compound 177)

1H NMR(300MHz，DMSO)δ8.41(t，J＝5.6Hz，1H)，7.89(d，J＝8.1Hz，1H)，7.83(d，J＝1.2Hz，1H)，7.73(dd，J＝8.1，1.4Hz，1H)，7.49(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.05(s，3H)，3.99(s，3H)，3.56(q，J＝6.4Hz，2H)，3.31-3.23(m，2H)，2.98(s，3H)，1.52(dd，J＝7.0，3.6Hz，2H)，1.38(dd，J＝7.1，3.6Hz，2H).

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5 ] s-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid benzylamide (Compound 178)

1H NMR(300MHz，DMSO)δ8.79(t，J＝5.8Hz，1H)，7.80(d，J＝1.1Hz，1H)，7.75(d，J＝8.1Hz，1H)，7.65(dd，J＝8.1，1.3Hz，1H)，7.45(d，J＝8.2Hz，1H)，7.32-7.19(m，6H)，4.37(d，J＝5.9Hz，2H)，4.04(s，3H)，3.92(s，3H)，1.55(dd，J＝7.0，3.5Hz，2H)，1.42(dd，J＝7.0，3.6Hz，2H).

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropanecarboxylic acid benzylamide (compound 179)

1H NMR(300MHz，DMSO)δ8.77(d，J＝5.8Hz，1H)，8.19(s，1H)，8.12(d，J＝8.1Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.38(d，J＝8.1Hz，1H)，7.28-7.17(m，6H)，5.37(s，2H)，4.38(d，J＝5.9Hz，2H)，4.04(s，3H)，1.55(dd，J＝6.9，3.6Hz，2H)，1.43(dd，J＝7.0，3.6Hz，2H).

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid isopropylamide (Compound 180)

1H NMR(300MHz，DMSO)δ8.46(d，J＝7.1Hz，1H)，7.98(d，J＝7.4Hz，1H)，7.82(d，J＝7.5Hz，1H)，7.62(t，J＝7.5Hz，1H)，7.28(d，J＝8.2Hz，1H)，7.24(d，J＝8.2Hz，1H)，4.05(s，3H)，3.85(dd，J＝13.7，6.7Hz，1H)，3.05-2.97(m，2H)，2.69-2.60(m，2H)，1.50(dd，J＝6.9，3.4Hz，2H)，1.39(dd，J＝7.0，3.4Hz，2H)，0.94(d，J＝6.6Hz，6H).

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid isopropylamide (Compound 181)

1H NMR(300MHz，DMSO)δ8.43(d，J＝7.5Hz，1H)，8.13(s，1H)，8.01(d，J＝7.9Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.38(d，J＝8.1Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.04(s，3H)，3.95(dd，J＝13.9，6.8Hz，1H)，3.23-3.15(m，2H)，2.76-2.66(m，2H)，1.52(dd，J＝6.9，3.4Hz，2H)，1.41(dd，J＝6.9，3.4Hz，2H)，1.08(d，J＝6.5Hz，6H).

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid benzylamide (compound 182)

1H NMR(300MHz，DMSO)δ8.80(t，J＝5.7Hz，1H)，8.11(s，1H)，7.95(d，J＝8.1Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.37(d，J＝8.1Hz，1H)，7.30-7.13(m，6H)，4.38(d，J＝5.9Hz，2H)，4.04(d，J＝6.2Hz，3H)，3.14-3.00(m，2H)，2.67(dd，J＝6.7，4.9Hz，2H)，1.55(dd，J＝6.8，3.6Hz，2H)，1.42(dd，J＝6.9，3.5Hz，2H).

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 183)

1H NMR(300MHz，DMSO)δ8.33(t，J＝5.6Hz，1H)，7.97(dd，J＝7.4，1.1Hz，1H)，7.81(d，J＝7.6Hz，1H)，7.62(t，J＝7.5Hz，1H)，7.27(d，J＝8.2Hz，1H)，7.24(d，J＝8.2Hz，1H)，4.05(s，3H)，3.59-3.47(m，2H)，3.21(t，J＝6.7Hz，2H)，3.07-2.96(m，2H)，2.93(s，3H)，2.66(dd，J＝6.6，4.7Hz，2H)，1.47(dd，J＝6.9，3.6Hz，2H)，1.32(dd，J＝7.0，3.6Hz，2H).

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 184)

1H NMR(300M Hz，DMSO)δ8.40(t，J＝6.0Hz，1H)，8.15(s，1H)，8.00(d，J＝8.1Hz，1H)，7.79(d，J＝8.1Hz，1H)，7.40(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.04(s，3H)，3.62-3.51(m，2H)，3.40-3.25(m，2H)，3.26-3.18(m，2H)，2.97(s，3H)，2.76-2.68(m，2H)，1.51(dd，J＝6.9，3.6Hz，2H)，1.38(dd，J＝7.0，3.6Hz，2H).

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid cyclohexyl methyl amide (Compound 185)

1H NMR(300MHz，DMSO)δ9.40(d，J＝2.1Hz，1H)，9.14(d，J＝1.9Hz，1H)，8.90(t，J＝2.0Hz，1H)，8.45(d，J＝5.4Hz，1H)，7.51(d，J＝8.1Hz，1H)，7.28(d，J＝8.3Hz，1H)，4.05(s，3H)，3.01(t，J＝6.3Hz，2H)，1.72-1.34(m，10H)，1.12(t，J＝10.2Hz，3H)，0.86(t，J＝10.8Hz，2H).

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 186)

1H NMR(300MHz，DMSO)δ9.44(d，J＝2.1Hz，1H)，9.12(d，J＝1.8Hz，1H)，8.91(t，J＝2.0Hz，1H)，8.34(t，J＝5.6Hz，1H)，7.55(d，J＝8.1Hz，1H)，7.29(d，J＝8.2Hz，1H)，4.05(s，3H)，3.63-3.49(m，2H)，3.29-3.22(m，2H)，2.98(s，3H)，1.55-1.48(m，2H)，1.43-1.34(m，2H).

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide (compound 187)

1H NMR(300MHz，DMSO)δ8.42(t，J＝5.8Hz，1H)，8.26(s，1H)，8.18(d，J＝8.1Hz，1H)，8.01(d，J＝8.1Hz，1H)，7.42(m，1H)，7.27(m，1H)，5.52(s，2H)，4.04(s，3H)，3.53(dd，J＝12.9，6.8Hz，2H)，3.17(t，J＝7.0Hz，2H)，2.77-2.70(m，7H)，1.52(dd，J＝7.0，3.6Hz，2H)，1.40(dd，J＝7.1，3.6Hz，2H).

Example 21

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Ethyl acid ester (Compound 188)

Under argon, 1- (5-iodo-8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid ethyl ester) (compound 305) (0.5g, 1.3mmol) was dissolved in 1, 4-dioxane (2.8mL) and H₂O (1.4 mL). Argon was bubbled through the mixture. 3-CN-Phenylboronic acid (0.19g, 1.3mmol) and K were added₃PO₄(0.96g, 4.5mmol) followed by addition of Pd₂(dba)₃(12mg, 0.013mmol) and PCy₃(9mg, 0.03 mmol). The mixture was heated in a microwave oven at 145 ℃ for 30 min. The reaction mixture was filtered, concentrated and purified by flash chromatography on silica gel using P. ether: EtOAc 2: 1 → 1: 5 as eluent. The title compound was obtained as a solid.

1H NMR(300MHz，CDCl3)δ8.25(t，J＝1.4Hz，1H)，8.21-8.15(m，1H)，7.74(dt，J＝7.7，1.3Hz，1H)，7.62(t，J＝7.8Hz，1H)，7.03(d，J＝8.1Hz，1H)，6.88(d，J＝8.1Hz，1H)，4.19(q，J＝7.1Hz，2H)，4.09(s，3H)，1.72(dd，J＝7.4，4.3Hz，2H)，1.60-1.56(m，2H)，1.27-1.19(m，3H).

Example 22 (Compound 190)

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester

The title compound was prepared according to the procedure described for the preparation of compound 188.

1H NMR(300MHz，CDCl3)δ8.50(d，J＝1.6Hz，1H)，8.24-8.12(m，1H)，8.10-8.00(m，1H)，7.61(t，J＝7.8Hz，1H)，7.06(d，J＝8.1Hz，1H)，6.88(d，J＝8.1Hz，1H)，4.22-4.13(m，2H)，4.08(s，3H)，2.67(s，3H)，1.71(dd，J＝7.4，4.2Hz，2H)，1.62-1.56(m，2H)，1.19(t，J＝7.0Hz，3H).

Example 23

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (Compound 191)

Heating 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2, 4%]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropanecarboxylic acid ethyl ester (compound 188) (0.32g, 0.88mmol) was dissolved in 1, 4-dioxane (10 mL). LiOH (0.06g, 1.4mmol) in H was added at room temperature₂Solution in O (2.5 mL). The suspension was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and H was added₂And O. The aqueous phase was washed with EtOAc and acidified to pH1 with 4N HCl. The aqueous phase was extracted with DCM (. times.2) and MgSO₄Drying, filtering and vacuum concentrating. The title compound was obtained as a solid.

1H NMR(300MHz，CDCl3)δ8.14-8.05(m，2H)，7.78(dt，J＝7.7，1.3Hz，1H)，7.70-7.59(m，1H)，7.11(d，J＝8.1Hz，1H)，7.05-6.96(m，1H)，4.12(s，3H)，1.99(dd，J＝7.9，3.6Hz，2H)，1.78(dd，J＝7.9，3.6Hz，2H).

Example 24

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane Formic acid (Compound 193)

The title compound was prepared according to the procedure described for the preparation of compound 191.

1H NMR(300MHz，CDCl3)δ13.93(s，1H)，8.44(d，J＝1.6Hz，1H)，8.06(ddd，J＝9.1，8.4，1.2Hz，2H)，7.64(t，J＝7.8Hz，1H)，7.14(d，J＝8.2Hz，1H)，7.01(d，J＝8.1Hz，1H)，4.11(s，3H)，2.67(s，3H)，1.98(dd，J＝7.8，3.5Hz，2H)，1.80(dd，J＝7.6，3.8Hz，2H).

Example 25

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid isopropylamide (Compound 194)

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] under argon]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropylAlkanoic acid) (compound 191) (0.026g, 0.08mmol) was dissolved in DMF (0.25 mL). Et was added₃N (0.23mL, 0.6mmol) and HATU (0.043g, 0.11 mmol). Isopropylamine (0.01mL, 0.11mmol) was added and the mixture was shaken overnight at room temperature. Addition of H₂O, aqueous phase extracted with EtOAc (. times.3), organic phase washed with brine, MgSO₄Drying, filtering and vacuum concentrating. Purification by flash chromatography (MeOH: DCM 2: 98 → 4: 96) afforded the title compound as a solid.

1H NMR(300MHz，CDCl3)δ8.72(d，J＝6.4Hz，1H)，8.15(d，J＝7.9Hz，2H)，7.79(dd，J＝7.7，1.1Hz，1H)，7.66(t，J＝7.7Hz，1H)，7.03(d，J＝8.1Hz，1H)，6.93(d，J＝8.2Hz，1H)，4.20-4.04(m，1H)，4.11(s，2H)，1.83(dd，J＝6.8，2.7Hz，2H)，1.69-1.63(m，2H)，1.15(d，J＝6.5Hz，6H).

