Piperidine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4, p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

 

This invention relates to compounds of the formula

,

where

hetaryl I is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N;

hetaryl II is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N, or is a binomial ring system containing 1-4 heteroatom selected from S, O or N, where at least one ring is aromatic in nature;

R1represents lower alkyl, lower alkoxy, lower alkyl substituted by halogen, or halogen;

R2represents halogen, lower alkyl, lower alkoxy, hydroxy, lower alkyl substituted by halogen, lower alkyl, substituted by hydroxy or benzo[1,3]dioxole, or

represents -(CHR)p-phenyl, possibly substituted by halogen, lower alkyl, lower alkoxy, S(O)2-lower alkyl, cyano, nitro, lower alkoxy substituted by halogen, dimethylamino, -(CH2)p-NHC(O)O-lower alkyl or lower alkyl substituted by halogen, and R represents hydrogen, halogen, hydroxy or lower alkoxy, or

is cycloalkenyl or cycloalkyl, possibly substituted by hydroxy or lower alkyl substituted by halogen, or

before�provide a five - or six-membered heteroaryl group, containing 1-3 heteroatom selected from O, S or N, which is possibly substituted by halogen, lower alkyl, lower alkoxy or dimethylamino, or

is an O-phenyl, possibly substituted by halogen, or

is heteroseksualci, possibly substituted by halogen, hydroxy, lower alkyl substituted by halogen, or C(O)O-lower alkyl;

R3represents hydrogen, lower alkyl, cyano or phenyl;

R4represents lower alkoxy, lower alkyl or halogen;

p is 0 or 1;

n is 0, 1 or 2; if n is 2, then R4may be the same or different;

m is 0, 1 or 2; if m is 2, then R1may be the same or different;

o is 0, 1, 2 or 3, if o is 2 or 3, then R2may be the same or different;

or to their pharmaceutically active salts accession acid.

To date, found that the compounds of formula I of the present invention are modulators of beta-amyloid, and thus, they can be useful for treating or preventing the disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multiinfarct�Naya dementia, the boxers dementia and down's syndrome.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. From the point of view of the pathology of AD is characterized by deposition of amyloid in the form of extracellular plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques mainly composed of amyloid peptides (β-peptides), which are formed from the precursor protein β-amyloid (RDAs) in a series of stages proteolytic cleavage. Identified several forms of ADR, the most common are length proteins of 695, 751 and 770 amino acids. They are formed by alternative splicing of a single gene. β peptides originate from the same domain RDAs.

β-peptides are formed from APP by sequential action of two proteolytic enzymes called β - and γ-secretases. First, β-secretase produces cleavage in the extracellular domain of APP near the transmembrane domain (TM) with the formation of the C-terminal fragment (CTFβ) of APP containing the TM - and cytoplasmatic domain. CTFβ is a substrate for γ-secretase, which breaks it into several closely spaced to each other positions within the TM with the formation β-peptides and the cytoplasmic fragment. Proteolytic cleavage in various�'s points mediated γ-secretases, leads to the formation β-peptides with different chain length, for example β38, β40 and β42. The last one is considered the most pathogenic amyloid peptide, because of its strong tendency to the formation of neurotoxic aggregates.

β-Secretase is a typical spartilas protease. γ Secretase is a complex with proteolytic activity consisting of several proteins, its exact composition is not yet fully understood. However, essential components exhibiting such activity, are presenilin, and they may represent a new group of atypical aspartyl proteases that cleave their substrates within the TM and which are polytope membrane proteins. Other essential components of γ-secretase can be nicastrin products and aph1 genes (anterior pharynx defective-1) and RET-2 (presenilin enhancer-2). The recognized substrates for γ-secretase are RDAs and proteins of the Notch family receptor, however, γ-secretase has a broad substrate specificity and can cleave other membrane proteins unrelated to APP and Notch family.

The expression of γ-secretase activity is absolutely necessary for the formation of β-peptides. This is demonstrated using genetic approaches, i.e., through the destruction of genes presenilin, and IP�altanium low molecular weight inhibitory compounds. Because according to the amyloid hypothesis for the occurrence of AD is the formation and deposition of Ar is the main cause of this disease, it is believed that selective and potent inhibitors of γ-secretase will be useful for the prevention and treatment of AD.

An alternative method of treatment is the modulation of γ-secretase activity, resulting in a selective decrease of β42. This will be reflected in the increased content of shorter isoforms β such as β38, β37 or others that have a reduced tendency to aggregation and plaque formation, and which are less neurotoxic. Compounds that demonstrate such an influence on the modulation of γ-secretase activity, include some nonsteroidal anti-inflammatory drug (NSAID) and related analogues (Weggen et al. Nature, 414 (2001) 212-16).

Thus, the compounds of the present invention are useful for treating or preventing the disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers and down's syndrome.

Modern conceptions of modulating γ-secretase describe�tsya in numerous documents, for example in the following publications:

Morihara et al., J. Neurochem., 83 (2002) 1009-12,

Jantzen et al., J. Neuroscience, 22 (2002) 226-54,

Takahashi et al., J. Biol. Chem., 278 (2003) 18644-70,

Beher et al., J. Biol. Chem. 279 (2004) 43419-26,

Lleo et al., Nature Med. 10 (2004) 1065-6,

Kukar et al., Nature Med. 11 (2005) 545-50,

Perretto et al., J. Med. Chem. 48 (2005) 5705-20,

Clarke et al., J. Biol. Chem. 281 (2006) 31279-89,

Stock et al., Bioorg. Med. Chem. Lett. 16 (2006) 2219-2223,

Narlawar et al., J. Med. Chem. 49 (2006) 7588-91.

For compounds of formula I using the following definitions.

Used in this description, the term "lower alkyl" denotes a saturated group with straight or branched chain, containing from 1 to 7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.

Used in this description, the term "lower alkyl substituted by halogen" denotes an alkyl group as defined above where at least one hydrogen atom replaced by a halogen atom, for example CF3, CHF2, CH2F, CH2CF3, CH2CH2CF3, CF2CHF2, CH2CF2CF3and such.

Used in this description, the term "lower alkyl, substituted by hydroxy" denotes an alkyl group as defined above where at least one hydrogen atom replaced by hydroxy group, e.g.�measures CH 2OH, SNSN3HE or(CH3)2OH.

Used in this description, the term "lower alkoxy" denotes alkyl group as defined above that is linked via an atom O.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S, or N" is selected from the group consisting of

,,,,,,,

,or.

The term "binomial ring system containing 1-4 heteroatom selected from S, O or N, where at least one ring is aromatic in nature selected from the group consisting of

,,,,,or

;.

Used in this description, the term "heteroseksualci" denotes an unsaturated or partially unsaturated ring containing heteroatoms such as O, S and N, and these groups are selected from morpholinyl, d�-hydropyridine, dihydropyrrole, piperidine or 6-Aza-Spiro[2,5]octane.

The term "cycloalkyl" refers to unsaturated alkyl ring of 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "cycloalkenyl" refers to a partially unsaturated alkyl ring of 3-6 carbon atoms, for example cyclohexenyl.

The term "pharmaceutically acceptable salt accession acid" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluensulfonate acid and the like.

The objectives of the present invention are compounds of formula I, the use of such compounds for the manufacture of medicaments for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome, their preparation and medicinal products based on the compound of formula I according to the invention.

Other objectives of the invention are all forms of optically pure enantiomers, racemate or diastereomeric mixture� for compounds of formula I.

One of the embodiments of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a binomial ring system containing 1-4 heteroatom, for example, the following connections:

[8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine,

[8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1 -(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-5,6,7,8-Tetra�Idro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2,4-debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-fluoro-4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[8-(3,4-debtor-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(6-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[8-(3,4-debtor-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine,

3-(2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,

N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2,3-dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-dichlorophenyl)-N - (1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3-chlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

[8-(5-dimethylamino-2-nitro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(4-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

[8-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(5-chloro-2-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

(8-benzo[1,3]dioxol-5-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(3,5-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid�n-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

(CIS, RAC)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

(3S,4R)- and (3R,4S)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

(CIS, RAC)-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

(CIS, RAC)-[3,4-debtor-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

N-(3,3-debtor-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

4-chloro-3-(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,

(4-fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)metanopoli

N-((3S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

In the following embodiment of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N, for example the following compounds:

[1-(3,5-dichloro-benzyl)-1H-[1,2,4]Tr�Azol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

[1-(3-chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,

2-[2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol,

2-{6-(4-chloro-phenyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-olili

2-{6-(4-chloro-benzyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol.

In the following embodiment of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a binomial ring system containing 1-4 heteroatom, for example the following compounds:

[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine,

[8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[8-(2,3-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-phenyl)-[1,2,4]three�zolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

3-(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,

[8-(3,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,

3-(2-(1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,

N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-aminieli

[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine.

In the following embodiment of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a binomial ring system containing 1-4 heteroatom, for example the following compounds:

2-{8-(4-chloro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,

8-(2-chloro-4-fluorophenyl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-6-fluoro-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(pyrimidine-4-yl)piperidine-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(2-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

[8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(6-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(2-chloro-thiophene-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(3,4-debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(3,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

[8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-Pipa�idin-4-yl]-amine,

3-{2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzonitrile,

[8-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

[8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

tert-butyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate,

8-(3,4-differenl)-N-(1-(6-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(6-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-Differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

2-{8-(3,4-debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,

4-(3-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-�ethylpyrimidine-4-yl)piperidine-4-yl)benzo[C1] - thiazol-2-amine,

[4-(3,4-debtor-phenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

(CIS, RAC)-[8-(3,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,

(CIS, RAC)-N-(3-fluoro-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

2-{8-(4-fluoro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,

2-{8-(3,4-debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-olili

N-(3,3-debtor-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

In the following embodiment of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a binomial ring system containing 1-4 heteroatom, for example the following compounds:

8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,5-bis(trifluoromethyl)phenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3-chlorophenoxy)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

(2'-chloro-3,4,5,6-tetrahydro-2H-[1,4 bipyridinyl-4-yl)-[8-(4-triptoreline-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,

3-(2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

6-chloro-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6,8-bis(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-ethoxyphenyl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

4-(3-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-4-(3,4-differenl)-6-methylbenzo[d]thiazol-2-amine,

4-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(4-foreperiod-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(4,4-deformability-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,

N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

[8-(3,5-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2'-methoxy-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amine,

1-(2-chloropyridin-4-yl)-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-4-carbonitrile,

(CIS, RAC)-N-(1-(2-chloropyridin-4-yl)-3-foreperiod-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

(CIS, RAC)-N-(3-fluoro-1-(2-methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-chloropyridin-4-yl)-4-phenylpiperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazole,5-a]pyridin-2-amine,

8-(2,4-differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,5-bis(trifluoromethyl)phenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-aminieli

4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-carbonitrile.

In the following embodiment of the invention are compounds of formula I, where hetaryl I is aand

hetaryl II is a binomial ring system containing 1-4 heteroatom, for example the following compounds:

8-(3,4-differenl)-6-fluoro-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(3,4-differenl)-6-methyl-N-(1-(6-methylpyridazin~4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

8-(2-chloro-4-fluorophenyl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,

6-chloro-8-(3,4-differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine or

8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

One of the embodiments of the invention apply to other compounds of the formula

,

where

hetaryl I is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N;

hetaryl II is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N, or is a binomial ring system containing 1-4 heteroatom selected from S or N, where at least one ring is aromatic in nature;

R1represents lower alkyl or halogen;

R2represents halogen, lower alkyl, lower alkyl substituted with hydroxy, or represents -(SSC)p-phenyl, possibly substituted by halogen, lower alkyl or lower alkyl substituted by halogen; if o is 2 or 3, then R2may be the same or different;

p is 0 or 1;

m is 0, 1 or 2;

o is 0, 1, 2 or 3,

or to their pharmaceutically active salts accession acid.