General procedure 4

The carboxylic acid (0.04mmol) was dissolved in DMF (0.25mL) under argon. Et was added₃N (0.016mL, 0.12mmol or 0.025mL, 0.18mmol amine HCl salt) and HATU (0.022g, 0.06 mmol). Amine (0.06mmol) was added and the mixture was shaken overnight at room temperature. The reaction mixture was filtered through a microfiltration plate, washed with DMF (0.05mL) and purified by HPLC.

Example 26:

compound 195-199 was prepared according to the general procedure 4 using compound 191(1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid) as the starting material.

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (pyridin-3-ylmethyl) -amide (Compound 195)

1H NMR(600MHz，DMSO)δ8.69(t，J＝6.0Hz，1H)，8.49(d，J＝1.9Hz，1H)，8.45(dd，J＝4.8，1.6Hz，1H)，8.41(t，J＝1.6Hz，1H)，8.31(ddd，J＝8.0，1.6，1.2Hz，1H)，7.97-7.93(m，1H)，7.69(t，J＝7.9Hz，1H)，7.65(dt，J＝7.8，1.9Hz，1H)，7.41(d，J＝8.1Hz，1H)，7.30(ddd，J＝7.7，4.8，0.5Hz，1H)，7.26-7.22(m，1H)，4.39(d，J＝6.0Hz，2H)，4.03(s，3H)，1.52(dd，J＝7.1，3.5Hz，2H)，1.40(dd，J＝7.2，3.5Hz，2H).

3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl]-[1，2，4]Triazolo- [1,5-a]Pyridine-5- Yl } -benzonitrile (Compound 196)

1H NMR(600MHz，DMSO)δ8.45(t，J＝1.6Hz，1H)，8.27(ddd，J＝8.0，1.6，1.2Hz，1H)，8.02-7.95(m，1H)，7.76(t，J＝7.9Hz，1H)，7.41(d，J＝8.2Hz，1H)，7.27-7.12(m，1H)，4.02(s，3H)，3.55(d，J＝10.6Hz，4H)，3.42(s，4H)，1.49-1.46(m，2H)，1.45-1.41(m，2H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid benzylamide (Compound 197)

1H NMR(600MHz，DMSO)δ8.73(t，J＝5.9Hz，1H)，8.41(t，J＝1.6Hz，1H)，8.30(ddd，J＝8.0，1.6，1.2Hz，1H)，7.98-7.92(m，1H)，7.66(t，J＝7.9Hz，1H)，7.40(d，J＝8.1Hz，1H)，7.32-7.17(m，6H)，4.37(d，J＝6.0Hz，2H)，4.03(s，3H)，1.53(dd，J＝7.1，3.4Hz，2H)，1.41(dd，J＝7.2，3.4Hz，2H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-sulfamoyl-ethyl) -amide (compound 198)

1H NMR(600MHz，DMSO)δ8.43-8.33(m，2H)，8.28(t，J＝5.8Hz，1H)，7.97(dt，J＝7.8，1.3Hz，1H)，7.77(t，J＝7.7Hz，1H)，7.44(d，J＝8.2Hz，1H)，7.31-7.17(m，1H)，6.89(s，2H)，4.04(s，3H)，3.59-3.45(m，2H)，3.13(dd，J＝8.0，6.5Hz，2H)，1.57-1.44(m，2H)，1.42-1.26(m，2H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-methanesulfonyl-ethyl) -amide (compound 199)

1H NMR(300MHz，CDCl3)δ9.35(s，1H)，8.20-8.11(m，2H)，7.78(dt，J＝7.7，1.3Hz，1H)，7.70(t，J＝7.8Hz，1H)，7.06(d，J＝8.1Hz，1H)，6.94(d，J＝8.2Hz，1H)，4.11(s，3H)，3.84(dd，J＝12.3，6.0Hz，2H)，3.32(t，J＝6.2Hz，2H)，2.95(s，3H)，1.83(dd，J＝7.3，3.6Hz，2H)，1.68(dd，J＝7.4，3.7Hz，2H).

Example 27:

the compound 191(1- [5- (3-cyano-phenyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl]Cyclopropanecarboxylic acid) was used as the starting material, compound 200-202 was prepared according to general procedure 4. By adding H to the reaction mixture₂The reaction mixture was worked up with O (4mL) and the aqueous phase was extracted with DCM. The organic phase was dried (MgSO)₄) Filtered, concentrated and purified by flash chromatography.

3- { 8-methoxy-2- [1- (pyrrolidine-1-carbonyl) -cyclopropyl ] -amide]-[1，2，4]Triazolo [1,5-a]Pyridine-5- Yl } -benzonitrile (Compound 200)

1H NMR(300MHz，CDCl3)δ8.26(t，J＝1.6Hz，1H)，8.16-8.10(m，1H)，7.72(dt，J＝7.8，1.4Hz，1H)，7.59(t，J＝7.9Hz，1H)，7.03(d，J＝8.1Hz，1H)，6.92-6.82(m，1H)，4.08(s，3H)，3.59(t，J＝6.7Hz，2H)，3.37(t，J＝6.4Hz，2H)，1.96-1.76(m，4H)，1.70-1.64(m，2H)，1.59-1.50(m，2H).

2-methyl-acrylic acid 2- ({1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine (II) Pyridin-2-yl]-cyclopropanecarbonyl } -amino) -ethyl ester (Compound 201)

1H NMR(300MHz，CDCl3)δ9.21(t，J＝5.3Hz，1H)，8.21-8.12(m，2H)，7.77(ddd，J＝7.7，3.5，2.1Hz，1H)，7.69-7.61(m，1H)，7.07(dd，J＝8.1，2.4Hz，1H)，6.94(dd，J＝8.0，3.6Hz，1H)，6.04(dd，J＝1.5，0.9Hz，1H)，5.49(p，J＝1.5Hz，1H)，4.29-4.21(m，2H)，4.10(d，J＝4.3Hz，3H)，3.75-3.65(m，2H)，1.90-1.86(m，3H)，1.83(dd，J＝7.4，3.4Hz，2H)，1.66-1.59(m，2H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-methoxy-ethyl) -amide (compound 202)

1H NMR(300MHz，CDCl3)δ9.09(s，1H)，8.23-8.17(m，1H)，8.17-8.11(m，1H)，7.77(dt，J＝7.7，1.2Hz，1H)，7.65(dd，J＝11.9，4.3Hz，1H)，7.05(d，J＝8.1Hz，1H)，6.97-6.89(m，1H)，4.11(s，3H)，3.62-3.52(m，2H)，3.49(dd，J＝8.1，3.3Hz，2H)，3.27(s，3H)，1.83(dd，J＝7.5，3.5Hz，2H)，1.65(dd，J＝7.5，3.5Hz，2H).

Example 28:

compound 203-209 was prepared according to general procedure 4 using the compound 1471- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid) as starting compound:

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (pyridin-3-ylmethyl) -amide (Compound 203)

1H NMR(600MHz，DMSO)δ8.64(t，J＝5.9Hz，1H)，8.50(d，J＝1.9Hz，1H)，8.47(dd，J＝4.8，1.6Hz，1H)，8.18-8.08(m，2H)，7.96-7.89(m，2H)，7.66(dt，J＝7.8，2.0Hz，1H)，7.41(d，J＝8.2Hz，1H)，7.35-7.28(m，1H)，7.27-7.20(m，1H)，4.38(d，J＝5.9Hz，2H)，4.03(s，3H)，1.52(dd，J＝7.1，3.5Hz，2H)，1.39(dd，J＝7.2，3.5Hz，2H).

4- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl]-[1，2，4]Triazolo [1,5-a]Pyridine (II) Pyridin-5-yl } -benzonitrile (Compound 204)

1H NMR(600MHz，DMSO)δ8.21-8.13(m，2H)，8.05-7.98(m，2H)，7.40(d，J＝8.2Hz，1H)，7.26-7.17(m，1H)，4.02(s，3H)，3.51(s，2H)，3.40-3.36(m，2H)，2.25(s，2H)，2.07(s，2H)，2.04(s，3H)，1.46(dd，J＝7.1，4.2Hz，2H)，1.40(dd，J＝7.1，4.1Hz，2H).

4- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl]-[1，2，4]Triazolo [1,5-a]Pyridine-5- Yl } -benzonitrile (Compound 205)

1H NMR(600MHz，DMSO)δ8.22-8.13(m，2H)，8.06-8.00(m，2H)，7.41(d，J＝8.2Hz，1H)，7.26-7.17(m，1H)，4.02(s，3H)，3.54(d，J＝10.5Hz，4H)，3.46-3.35(m，4H)，1.47(dd，J＝7.1，4.2Hz，2H)，1.43(dd，J＝7.1，4.2Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid benzylamide (Compound 206)

1H NMR(600MHz，DMSO)δ8.71(t，J＝5.9Hz，1H)，8.16-8.07(m，2H)，7.92-7.81(m，2H)，7.40(d，J＝8.2Hz，1H)，7.24-7.22(m，1H)，4.37(d，J＝5.9Hz，2H)，4.03(s，3H)，1.54(dd，J＝7.1，3.4Hz，2H)，1.41(dd，J＝7.2，3.4Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-sulfamoyl-ethyl) -amide (compound 207)

1H NMR(600MHz，DMSO)δ8.27(t，J＝5.7Hz，1H)，8.23-8.18(m，2H)，8.04-7.99(m，2H)，7.44(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，6.92(s，2H)，4.04(s，3H)，3.59-3.48(m，2H)，3.14(dd，J＝7.9，6.5Hz，2H)，1.50(dd，J＝7.1，3.5Hz，2H)，1.37(dd，J＝7.2，3.5Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-methanesulfonyl-ethyl) -amide (compound 208)

1H NMR(600MHz，DMSO)δ8.35(t，J＝5.7Hz，1H)，8.22-8.17(m，2H)，8.06-7.99(m，2H)，7.44(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，4.05(d，J＝15.5Hz，3H)，3.55(dd，J＝12.6，6.6Hz，2H)，3.27(t，J＝6.7Hz，2H)，2.98(s，3H)，1.51(dd，J＝7.1，3.5Hz，2H)，1.37(dd，J＝7.2，3.5Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid isopropylamide (Compound 209)

1H NMR(300MHz，CDCl3)δ8.73(m，H)，8.06-7.99(m，2H)，7.85-7.78(m，2H)，7.07(d，J＝8.1Hz，1H)，6.93(d，J＝8.2Hz，1H)，4.20-4.05(m，4H)，1.83(m，2H)，1.71-1.57(m，2H)，1.16(s，3H)，1.14(s，3H).

Example 29:

with the compound 192(1- [5- (4-cyano-phenyl) -8-methoxy- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl]Cyclopropanecarboxylic acid) as starting compound, compound 210-220 was prepared according to general procedure 4. Adding H to the reaction mixture₂O (4mL) worked up the reaction mixture or Na was added for the reaction with amine HCl salt₂CO₃An aqueous solution. The aqueous phase was extracted with DCM (2X 4 mL). The organic phase was placed on a separation cartridge (PTS), concentrated and purified by preparative HPLC/MS.