Compounds of formula I of the present invention and their pharmaceutically acceptable salts can be obtained by methods known in the art, for example, the methods described below, including:

(a) bringing into interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

where X is a halogen, and other groups have the meanings described above, and,

if you want�till then, the transformation of the compounds in pharmaceutically acceptable salt accession acid;

or

(b) bringing in the interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

,

where X represents a halogen, and other groups have the meanings described above, or

(C) bringing in the interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

where groups have the meanings described above and R3represents hydrogen, and,

if desired, the conversion of the compounds in pharmaceutically acceptable salt accession acid.

Obtaining compounds of formula I of the present invention may be accomplished by sequential or convergent synthesis. The synthesis of compounds according to the invention is shown in the following schemes. Professionals in this field know what skills are needed to complete the reaction and purification of the products obtained. The substituents and indices used in the following description of the methods have the meanings given in the description previously, if� no indications of the opposite.

In more detail, the compounds of formula I can be obtained by the methods given below, by methods described in the Examples section, or similar ways. The reaction conditions suitable for individual stages of the reactions known to the person skilled in the art. The reaction sequence is not limited to that shown in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction stages can be easily changed. The source materials are either commercially available or can be obtained by methods analogous to the methods given below, by methods described in the Examples or by methods known in this field.

Scheme 1

Compounds of formula I of the present invention and their pharmaceutically acceptable salts can be obtained by combining amines of General formula 2 and halides of the General formula 3 (see Scheme 1). This reaction can be accomplished using well-known techniques, such as substitution reactions in terms of the use of a catalyst (like, for example, catalysis in the presence of palladium(0) or copper(II)), or under certain temperature conditions, or in the presence of base.

Scheme 2

Alternatively, you can implement a combination of halides 3 in describing�tions above conditions with amines of the General formula 4, bearing a protective group PG, such as Boe (tert-butoxycarbonyl), on the nitrogen atom of the piperidine (see Scheme 2). After removal of protection using, for example, trifluoroacetic acid, can be combination of piperidino 6 (hetaryl (I)-halides of formula 7 with obtaining the compounds of formula I.

Figure 3

Alternative, aniline of the General formula 9 can be applied in the reaction of reductive amination with ketones of the General formula 8 or 10 (see Scheme 3), to obtain compounds I, either directly or after cleavage of the protective group PG in compound 5, followed by combination with (heteroaryl (I)-halide 7 as described in Scheme 2. Reducing amination can be performed using methods known to the expert in the field of organic synthesis, for example by heating the amine and the ketone in a suitable solvent (e.g., toluene, dichloroethane, THF (tetrahydrofuran)), possibly in the presence of acid (e.g., acetic acid, tetraisopropyl-orthotitanate), and restore intermediate imina appropriate reducing agent (e.g. triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, hydrogen in the presence of palladium on charcoal).

Aniline of the General formula 9, which can be used as starting substances� to obtain the compounds of formula I, can be obtained as represented by the following schema.

Scheme 4

The combination of anilines of General formula 9 with ketones of the General formula 8 or 10 alternative can be performed in accordance with the Protocol of the reaction Aza-Wittig/restore (see Scheme 4). First aniline of the General formula 9 can be converted to the corresponding trialkylphosphine 11 by interacting with dialkyldithiophosphoric (e.g. dichlorodimethyl-postrana obtained in the reaction of trimethylphosphine with hexachloroethane in THF or dichloromethane) and a base is an organic amine (e.g., triethylamine, di-isopropylacrylamide) in a suitable solvent (e.g., THF, dichloromethane). Then the reaction mixture obtained in situ phosphazene 11, add ketones of the General formula 8 or 10, and the mixture was heated. Received imini/enamine 12 or 13 further treated with an appropriate reducing agent (e.g. triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, decaborane, a complex of borane-THF, with hydrogen in the presence of palladium on charcoal) in a suitable solvent (THF, DCM (dichloromethane), MeOH and their mixtures), using or not using acid catalysis (e.g., acetic acid) at ambient temperature or at elevated temperatures to obtain �of soedinenii General formula 5 or I (for the case when R3represents hydrogen).

Scheme 5

But it is aor.

Triazolopyridine General formula 5a alternative can be created as a result of transformation of amines of General formula 14 in the corresponding isothiocyanates 15 (for example, as a result of interaction with thiophosgene or 1,1'-thiocarbonyldiimidazole in dichloromethane in the presence of organic or aqueous inorganic bases) and interaction with amines of General formula 4 (see Scheme 5). The obtained thiourea 16 can be activated by alkylation with iodomethane and further subjected to cyclization to triazolopyridines 5a by strong heating (>130°C) in the presence of correspondingly functionalized derivative of hydroxylamine, such as O-(trimethylsilyl)-hydroxylamine in a polar solvent, such as dimethylacetamide (DMA).

Scheme 6

D represents carbocyclic ring, preferably.

Triazolopyridine General formula 5b can be prepared by initial condensation of cyclic hydrazides 18 and isothiocyanates 19 (obtained by methods known to those skilled in the art) to form thiourea 20 (see Scheme 6). List�I sulfur-containing groups by alkylation (for example, iodomethane in DMF (dimethylformamide) at elevated temperatures) allows you to replace its azide (e.g. sodium azide in DMF at elevated temperatures), which gives the possibility to obtain azidoaniline 22. After the restoration in the reaction of Staudinger with trimethylphosphine obtained intermediate fosfato 23, which cyclizes when heated with the formation of triazolopyridine 5b.

Aniline of the General formula 9, which can be used as starting materials to obtain the compounds of formula I can be obtained as represented by the following schema.

Scheme 7

But it is aor, a X represents Cl or Br.

Aniline 9a, in which heteroaryl II is annelirovaniya triazole group (see Scheme 7) can be generated from the corresponding amine derivatives 14. which are either commercially available, or can be obtained from the corresponding halides 24 in palladium catalyzed reaction combinations Suzuki with baronowie acids or esters Baranovich acids (for example, complex pinacolone ether). Amines 14 can result in interaction with ethoxycarbonylmethylene with obtaining derivatives of thiourea 25 which undergo a cyclization reaction p�after treatment with hydroxylamine in the presence of base with the release of carbon dioxide, obtaining analyoung triazoles 9a (as described, for example, in M. Nettekoven et al., Synthesis 2003, 11, 1649-1652).

Scheme 8

Alternatively, the order of stages in Scheme 7 can be changed (see figure 8). Halides 24 (which are either commercially available or can be synthesized by methods known in the art) can result in interaction with ethoxycarbonylmethylene, then treated with hydroxylamine to obtain analyoung triazoles 28. These halides can be further subjected to, for example, palladium catalyzed reaction combinations Suzuki with baronowie acids, or catalyzed by copper(I) reaction of a combination with phenols (for example, in accordance with D. Maiti et al. JOC 2010, 75, 1791-1794), to obtain the substituted aminotriazoles 9a.

Scheme 9

But it is aor,

Represents aor.

Compound 9a can be subjected to hydrogenation, using palladium on charcoal as catalyst, to obtain relevant partially saturated compounds 9b (see chart 9). Depending on the nature of the ring And for carrying out this reaction may require elevated temperature or elevated pressure of hydrogen or the presence of acid (eg�emer, HCl). Alternatively, compounds 9a can be restored using metals such as magnesium in a solution of alcohol (such as ethanol), with or without activation activation metal (for example, activation of catalytic amounts of iodine).

If the ring Into compounds 9b contains an NH group, it can be modified, for example by reductive amination using aldehydes or ketones in the presence of a reducing agent, such triacetoxyborohydride sodium, to obtain the alkylated amines; by acylation with the use of anhydrides or acid chlorides of the acids in the presence of base to obtain amides; through interaction with sulphonylchloride with receiving sulfonamides; through interaction with carbonyldiimidazole or triphosgene and alcohols or amines with obtaining carbamates or ureas, respectively.

To implement these modifications may be necessary to protect the amino group of the triazole 9a before the stage of hydrogenation, e.g., by use of the protective group Boc, which you can enter, for example using BOC-anhydride, and can be removed after hydrogenation and modifications using, for example trifluoroacetic acid.

Scheme 10

The introduction of the Deputy for Amina (R2is a RR'N (R and R' are preferably methyl) in regulation 8 of triazolopyridine 9c (see Scheme 10) may be effected by treating 3-bromo-2-nitropyridine Amin RR'NH in the presence of base (e.g. potassium carbonate), catalyst (for example, TBAI (iodide of tetrabutylammonium)) at temperatures from ambient to higher temperatures in a polar solvent (e.g., DMSO (dimethylsulfoxide)). As a result of the restoration of the nitro group using, or metal, or a metal salt, or hydrogen in the presence of a catalyst (e.g. Pd on charcoal) is produced by aminopyridin 14C, which can be converted according to Scheme 7 in the corresponding derived aminotriazole 9c.

Scheme 11

R and R' represent lower alkyl.

8-Alkyl - or 8-cycloalkyl-substituted triazolopyridine may be obtained by directed ortho-metallation proceeds of suitable protected aminopyridine (e.g., bialoleka derived) by double deprotonation using n-utility (Scheme 11). As a result of interaction of the obtained dianion at low temperature with aldehyde or ketone get derived 3-carbinol-pyridine 30 or 32. The pivaloyl-guide replacement group can be removed under alkaline conditions, using, for example, potassium hydroxide at elevated temperature. If the available hydrogen atom in the alpha position, we can praiseit� subsequent elimination of water from ethanol to provide the corresponding olefin 34. Received aminopyridines 31. 33 or 34 can be converted according to Scheme 7 into the corresponding derivatives of aminotriazole 9d, 9e or 9f.

Scheme 12

R2'represents a phenyl, possibly substituted by halogen or lower alkyl. Aminotriazole of the General formula 9a can be obtained on the basis of mandelate derivative 35 (see Scheme 12). After arilirovaniya followed by ozonolysis of the double bond receives the aldehyde 37. which forms hydrazon 38 after treatment with BOC-protected hydrazine. As a result of catalytic hydrogenation in the presence of a Nickel get a connection 39. The heating of the water causes lactonization and the removal of protection (similar to J. W. ilsson et al. J. Med. Chem. 2003, 46, 3985-4001). Hydrazide 40 is subjected to a cyclization reaction with cyanamide by heating first in acidic conditions, and then heating under alkaline conditions (in analogy to WO 2010/098487, preparatory Example 2-7) to give aniline 9a.

Scheme 13

Amines 41 can be subjected to acylation using N-sinodefence-amidocarbonyl (see Scheme 13) and alkylation with the use of appropriately protected 3-halogeno-propanol (for example, bromine-containing alcohol, protected in the form of TPR(tetrahydropyranyl)new ether) in the presence of base (e.g., carbonate� potassium) at ambient temperature or a higher temperature in a polar solvent (e.g., DMF). After removal from the protection of alcohol group of compound 44 cyclized, for example under the reaction conditions of Mitsunobu or using tetrabromomethane and triphenylphosphine with obtaining the amine 9h.

Scheme 14

3-Bromo-5-nitro-4H-[1,2,4]triazole can be subjected to alkylation using appropriately protected bromine-containing alcohol (e.g., tert-butyldimethylsilyloxy (TBDMS) group) in the presence of base (e.g. potassium carbonate). To remove protection from a protected alcohol 45 can lead to spontaneous cyclization freed spirit of the group through an atom of bromine, or cyclization may kataliziruetsa base with getting bicyclic derivative 46. After the restoration of the nitro group with hydrogen, catalyzed by a metal catalyst (e.g. Pd on charcoal), or metal salts, or metals, Amin get 9i (see Scheme 14).