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid methyl amide (Compound 210)

1H NMR(300MHz，CDCl3)δ8.81(s，1H)，8.09-7.95(m，2H)，7.86-7.74(m，2H)，7.09(d，J＝8.2Hz，1H)，7.00-6.86(m，1H)，4.11(s，3H)，2.90(d，J＝4.8Hz，3H)，1.83(dd，J＝7.5，3.4Hz，2H)，1.60(dd，J＝7.4，3.5Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid Ethylamide (Compound 211)

1H NMR(300MHz，CDCl3)δ8.79(s，1H)，8.05-7.99(m，2H)，7.86-7.79(m，2H)，7.08(d，J＝8.2Hz，1H)，6.94(d，J＝8.2Hz，1H)，4.11(s，3H)，3.37(qd，J＝7.3，5.3Hz，2H)，1.83(dd，J＝7.4，3.4Hz，2H)，1.63(dd，J＝7.4，3.4Hz，3H)，1.16(t，J＝7.3Hz，3H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid propylamide (Compound 212)

1H NMR(300MHz，CDCl3)δ8.87(s，1H)，8.08-7.92(m，2H)，7.87-7.73(m，2H)，7.06(d，J＝8.1Hz，1H)，6.93(d，J＝8.2Hz，1H)，4.11(s，3H)，3.30(td，J＝7.0，5.5Hz，2H)，3.30(td，J＝7.0，5.5Hz，2H)，1.88-1.75(m，2H)，1.64(dd，J＝7.5，3.4Hz，2H)，1.60-1.46(m，2H)，0.90(t，J＝7.4Hz，3H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid cyclopropylamide (Compound 213)

1H NMR(300MHz，CDCl3)δ8.96(s，1H)，8.04-7.96(m，2H)，7.87-7.77(m，2H)，7.07(d，J＝8.1Hz，1H)，6.93(d，J＝8.2Hz，1H)，4.11(s，3H)，2.83(dq，J＝11.0，3.7Hz，1H)，1.85(dd，J＝7.5，3.3Hz，2H)，1.64(dd，J＝7.5，3.3Hz，2H)，0.87-0.70(m，2H)，0.52-0.38(m，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid isobutyl amide (Compound 214)

1H NMR(300MHz，CDCl3)δ8.96(s，1H)，8.06-7.95(m，2H)，7.85-7.73(m，2H)，7.066(d，J＝8.1Hz，1H)，6.93(d，J＝8.1Hz，1H)，4.11(s，3H)，3.16(dd，J＝6.7，5.6Hz，2H)，1.83(dd，J＝7.4，3.4Hz，2H)，1.80-1.69(m，1H)，1.65(dd，J＝7.4，3.4Hz，3H)，0.88(d，J＝6.7Hz，6H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid cyanomethyl amide (Compound 215)

1H NMR(300MHz，CDCl3)δ9.74(t，J＝5.2Hz，1H)，8.07-7.94(m，2H)，7.92-7.78(m，2H)，7.11(d，J＝8.1Hz，1H)，6.97(d，J＝8.2Hz，1H)，4.30(d，J＝5.6Hz，2H)，4.12(s，3H)，1.89(dd，J＝7.5，3.6Hz，2H)，1.72(dd，J＝7.5，3.7Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-acetylamino-ethyl) -amide (compound 216)

1H NMR(300MHz，CDCl3)δ9.16(d，J＝5.6Hz，1H)，8.06-7.98(m，2H)，7.83(d，J＝8.6Hz，2H)，7.10(d，J＝8.2Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.50(s，1H)，4.11(s，3H)，3.51(dd，J＝11.7，5.6Hz，2H)，3.41(dd，J＝11.1，5.3Hz，2H)，1.95(s，3H)，1.81(dd，J＝7.4，3.6Hz，2H)，1.64(dd，J＝7.4，3.6Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-Methanesulfonylamino-ethyl) amide (Compound 217)

1H NMR(300MHz，DMSO)δ8.33(t，J＝5.6Hz，1H)，8.24-8.16(m，2H)，8.08-7.96(m，2H)，7.44(d，J＝8.2Hz，1H)，7.26(d，J＝8.3Hz，1H)，7.09(s，1H)，4.05(s，3H)，3.28(dd，J＝12.5，6.3Hz，2H)，3.03(s，2H)，2.90(s，3H)，1.52(dd，J＝7.0，3.6Hz，2H)，1.38(dd，J＝7.0，3.5Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (3-morpholin-4-yl-3-oxo-propyl) amide (Compound 218)

1H NMR(300MHz，CDCl3)δ9.09(t，J＝5.8Hz，1H)，8.12-8.06(m，2H)，7.90-7.85(m，2H)，7.10-7.06(m，1H)，6.93(d，J＝8.3Hz，1H)，4.10(d，J＝4.3Hz，3H)，3.70-3.61(m，6H)，3.58(d，J＝4.9Hz，2H)，3.50-3.39(m，2H)，2.60(t，J＝6.1Hz，2H)，1.80(dd，J＝7.3，3.6Hz，2H)，1.63(dd，J＝7.5，3.SHz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-dimethylsulfamoyl-ethyl) -amide (compound 219)

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid [2- (methylsulfonyl-methyl-amino) -ethyl]Amides (Compound 220)

Example 30:

compound 221-226 was prepared according to general procedure 4 using compound 193(1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid) as the starting compound.

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropylAlkane (I) and its preparation method Carboxylic acid (pyridin-3-ylmethyl) -amide (Compound 221)

1H NMR(600MHz，DMSO)δ8.77(t，J＝6.0Hz，1H)，8.50(t，J＝1.7Hz，1H)，8.47(d，J＝1.8Hz，1H)，8.44(dd，J＝4.8，1.6Hz，1H)，8.21-8.17(m，1H)，8.07-8.03(m，1H)，7.64(ddd，J＝7.7，4.8，2.8Hz，2H)，7.38(d，J＝8.1Hz，1H)，7.31-7.26(m，1H)，7.25-7.21(m，1H)，4.39(d，J＝6.0Hz，2H)，4.03(s，3H)，2.62(s，3H)，1.52(dd，J＝7.1，3.5Hz，2H)，1.40(dd，J＝7.2，3.5Hz，2H).

1- (3- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl]-[1，2，4]Triazolo [1,5-a] Pyridin-5-yl } -phenyl) -ethanone (Compound 222)

1H NMR(600MHz，DMSO)δ8.51(t，J＝1.7Hz，1H)，8.20-8.17(m，1H)，8.10-8.06(m，1H)，7.69(dd，J＝9.7，5.9Hz，1H)，7.36(d，J＝8.2Hz，1H)，7.22-7.19(m，1H)，4.02(s，3H)，3.49(s，2H)，3.41-3.36(m，2H)，2.65(s，3H)，2.20(s，2H)，2.07(s，2H)，2.01(s，3H)，1.47(dd，J＝7.1，4.2Hz，2H)，1.39(dd，J＝7.1，4.1Hz，2H).

1- (3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] -amide derivatives]-[1，2，4]Triazolo [1,5-a]Pyridine-5- Phenyl-ethanone (compound 223)

1H NMR(600MHz，DMSO)δ8.52(t，J＝1.7Hz，1H)，8.19-8.13(m，1H)，8.11-8.05(m，1H)，7.70(dd，J＝9.7，5.9Hz，1H)，7.36(d，J＝8.1Hz，1H)，。7.23-7.17(m，1H)，4.02(s，3H)，3.51(s，4H)，3.42(d，J＝15.2Hz，4H)，2.65(s，3H)，1.49-1.45(m，2H)，1.45-1.40(m，2H).

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane Carboxylic acid benzylamide (Compound 224)

1H NMR(600MHz，DMSO)δ8.84(t，J＝5.9Hz，1H)，8.50(t，J＝1.7Hz，1H)，8.26-8.13(m，1H)，8.10-7.99(m，1H)，7.61(dd，J＝9.7，5.9Hz，1H)，7.37(d，J＝8.1Hz，1H)，7.30-7.17(m，6H)，4.38(d，J＝6.0Hz，2H)，4.03(s，3H)，2.61(s，3H)，1.54(dd，J＝7.1，3.4Hz，2H)，1.42(dd，J＝7.2，3.4Hz，2H).

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane Formic acid (2-sulfamoyl-ethyl) -amide (compound 225)

1H NMR(600MHz，DMSO)δ8.52(t，J＝1.7Hz，1H)，8.36(t，J＝5.8Hz，1H)，8.24(ddd，J＝7.7，1.7，1.1Hz，1H)，8.10-8.05(m，1H)，7.71(dd，J＝9.7，5.9Hz，1H)，7.40(d，J＝8.1Hz，1H)，7.27-7.21(m，1H)，6.90(s，2H)，4.04(s，3H)，3.58-3.49(m，2H)，3.17-3.07(m，2H)，2.66(s，3H)，1.50(dd，J＝7.1，3.5Hz，2H)，1.37(dd，J＝7.2，3.5Hz，2H).

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane Formic acid (2-methanesulfonyl-ethyl) -amide (Compound 226)

1H NMR(600MHz，DMSO-SPE)δ8.53(t，J＝1.7Hz，1H)，8.46(t，J＝5.7Hz，1H)，8.25-8.18(m，1H)，8.11-8.06(m，1H)，7.72(dd，J＝9.7，5.9Hz，1H)，7.40(d，J＝8.1Hz，1H)，7.27-7.22(m，1H)，4.04(s，3H)，3.57(dd，J＝12.9，6.6Hz，2H)，3.27(t，J＝6.8Hz，2H)，2.97(s，3H)，2.66(s，3H)，1.51(dd，J＝7.1，3.5Hz，2H)，1.39(dd，J＝7.3，3.5Hz，2H).

Example 31

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-hydroxy-ethyl) -amide (compound 228)

Compound 201(0.03g, 0.07mmol) was dissolved in 1, 4-dioxane (3 mL). LiOH (0.09g, 0.21mmol) in H was added₂O (0.5mL) solution. The suspension was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and H was added₂And O. The aqueous phase was acidified to pH1 with 4N HCl. The aqueous phase was extracted with EtOAc (. times.2) and DCM (. times.2). With MgSO₄The combined organic phases were dried, filtered and concentrated in vacuo. The title compound was obtained.

1H NMR(300MHz，CDCl3)δ9.22(s，1H)，8.20(s，1H)，8.16-8.08(m，1H)，7.77(d，J＝7.8Hz，1H)，7.66(t，J＝7.8Hz，1H)，7.06(d，J＝8.1Hz，1H)，6.94(d，J＝8.1Hz，1H)，4.11(s，3H)，3.81-3.73(m，2H)，3.54(dd，J＝10.0，5.4Hz，2H)，1.85(dd，J＝7.5，3.5Hz，2H)，1.68(dd，J＝7.4，3.6Hz，2H).

General procedure 5

Mixing [1- (5-iodo-8-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methanol (0.1g, 0.29mmol) to CH₃CN (2 mL). Et was added₃N (0.29g, 2.9mmol) and isocyanate (3.5 mmol). The solution was stirred at 65 ℃ overnight. The crude product was purified by preparative HPLC/MS.

General procedure 6

Compound 308([1- (5-iodo-8-methoxy- [1,2, 4))]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropyl]Methanol) (0.8g, 0.23mmol) dissolved in CH₃In CN. 1, 1-carbonyl-diimidazole (0.19g, 1.2mmol) was added and the mixture was stirred at room temperature for 15 min. Amine (2.3mmol) was added and the suspension was heated in a microwave oven at 100 ℃ for 10 min. The crude product was purified by preparative HPLC/MS.

General procedure 7 (Suzuki coupling of iodo derivatives)

The dioxane and water were degassed. Iodide (0.017g, 0.04mmol) and boronic acid or boronic acid pinacol ester (0.12mmol) were dissolved in 1, 4-dioxane (0.3mL) under argon. Adding Pd₂(dba)₃(about 0.4mg, 0.0004mmol) and PCy₃(about 0.2mg, 0.0008 mmol). Adding K₃PO₄(0.03g, 0.14mmol) of H₂O (0.14mL) solution. The suspension was heated at 120 ℃ for 10min in a microwave oven, then filtered and purified by preparative HPLC/MS.

Example 32:

compounds 229, 230, 232, 233, 235-237, 239-241 were prepared according to general procedure 5, then according to general procedure 7.

Preparation example 33:

compounds 231, 234, 238, 242-247 were prepared according to general procedure 6, then according to general procedure 7.

Cyclohexyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridine 2-yl]-cyclopropylmethyl ester (compound 229)

1H NMR(300MHz，DMSO)δ9.46(d，J＝1.7Hz，1H)，9.10(d，J＝1.8Hz，1H)，8.89(s，1H)，7.60-7.53(m，1H)，7.51(d，J＝8.1Hz，1H)，7.22(d，J＝8.3Hz，1H)，6.92(d，J＝7.7Hz，1H)，4.41(s，2H)，4.02(s，3H)，3.30-3.10(bs，1H)，1.72-1.43(m，5H)，1.31-0.89(m，9H).

Propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 230)

1H NMR(300MHz，DMSO)δ8.20(s，1H)，8.00(dd，J＝8.1，1.2Hz，1H)，7.73(d，J＝8.1Hz，1H)，7.36(d，J＝8.2Hz，1H)，7.20-7.14(m，1H)，7.05(t，J＝5.5Hz，1H)，4.40(s，2H)，4.01(s，3H)，3.24-3.15(m，2H)，2.88(dd，J＝13.2，6.6Hz，2H)，2.77-2.65(m，2H)，1.39-1.21(m，4H)，1.12(dd，J＝6.6，4.0Hz，2H)，0.76(t，J＝7.4Hz，3H).

Dimethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 231)

1H NMR(300MHz，DMSO)δ8.00(d，J＝1.4Hz，1H)，7.86(d，J＝8.1Hz，1H)，7.68(dd，J＝8.2，1.5Hz，1H)，7.46(d，J＝8.2Hz，1H)，7.18(d，J＝8.3Hz，1H)，4.44(s，2H)，4.02(s，3H)，4.00(s，3H)，2.73(bs，6H)，1.28(dd，J＝6.7，4.1Hz，2H)，1.15(dd，J＝6.6，4.0Hz，2H).

Isopropyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 232)

1H NMR(300MHz，DMSO)δ9.46(d，J＝2.2Hz，1H)，9.10(d，J＝1.9Hz，1H)，8.89(t，J＝2.1Hz，1H)，7.51(d，J＝8.2Hz，1H)，7.22(d，J＝8.3Hz，1H)，6.91(d，J＝7.1Hz，1H)，4.41(s，2H)，4.04(s，3H)，3.66-3.46(m，1H)，1.26(dd，J＝6.6，4.1Hz，2H)，1.13(dd，J＝6.6，4.0Hz，2H)，0.97(d，J＝6.5Hz，6H).

Propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 233)

1H NMR(300MHz，DMSO)δ7.87(dd，J＝7.5，1.0Hz，1H)，7.83-7.76(m，1H)，7.59(t，J＝7.6Hz，1H)，7.21-7.12(m，2H)，7.04(t，J＝5.7Hz，1H)，4.31(s，2H)，4.02(s，3H)，3.05-2.96(m，2H)，2.85(dd，J＝13.3，6.6Hz，2H)，2.63(dd，J＝6.7，4.8Hz，2H)，1.40-1.24(m，2H)，1.21(dd，J＝6.5，4.1Hz，2H)，1.08(dd，J＝6.5，4.0Hz，2H)，0.78(t，J＝7.4Hz，3H).

Pyrrolidine-1-carboxylic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 234)

1H NMR(300MHz，DMSO)δ8.01(d，J＝1.2Hz，1H)，7.86(d，J＝8.2Hz，1H)，7.67(dd，J＝8.2，1.4Hz，1H)，7.46(d，J＝8.3Hz，1H)，7.18(d，J＝8.3Hz，1H)，4.44(s，2H)，4.02(s，3H)，4.00(s，3H)，3.25-3.15(m，2H)，3.15-3.00(m，2H)，1.68(bs，4H)，1.27(dd，J＝7.1，4.1Hz，2H)，1.15(dd，J＝7.1，4.1Hz，2H).

Isopropyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 235)

1H NMR(300MHz，DMSO)δ8.03(s，1H)，7.87-7.81(m，1H)，7.68(dd，J＝8.2，1.3Hz，1H)，7.48(d，J＝8.2Hz，1H)，7.19(d，J＝8.3Hz，1H)，6.94(d，J＝7.5Hz，1H)，4.41(s，2H)，4.02(s，3H)，4.01(s，3H)，3.60-3.44(m，1H)，1.27(dd，J＝6.5，4.1Hz，2H)，1.14(dd，J＝6.5，4.0Hz，2H)，0.96(d，J＝6.5Hz，6H).

Propyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 236)

1H NMR(300MHz，DMSO)δ9.46(d，J＝2.1Hz，1H)，9.10(d，J＝1.9Hz，1H)，8.89(t，J＝2.1Hz，1H)，7.51(d，J＝8.3Hz，1H)，7.22(d，J＝8.3Hz，1H)，7.02(s，1H)，4.41(s，2H)，4.02(s，3H)，2.88(q，7.4Hz，2H)，1.40-1.20(m，4H)，1.13(dd，J＝6.6，4.0Hz，2H)，0.76(t，J＝7.4Hz，3H).

Propyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 237)

1H NMR(300MHz，DMSO)δ8.04(s，1H)，7.85(d，J＝8.1Hz，1H)，7.68(d，J＝7.7Hz，1H)，7.48(d，J＝8.2Hz，1H)，7.19(d，J＝8.3Hz，1H)，7.03(bs，1H)，4.42(s，2H)，4.02(s，3H)，4.01(s，3H)，2.86(q，J＝5.8Hz，2H)，1.35-1.25(m，4H)，1.15(d，J＝3.4Hz，2H)，0.76(t，J＝7.4Hz，3H).

Pyrrolidine-1-carboxylic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 238)

1H NMR(300MHz，DMSO)δ8.20(s，1H)，7.99(d，J＝8.1Hz，1H)，7.73(d，J＝8.1Hz，1H)，7.35(d，J＝8.1Hz，1H)，7.18(d，J＝8.2Hz，1H)，4.42(s，2H)，4.02(s，3H)，3.25-3.07(m，6H)，2.72(dd，J＝6.6，5.0Hz，2H)，1.70(bs，4H)，1.30-1.22(m，2H)，1.18-1-13(m，2H).

Isopropyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 239)

1H NMR(300MHz，DMSO)δ8.19(s，1H)，8.00(dd，J＝8.1，1.3Hz，1H)，7.74(d，J＝8.1Hz，1H)，7.35(d，J＝8.1Hz，1H)，7.20-7.14(m，1H)，6.95(d，J＝7.5Hz，1H)，4.40(s，2H)，4.01(s，3H)，3.64-3.48(m，1H)，3.24-3.14(m，2H)，2.77-2.64(m，2H)，1.26(dd，J＝6.5，4.0Hz，2H)，1.12(dd，J＝6.5，4.0Hz，2H)，0.97(d，J＝6.5Hz，6H).

Cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (Compound 240)

1H NMR(300MHz，DMSO)δ7.87(dd，J＝7.4，0.9Hz，1H)，7.80(d，J＝7.6Hz，1H)，7.59(t，J＝7.6Hz，1H)，7.21-7.13(m，2H)，6.95(d，J＝8.1Hz，1H)，4.30(s，2H)，4.02(d，J＝3.6Hz，3H)，3.23-3.06(m，1H)，3.05-2.92(m，2H)，2.69-2.59(m，2H)，1.80-1.40(m，5H)，1.29-0.93(m，9H).

Cyclohexyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 241)

1H NMR(300MHz，DMSO)δ8.04(s，1H)，7.85(d，J＝8.1Hz，1H)，7.67(d，J＝8.1Hz，1H)，7.47(d，J＝8.2Hz，1H)，7.18(d，J＝8.3Hz，1H)，6.93(d，J＝7.9Hz，1H)，4.41(s，2H)，4.02(s，3H)，4.01(s，3H)，3.25-3-10(m，1H)，1.70-1-45(m，5H)，1.32-0.89(m，9H).

Pyrrolidine-1-carboxylic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 242)

1H NMR(300MHz，DMSO)δ9.45(d，J＝2.1Hz，1H)，9.11(d，J＝2.0Hz，1H)，8.90(t，J＝2.1Hz，1H)，7.50(d，J＝8.2Hz，1H)，7.22(d，J＝8.2Hz，1H)，4.41(s，2H)，4.02(s，3H)，3.30-3.10(m，4H)，1.72(bs，4H)，1.31-1.24(m，2H)，1.19-1.14(m，2H).

Dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 243)

1H NMR(300MHz，DMSO)δ8.20(d，J＝0.6Hz，1H)，7.98(dd，J＝8.1，1.4Hz，1H)，7.74(d，J＝8.1Hz，1H)，7.35(d，J＝8.2Hz，1H)，7.18(d，J＝8.3Hz，1H)，4.41(s，2H)，4.02(s，3H)，3.22-3.12(m，2H)，2.84-2.65(m，8H)，1.27(dd，J＝6.6，4.1Hz，2H)，1.14(dd，J＝6.9，4.3Hz，2H).

Dimethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 244)

1H NMR(300MHz，DMSO)δ9.45(d，J＝2.2Hz，1H)，9.10(d，J＝1.9Hz，1H)，8.90(t，J＝2.1Hz，1H)，7.50(d，J＝8.2Hz，1H)，7.21(d，J＝8.3Hz，1H)，4.41(s，2H)，4.03(s，3H)，2.78(s，6H)，1.28(dd，J＝6.5，4.1Hz，2H)，1.16(dd，J＝6.5，4.1Hz，2H).

Diethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4]Triazolo compounds [1，5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 245)

1H NMR(300MHz，DMSO)δ8.01(s，1H)，7.85(d，J＝8.1Hz，1H)，7.67(dd，J＝8.2，1.4Hz，1H)，7.47(d，J＝8.3Hz，1H)，7.19(d，J＝8.3Hz，1H)，4.43(s，2H)，4.02(s，3H)，4.00(s，3H)，3.10(s，4H)，1.29(d，J＝7.1Hz，2H)，1.15(t，J＝3.0Hz，2H)，0.88(2s，6H).

Diethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4 [ ]]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 246)

1H NMR(300MHz，DMSO)δ7.86(d，J＝7.1Hz，1H)，7.80(d，J＝7.6Hz，1H)，7.59(t，J＝7.6Hz，1H)，7.17(s，2H)，4.33(s，2H)，4.02(s，3H)，3.07(s，4H)，3.00(d，J＝5.5Hz，2H)，2.63(d，J＝5.7Hz，2H)，1.22(m，2H)，1.09(m，2H)，0.94(s，3H)，0.82(s，3H).

Diethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropylmethyl ester (compound 247)

1H NMR(300MHz，DMSO)δ9.45(d，J＝2.2Hz，1H)，9.10(d，J＝1.9Hz，1H)，8.89(t，J＝2.1Hz，1H)，7.53-7.46(m，1H)，7.21(d，J＝8.3Hz，1H)，4.42(s，2H)，4.02(s，3H)，3.13(m，4H)，1.28(dd，J＝6.6，4.1Hz，2H)，1.20-1.10(m，2H)，0.96(m，6H).