Scheme 15

Z represents C or N, Q represents a leaving group.

Aniline 9k, in which heteroaryl II is a substituted triazole or pyrazole group (see Scheme 15) can be obtained, for example by deprotonation of compounds 47 and 48 with the use of sodium hydride in DMF and subsequent alkylation with the use of Q-R2. Q represents a leaving�General group (e.g., Cl, Br, I, tosylate, mesilate). Nitro compounds 49 can be restored to amines 9k, using well-known techniques, such as catalytic hydrogenation in the presence of a catalyst such as palladium on carbon, or recovery of metals, such as tin chloride in HCl, or with hydrazine in the presence of palladium on coal.

The initial substance 47, 48, or are commercially available, or can easily be obtained by methods known to those skilled in the field of organic synthesis. Examples of compounds 47 are, but not limited to, 1H-[1,2,4]triazole-3-ylamine and 1H-pyrazol-3-ylamine. An example of the connection 48 is 4-nitro-1H-pyrazol but im not limited.

Scheme 16

With is a carbocyclic ring, preferably.

Aniline 9l in which heteroaryl II is annelirovannymi the thiazole (see Scheme 16) can be obtained by condensation of α-bromoketones 50 with thiourea (for example, by heating in an appropriate solvent, for example ethanol). α-Bromacetone or are commercially available, or can easily be obtained by methods known to those skilled in the field of organic synthesis, for example as a result of interaction of the corresponding ketone with bromine in chloroform.

The halides of the General formula 3, which can be used�systems that can be used as starting materials to obtain the compounds of formula I, can be obtained as represented by the following schema.

Scheme 17

Halogenerator 3 can be obtained from aniline 9 (see Scheme 17) by means of the corresponding salt diakonia and subsequent disintegration in the presence of a source of halide, similar to the halide of copper (I) halide or hydrogen (X represents chlorine or bromine).

Scheme 18

Aniline 9m of the General formula or the corresponding bromides with 3m group 2-propan-2-ol in position 5 triazolopyridine (see figure 18) can be obtained on the basis of ester 51 by means of bromination in chloroform, followed by cyclization, as already described in Scheme 8, to obtain 2-amino-triazolopyridine 53. Then the ether 53 can be treated with bromide Metalmania with tertiary alcohol 54. After transformation of the bromide, for example in Suzuki reactions, get aniline 9m, or after the reaction of Sandmeyer, bromide 3m. The original substance 51 or commercially available, or can be synthesized by methods known in this field, for example in the case where R represents Me, 51 can be obtained from the corresponding bromide through interaction with trimethylboroxine in the presence of palladium catalyst.

Scheme 19

R2', R2"and R2"'are �Wallpaper lower alkyl, lower alkyl, substituted hydroxy, -(CH2)p-phenyl, possibly substituted by halogen, lower alkyl or lower alkyl substituted by halogen.

Halides 3A, in which heteroaryl II is a pyrimidine (see Scheme 19) can be obtained, as described for example in K. Baumann et al., WO 2009103652, by restoring trichloropyridinol 55 with getting dichloropropanol 56, for example as a result of processing by zinc in aqueous ammonia at 0°C. After that, the Deputy 4-chloro connection 56 may be substituted in the reaction of nucleophilic substitution (similar reactions using Grignard reagent R2'MgX, for example, chloride benzylamine in tetrahydrofuran at a temperature from -80 to +20°C) or in the substitution reaction using a metal catalyst (e.g. palladium acetate, 2-(dicyclohexylphosphino)-biphenyl, tetrahydrofuran (THF) in a microwave oven, 30 min, 200°C). Alternative, first one reactive chlorine atoms in the compound 55 is replaced by a group R2'and a second chlorine-substituent in the intermediate coupling 57 is replaced by a group R2"that allows to obtain the compound 3A.

Scheme 20

R2represents -(CH2)p-phenyl, possibly substituted by halogen, lower alkyl or lower alkyl substituted with halo�ene.

Halides 3b, in which heteroaryl II is a pyrimidine (see Scheme 20) can be obtained from 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester as a result of interaction such as chloride Metalmania in THF at temperatures from -78°C to 0°C with obtaining 2-(2,6-dichloro-pyrimidine-4-yl)-propan-2-ol. The chlorine atom in position 4 of the 2-(2,6-dichloro-pyrimidine-4-yl)-propan-2-ol can be substituted by a substituent R2for example , in the reaction combinations Suzuki with aryl-/heteroarylboronic acid/ester, R2-B(OH/OR')2in the presence of palladium catalyst and base (e.g., sodium carbonate), for example in dimethoxyethane as the solvent for the chloride 3b. Alternatively, the under 4-chloro can be brought into interaction with the chloride linkorganization connection R2ZnCl, for example chloride Benzedrine, in the presence of a palladium catalyst with obtaining chloride 3b. To perform these modifications might need the protection of the alcohol group, 2-(2,6-dichloro-pyrimidine-4-yl)-propan-2-ol before the second stage, for example, trimethylsilyl protection group which can be introduced, for example with the use of bis(trimethylsilyl)acetamide, and may be removed after carrying out modifications using, for example n-TsOH in a mixture of THF/water.

Scheme 21

/p>

Ketones 10d can be obtained in accordance with A. A. Calabrese et al., US 20050176772 based on dimethyl-3-oxopentanoate by DIMETHYLPROPANE with methyl iodide, followed by cyclization using benzylamine and formaldehyde. Hydrolysis of the ester and decarboxylation takes place when boiling to reflux in aqueous HCl solution, resulting in the ketone 10d. Replacement of the benzyl protective group is a BOC group can be carried out by hydrogenation in the presence of BOC-anhydride with obtaining ketone 10E (see Scheme 21). Treatment of ketone 10E amine of General formula 9 can be carried out in accordance with the Protocol of the reaction Aza-Wittig/restore as described in Scheme 4.

Ketones of the General formula 8, which can be used as starting materials to obtain the compounds of formula I can be obtained as represented by the following schema.

Scheme 22

Ketone 8A, in which heteroaryl I represents 3-methyl-[1,2,4]thiadiazole, (see Scheme 22) can be obtained on the basis of 5-chloro-3-methyl-[1,2,4]thiadiazole, which may be obtained by condensing acetamidine with perchloromethylmercaptan in the presence of sodium hydroxide. You can hold a mixture of this chloride with 1,4-dioxa-8 azaspiro(4,5)the Dean in the presence of palladium catalyst and base (e.g.�measures tert-butylate sodium). The result is catalyzed by acid (e.g., HCl) digestion of ketala get further ketone 8A.

Scheme 23

The ketone 8b, in which heteroaryl I represents [1,3,4]-oxadiazole, (see Scheme 23) can be obtained on the basis of 5-methyl-[1,3,4]oxidiazol-2-ylamine, by base-catalyzed condensation with complex acrylic ester. The decarboxylation of ketone 8b may be implemented, in the case of the allyl ether, catalyzed by palladium(0) dealkilirovania in the presence of the trap (trapping agent), for example formic acid or amine, etc. In the case of complex alkoxy-containing ether it is possible to apply standard methods of decarboxylation.

Amines of General formula 2, which can be used as starting materials to obtain the compounds of formula I can be obtained as represented by the following schema.

Scheme 24

The ketone 8 can be easily transformed into amines 2 by reductive amination with ammonia or hydroxylamine, or other suitable amine precursor (see Scheme 24).

Scheme 25

Amines 2a, in which heteroaryl I represents [1,2,4]oxidiazol (see figure 25), can be derived from N-BOC-protected AMI�of piperidino, through interaction with braciano and subsequent cyclization with acetamidoxime in the presence of a Lewis acid such as zinc chloride(II), the preparation of amines 2A after removal of the protection.

Scheme 26

Amines 2b, in which heteroaryl I represents 3-methyl-[1,2,4]thiadiazole, (see figure 26) can be obtained, for example, catalyzed by palladium combination of 5-chloro-3-methyl-[1,2,4]thiadiazole with tert-butyl ether piperidine-4-yl-carbamino acid and subsequent removal of the protective Boc group in the presence of acid. Alternatively, amines 2b can be obtained from the BOC-protected aminopiperidine as a result of interaction with the source of isothiocyanate, such as benzoylisothiocyanate, metal isothiocyanate, thiophosgene or activated derivative of thiourea to obtain relevant derivatives of thiourea. As a result of condensation with 1,1-dimethoxymethyl-dimethylamine and subsequent cyclization with hydroxylamine-O-sulfonic acid in the presence of base, such pyridine, amines 2b after removal of the protection.

Amines of formula 4A and 4b and ketones of the formula 10A, 10b, 10C (that might exist preferably in the form of their hydrates, depending on the nature of ketones), which can be used as starting materials to obtain the compounds of formula I, can� to be obtained, as shown on the following schema.

Scheme 27

the α-Fluorination of N-protected 4-piperidinol can be realized, for example, following the methods of M. van Niel et al. J. Med. Chem. 1999, 42, 2987-2104, using the interaction of the corresponding simple silyl-enol ether with an electrophilic fluorinating reagent, such as selectfluor (Selectfluor). As a result the reductive amination of the ketone 10A with benzylamine and triacetoxyborohydride sodium are mainly CIS-isomer of 4-amino-3-foreveryday (the ratio of CIS:TRANS ~ 5:1). These two isomers can be separated, using chromatography on silica gel. After removal of the benzyl group, e.g. by hydrogenation, get amine 4A (see Scheme 27).

Scheme 28

Direcroty 10b, 10c and 4b can be obtained on the basis of ester of 3-benzylamino-propionic acid (see Scheme 28). As a result of interaction with formaldehyde and benzotriazole, and then the reaction type of reaction are appropriately reformed acyclic debtorprovidian (as described O. Bezencon et WO V. 2005040120). Can be realized, for example, the cyclization of dikman, using tert-butylate potassium in NMP (N-methylpyrrolidone). After hydrolysis of the ester and decarboxylation by heating in an aqueous solution�e HCl get 3,3-ceftobiprole 10c in the form of its hydrate. Replacement of the benzyl protective group is a Boc group can be carried out by hydrogenation in the presence of BOC-anhydride. In the result of the reductive amination with benzylamine, for example, sodium borohydride, followed by removal of the benzyl groups receive 3,3-debtor-4-aminopiperidin 4b.

Scheme 29

Compounds of the General formula Ia in which R1is a halogen, such as Cl, can be converted into compounds of the General formula Ib, in which R1is a group of alkoxy, such as OMe, OEt, after treatment with the corresponding sodium salt (NaOMe or NaOEt) in a suitable alcoholic solvent, such as methanol or ethanol, respectively (see Scheme 29).

Scheme 30

Compounds of the General formula Ic, where R3represents cyano, can be obtained by reacting compounds of the General formula 8 with compounds of the General formula 9 in the presence tianyoude agent, such as trimethylsilane, in the presence of acetic acid (see Scheme 30).

Scheme 31

Compounds of the General formula Id can be obtained by reacting compounds of the General formula Ic with Grignard reagents in a suitable solvent, such as THF (see Scheme 31).

Scheme 32

With�organisations of the General formula Ie can be obtained proceeding from N-BOC-protected 4-methyl-piperidine-4-carboxylic acid (see Scheme 32), which may be treated with an activating agent such as CDI in the presence of ammonium hydroxide with formation of the corresponding amide. This amide can be converted to amine after treatment with 1,3-dibrom-5,5-dimethylhydantoin in potassium hydroxide and sodium sulfite. By removal of the protective group Boc receive 4-methyl-piperidine-4-ylamine, which in turn can be converted to compound 2C as a result of interaction with 4-chloro-6-methyl-pyrimidine in the presence of potassium phosphate in a suitable solvent, such as NMP. Compound 2C can be converted to the isothiocyanate by reacting with 1,1'-thiocarbonyldiimidazole-2(1H)-one in a suitable solvent such as DCM. After treatment with ammonia to obtain the corresponding thiourea. After treatment with methyl iodide in a suitable solvent, such as ethanol, are methylisothiazoline, which undergoes a cyclization reaction with (3-chlorpropyl)-phenylacetic acid of the formula 58 in the presence of EDCI (), HOBt (1-hydroxybenzotriazole), DIPEA (diisopropylethylamine) and hydrazine with obtaining compounds of General formula Ie.

These compounds were investigated in accordance with the following test.

Description of the analysis of γ-secretase

Analysis of cell �-secretase

Cell N4 of neuroglioma person, sverkhekspressiya RDAs man, were sown in the amount of 30,000 cells/well/200 μl in 96-well plates in IMDM medium (Wednesday, Dulbecco, modified according to the method Iscove containing 10% FCS (fetal calf serum), hygromycin In (0.2 mg/l), and incubated for 2 hours at 37°C, 5% CO2after which was added the test compound.

Be tested compounds were dissolved in 100% Me2SO, getting a 10 mm concentrated solution. In the typical case, 12 µl of these solutions were diluted in 1000 μl of IMDM medium (without FCS). As a result of successive dilution (1:1) obtained a curve of dose-response by ten points. To the cells in 96-well plates was added 100 µl of each dilution. In this analysis used appropriate controls using only the diluent and compound comparison. The final concentration of Me2SO was 0.4%.

After incubation for 22 hours at 37°C, 5% CO250 µl of the supernatant was transferred into a 96-well polypropylene plates with holes, round bottom for detection β42. The wells were added 50 μl of buffer for analysis (50 mm Tris/Cl; pH 7.4; 60 mm NaCl; 0,5% BSA (bovine serum albumin); 1% Tuina), was then added 100 µl of a solution identifying antibodies (ruthenorumano WAR; of 0.0625 μg/ml in the buffer for analysis). Before�artelino for 1 hour at room temperature (CT) were incubated with 50 ál of the prepared mixture of exciting antibodies (biotinylating antibodies E; 1 μg/ml) and covered with the magnetic bead streptavidin (Dynal M-280; 0.125 mg/ml) was then added to the plates for analysis. Tablets for analysis were incubated on a shaker for 3 hours at room temperature and in the conclusion were read using the analyzer Bioveris M8 in accordance with the manufacturer's instructions (Bioveris).

The toxicity of the compounds was recorded in the analysis of the viability of cells treated with compounds of cells, using a colorimetric method of analysis (analysis of CellTiter 96TM AQ, Promega) according to the manufacturer's instructions. Briefly, after extraction, 50 µl of cell culture supernatant for detection of β42, to the cells was added to 20 μl of a solution of 1 × MTS/PES (methotrexate/ethosulfate of phenazine) and incubated for 30 minutes at 37°C, 5% CO2. Then recorded the optical density at 490 nm.

The magnitude of IC50for inhibiting secretion β42 was calculated using the approximation method of nonlinear regression using the software XLfit 4.0 (IDBS).

Preferred compounds exhibit IC50<a 0.5 (μm). The list below presents data on the inhibition of secretion β42 for all connections.

No. exampleEC50for β42 (μm) No. exampleEC50for β42 (μm)
10,371431,735
20,221440,126
30,551450,443
40,261460,404
50,311470,155
60,651480,177
71,291490,394
80,751500,422
9To 1.861510,191
100,721520,325
110,611530,572
121,251541,208
130,261550,380
141,391560,187
150,721570,361
160,771580,545
170,711590,578
180,761601,134
191,31161Is 0.450
201,431620,645
210,86163 0,827
222,18164Of 0.786
230,221650,758
24Of 1.821660,841
250,271671,926

261,471681,431
274,171690,051
280,861700,393
290,861710,501
300,751720,480
310,551730,867
32To 1.341740,564
33To 6.881750,659
341,971760,542
351,491770,722
360,681781,181
370,161791,474
380,29180Of 0.056
390,091810,129
400,961820,180
411,381830.174 were revealed
420,68184 0,279
431,481850,285
443,311860,186
451,111870,312
460,141880,463
470,171890,410
481,0611900,497
490,3001910,042
500,5911920,408
510,8961930,519
520,2131941,118
530,228 1950,727
540,2851960,379
550,3601970,941
560,5211980,535
572,0521990,157
580,1582000,411
590,8432010,455

600,2582020,283
610,2782030,259
620,8892040,220
63Of 0.382205 0,332
64Was 0.1382060,246
650,1552070,457
660,2472080,318
67Ends 0.2452090,796
680,2572100,186
690,2722110,872
700,2352120,161
710,2552130,455
720,2312140,512
730,3282150,488
740,180 2160,334
751,1042170,190
760,2792180,506
770,1722190,155
780,2212200,276
790,2592210,185
800,1432220,301
810,2312230,205
820,2932240,506
831,1422250.174 were revealed
840,3062260,170
85 0,2722271,571
860,1802280,131
870,5512290,185
880,1482300,311
890,2042310,694
900,5232320,484
910,2432331,495
920,2542341,162
930,3572351,156

117
940,3482361,067
950,843 2370,723
960,2322380,253
970,7272390,284
980,4102400,215
990,5002410,246
1000,9122420,377
1010,3992430,166
1020,1642440,385
1030,7802450,321
1040,5192460,423
1050,3602470,233
106 0,4702480,363
1070,7072490,965
1082,5162500,075
1090,2852510,205
1100,8042520,434
1110,4922530,285
112To 0.4482540,496
1130,7362550,67
1140,2702560,256
1150,328257Of 0.798
1160,1112580,21
0,3682590,818
1180,3382601,934
1190,1692611,68
1200,2552620,265
1210,6212630,624
122Of 0.7862640,945
1230,2102652,77
1240,1092661,404
1250,3482670,487
1260,3682681,447
1270,851269 0,595

1280,1152701,063
1290,5972711,107
1300,2262721,127
1310,4672731,11
1320,2802741,356
1330,3762750,424
1340,1872760,558
1350,1962770,416
1360,1922781,539
1370,769279-
1380,097280-
1390,165281-
1400,157282-
1410,160283-
1420,333

Compounds of formula I and pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, you can also enter them rectally, for example in the form of suppositories, parenterally, e.g. in the form of solutions for injection.

For the manufacture of pharmaceutical preparations the compounds of formula I can be processed using pharmaceutically inert inorganic or organic carriers. For example, as such carriers for tablets tablets coated dragees and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like. Suitable carriers for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. In the case of soft gelatin capsules any carriers are usually not required, but it depends on the nature of the active substance. Suitable carriers for the production of solutions and syrups are e.g. water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are e.g. natural or solidified fats, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigent, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain additional therapeutically useful substances.

Medicinal product containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, and the method of their manufacture, �which comprises introducing one or more than one compound of formula I and/or one or more than one pharmaceutically acceptable salt accession acid and, if desired, one or more other therapeutically useful substances in the form Galanova drug to together with one or more than one therapeutically inert carrier.

According to the present invention compounds of formula I and their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the inhibition of secretion β42, such as Alzheimer's disease.

The dosage can be varied within wide limits, and undoubtedly, in each case, it must be adjusted to suit individual needs. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day for compounds of the General formula I or a corresponding amount of its pharmaceutically acceptable salts. The daily dose can be administered in a single dose or in divided doses and, in addition, can also be exceeded, if there is the reading.

Tablet composition (wet granulation)

PositionIngredientsmg tablet
525100 500
1.The compound of the formula I525100500
2.Lactose anhydrous DTG12510530150
3.Sta-Rx150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
Total167167167831

The method of manufacture

1. Mix position 1, 2, 3 and 4 and to carry out granulation, using purified water.

2. Dry the granules at 50°C.

. Skip the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; to perform compression on a suitable press.

The composition is in the form of capsules

PositionIngredientsmg/capsule
525100500
1.The compound of the formula I525100500
2.Lactose water159123148-
3.Corn starch25354070
4.Talc10151025
5. Magnesium stearate1225
Total200200300600

The method of manufacture

1. Mix position 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add positions 4 and 5 and mix for 3 minutes.

3. Add in a suitable capsule.

Example 1

[8-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 5-Chloro-3-methyl-[1,2,4]thiadiazole

To a suspension of acetamidine hydrochloride (7 g; 0.07 mole) in dichloromethane (75 ml) at room temperature in an argon atmosphere was added perchloromethylmercaptan (12 g; 0,063 mol). After cooling to -10°C was slowly added a solution of sodium hydroxide (14 g; 0,348 mol) in water (22.5 ml). The reaction mixture was stirred at 0°C for 12 hours. Was added water, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent evaporated. The residue was purified molecular vacuum distillation (75°C, 30 mbar (3 kPa)), receiving specified in the title compound as colorless Jew�spine.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=2.64 (s, 3H).

b) 8-(3-Methyl-[1,2,4]thiadiazole-5-yl)-1,4-dioxa-8-Aza-Spiro[4.5]Dean

To a premixed solution (10 minutes at room temperature) of palladium acetate(II) (180 mg; 0.001 mmol) and 2-(aizicovici-phosphino)biphenyl (572 mg; and 0.002 mmol) in dioxane (10 ml) was added 1,4-dioxa-8 azaspiro(4,5)Dean (1.3 ml; 10 mmol), 5-chloro-3-methyl-[1,2,4]thiadiazole (1,48 g; 11 mmol) and tert-butylate sodium (1.47 g; 15 mmol) and heated in a microwave at 130°C for 15 minutes. The reaction mixture was half diluted with saturated brine, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel, using ethyl acetate as eluent. Specified in the title compound was obtained as a light yellow solid (1.87 g; 77%).

MS (mass spectrometry) ISP (inductively coupled plasma) (m/e): 242,4 (23) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=4.00 (s, 4H), 3.64-3.60 (m, 4H), 2.40 (s, 3H), 1.83-1.79 (m, 4H).

c) 1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it

To a solution of 8-(3-methyl-[1,2,4]thiadiazole-5-yl)-1,4-dioxa-8-Aza-Spiro[4.5]Decan (1,75 g; 7 mmol) in acetone (15 ml) was added 2 n aqueous solution of HCl (50 ml) and stirred at 50°C for 3 hours. The reaction mixture was cooled to 0°C and dropwise to�alali saturated aqueous solution of NaHCO 3to pH 7. The aqueous phase three times were extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent evaporated, getting mentioned in the title compound as a light brown solid (1.29 g; 90%).

MS ISP (m/e): 198,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=3.88-3.84 (m, 4H), 2.64-2.60 (m, 4H), 2.44 (s, 3H).

a) 3-(4-Fluoro-Phenyl)-pyridin-2-ylamine

A mixture of 2-amino-3-bromopyridine (2.0 g; and 11.2 mmol), 4-ftorhinolonovy acid (3,23 g, of 22.4 mmol), dichlormethane adduct dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (733 mg; 0.001 mmol) and aqueous solution of Na2CO3(2 n; 11,2 ml; 22,4 mmol) in dioxane (30 ml) was heated to 110°C for 2 hours. The reaction mixture was diluted with water and was extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of n-heptane/diethyl ether as eluent. Specified in the title compound was obtained as a light yellow solid (1.95 g; 92%).

MS ISP (m/e): 189,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.08-8.06 (m, 1H), 7.44-7.39 (m, 2H), 7.34-7.31 (m, 1H), 7.17-7.12 (m, 2H), 6.76-6.72 (m, 1H), 4.57 (bs, 2H).

e) N-(3-(4-Fluoro-phenyl)-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea

To a solution of 3-(4-fluoro-phenyl)-pyridine-2-ylamine (200 mg; 1.06 m�ol) in dioxane (10 ml) was added ethoxycarbonylmethylene (141 µl; 1,17 mmol) and stirred at room temperature for 12 hours. The solvent was evaporated and the residue was used for next step without purification. Specified in the title compound was obtained as a light yellow solid (340 mg; 100%).