Example 34

5- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2, 4%]Triazolo [1,5-a]Pyridin-5-yl]-smoke Nitrile (Compound 248)

The title compound was prepared according to general procedure 7 starting from compound 308.

1H NMR(300MHz，DMSO)δ9.47(d，J＝2.2Hz，1H)，9.10(d，J＝1.9Hz，1H)，8.92(t，J＝2.1Hz，1H)，7.48(d，J＝8.2Hz，1H)，7.20(d，J＝8.2Hz，1H)，4.65(t，J＝5.8Hz，1H)，4.02(s，3H)，3.89(d，J＝5.7Hz，2H)，1.12(dd，J＝6.3，3.8Hz，2H)，1.04(dd，J＝6.3，3.9Hz，2H).

Preparation example 11

8-bromo-2-cyclopropyl-5-methoxy- [1,2, 4-]Triazolo [1,5-a]Pyridine (Compound 311)

2-amino-6-hydroxy-pyridine (19.6g, 178mmol) was suspended in acetic acid (100%, 390mL) under argon. Adding Br at 20 deg.C within 5min₂(9.2mL, 178 mmol). Suspending the green colorThe solution was stirred at room temperature for 20 min. The mixture was poured into H₂O (400mL), and filtered. The filtrate was combined with brine (200mL) and extracted with EtOAc (10X 400 mL). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated to give 6-amino-5-bromo-pyridin-2-ol as a yellow solid (23 g).

6-amino-5-bromo-pyridin-2-ol (23g, 122mmol) was dissolved in DMF (300mL) under argon. Adding K₂CO₃(50.6g, 366mmol) followed by methyl iodide (11.4mL, 183 mmol). The mixture was stirred for 4h, maintaining the temperature at 20-25 ℃. The suspension was poured into H₂O (1L), the aqueous phase was extracted with EtOAc (. times.2). Combined organic phases with H₂O (0.5L) and brine (200mL), Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by flash chromatography (eluent: toluene: n-heptane 2: 1 → 100: 0, followed by toluene: EtOAc 95: 5) to give 3-bromo-6-methoxy-pyridin-2-ylamine as a solid (3 g).

Under argon, the mixture is subjected toEthyl arylsulfoacetate (0.88gg, 3.0mmol, 97% pure) and dioxane (0.56mL) were combined. The suspension was ice-cooled and 70% HClO was added₄(0.34 mL). Stirring was maintained for 10 min. Then ice cold water (4mL) was added and stirred well. The white precipitate was filtered and washed with additional ice cold water (2 × 3 mL). The precipitate was redissolved in DCM (5mL) and Na₂SO₄And (5) drying. After filtration, the DCM solution was used directly in the next step.

The solution was slowly added (3min) to a cold (0 ℃) solution of 3-bromo-6-methoxy-pyridin-2-ylamine (0.51g, 2.5mmol) in DCM (3.9mL) under argon. The yellow suspension was stirred at room temperature for 2h, then treated with tert-butyl methyl ether (5 mL). The precipitate formed was filtered and washed with DCM: tert-butyl methyl ether (1: 1) to give 0.62g of a white solid (2,4, 6-trimethyl-benzenesulfonate 1, 2-diamino-3-bromo-6-methoxy-pyridinium).

0.82g (2.0mmol) of the above product was dissolved in dioxane (7.5mL) under argon, treated with cyclopropanecarboxaldehyde (0.29mL, 4.0mmol) and heated to 90 ℃ for 2 hours and 15 minutes. The red solution was cooled to room temperature, treated with 1N KOH in MeOH (2.0mL), and allowed to stand at room temperature for 18 h. The solvent was evaporated in vacuo and NaCl solution was added to the product. The product was extracted with DCM (. times.3) and the combined organic phases were extracted with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by flash chromatography on silica gel using DCM: EtOAc 96: 4 → 90: 10 as eluent. The title compound (0.3g) was obtained as a pale yellow solid.

1H NMR(300MHz，CDCl3)δ7.63(d，J＝8.2Hz，1H)，6.16(d，J＝8.2Hz，1H)，4.15(s，3H)，2.35-2.25(m，1H)，1.25-1.18(m，2H)，1.12-1.04(m，2H).

Example 35

4- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl) -2-methoxy-benzonitrile (Compound 249)

Compound 311 (8-bromo-2-cyclopropyl-5-methoxy- [1,2, 4) in a screw vial under argon]Triazolo [1,5-a]Pyridine) (0.025g, 0.093mmol) dissolved in DME (0.6mL) and 1MK₂CO₃(0.2 mL). 4-CN-3-Methoxyphenylboronic acid (0.033g, 0.19mmol) and Pd (PPh) were added₃)₄(0.005g, 0.005 mmol). The suspension was shaken at 80 ℃ for 5h, then brine was added and the aqueous phase was extracted with DCM (. times.3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography (eluent DCM: EtOAc 9: 1). The title compound was obtained as a solid.

1H NMR(300MHz，DMSO)δ8.14(d，J＝8.3Hz，1H)，8.11(d，J＝1.3Hz，1H)，7.87(dd，J＝8.1，1.5Hz，1H)，7.80(d，J＝8.2Hz，1H)，6.74(d，J＝8.4Hz，1H)，4.18(s，3H)，4.01(s，3H)，2.21(tt，J＝8.0，5.0Hz，1H)，1.13-0.97(m，4H).

Example 36

4- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl) -2-methyl-benzonitrile Compound 250)

This compound was prepared according to the procedure described for the preparation of compound 249.

1H NMR(300MHz，DMSO)δ8.22-8.12(m，2H)，8.04(d，J＝8.3Hz，1H)，7.90-7.80(m，1H)，6.73(d，J＝8.4Hz，1H)，4.17(s，3H)，2.56(s，3H)，2.21(tt，J＝8.1，5.1Hz，1H)，1.13-0.94(m，4H).

Example 37

3- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl) -benzonitrile (Compound 251)

This compound was prepared according to the procedure described for the preparation of compound 249.

Example 38

5- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl-indan-1-ones Thing 252)

This compound was prepared according to the procedure described for the preparation of compound 249.

1H NMR(300MHz，DMSO)δ8.29(s，1H)，8.15(dd，J＝8.1，1.4Hz，1H)，8.03(d，J＝8.3Hz，1H)，7.72(d，J＝8.1Hz，1H)，6.74(d，J＝8.3Hz，1H)，4.17(s，3H)，3.24-3.10(m，2H)，2.74-2.64(m，2H)，2.21(tt，J＝8.0，5.1Hz，1H)，1.05-0.98(m，3H).

Example 39

4- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl-indan-1-ones Thing 253)

This compound was prepared according to the procedure described for the preparation of compound 249.

1H NMR(300MHz，DMSO)δ7.83(dd，J＝7.4，1.2Hz，1H)，7.75-7.65(m，2H)，7.56(t，J＝7.5Hz，1H)，6.72(d，J＝8.2Hz，1H)，4.17(s，3H)，3.13-3.01(m，2H)，2.69-2.57(m，2H)，2.15(tt，J＝8.3，4.9Hz，1H)，1.04-0.88(m，4H).

Preparation example 12

1- (8-bromo-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-cyclopropanecarboxylic acid ethyl ester (Compound No.) Thing 312)

1.0g (2.6mmol) of crude 2,4, 6-trimethyl-benzenesulfonate 1, 2-diamino-3-bromo-6-methoxy-pyridinium salt (see preparation of compound 311) was dissolved in dioxane (8.5mL) under argon, treated with 1-formyl-cyclopropanecarboxylic acid ethyl ester (0.56g, 3.9mmol) and heated to 90 ℃ for 22 hours. The brown solution was cooled to room temperature, treated with 1N KOH in MeOH (2.6mL), and allowed to stand at room temperature for 6 hours. The solvent was evaporated in vacuo and NaCl solution and NaHCO were added to the product₃An aqueous solution. The product was extracted with DCM (. times.3), and the combined organic phases were taken up with Na₂SO₄Drying, filtering and vacuum concentrating. The product was purified by flash chromatography on silica gel using DCM: EtOAc 96: 4 → 85: 15 as eluent. The title compound (0.22g) was obtained as a colorless solid.

1H NMR(300MHz，CDCl3)δ7.69(d，J＝8.2Hz，1H)，6.23(d，J＝8.3Hz，1H)，4.16(s，3H)，4.15(q，J＝7.1Hz，2H)，1.74(dd，J＝7.5，4.3Hz，2H)，1.58(dd，J＝7.1，3.9Hz，3H)，1.18(t，J＝7.1Hz，3H).

Preparation example 13

1- (8-bromo-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-cyclopropanecarboxylic acid (compound) 313)

1- (8-bromo-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -cyclopropanecarboxylic acid ethyl ester (0.22g, 0.64mmol) was dissolved in 1, 4-dioxane (15 mL). AddingCharging LiOH (0.085g, 1.9mmol) in H₂O solution (3 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated. Addition of H₂O (50mL), the aqueous phase was adjusted to pH1 with 2N HCl. The aqueous phase was extracted with EtOH/DCM 1/10 (. times.3). The combined organic phases were washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the title compound as a solid.

1H NMR(300MHz，DMSO)δ7.96(d，J＝8.3Hz，1H)，6.63(d，J＝8.4Hz，1H)，4.13(s，3H)，1.54(dd，J＝7.2，4.1Hz，2H)，1.42(dd，J＝7.2，4.1Hz，2H).

Preparation example 14

4- (4, 4,5, 5-tetramethyl- [1, 3, 2 ]]Bioxaborolan-2-yl) -indan-1-one compound (314)

4-bromo-indan-1-one (1.0g, 4.9mmol) was dissolved in 1, 4 dioxane (40mL) and the mixture was bubbled with argon. Bis- (pinacol) -diborane (1, 3g, 5.1mmol) and PdCl were added₂(dppf)₂＊CH₂Cl₂(0.16g, 0.19mmol) followed by KOAc (1.4g, 14.6 mmol). The mixture was stirred at 80 ℃ for 3h under argon. The mixture was diluted with EtOAC and filtered. The filtrate was purified by flash chromatography using heptane: EtOAc as eluent. The title compound was obtained as a solid.

Preparation example 15

5- (4, 4,5, 5-tetramethyl- [1, 3, 2 ]]Bioxaborolan-2-yl) -indan-1-one (Compound 315)

The title compound was prepared as described for preparation 14 using 5-bromo-indan-1-one as the starting material.

Preparation example 16

5- (4, 4,5, 5-tetramethyl- [1, 3, 2 ]]Bioxaborolan-2-yl) -3H-isobenzofuran-1-one (Compound 316)

The title compound was prepared as described for preparation 14 using 5-bromo-3H-isobenzofuran-1-one as starting material.

Example 40:

compounds 254, 258, 259, 261 and 264-membered carboxylic acid were prepared according to general procedure 3 using compound 313(1- (8-bromo-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -cyclopropanecarboxylic acid) as starting compound.

Example 41:

compounds 257 and 268 were prepared according to general procedure 2 using compound 313(1- (8-bromo-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -cyclopropanecarboxylic acid) as the starting compound.