MS ISP (m/e): to 320.1 (100) [(M+H)+].

f) 8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

To a solution of hydroxylamine hydrochloride (370 mg; 5,32 mmol) and N,N-diisopropylethylamine (543 μl; 3,19 mmol) in MeOH (2 ml) and EtOH (2 ml) was added a solution of N-(3-(4-fluoro-phenyl)-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (340 mg; 1.06 mmol) in MeOH (2 ml) and EtOH (2 ml). The reaction mixture was stirred at room temperature for 1 hour and then at 60°C for 3 hours. The solvent was evaporated and to the residue was added a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol (with 10% ammonia) as eluent. Specified in the title compound was obtained as white solid (205 mg; 84%).

MS ISP (m/e): 229,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.31-8.28 (m, 1H), 7.96-7.91 (m, 2H), 7.50-7.47 (m, 1H), 7.22-7.16 (m, 2H), 6.94-6.89 (m, 1H), 4.51 (bs, 2H).

g) 8-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

8(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (232 mg; 1,02 mmol) in EtOH (10 ml) and aqueous HCl (25%; 162 ml, 1.12 mmol) was gidrirovanie in the presence of palladium on charcoal (10%; 232 mg; 0.22 mmol) at 50 bar (5 MPa) and 50°C for 18 hours. The catalyst was filtered and washed thoroughly with EtOH and the solvent was removed from the combined filtrates. To the residue was added a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol (with 10% ammonia) as eluent. Specified in the title compound was obtained as white solid (174 mg; 74%).

MS ISP (m/e): to 233.1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.14-7.09 (m, 2H), 7.04-6.98 (m, 2H), 4.14-4.03 (m, 5H), 2.30-2.24 (m, 1H), 2.15-1.90 (m, 3H).

(h) [8-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

To a solution of 8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (60 mg; 0,258 mmol) and 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (76 mg; 0.387 mmol) in anhydrous dichloroethane (3 ml) was added in argon atmosphere tetraisopropyl-orthotitanate (236 µl; 0,775 mmol) and heated to 85°C for 12 hours. The reaction mixture was cooled to room temperature, was added sodium borohydride (20 mg; 0,517 mmol) and �canal (1.5 ml) and stirred at room temperature for 3 hours and at 50°C for 30 minutes. The reaction mixture was cooled to room temperature and was evaporated. To the residue was added an aqueous solution of Na2CO3(2 M). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol (with 10% ammonia) as eluent. Specified in the title compound was obtained as white solid (28.8 mg; 27%).

MS ISP (m/e): 414,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.13-7.09 (m, 2H), 7.04-6.98 (m, 2H), 4.14-4.01 (m, 4H), 3.86-3.68 (m, 3H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.31-1.91 (m, 6H), 1.64-1.51 (m, 2H).

Example 2

[8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (example 1f). Specified in the title compound was obtained as white solid (yield=28%).

MS ISP (m/e): 410,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.32-8.30 (m, 1H), 7.96-7.91 (m, 2H), 7.50-7.47 (m, 1H), 7.21-7.15 (m, 2H), 6.92-6.87 (m, 1H), 4.53-4.51 (m, 1H), 3.99-3.86 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.73-1.60 (m, 2H).

Example 3

[5-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-�piperidin-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 5-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine. The latter compound can be obtained analogously to example 1, stage d to g on the basis of 2-amino-6-bromo-pyridine. Specified in the title compound was obtained as white solid (yield=30%).

MS ISP (m/e): 414,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.06-6.94 (m, 4H), 5.28-5.24 (m, 1H), 4.00-3.97 (m, 1H), 3.87-3.69 (m, 3H), 3.31-3.21 (m, 2H), 2.92-2.85 (m, 2H), 2.40 (s, 3H), 2.38-2.32 (m, 1H), 2.18-1.83 (m, 5H), 1.53-1.49 (m, 2H).

Example 4

[5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine. The latter compound can be obtained analogously to example 1, stage (d-f on the basis of 2-amino-6-bromo-pyridine. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 410,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.95-7.90 (m, 2H), 7.49-7.39 (m, 2H), 7.23-7.18 (m, 2H), 6.90-6.87 (m, 1H), 4.47-4.44 (m, 1H), 4.04-3.87 (m, 3H), 3.39-3.30 (m, 2H), 2.41 (s, 3H), 2.27-2.21 (m, 2H), 1.71-1.59 (m, 2H).

Example 5

[1-(3,5-Dichloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]t�diazol-5-yl)-piperidine-4-yl]-amine

a) 1-(3,5-Dichloro-benzyl)-1H-[1,2,4]triazole-3-ylamine

3-Amino-1,2,4-triazole (420 mg; 5.0 mmol) was dissolved in DMF (3 ml) in an argon atmosphere at room temperature was added sodium hydride (55%; 218 mg; 5.0 mmol) in small portions and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, was added 3,5-DICHLOROSILANE (977 mg; 5.0 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4was filtered , the solvent evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol as eluent. Specified in the title compound was obtained as white solid (357 mg; 29%).

MS ISP (m/e): 243,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.75 (s, 1H), 7.34-7.32 (m, 1H), 7.13-7.12 (m, 2H), 5.07 (s, 2H).

(b) [1-(3,5-Dichloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3,5-dichloro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as white solid (yield=27%).

MS ISP (m/e): USD 424.2 (100) [(M+H)+ ].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.75 (s, 1H), 7.34-7.33 (m, 1H), 7.13-7.12 (m, 2H), 5.09 (s, 2H), 4.12-4.10 (m, 1H), 3.91-3.70 (m, 3H), 3.35-3.26 (m, 2H), 2.41 (s, 3H), 2.23-2.15 (m, 2H), 1.65-1.52 (m, 2H).

Example 6

[1-(4-Methyl-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(4-methyl-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 370,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.61 (s, 1H), 7.17 (m, 4H), 5.09 (s, 2H), 4.13-4.11 (m, 1H), 3.89-3.70 (m, 3H), 3.34-3.25 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.21-2.16 (m, 2H), 1.64-1.51 (m, 2H).

Example 7

[1-(3-Fluoro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-fluoro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as a colorless oil.

MS ISP (m/e): 374,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.70 (s, 1H), 7.36-7.30 (m, 1H), 7.05-6.92 (m, 3H), 5.13 (s, 2H), 4.19-4.17 (m, 1H), 3.88-3.69 (m, 3H), 3.34-3.24 (m, 2H), 2.40 (s, 3H), 2.21-2.15 (m, 2H), 1.64-1.51 (m, 2H).

Example 8

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazole-3-yl]-AMI�

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 424,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.73 (s, 1H), 7.61-7.58 (m, 1H), 7.52-7.41 (m, 3H), 5.19 (s, 2H), 4.20-4.18 (m, 1H), 3.89-3.70 (m, 3H), 3.33-3.24 (m, 2H), 2.40 (s, 3H), 2.21-2.15 (m, 2H), 1.64-1.51 (m, 2H).

Example 9

[1-(4-Fluoro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(4-fluoro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 374,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.65 (s, 1H), 7.27-7.22 (m, 2H), 7.09-7.02 (m, 2H), 5.10 (s, 2H), 4.17-4.14 (m, 1H), 3.88-3.69 (m, 3H), 3.34-3.24 (m, 2H), 2.40 (s, 3H), 2.20-2.15 (m, 2H), 1.64-1.51 (m, 2H).

Example 10

[1-(4-Chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(4-chloro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as a white t�ejogo substances.

MS ISP (m/e): 390,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.65 (s, 1H), 7.36-7.33 (m, 2H), 7.20-7.17 (m, 2H), 5.11 (s, 2H), 4.13-4.11 (m, 1H), 3.88-3.67 (m, 3H), 3.34-3.25 (m, 2H), 2.40 (s, 3H), 2.21-2.15 (m, 2H), 1.64-1.52 (m, 2H).

Example 11

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[1-(3,4,5-Cryptor-benzyl)-1H-[1,2,4]triazole-3-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3,4,5-Cryptor-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 410,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.75 (s, 1H), 6.90-6.85 (m, 2H), 5.07 (s, 2H), 4.17-4.14 (m, 1H), 3.90-3.66 (m, 3H), 3.35-3.25 (m, 2H), 2.41 (s, 3H), 2.21-2.16 (m, 2H), 1.64-1.53 (m, 2H).

Example 12

[1-(2-Chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 390,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.73 (s, 1H), 7.43-7.15 (m, 4H), 5.26 (s, 2H), 4.17-4.14 (m, 1H), 3.90-3.70 (m, 3H), 3.34-3.25 (m, 2H), 2.40 (s, 3H), 2.21-2.16 (m, 2H), 1.65-1.52 (m, 2H).

Example 13

[1-(3-Chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as a colorless oil.

MS ISP (m/e): 390,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.71 (s, 1H), 7.32-7.30 (m, 2H), 7.25-7.24 (m, 1H), 7.14-7.11 (m, 1H), 5.12 (s, 2H), 4.14-4.12 (m, 1H), 3.89-3.72 (m, 3H), 3.35-3.26 (m, 2H), 2.41 (s, 3H), 2.22-2.16 (m, 2H), 1.66-1.52 (m, 2H).

Example 14

[1-(2,4-Dichloro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 1-(2,4-Dichloro-benzyl)-1H-pyrazol-3-ylamine

3-Aminopyrazole (506 mg; 5.8 mmol) was dissolved in DMF (2 ml) in an argon atmosphere at room temperature was added sodium hydride (55%; 241 mg; 5.5 mmol) in small portions and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, was added 2,4-DICHLOROSILANE (1100 mg; 5.5 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4was filtered , the solvent evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol as eluent. Specified in the header connect�tion was obtained as white solid (700 mg; 52%).

MS ISP (m/e): of 242.2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.39-7.38 (m, 1H), 7.21-7.20 (m, 1H), 7.17 (m, 1H), 6.90-6.87 (m, 1H), 5.65-5.64 (m, 1H), 5.16 (s, 2H), 3.66 (bs, 2H).

(b) [1-(2,4-Dichloro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(2,4-dichloro-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as a colorless oil (yield=56%).

MS ISP (m/e): 423,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.40-7.39 (m, 1H), 7.24-7.23 (m, 1H), 7.20-7.17 (m, 1H), 6.87-6.84 (m, 1H), 5.62-5.61 (m, 1H), 5.18 (s, 2H), 3.90-3.83 (m, 2H), 3.60-3.51 (m, 2H), 3.33-3.23 (m, 2H), 2.41 (s, 3H), 2.21-2.15 (m, 2H), 1.61-1.48 (m, 2H).

Example 15

[1-(4-Fluoro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as a colorless oil.

MS ISP (m/e): 373,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.18-7.13 (m, 3H), 7.03-6.98 (m, 2H), 5.58-5.57 (m, 1H), 5.07 (s, 2H), 3.89-3.82 (m, 2H), 3.58-3.48 (m, 2H), 3.32-3.23 (m, 2H), 2.40 (s, 3H), 2.18-2.14 (m, 2H), 1.60-1.47 (m, 2H).

Example 16

[1-(4-Chloro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

/p>

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as white solid (yield=70%).

MS ISP (m/e): 389,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31-7.28 (m, 2H), 7.16-7.15 (m, 1H), 7.12-7.09 (m, 2H), 5.59-5.58 (m, 1H), 5.07 (s, 2H), 3.89-3.82 (m, 2H), 3.59-3.49 (m, 2H), 3.32-3.23 (m, 2H), 2.41 (s, 3H), 2.19-2.14 (m, 2H), 1.61-1.49 (m, 2H).

Example 17

11-(3-Chloro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-chloro-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 389,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.27-7.25 (m, 2H), 7.19-7.18 (m, 1H), 7.17-7.15 (m, 1H), 7.07-7.04 (m, 1H), 5.61-5.60 (m, 1H), 5.08 (s, 2H), 3.90-3.83 (m, 2H), 3.62-3.50 (m, 2H), 3.33-3.24 (m, 2H), 2.41 (s, 3H), 2.21-2.15 (m, 2H), 1.61-1.49 (m, 2H).

Example 18

[1-(3,4,5-Cryptor-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3,4,5-Cryptor-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as bestv�Togo oil (yield=42%).

MS ISP (m/e): 409,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.21-7.20 (m, 2H), 6.79-6.75 (m, 2H), 5.62 (m, 1H), 5.03 (s, 2H), 3.90-3.83 (m, 2H), 3.59-3.51 (m, 2H), 3.33-3.24 (m, 2H), 2.41 (s, 3H), 2.21-2.15 (m, 2H), 1.61-1.48 (m, 2H).

Example 19

[1-(3-Fluoro-benzyl)-1H-pyrazol-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage h, based on 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (example 1C) and 1-(3-fluoro-benzyl)-1H-pyrazol-3-ylamine. Specified in the title compound was obtained as yellow oil (yield=73%).

MS ISP (m/e): 373,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.30-7.27 (m, 1H), 7.19-7.18 (m, 1H), 7.00-6.94 (m, 2H), 6.87-6.82 (m, 1H), 5.61-5.60 (m, 1H), 5.11 (s, 2H), 3.90-3.83 (m, 2H), 3.64-3.50 (m, 2H), 3.33-3.24 (m, 2H), 2.40 (s, 3H), 2.21-2.14 (m, 2H), 1.62-1.48 (m, 2H).

Example 20

[1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 4-[1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

Was prepared analogously to example 1, stage h, based on 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-ylamine. Specified in the title compound was obtained as pale-yellow solids (yield=34%).

MS ISP (m/e): 426,1 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1 )=7.91 (s, 1H), 7.65-7.55 (m, 2H), 5.99 (d, 1H), 3.80-3.70 (m, 2H), 3.50-3.40 (m, 1H), 2.90-2.75 (m, 2H), 2.17 (s, 3H), 1.87 (d, 2H), 1.39 (s, 9H), 1.20-1.35 (m, 2H).

(b) [1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-yl]-piperidine-4-yl-amine hydrochloride

4-[1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (120 mg; 0.28 mmol) was dissolved in dioxane (2 ml) saturated with gaseous HCl. The mixture was stirred over night at room temperature, concentrated and the residue was triturated with diethyl ether, obtaining mentioned in the title compound as brownish solid (57 mg; 56%).

MS ISP (m/e): to 326.1 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=9.22 (s extended, 1H), 9.00 (s extended, 1H), 8.82 (s extended, 1H), 7.93 (s, 1H), 7.70-7.60 (m, 2H), 3.60-3.55 (m, 1H), 3.23 (d, 2H), 2.94 (qa, 2H), 2.15 (s, 3H), 2.05 (d, 2H), 1.68 (qa, 2H).

(C) [1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1, stage b, on the basis of [1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-yl]-piperidine-4-yl-amine hydrochloride and 5-chloro-3-methyl-[1,2,4] thiadiazole (example 1, step a). Specified in the title compound was obtained as a slightly yellow solid (yield=10%).

MS ISP (m/e): 424,1/426,0 (100/72) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.91 (s, 1H), 7.65-7.55 (m, 2H), 6.10 (d, 1H), 3.76 (s widened, 2H), 3.65-3.55 (m, 1H), 3.27 (t, 2H), 2.27 (s, 3H), 2.12 (s, 3H), 2.00 (d, H), 1.50 (qa, 2H).

Example 21

[1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

a) 2-Bromo-6-phenyl-cyclohexanone

To a solution of 2-phenyl-cyclohexanone (10.0 g; 57 mmol) in CHCl3(20 ml) at -10°C was added a solution of bromine (9.6 g; 3,1 ml; 60 mmol) in CHCl3(10 ml) and the reaction mixture was allowed to warm to 0°C. After 2 hours the solvent was evaporated, to the residue was added methanol (30 ml), cooled to 0°C, stirred for 30 minutes and a white solid was filtered, receiving specified in the title compound as a white solid (5,48 g; 38%).

MS ISP (m/e): 253,0/255,1 (31/32) [(M+H)+], 270,1/272,1 (100/95) [(M+NH4)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.37-7.28 (m, 3H), 7.16-7.13 (m, 2H), 4.83-4.76 (m, 1H), 3.74-3.68 (m, 1H), 2.80-2.75 (m, 1H), 2.36-2.19 (m, 2H), 2.13-1.93 (m, 3H).

b) 4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamine

A solution of 2-bromo-6-phenyl-cyclohexanone (4,32 g; 17 mmol) and thiourea (1.18 g; 16 mmol) in EtOH (150 ml) was heated to a temperature of delegatie within 12 hours. The solvent was evaporated, to the residue was added diethyl ether and stirred at room temperature for 1 hour, the solid was filtered and washed with diethyl ether. The solid was dissolved in ethyl acetate and the organic phase was three times washed with sodium carbonate solution. Organic �ABC was dried over sodium sulfate, the solvent was evaporated, getting mentioned in the title compound as a white solid (of 3.46 g; 88%).

MS ISP (m/e): the amount of 231.1(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1, HBr salt)=8.91 (bs, 2H), 7.39-7.26 (m, 3H), 7.15-7.13 (m, 2H), 4.02 (m, 1H), 2.63-2.57 (m, 2H), 2.15-2.05 (m, 1H), 1.73-1.66 (m, 3H).

c) 4-(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamine (1,15 mg; 5 mmol) in dichloroethane (15 ml) with stirring at room temperature was added 1-Boc-4-piperidone (1,57 g; 7.5 mmol) and tetraisopropyl-orthotitanate (4,44 ml; 15 mmol). The reaction mixture was stirred overnight at 85°C in a sealed tube. At room temperature was added ethanol (15 ml) and sodium borohydride (378 mg; 10 mmol) and the reaction mixture was stirred at 85°C for 4.5 hours. Was added water, the reaction mixture was stirred for 30 minutes, the precipitate was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure. Added water and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers were washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradi�NT n-heptane/EtOAc from 9:1 to 1:1 (vol./about.) as eluent and receiving specified in the title compound as a light yellow viscous oil (1.58 g; 76%).

MS ISP (m/e): 414,4 (100) [(M+H)+], 358,3 (34) [(M-isobutene+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.26 (t, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 3.88 (m, 2H), 3.27 (m, 2H), 2.94 (m, 2H), 2.59 (m, 1H), 2.05 (m, 1H), 1.82 (m, 2H), 1.65 (m, 3H), 1.38 (s. 9H), 1.25 (m, 3H).

(d) (4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidine-4-yl-amine dihydrochloride

To a solution of 4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1,575 g; 3.8 mmol) in methylene chloride (13,8 ml) was added 2 m solution of HCl in diethyl ether (6,9 ml). The reaction mixture was stirred at room temperature over a weekend. The solvent was removed under reduced pressure, the residue treated with diethyl ether and was evaporated. Specified in the title compound was obtained as a light yellow solid (1,32 g; 90%).

MS ISP (m/e): 314,2 (100) [(M+H)+], 231,2 (34) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=9.08 (br m, 2H), 7.36 (t, 2H), 7.25 (t, 1H), 7.10 (d, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.27 (m, 2H), 2.90 (m, 2H), 2.64 (m, 1H), 2.07 (m, 3H), 1.80 (m, 3H), 1.60 (m, 1H).

(e) [1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidine-4-yl-amine dihydrochloride (77,3 mg; 0.2 mmol) was suspended in tetrahydrofuran (2 ml). At room temperature in a nitrogen atmosphere and with stirring was added at 0°With N,N-diisopropylethylamine (110 μl; 064 mmol). To the yellow solution was added 4-chloro-6-methylpyrimidin (28.9 mg, 0,22 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was heated to a temperature of delegatie over night and then heated with N-methylpyrrolidone in a microwave oven to 200°C for 30 minutes. Added water and the reaction mixture was twice extracted with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from EtOAc to EtOAc/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as a light yellow solid (55 mg; 68%).

MS ISP (m/e): 406,3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.34 (s, 1H), 7.31-7.24 (m, 3H), 7.26 (t, 1H), 7.06 (d, 2H), 6.70 (s, 1H), 4.17 (m, 2H), 3.89 (m, 1H), 3.06 (m, 2H), 2.58 (m, 1H), 2.23 (s, 3H), 2.04 (m, 1H), 1.99 (m, 2H), 1.68 (m, 3H), 1.25 (m, 3H).

Example 22

[1-(2-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidine-4-yl-amine dihydrochloride (USD 115.9 mg; 0.3 mmol) was dissolved in N-methylpyrrolidone (3 ml). At room temperature in a nitrogen atmosphere was added N,N-diisopropylethylamine (165 ml, 0.96 mmol) and 4-chloro-2-methylpyrimidin (44,7 �g; 0.33 mmol) and stirred. The reaction mixture was heated in a microwave oven to 200°C for 30 minutes. Added water and the reaction mixture was twice extracted with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from EtOAc to EtOAc/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as light yellow viscous oil (34 mg; 28%).

MS ISP (m/e): of 406.4 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.03 (d, 1H), 7.31-7.24 (m, 3H), 7.16 (t, 1H), 7.06 (d, 2H), 6.61 (d, 1H), 4.07 (m, 2H), 3.89 (m, 1H), 3.59 (m, 1H), 3.04 (m, 2H), 2.58 (m, 1H), 2.04 (m, 1H), 1.90 (m, 2H), 1.68 (m, 3H), 1.30 (m, 3H).

Example 23

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

The palladium acetate(II) (3.6 mg; 0,016 mmol) and 2-(dicyclohexylphosphino)-biphenyl (11.6 mg, to 0.032 mmol) was stirred in a nitrogen atmosphere at room temperature in dioxane (1.8 ml) for 10 minutes. Was added tert-butylate sodium (29 mg; 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidine-4-yl-amine dihydrochloride (77,3 mg; 0.2 mmol), N,N-diisopropylamino-amine (69 μl; 0.4 mmol) and 5-chloro-3-methyl-[1,2,4]thiadiazole (29,6 mg; 0.22 mmol) and the reaction mixture was heated to 200°C for 30 minutes� in the microwave. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of heptane/EtOAc from 4:1 to 1:4 (vol./about.) as eluent. Specified in the title compound was obtained as white solid (55 mg; 67%).

MS ISP (m/e): 412,2 (100) [(M+H)+]

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.29 (d, 1H), 7.26 (t, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 3.89 (m, 1H), 3.65 (m, 3H), 3.25 (m, 1H), 2.60 (m, 1H), 2.26 (s, 3H), 2.04 (m, 2H), 1.68 (m, 3H), 1.49 (m, 2H), 1.85 (m, 3H).

Example 24

[1-(5-Methyl-[1,3,4]thiadiazole-2-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

The palladium acetate(II) (3.6 mg; 0,016 mmol) and 2-(dicyclohexylphosphino)-biphenyl (11.6 mg, to 0.032 mmol) was stirred in a nitrogen atmosphere at room temperature in dioxane (1.8 ml) for 10 minutes. Was added tert-butylate sodium (29 mg; 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidine-4-yl-amine dihydrochloride (77,3 mg; 0.2 mmol), N,N-diisopropylamino-amine (69 μl; 0.4 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (40,2 mg; 0.22 mmol) and the reaction mixture was heated to 200°C for 30 minutes in a microwave oven. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic�ski layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent. Specified in the title compound was obtained as a yellow solid (23 mg; 28%).