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid isopropylamide (Compound 254)

1H NMR(300M Hz，DMSO)δ8.78(d，J＝7.3Hz，1H)，8.20(d，J＝8.2Hz，1H)，7.95-7.87(m，2H)，7.85-7.81(m，1H)，6.85(d，J＝8.4Hz，1H)，4.21(s，3H)，4.03(s，3H)，4.00-3.87(m，1H)，1.60-1.51(m，2H)，1.51-1.41(m，2H)，1.13(s，3H)，1.10(s，3H).

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropanecarboxylic acid isopropylamide (Compound 255)

1H NMR(300MHz，DMSO)δ8.89(d，J＝7.2Hz，1H)，8.37(s，1H)，8.33(d，J＝8.2Hz，1H)，8.14(d，J＝8.3Hz，1H)，7.95(d，J＝8.1Hz，1H)，6.88(d，J＝8.4Hz，1H)，5.49(s，2H)，4.21(s，3H)，3.96(dq，J＝13.4，6.6Hz，1H)，1.57(dd，J＝6.8，3.5Hz，2H)，1.51-1.41(m，2H)，1.15(s，3H)，1.12(s，3H).

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid isopropylamide (Compound 256)

1H NMR(300MHz，DMSO)δ9.00(d，J＝7.2Hz，1H)，8.29(s，1H)，8.13(m，1H)，7.74(d，J＝8.5Hz，2H)，6.85(d，J＝8.4Hz，1H)，4.20(s，3H)，3.98(dq，J＝13.2，6.6Hz，1H)，3.25-3.13(m，2H)，2.70(m，2H)，1.58(dd，J＝7.0，3.5Hz，2H)，1.46(dd，J＝7.0，3.5Hz，2H)，1.16(s，3H)，1.14(s，3H).

1- [ 5-hydroxy-8- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane Formic acid isopropylamide (Compound 257)

1H NMR(300MHz，DMSO)δ9.27-8.94(m，1H)，7.87(d，J＝7.3Hz，1H)，7.69-7.56(m，2H)，7.51(t，J＝7.5Hz，1H)，6.18(d，J＝8.4Hz，1H)，3.89(dt，J＝13.3，6.7Hz，2H)，3.11(m，2H)，2.67-2.59(m，2H)，1.56-1.46(m，2H)，1.45-1.36(m，2H)，1.05(s，3H)，1.03(s，3H).

1- [ 5-methoxy-8- (1-oxo-indan-4-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 258)

1H NMR(300MHz，DMSO)δ8.45(t，J＝5.7Hz，1H)，7.94(dd，J＝7.5，1.1Hz，1H)，7.84(d，J＝8.1Hz，1H)，7.73(d，J＝6.6Hz，1H)，7.59(t，J＝7.5Hz，1H)，6.82(d，J＝8.1Hz，1H)，4.20(s，3H)，3.52(m，2H)，3.24(m，2H)，3.16-3.07(m，3H)，2.94(s，3H)，2.74-2.61(m，2H)，1.50(dd，J＝7.0，3.6Hz，2H)，1.37(dd，J＝7.1，3.6Hz，2H).

1- [8- (5-cyano-pyridin-3-yl) -5-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 259)

1H NMR(300MHz，DMSO)δ9.61(d，J＝2.1Hz，1H)，9.03(d，J＝1.9Hz，2H)，8.99(t，J＝2.1Hz，1H)，8.40(t，J＝5.4Hz，1H)，8.24(d，J＝8.3Hz，1H)，6.89(d，J＝8.4Hz，1H)，4.22(s，3H)，3.58(dd，J＝12.5，6.5Hz，2H)，3.27(dd，J＝13.9，7.3Hz，2H)，3.03-2.98(s，3H)，1.55(dd，J＝6.9，3.7Hz，2H)，1.42(dd，J＝6.9，3.7Hz，2H).

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid isobutyl amide (Compound 261)

1H NMR(300MHz，DMSO)δ8.85(t，J＝5.6Hz，1H)，8.26(s，1H)，8.11(m，2H)，7.72(d，J＝8.1Hz，1H)，6.84(d，J＝8.4Hz，1H)，4.20(s，3H)，3.22-3.13(m，2H)，3.09-2.95(m，2H)，2.72-2.64(m，2H)，1.85-1.69(m，2H)，1.62-1.51(m，2H)，1.50-1.40(m，2H)，0.89(s，3H)，0.86(s，3H).

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide (compound 264)

1H NMR(300MHz，DMSO)δ8.55-8.48(m，1H)，8.21(d，J＝8.4Hz，1H)，7.99(d，J＝1.2Hz，1H)，7.93(dd，J＝8.1，1.4Hz，1H)，7.84(d，J＝8.1Hz，1H)，6.85(d，J＝8.4Hz，1H)，4.21(s，3H)，4.02(s，3H)，3.58(q，J＝6.4Hz，2H)，3.30-3.23(m，2H)，3.00(s，3H)，1.55(dd，J＝6.9，3.6Hz，2H)，1.44(dd，J＝7.0，3.7Hz，2H).

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-methanesulfonyl-ethyl) -amide (compound 265)

1H NMR(300MHz，DMSO)δ8.62(t，J＝5.5Hz，1H)，8.29(s，1H)，8.16(d，J＝8.3Hz，1H)，8.11(d，J＝8.3Hz，1H)，7.77(d，J＝8.1Hz，1H)，6.85(d，J＝8.3Hz，1H)，4.20(s，3H)，3.59(q，J＝6.4Hz，2H)，3.44-3.26(m，2H)，3.20(dd，J＝12.0，6.0Hz，2H)，2.98(s，3H)，2.75-2.66(m，2H)，1.56(dd，J＝7.0，3.6Hz，2H)，1.43(dd，J＝7.0，3.6Hz，2H).

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide (compound 266)

1H NMR(300MHz，DMSO)δ8.64(t，J＝5.7Hz，1H)，8.43(s，1H)，8.30(d，J＝8.1Hz，1H)，8.17-8.11(m，1H)，7.98(d，J＝8.1Hz，1H)，6.87(d，J＝8.4Hz，1H)，5.52(s，2H)，4.21(s，3H)，3.60(q，J＝6.3Hz，2H)，3.3(m.2H)，3.00(s，3H)，1.56(dd，J＝6.9，3.6Hz，2H)，1.44(dd，J＝7.1，3.6Hz，2H).

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridine-2-radical]Cyclopropanecarboxylic acid isobutyl amide (Compound 267)

1H NMR(300MHz，DMSO)δ8.75(t，J＝5.5Hz，1H)，8.35(s，1H)，8.30(dd，J＝8.1，1.3Hz，1H)，8.12(d，J＝8.3Hz，1H)，7.94(d，J＝8.0Hz，1H)，6.87(d，J＝8.4Hz，1H)，5.49(s，2H)，4.21(s，3H)，3.02(dd，J＝6.5，5.9Hz，2H)，1.55(dd，J＝6.9，3.6Hz，2H)，1.46(dd，J＝7.0，3.5Hz，2H)，0.87(s，3H)，0.85(s，3H).

1- [ 5-hydroxy-8- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [ l, 5-a]Pyridin-2-yl]-cyclopropane Formic acid isopropylamide (Compound 268)

1H NMR(300MHz，DMSO)δ9.14-8.85(m，1H)，8.19(s，1H)，8.05(s，1H)，7.96(d，J＝8.4Hz，1H)，7.69(d，J＝8.1Hz，1H)，6.43(s，1H)，4.00(m，1H)，3.25-3.08(m，2H)，2.73-2.64(m，2H)，1.56(dd，J＝6.7，3.4Hz，2H)，1.46(dd，J＝6.8，3.4Hz，2H)，1.16(s，3H)，1.14(s，3H).

Example 42:

compound 269-270 was prepared according to general procedure 3.

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]Triazolo [1,5-a] Pyridin-2-yl]-cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide (compound 269)

1H NMR(300MHz，DMSO)δ8.39(t，J＝5.7Hz，1H)，8.26(d，J＝0.6Hz，1H)，8.15(dd，J＝8.1，1.2Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.41(d，J＝8.2Hz，1H)，7.27(d，J＝8.3Hz，1H)，5.52(s，2H)，4.05(s，3H)，3.63-3.49(m，2H)，3.26(m，2H)，2.97(s，3H)，1.52(dd，J＝7.0，3.6Hz，2H)，1.39(dd，J＝7.1，3.6Hz，2H).

1- [ 8-Methylyl-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4]]Triazolo [1,5-a] Pyridin-2-yl]Cyclopropanecarboxylic acid cyclohexylmethylamide (compound 270)

1H NMR(300MHz，DMSO)δ8.55(s，1H)，8.19(s，1H)，8.15(d，J＝8.0Hz，1H)，7.99(d，J＝8.0Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.27(d，J＝8.2Hz，1H)，5.51(s，2H)，4.05(s，3H)，3.00(t，J＝6.2Hz，2H)，1.53-0.81(m，15H).

Example 43

Compound 273 was prepared according to general procedure 6, then according to general procedure 7.

Dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-) Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 273)

1H NM R(300MHz，DMSO)δ8.28(s，1H)，8.16(d，J＝8.1Hz，1H)，7.96(d，J＝8.1Hz，1H)，7.38(d，J＝8.2Hz，1H)，7.20(d，J＝8.3Hz，1H)，5.50(s，2H)，4.42(s，2H)，4.04(d，J＝8.7Hz，3H)，2.75(s，6H)，1.27(dd，J＝6.6，4.1Hz，2H)，1.14(dd，J＝6.6，4.1Hz，2H).

Example 44:

cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-) Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropylmethyl ester (compound 276)

Compound 276 was prepared according to general procedure 5, then according to general procedure 7.

1H NMR(300MHz，DMSO)δ8.33(d，J＝0.5Hz，1H)，8.16(dd，J＝8.1，1.2Hz，1H)，7.9δ(d，J＝8.1Hz，1H)，7.39(d，J＝8.1Hz，1H)，7.20(d，J＝8.3Hz，1H)，5.49(s，2H)，4.41(s，2H)，4.01(s，3H)，3.17(m，1H)，1.54(m，5H)，1.33-0.87(m，9H).

Example 45

4- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4 [ ]]Triazolo [1,5-a]Pyridin-5-yl]-2- Methoxy-benzonitrile (Compound 277)

Starting from compound 308, the title compound was prepared according to general procedure 7.

1H NMR(300MHz，DMSO)δ8.04(s，1H)，7.88(d，J＝8.1Hz，1H)，7.70(dd，J＝8.1，1.4Hz，1H)，7.45(d，J＝8.3Hz，1H)，7.17(d，J＝8.3Hz，1H)，4.60(t，J＝5.8Hz，1H)，4.02(m，6H)，3.95-3.85(m，2H)，1.17-1.09(m，2H)，1.04(dd，J＝6.2，3.8Hz，2H).

Example 46

4- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine-5- Base of]-2-methoxy-benzonitrile (Compound 278)

The title compound was prepared according to the procedure for preparing compound 283 described in example 48, starting from compound 277.

1H NMR(300MHz，DMSO)δ7.96(s，1H)，7.87(d，J＝8.2Hz，1H)，7.71(d，J＝8.1Hz，1H)，7.44(d，J＝8.3Hz，1H)，7.17(d，J＝8.2Hz，1H)，4.02(m，6H)，3.85(s，2H)，3.19(d，J＝6.6Hz，2H)，1.72(dd，J＝13.4，6.6Hz，1H)，1.19(t，J＝5.0Hz，2H)，1.06(t，J＝2.9Hz，2H)，0.77(s，3H)，0.75(s，3H).