MS ISP (m/e): 412,2 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.33 (d, 1H), 7.26 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 3.89 (m, 1H), 3.67 (m, 2H), 3.52 (m, 1H), 3.17 (m, 2H), 2.59 (m, 1H), 2.04 (m, 1H), 1.92 (m, 3H), 1.68 (m, 3H), 1.46 (m, 2H).

Example 25

[1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

a) 4-Hydroxy-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid allyl ester potassium salt

To a solution of 5-methyl-1,3,4-oxadiazol-2-ylamine (198,2 mg; 2 mmol) and allyl acrylate (851 ml, 6 mmol) in N-methylpyrrolidone (4 ml) was added at room temperature under stirring and in a nitrogen atmosphere tert-butylate potassium (359,1 mg; 3.2 mmol). The reaction mixture was stirred over night. To the resulting suspension was added a tetrahydrofuran specified in the title compound was filtered, washed with tetrahydrofuran, dried and specified in the title compound was obtained as crystals white solid (255 mg; 42%).

MS ISP (m/e): 266,1 (84) [(M-K+H)+], To 208.2 (100).

1H NMR (DMSO-D6, 300 MHz): δ (mn- )=5.90 (m, 1H), 5.25 (d, 1H), 5.06 (d, 1H), 4.37(d, 2H), 4.13 (s, 2H), 3.43 (t, 2H), 2.31 (s, 3H), 2.03 (t, 2H).

b) 1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it

4-Hydroxy-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid allyl ester potassium salt (163 mg; 0,54 mmol) was dissolved in a minimum amount of 25% aqueous HCl solution and the solvent was removed under reduced pressure. The residue was evaporated twice with a mixture of toluene/tetrahydrofuran. The residue was suspended in tetrahydrofuran (0,26 ml). To a solution of triethylamine (263 μl; at 1.88 mmol) and formic acid (42 μl; 1,08 mmol) in tetrahydrofuran (0,51 ml) in a nitrogen atmosphere with stirring was added a solution of palladium acetate(II) (3.0 mg; 0,013 mmol) and triphenylphosphine (7,3 mg; 0.027 mmol) in tetrahydrofuran (0,77 ml). After stirring for 5 minutes at room temperature the resulting solution of catalyst was added to the suspension. The reaction mixture was stirred at room temperature for 1 hour, poured into water and twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a yellow viscous oil (54 mg; 55%).

MS ISP (m/e): 279,1(100) [(M+H)+], 182,1(36), 222,1 (21).

1H NMR (DMSO-D6, 300 MHz): δ (ml� -1)=3.72 (t, 4H), 2.47 (t, 4H), 2.35 (s, 3H).

(C) [1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine

To a solution of 4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamine (46 mg; 0.2 mmol) in dichloroethane (0.6 ml) was added at room temperature with stirring 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it (50 mg; 0.28 mmol) and tetraisopropyl-orthotitanate (178 ml, 0.6 mmol). The reaction mixture was stirred over night at 90°C in a sealed vial in a nitrogen atmosphere. At room temperature was added ethanol (0.6 ml) and sodium borohydride (15 mg; 0.4 mmol) and the reaction mixture was stirred at 85°C for 4.5 hours. Was added water, the reaction mixture was stirred for 30 minutes and the precipitate was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure. Added water and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers were washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was twice purified by column chromatography on silica gel using a mixture of CH2Cl2/MeOH 19:1 (vol./about.) and then a gradient from AcOEt to AcOEt/EtOH 1:9 (vol./about.) as allentow, receiving specified in the title compound as a light yellow viscous oil (28 mg; 35%).

MSISP (m/e): 396,1 (100) [(M+H) +].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.32 (d, 1H), 7.26 (d, 2H), 7.15 (t, 1H), 7.05 (d, 2H), 3.89 (m, 1H), 3.67 (m, 2H), 3.52 (m, 1H), 3.09 (m, 2H), 2.59 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.94 (m, 3H), 1.68 (m, 3H), 1.38 (m, 2H).

Example 26

[1-(3-Chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

A solution of 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it (91 mg; 0.5 mmol) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazole-3-ylamine (104 mg; 0.5 mmol) in anhydrous toluene (8 ml) and acetic acid (0.4 ml) was heated at reflux with a trap Dean-stark for 12 hours. The reaction mixture was cooled to room temperature, was added ethanol (5 ml), then sodium borohydride (19 mg; 0.5 mmol) and stirred at room temperature over night. The reaction mixture was extracted with water and ethyl acetate, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol as eluent. Specified in the title compound was obtained as white solid (91 mg; 49%).

MS ISP (m/e): 374,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.70 (s, 1H), 7.31-7.29 (m, 2H), 7.24-7.23 (m, 1H), 7.14-7.11 (m, 1H), 5.11 (s, 2H), 4.12-4.09 (m, 1H), 3.96-3.89 (m, 2H), 3.75-3.65 (m, 1H), 3.22-3.12 (m, 2H), 2.38 (s, 3H), 2.20-2.12 (m, 2H), 1.60-1.47 (m, 2H).

Example 27

(4-Benzyl-6-methyl-pyrimido�-2-yl)-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amine dihydrochloride

To a suspension of 4-benzyl-2-chloro-6-methyl-pyrimidine (WO 2009103652; 70 mg; 0,32 mmol) and 4-(4-aminopiperidine)pyridine dihydrochloride (ABCR; 80 mg; 0,32 mmol) in dioxane (2 ml) was added potassium carbonate (885 mg; 6,4 mmol), palladium acetate(II) (3 mg; 0,013 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg; 0.031 inch mmol). The reaction mixture was heated to reflux overnight, concentrated, hydrolysable and was extracted with ethyl acetate. After chromatography on laminirovannom silica gel Si-amine (from Silicycle, 10 g) using a mixture of cyclohexane/ethyl acetate as eluent received Salobrena solid, which was dissolved in dioxane and treated with a few drops of dioxane saturated with gaseous HCl, receiving specified in the title compound as a slightly yellow solid (70 mg; 51%).

MS ISP (m/e): 360,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.25 (t, 2H), 7.40-7.20 (m, 7H), 6.62 (s, 1H), 4.40-4.25 (m, 1H), 4.17 (d, 2H), 3.96 (s, 2H), 3.50-3.35 (m, 2H), 2.34 (s, 3H), 2.03 (d, 2H), 1.55 (q, 2H).

Example 28

(4-Benzyl-6-methyl-pyrimidine-2-yl)-[1-(2-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

(a) [1-(2-Methyl-pyrimidine-4-yl)-piperidine-4-yl-carbamino acid tert-butyl ester

A suspension of BOC-4-aminopiperidine (715,3 mg; 3.5 mmol), 4-chloro-2-methylpyrimidine (521 mg; a 3.85 mmol) and N,N-diisopropylethylamine (ml; The 5.25 mmol) in dioxane (14 ml) was heated to 150°C in microwave oven for 30 minutes. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. After stirring the crude product with diethyl ether and drying, the received specified in the title compound as white crystals (649,5 mg; 64%).

MS ISP (m/e): 293,2 (100) [(M+H)+], 237,1 (37) [(M-isobutene+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.11 (d, 1H), 6.33 (d, 1H), 4.46 (m, 1H), 4.32 (m, 2H), 3.72 (s, 1H), 3.00 (m, 2H), 2.50 (s, 3H), 2.03 (m, 2H), 1.46 (s, 9H), 1.38 (m, 2H).

b) 1-(2-Methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride

To a solution of [1-(2-methyl-pyrimidine-4-yl)-piperidine-4-yl]-carbamino acid tert-butyl ester (818,7 mg; 2.8 mmol) in CH2Cl2(14 ml) was added at room temperature under stirring a 2 m solution of HCl in diethyl ether (7 ml) and stirred at room temperature over a weekend. The solvent was removed under reduced pressure and the residue was twice treated with diethyl ether. Specified in the title compound was obtained after removal of the solvent under reduced pressure as a pale brown solid (869 mg; 100%).

MS ISP (m/e): 193,2 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1/sup> )=8.44 (br s, 2H), 8.31 (d, 1H), 7.14 (d, 1H), 4.92 (m, 1H), 4.28 (m, 1H), 3.38 (m, 2H), 3.18 (m, 1H), 2.54 (s, 3H), 2.09 (m, 2H), 1.60 (m, 2H).

(C) (4-Benzyl-6-methyl-pyrimidine-2-yl)-[1-(2-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

A solution of 1-(2-methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride (53 mg; 0.2 mmol), 4-benzyl-2-chloro-6-methylpyrimidine (48,1 mg; 0.22 mmol) and N,N-diisopropylethylamine (120 ml, 0.7 mmol) in N-methyl-pyrrolidinone (1 ml) was heated at 200°C in the microwave for 1 hour. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of AcOEt/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as a light yellow solid (16 mg; 21%).

MS ISP (m/e): 375,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.11 (d, 1H), 7.28 (m, 5H), 6.34 (d, 1H), 6.24 (s, 1H), 4.91 (d, 1H), 4.32 (m, 2H), 4.15 (m, 1H), 3.86 (s, 2H), 3.13 (m, 2H), 2.50 (s, 3H), 2.25 (s, 3H), 2.12 (m, 2H), 1.46 (m, 2H).

Example 29

2-[2-[1-(2-Methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

A mixture of palladium acetate(II) (2.7 mg; 0,012 mmol) and 2-(DICYCLOHEXYL-phosphino)-biphenyl (8.4 mg, 0,024 mmol) in dioxane (1 ml) was stirred under argon atmosphere at 20�C for 10 minutes. The resulting solution of catalyst was added to suspension of potassium carbonate (692 mg; 5.0 mmol), 1-(2-methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride (80 mg; 0.3 mmol) and 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol (95 mg; 0.3 mmol) in dioxane (1.7 ml). The reaction mixture was heated to 170°C in a microwave for 30 minutes. The reaction mixture was cooled, diluted with water and was extracted with twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified column chromatography on silica gel using a mixture of CH2Cl2/0-10% MeOH as eluent. Specified in the title compound was obtained as a light yellow solid (9 mg; 6%).

MS ISP (m/e): 473,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.14 (d, 2H), 8.11 (d, 1H), 7.75 (d, 2H), 7.06 (s, 1H), 6.39 (d, 1H), 5.20 (d, 1H), 4.35-4.50 (m, 3H), 4.25 (or s, 1H), 3.18 (m, 2H), 2.52 (s, 3H), 2.22 (m, 2H), 1.60 (m, 2H), 1.55 (s, 6H).

Example 30

2-[2-[1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

(a) [1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-carbamino acid tert-butyl ester

A suspension of BOC-4-aminopiperidine (613 mg; 3 mmol), 4-chloro-6-methylpyrimidine (433 mg; 3.3 mmol) and N,N-diisopropylethylamine (771 ml, 4.5 mmol) in dioxane (12 �l) was heated to 150°C in microwave oven for 30 minutes. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified column chromatography on silica gel, using a gradient from AcOEt to AcOEt/EtOH 9:1 as eluent. Specified in the title compound was obtained as a light yellow solid (693 mg; 79%).

MS ISP (m/e): 293,2 (100) [(M+H)+], 237,1 (58) [(M-isobutene+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (s, 1H), 6.38 (s, 1H), 4.45 (m, 1H), 4.32 (m, 2H), 3.73 (m, 1H), 3.02 (m, 2H), 2.35 (s, 3H), 2.04 (m, 2H), 1.45 (s, 9H), 1.35 (m, 2H).

b) 1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride

To a solution of [1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-carbamino acid tert-butyl ester (686 mg; 2.3 mmol) in CH2Cl2(12 ml) was added at room temperature under stirring a 2 m solution of HCl in diethyl ether (6 ml) and stirred at room temperature over night. The precipitate was filtered, washed with CH2Cl2and diethyl ether and dried, obtaining specified in the title compound as a light yellow solid (610 mg; 98%).