Example 47:

compound 279-282 was prepared according to general procedure 4 using compound 191 as the starting material.

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid isobutyl-amide (Compound 279)

1H NMR(300MHz，DMSO)δ8.51(t，J＝5.5Hz，1H)，8.4(m，1H)8.31-8.23(m，1H)，8.01-7.93(m，1H)，7.74(t，J＝7.8Hz，1H)，7.38(d，J＝8.1Hz，1H)，7.24(d，J＝8.3Hz，1H)，4.04(s，3H)，3.00(dd，J＝6.7，5.9Hz，2H)，1.80-1.62(m，1H)，1.52(dd，J＝6.9，3.5Hz，2H)，1.41(dd，J＝7.0，3.5Hz，2H)，0.82(s，3H)，0.80(s，3H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-methanesulfonylamino-ethyl) amide (Compound 280)

1H NMR(300MHz，DMSO)δ8.4(m，1H)，8.34(m，2H)，8.06-7.87(m，1H)，7.77(t，J＝7.9Hz，1H)，7.43(d，J＝8.2Hz，1H)，7.25(d，J＝8.3Hz，1H)，7.07(t，J＝5.9Hz，1H)，4.04(s，3H)，3.27(m，2H)，3.09-2.94(m，2H)，2.88(s，3H)，1.51(dd，J＝7.0，3.6Hz，2H)，1.37(dd，J＝7.1，3.5Hz，2H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid cyclopropylamide (Compound 281)

1H NMR(300MHz，DMSO)δ8.40(m，2H)，8.30-8.23(m，1H)，7.98(m，1H)，7.75(m，1H)，7.39(m，1H)，7.23(m，1H)，4.02(s，3H)，2.72(tq，J＝7.8，4.0Hz，4H)，1.57-1.46(m，7H)，1.39(dd，J＝7.0，3.6Hz，8H)，1.37(s，2H)，0.70-0.58(m，7H)，0.42(dt，J＝7.0，4.6Hz，7H).

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid cyclohexylmethyl-amide (Compound 282)

1H NMR(300MHz，DMSO)δ8.54(d，J＝5.6Hz，1H)，8.41(t，J＝1.4Hz，1H)，8.28(dd，J＝8.0，1.2Hz，1H)，7.99(dd，J＝7.9，1.2Hz，1H)，7.75(t，J＝7.9Hz，1H)，7.39(d，J＝8.1Hz，1H)，7.24(d，J＝8.3Hz，1H)，4.04(s，3H)，3.01(t，J＝6.2Hz，2H)，1.61(m，5H)，1.54-1.48(m，2H)，1.45-1.38(m，3H)，1.10(m，3H)，0.84(m，2H).

Example 48:

5- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridine-5- Base of]Nicotinonitrile (Compound 283)

Compound 248(0.02g, 0.06mmol) was dissolved in DCM (2 mL). TEA (0.035mL, 0.25mmol) and methanesulfonyl chloride (0.007mL, 0.09mmol) were added and stirred under argon for 30 min. Subjecting the reaction mixture toH₂O wash and filter the organic phase through a phase separation cartridge (chromabondPTS). The solvent was concentrated and the crude product was suspended in isobutanol (6mL) under argon. DIPEA (0.05mL, 0.31mmol) was added and the mixture was stirred at 60 ℃ for 18 h. The isobutanol was evaporated and the crude product was purified by preparative HPLC/MS to give the title compound.

1H NMR(300MHz，CDCl3)δ9.29(d，J＝2.2Hz，1H)，8.92(d，J＝2.0Hz，1H)，8.79(t，J＝2.1Hz，1H)，7.06(d，J＝8.1Hz，1H)，6.86(d，J＝8.2Hz，1H)，4.09(s，3H)，3.90(s，2H)，3.29(d，J＝6.8Hz，2H)，1.87(dp，J＝13.4，6.7Hz，1H)，1.43(q，J＝4.2Hz，2H)，1.17-1.08(m，2H)，0.86(s，3H)，0.84(s，3H).

Example 49

5- (2-cyclopropyl-5-methoxy- [1,2,4]]Triazolo [1,5-a]Pyridin-8-yl) -nicotinonitrile (Compound 284)

Compound was prepared according to the procedure described for the preparation of compound 249.

1H NMR(300MHz，DMSO)δ9.62(d，J＝2.2Hz，1H)，9.04-8.91(m，2H)，8.17(d，J＝8.3Hz，1H)，6.78(d，J＝8.3Hz，1H)，4.19(s，3H)，2.22(tt，J＝8.1，5.0Hz，1H)，1.17-0.99(m，4H).

Example 50:

compounds 285 and 286 were prepared according to general procedure 4 using compound 192 as the starting material.

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid (2-dimethylsulfamoyl-ethyl) -amide (compound 285)

1H NMR(300MHz，CDCl3)δ9.34(t，J＝5.7Hz，1H)，8.08-8.00(m，2H)，7.90-7.80(m，2H)，7.08(d，J＝8.1Hz，1H)，6.97-6.88(m，1H)，4.10(s，3H)，3.80(dd，J＝12.3，6.0Hz，2H)，3.18(t，J＝6.2Hz，2H)，2.87(s，6H)，1.82(dd，J＝7.3，3.6Hz，2H)，1.67(dd，J＝7.4，3.6Hz，2H).

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropane carboxylic acid methyl ester Acid [2- (methylsulfonyl-methyl-amino) -ethyl]-amides (Compound 286)

1H NMR(300MHz，CDCl3)δ9.10(d，J＝5.5Hz，1H)，8.07-7.98(m，2H)，7.88-7.80(m，2H)，7.08(dd，J＝8.1，2.7Hz，1H)，6.98-6.89(m，1H)，4.10(s，3H)，3.57(q，J＝6.1Hz，2H)，3.31(t，J＝6.2Hz，2H)，2.92(s，3H)，2.80(s，3H)，1.81(dd，J＝7.4，3.6Hz，2H)，1.68-1.61(m，2H).

Example 51

Compound 287-289 was prepared according to general procedure 2.

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- Cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide (compound 287)

1H NMR(300MHz，DMSO)δ8.43(s，1H)，7.92-7.82(m，2H)，7.73(d，J＝8.1Hz，1H)，7.50(d，J＝8.2Hz，1H)，7.26(d，J＝8.2Hz，1H)，4.05(s，3H)，3.99(s，3H)，3.49(dd，J＝15.3，9.4Hz，2H)，3.16(t，J＝7.1Hz，2H)，2.75(s，6H)，1.52(d，J＝3.4Hz，2H)，1.39(d，J＝3.4Hz，2H).

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-dimethylsulfamoyl-ethyl) -amide (compound 288)

1H NMR(300MHz，DMSO)δ9.46(d，J＝2.1Hz，1H)，9.12(d，J＝1.8Hz，1H)，8.91(s，1H)，8.34(s，1H)，7.56(d，J＝8.1Hz，1H)，7.29(d，J＝8.2Hz，1H)，4.05(s，3H)，3.52(d，J＝7.9Hz，2H)，3.21-3.12(m，2H)，2.76(s，6H)，1.52(m，2H)，1.40(m，2H).

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-cyclopropyl Alkanoic acid (2-dimethylsulfamoyl-ethyl) -amide (compound 289)

1H NMR(300MHz，DMSO)δ8.45(d，J＝5.7Hz，1H)，8.15(s，1H)，8.01(d，J＝8.1Hz，1H)，7.78(d，J＝8.0Hz，1H)，7.41(d，J＝8.3Hz，1H)，7.26(d，J＝8.3Hz，1H)，4.04(s，3H)，3.56-3.45(m，2H)，3.19(m，4H)，2.79-2.67(m，8H)，1.57-1.48(m，2H)，1.39(m，2H).

Example 52

PDE4 determination

Human recombinant PDE4(Genbank accession No. NM-006203) was combined with test compound, cAMP (1X 10), at a concentration of up to 10. mu.M^-5M) and a small amount (0.021MBq) of radiolabeled cAMP for 1 hour. At the end of the incubation, the cleavage of the substrate was assessed by the binding of AMP product to SPA beads, which produce chemiluminescence upon binding to the radiotracer. AMP products inhibit the binding of the radiotracer to the beads, thereby competing for the luminescent signal.

The results were calculated as the molar concentration that produced 50% inhibition of substrate cleavage compared to the control sample and expressed as IC₅₀Range (M).

PDE4IC₅₀Range of

It represents IC₅₀The value is more than or equal to 1000nM

IC of expression₅₀The value is more than or equal to 500 and less than 1000nM

IC₅₀Values < 500nM

Example 53

The PDE4 assay as disclosed in example 52 above was performed. The results were calculated as the molar concentration that produced 50% inhibition of substrate cleavage compared to the control sample and expressed as IC₅₀Range (M).

PDE4IC₅₀Range of

It represents IC₅₀The value is more than or equal to 1000nM

IC of expression₅₀The values are ≥ 500 and < 1000nM

IC₅₀Values < 500nM

Claims (33)

1. A compound of formula I and pharmaceutically acceptable salts or N-oxides thereof,

wherein R is₁Is C_1-6An alkoxy group or a hydroxyl group, or a salt thereof,

R₂is cycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more substituents selected from R₄Substituted by a substituent of；

R₃Is hydrogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, alkylamino or dialkylamino;

R₄is hydrogen, halogen, hydroxy or cyano,

or R₄Is NR₅R₆、-C(O)NR₇R₈、-C(O)R₇、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-OC(O)R₃、NC(O)R₇、-OR₇、-NC(O)OR₃、-NSO₂R₇、-SO₂NR₇R₈or-SO₂R₇R₈Alkyl, each of which is optionally substituted by one or more groups selected from R₉Substituted with the substituent(s);

R₅and R₆Each independently represents hydrogen, -C (O) alkyl, -S (O)₂An alkyl group;

R₇and R₈Each independently represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkyloxyalkyl, arylalkyl, heteroarylalkyl, any of which is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -C (O) N-alkyl, -NR₁₁SO₂-alkyl, -S (O) -alkyl, or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

R₉is a hydroxyl group;

x and Y are C and N respectively, or N and C;

a is aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is optionally substituted with one or more groups selected from R₁₀Substituted with a substituent group of (1);

R₁₀is hydrogen, cyano, halogen or oxo,

or R₁₀Is alkyl, alkoxy, alkylthio, -S (O) alkyl, -S (O)₂-alkyl, sulfamoyl, -C (O) OR₃、-C(O)R₃、-NR₅R₆-alkyl (NR)₅R₆) or-C (O) NR₇R₈Each of which is optionally substituted by one or more groups selected from R₄Substituted with the substituent(s);

R₁₁and R₁₂Each independently represents hydrogen or an alkyl group,

wherein

The term "aryl" means an aromatic carbocyclic group which is a 6-membered ring, or an optionally fused carbocyclic ring having at least one aromatic ring;

the term "heteroaryl" means a heterocyclic aromatic ring group, a 5-or 6-membered ring having 1-4 heteroatoms selected from O, S and N, or an optionally fused bicyclic ring having 1-4 heteroatoms, and wherein at least one ring is aromatic;

the term "alkyl" means a group, branched or straight chain, obtained when one hydrogen atom is removed from a hydrocarbon, and containing from 1 to 20 carbon atoms;

the term "cycloalkyl" means a saturated cycloalkane group, including polycyclic groups, containing 3-20 carbon atoms; the term "cycloalkenyl" means a mono-, di-, tri-, or tetra-unsaturated non-aromatic cyclic hydrocarbon group, including polycyclic groups, containing from 3 to 20 carbon atoms;

the term "heterocycloalkyl" means a cycloalkyl group as defined above, containing from 1 to 6 heteroatoms selected from O, N or S;

the term "heterocycloalkenyl" means a cycloalkenyl group as defined above, including polycyclic groups, optionally fused with carbocyclic rings, comprising 1 to 6 heteroatoms selected from O, N and S;

the term "halogen" means fluorine, chlorine, bromine and iodine;

the term "alkoxy" means a group of formula-OR ', wherein R' is alkyl as defined above;

the term "amino" means a compound of the formula-N (R)₂Wherein each R independently represents hydrogen.

2. A compound according to claim 1, wherein R₁Is methoxy.

3. A compound according to claim 1, wherein A is optionally substituted with R₁₀Is substituted in which R₁₀Is not hydrogen.

4. The compound according to claim 1, wherein a is optionally substituted aryl.

5. A compound according to claim 1, wherein a is optionally substituted phenyl or optionally substituted indanyl.

6. A compound according to claim 5, wherein R₁₀Is cyano, halogen, alkyl, sulfamoyl, -C (O) R₃、-C(O)OR₃、-NR₅R₆Wherein R is₃、R₅And R₆As defined in claim 1.

7. The compound according to claim 1, wherein a is optionally substituted heteroaryl.

8. The compound according to claim 7, wherein a is optionally substituted pyridyl, optionally substituted benzofuranyl, optionally substituted 3H-isobenzofuran-1-one-yl or optionally substituted 2, 3-dihydro-isoindol-1-one-yl.

9. The compound according to claim 1, wherein a is optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl.

10. A compound according to claim 9 wherein a is optionally substituted piperidinyl or optionally substituted pyridazinyl.

11. A compound according to any one of claims 4,5, 7, 8, 9 or 10, wherein R₁₀Is hydrogen, cyano, halogen, oxo, alkyl, alkoxy, -S (O) alkyl, -S (O)₂Alkyl, -C (O) R₃、-C(O)OR₃、-C(O)NR₇R₈Wherein R is₃、R₇And R₈As defined in claim 1.

12. A compound according to claim 11, wherein R₁₀Is cyano, halogen, oxo, alkyl, alkoxy or-C (O) R₃Wherein R is₃As defined in claim 1.

13. A compound according to claim 1 of the formula Ia

Wherein R is₁、R₂And A is as defined in claim 1.

14. A compound according to claim 1 of the formula Ib

Wherein R is₁、R₂And A is as defined in claim 1.

15. The compound according to any one of claims 1-10 and 13-14, wherein R₂Is optionally substituted C_3-6A cycloalkyl group.

16. A compound according to claim 15, wherein R₂Is an optionally substituted cyclopropyl group.

17. The compound according to any one of claims 1-10 and 13-14, wherein R3 is halogen, alkyl, cycloalkyl, or heterocycloalkyl.

18. A compound according to claim 17, wherein R₃Is alkyl or heterocycloalkyl.

19. The compound according to any one of claims 1-10 and 13-14, wherein R₄Is halogen, hydroxy or cyano, or R₄Is NR₅R₆、-C(O)NR₇R₈、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-OC(O)R₃、-NC(O)R₇、-OR₇、-NC(O)OR₃、-NSO₂R₇、-SO₂NR₇R₈、-SO₂R₇R₈Alkyl, each of which is optionally substituted by one or more groups selected from R₉Substituted with the substituent(s); wherein R is₃、R₅、R₆、R₇、R₈And R₉As defined in any one of the preceding claims.

20. A compound according to claim 19, wherein R₄Is hydroxy or cyano, or R₄is-C (O) NR₇R₈、-COOR₇、-NR₅C(O)NR₇R₈、-OC(O)NR₇R₈、-NC(O)R₇、-OR₇、-NC(O)OR₃Alkyl optionally substituted by one or more groups selected from R₉Substituted with the substituent(s); wherein R is₉Is hydroxy, and wherein R₃、R₇And R₈As defined in any one of the preceding claims.

21. The compound according to any one of claims 1-10 and 13-14, wherein R₅And R₆Each independently represents hydrogen.

22. The compound according to any one of claims 1-10 and 13-14, wherein R₇And R₈Each independently represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -C (O) N-alkyl, -NR₁₁SO₂-alkyl, -S (O) -alkyl, or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; wherein R is₁₁And R₁₂Is hydrogen or C_1-4An alkyl group.

23. A compound according to claim 22, wherein R₇And R₈Each independently represents hydrogen, alkyl, cycloalkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, cyano, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -S (O)₂-alkyl, -S (O)₂-NR₁₁R₁₂-NC (O) -alkyl, -NR₁₁SO₂-alkyl, or R₇And R₈Together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; wherein R is₁₁And R₁₂Is hydrogen or C_1-4An alkyl group.

24. A compound selected from:

2-cyclopropyl-8-methoxy-5- (3-acetyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-phenyl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (4-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (4-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3, 4-dimethoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-thiophen-2-yl- [1,2,4] triazolo [1,5-a ] pyridine,

n- [3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -acetamide,

2-cyclopropyl-8-methoxy-5- (3-trifluoromethoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- (3-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

1- [5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -thiophen-2-yl ] -ethanone,

2-cyclopropyl-8-methoxy-5-pyrimidin-5-yl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3-methanesulfonyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

n- [3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -methanesulfonamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N-methyl-benzamide,

2-cyclopropyl-8-methoxy-5- (4-acetyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -acetamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid methyl ester,

2-cyclopropyl-8-methoxy-5-pyridin-3-yl- [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid methyl ester,

2-cyclopropyl-5- (4-methanesulfonyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (2-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- [4- (2-methoxy-ethoxy) -phenyl ] - [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzamide

5- (3-butoxy-phenyl) -2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (3-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5-pyridin-4-yl- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-5- (2, 4-dichloro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

2-cyclopropyl-8-methoxy-5- [4- (morpholine-4-sulfonyl) -phenyl ] - [1,2,4] triazolo [1,5-a ] pyridine,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzyl ] -acetamide,

n- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzyl ] -methanesulfonamide,

2-cyclopropyl-5- (4-fluoro-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzonitrile,

3- [4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -propionic acid methyl ester,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N- (2-hydroxy-ethyl) -benzenesulfonamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzonitrile,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid,

[3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -methanol,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N, N-dimethyl-benzamide,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzamide,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -benzoic acid,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N, N-dimethyl-benzamide,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -N-methyl-benzamide,

2-cyclopropyl-8-methoxy-5-piperidin-1-yl- [1,2,4] triazolo [1,5-a ] pyridine,

1- [3- (2-cyclopropyl-8-hydroxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -phenyl ] -ethanone,

2- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -isonicotinonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

3- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -benzonitrile,

pyrrolidine-1-carboxylic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

3- [2- (1-benzyloxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -benzonitrile,

n- {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } -isobutyramide,

{1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } -carbamic acid cyclopentyl ester,

pyrrolidine-1-carboxylic acid {1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl } amide,

6- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-methyl-4, 5-dihydro-2H-pyridazin-3-one,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -nicotinonitrile,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -indan-1-one,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-methyl-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -indan-1-one,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-fluoro-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-fluoro-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-methoxy-benzonitrile,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -3H-isobenzofuran-1-one,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-hydroxymethyl-benzonitrile,

3- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -5-methoxy-benzonitrile,

4- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -3H-isobenzofuran-1-one,

5- (2-cyclopropyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2, 3-dihydro-isoindol-1-one,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo- [1,5-a ] pyridin-5-yl } -benzonitrile,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

3- { 8-methoxy-2- [1- (pyrrolidine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

2-methyl-acrylic acid 2- ({1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarbonyl } -amino) -ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methoxy-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

4- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

4- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -benzonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid methylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid ethylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid propylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclopropylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyanomethylamide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-acetylamino-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonylamino-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (3-morpholin-4-yl-3-oxo-propyl) amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid [2- (methanesulfonyl-methyl-amino) -ethyl ] -amide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (pyridin-3-ylmethyl) -amide,

1- (3- { 8-methoxy-2- [1- (4-methyl-piperazine-1-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -phenyl) -ethanone,

1- (3- { 8-methoxy-2- [1- (morpholine-4-carbonyl) -cyclopropyl ] - [1,2,4] triazolo [1,5-a ] pyridin-5-yl } -phenyl) -ethanone,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid benzylamide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-sulfamoyl-ethyl) -amide,

1- [5- (3-acetyl-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

2-methyl-acrylic acid 2- ({1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarbonyl } -amino) -ethyl ester,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-hydroxy-ethyl) -amide,

cyclohexyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

propyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

isopropyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

pyrrolidine-1-carboxylic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy-1, 2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

5- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -nicotinonitrile,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2-methoxy-benzonitrile,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2-methyl-benzonitrile,

3- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -benzonitrile,

5- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -indan-1-one,

4- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -indan-1-one,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-hydroxy-8- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [8- (5-cyano-pyridin-3-yl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 5-methoxy-8- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [8- (4-cyano-3-methoxy-phenyl) -5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [ 5-hydroxy-8- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isopropylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

diethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-indan-4-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

dimethyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

diethyl-carbamic acid 1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

cyclohexyl-carbamic acid 1- [ 8-methoxy-5- (1-oxo-1, 3-dihydro-isobenzofuran-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropylmethyl ester,

4- [2- (1-hydroxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -2-methoxy-benzonitrile,

4- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -2-methoxy-benzonitrile,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid isobutylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-methanesulfonylamino-ethyl) -amide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclopropylamide,

1- [5- (3-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid cyclohexylmethylamide,

5- [2- (1-isobutoxymethyl-cyclopropyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-5-yl ] -nicotinonitrile,

5- (2-cyclopropyl-5-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -nicotinonitrile,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (4-cyano-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid [2- (methanesulfonyl-methyl-amino) -ethyl ] -amide,

1- [5- (4-cyano-3-methoxy-phenyl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [5- (5-cyano-pyridin-3-yl) -8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

1- [ 8-methoxy-5- (1-oxo-indan-5-yl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -cyclopropanecarboxylic acid (2-dimethylsulfamoyl-ethyl) -amide,

and pharmaceutically acceptable salts or N-oxides.

25. A pharmaceutical composition comprising a compound according to any one of claims 1-24 and a pharmaceutically acceptable vehicle or excipient or a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25, further comprising one or more additional therapeutically active compounds.

27. Use of a compound according to any one of claims 1-24 in the manufacture of a medicament for the prevention, treatment or amelioration of a disease or condition of the skin.

28. Use of a pharmaceutical composition according to claim 25 or 26 in the manufacture of a medicament for the prevention, treatment or amelioration of a skin disease or condition.

29. Use according to claim 27 or 28, wherein the skin disease or condition is an acute or chronic skin wound disorder.

30. Use according to claim 27 or 28, wherein the skin disease or condition is selected from proliferative and inflammatory skin disorders, cancer, alopecia, skin atrophy, skin ageing, acne, urticaria, pruritus and eczema.

31. Use according to claim 27 or 28, wherein the skin disease or condition is selected from psoriasis or dermatitis.

32. Use according to claim 31, wherein the skin disease or condition is selected from epidermal inflammation.

33. Use according to claim 27 or 28, wherein the skin disease or condition is selected from steroid induced skin atrophy, skin photoaging, atopic dermatitis, seborrheic dermatitis or contact dermatitis.