MS ISP (m/e): 193,2 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.77 (s, 1H), 8.42 (br s, 2H), 7.20 (s, 1H), 3.45 (m underwater peak, 3H), 2.42 (s, 3H), 2.08 (m, 2H), 1.59 (m, 2H).

c) 2-[2-[1-(6-Methyl-�eremiten-4-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

A solution of 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride (53 mg; 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol (69.7 mg, 0,22 mmol) and N,N-diisopropylethylamine (120 ml, 0.7 mmol) in N-methyl-pyrrolidinone (1 ml) was heated at 160°C in a microwave oven for 5 hours. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from AcOEt to AcOEt/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as white solid (36 mg; 38%).

MS ISP (m/e): 473,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.53 (s, 1H), 8.12 (d, 2H), 7.73 (d, 2H), 7.06 (s, 1H), 6.43 (s, 1H), 5.22 (d, 1H), 4.37 (m, 2H), 4.26 (m, 1H), 3.20 (m, 2H), 2.38 (s, 3H), 2.24 (m, 2H), 1.60 (m, 2H), 1.55 (s, 6H).

Example 31

2-{6-(4-Chloro-benzyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol

To a solution of 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride (53 mg; 0.2 mmol) and N,N-diisopropylethylamine (120 ml, 0.7 mmol) in N-methyl-pyrrolidinone (0.5 ml) was added a solution of 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-ol (65,4 mg; 0.22 mmol) in dioxane (1.5 ml). The reaction mixture heating�and at 160°C in a microwave oven for 5 hours. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from AcOEt to AcOEt/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as white solid (27 mg; 30%).

MS ISP (m/e): 453,3/455,2 (100/39) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (s, 1H), 7.29 (d, 2H), 7.20 (d, 2H), 6.41 (s, 1H), 5.10 (m,1H), 4.52 (m, 1H), 4.30 (m, 2H), 4.11 (m, 1H), 3.87 (s, H), 3.14 (m, H), 2.37 (s, 3H), 2.06 (m, 2H), 1.52 (m, 2H), 1.43 (s, 6H).

Example 32

(2'-Chloro-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-(4,6-dimethyl-pyrimidine-2-yl)-amine

a) 4-(4,6-Dimethyl-pyrimidine-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of 2-chloro-4,6-dimethylpyrimidine (5,00 g; 0,035 mol), 4-amino-1-BOC-piperidine (7,023 g; 0,035 mol), tert-butylate sodium (5,055 g; 0.53 mole) in dioxane (120 ml) was added in argon atmosphere, palladium acetate(II) (0,630 g; 0,003 mol) and 2-(dicyclohexylphosphino)biphenyl (is at 1,966 g; 0,006 mmol). The reaction mixture was stirred for 5 hours at 130°C. It was diluted with ethyl acetate (400 ml) and washed with aqueous sodium carbonate (1m; 200 ml), water (200 ml) and brine (150 ml). The combined aqueous layers were extracted with ethyl acetate (40 ml) and the combined organic layers were dried over sodium sulfate. Concentrated and purification by chromatography (SiO2; n-heptane/ethyl acetate from 2:1 to 1:1) allowed us to obtain specified in the title compound (5.44 g; 51%) as an orange oil.

MS ISP (m/e): 307,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.30-1.45 (m, 2H), 1.47 (s, 9H), 1.95-2.05 (m, 2H), 2.27 (s, 6H), 2.90-3.05 (m, 2H), 3.95-4.10 (m, 3H), 4.75 (d br, 1H), 6.31 (s, 1H).

(b) (4,6-Dimethyl-pyrimidine-2-yl)-piperidine-4-yl-amine

To a solution of 4-(4,6-dimethyl-pyrimidine-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in THF (50 ml) was added dropwise at 0°With hydrochloric acid (4M in dioxane; 44,3 ml) and the reaction mixture was stirred for 22 hours at ambient temperature. The resulting suspension was filtered and dried. The residue was diluted with water (160 ml) and washed with ethyl acetate (130 ml). To the aqueous layer was added ethyl acetate (160 ml) and sodium carbonate (28.5 g) and was extracted with ethyl acetate (160 ml). Drying of the combined organic layers over sodium sulfate allowed us to obtain specified in the title compound (2.15 g; 59%) as a light yellow solid substance.

MS ISP (m/e): 207,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.30-1.45 (m, 2H), 1.60 (br s, 1H), 2.00-2.10 (m, 2H), 2.27 (s, 6H), 2.75 ("td", 2H), 3.10 ("dt", 2H), 3.90-4.05 (m, 1H), 4.85 (d br, 1H), 6.29 (s, 1H).

(C) (2'-Chloro-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-(4,6-dimethyl-pyrimidine-2-yl)-amine

To a solution of 4,6-dimethyl-pyrimidine-2-yl)-Pieper�DIN-4-yl-amine (100 mg; 0,49 mmol) in DMF (1.0 ml) was added 2-chloro-4-herperidin (57 µl; 0,63 mmol) and N,N-diisopropylethylamine (117 ml, of 0.68 mmol). In argon atmosphere, the reaction mixture was heated to 150°C for 30 minutes in a microwave oven. It was diluted with ethyl acetate (15 ml), washed with water (15 ml) and brine (10 ml). The aqueous layers were extracted with ethyl acetate (15 ml) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2; heptane/ethyl acetate/methanol from 100:0:0 to 0:90:10) allowed us to obtain specified in the title compound (121 mg; 79%) as a white solid.

MS ISP (m/e): 318,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.40-1.60 (m, 2H), 2.10-2.20 (m, 2H), 2.28 (s, 6H), 3.10 ("td", 2H), 3.80 ("dt", 2H), 4.05-4.20 (m, 2H), 4.75 (d br, 1H), 6.33 (s, 1H), 6.07 (dd, 1H), 6.15 (d, 1H), 8.00 (d, 1H).

Example 33

(4,6-Dimethyl-pyrimidine-2-yl)-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

In analogy to the procedure described for the synthesis of the compound from example 32 (stage C) specified in the title compound (4,6-dimethyl-pyrimidine-2-yl)-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine was obtained from 4,6-dimethyl-pyrimidine-2-yl)-piperidine-4-yl-amine using 4-chloro-6-methylpyrimidin instead of 2-chloro-4-herperidin, in the form of a colorless oil.

MS ISP (m/e): 299,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.40-1.52 (m, 2H), 2.10-2.20 (m, 2H), 2.29 (s, 6H), 2.36 (s, 3H), 3.10-3.5 (m, 2H), 4.10-4.20 (m, 1H), 4.25-4.40 (m, 2H), 4.95 (d br, 1H), 6.32 (s, 1H), 6.39 (s, 1H), 8.51 (s, 1H).

Example 34

2-[6-(4-Chloro-benzyl)-2-(2',5'-dimethyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)-pyrimidine-4-yl]-propan-2-ol

a) 4-Chloro-2,5-dimethyl-pyridine 1-oxide

A mixture of bromide 2,5-dimethyl-1-oxy-pyridin-4-ol (5.00 g; 22,7 mmol) in phosphorus oxychloride (4,15 ml; a 45.5 mmol) was stirred for 3 hours at 130°C. After cooling to ambient temperature, it was carefully poured into aqueous sodium carbonate (1 M; 100 ml). After stirring for 15 minutes was added a simple tert-butylmethylamine ether (50 ml) and the resulting mixture was stirred for 18 hours at ambient temperature. The aqueous layer was separated and was extracted with tert-butylmethylamine ether (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo, which allowed us to obtain brown oil. Further exhaustive extraction of the aqueous layer with ethyl acetate (50 ml) and drying over sodium sulfate allowed us to obtain specified in the title compound (1.2 g; 41%) as a white solid.

MS ISP (m/e): 157,0 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=2.26 (s, 6H), 2.45 (s, 3H), 7.21 (s, 1H), 8.12 (s, 1H).

b) 2',5'-Dimethyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamine

A mixture of 4-chloro-2,5-dimethyl-pyridine 1-oxide (200 mg; 1.41 mmol), BOC-4-aminopiperidin�on (311 mg; A 1.55 mmol) and N,N-diisopropylethylamine (484 ml, 2.82 mmol) in sulfolane (1 ml) was heated to 160°C for 30 minutes in the microwave, then heated to 220°C for 30 minutes. After adding aqueous hydrochloric acid (25% in water; 0.5 ml) and the mixture was stirred for 18 h at ambient temperature. It was treated with ammonia in methanol and concentrated. Purification by chromatography (SiO2; dichloro methane/methanol/ammonia from 95:4,5:0.5 to 90:9:1) allowed us to obtain specified in the title compound (99 mg; 40%) as a light brown oil.

MS ISP (m/e): 206,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.45-1.60 (m, 2H), 1.63 (br s, 2H), 1.85-1.95 (m, 2H), 2.17 (s, 3H), 2.43 (s, 3H), 2.65-2.75 (m, 2H), 2.75-2.90 (m, 1H), 3.20-3.35 (m, 2H), 6.65 (s,1H), 8.11 (s, 1H).

c) 2-[6-(4-Chloro-benzyl)-2-(2',5'-dimethyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)-pyrimidine-4-yl]-propan-2-ol

To a mixture of 2',5'-dimethyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamine (143 mg; 0.48 mmol), 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-ol (99 mg; 0.48 mmol), finely ground potassium carbonate (100 mg, to 0.72 mmol) in dioxane (2 ml) was added in argon atmosphere, palladium acetate(II) (5 mg; 0,02 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg; 0.05 mmol) and the reaction mixture was heated at 150°C for 30 minutes. Concentrated and purification by chromatography (SiO2; n-heptane/ethyl acetate/ethyl acetate/triethylamine (95:5)) 50:50:0 to 0:80:20) call�Lily to obtain specified in the title compound (67 mg; 30%) as a light brown foam.

MS EI (electron impact ionization) (m/e): 466,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.43 (s, 3H), 1.56 (s, 3H), 1.60-1.71 (m, 2H), 2.10-2.25 (m, 2H), 2.20 (s, 3H), 2.47 (s, 3H), 2.75-2.90 (m, 2H), 3.22-3.35 (m, 2H), 3.87 (s, 2H), 3.90-4.15 (m, 1H), 4.57 (s, 1H), 5.30 (br s, 1H), 6.39 (s, 1H), 6.68 (s, 1H), 7.18-7.35 (m, 4H), 8.16 (s, 1H).

Example 35

2-[6-(4-Chloro-benzyl)-2-(2'-methyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)-pyrimidine-4-yl]-propan-2-ol

a) 4-[4-(4-Chloro-benzyl)-6-(1-hydroxy-1-methyl-ethyl)-pyrimidine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-ol (500 mg; 1.68 mmol), 4-amino-1-BOC-piperidine (404 mg; 2,02 mmol), tert-butylate sodium (243 mg; 2,52 mmol) in dioxane (2.5 ml) was added in argon atmosphere, palladium acetate(II) (30 mg; 0.14 mmol) and 2-(dicyclohexylphosphino)biphenyl (94 mg; 0,27 mmol) and the reaction mixture was heated to 150°C for 30 minutes in a microwave oven. It was diluted with ethyl acetate (15 ml), washed with water (15 ml) and brine (15 ml). The aqueous layers were extracted with ethyl acetate (15 ml) and dried over sodium sulfate. Purification by chromatography (SiO2; heptane: ethyl acetate from 80:20 to 60:40) allowed us to obtain specified in the title compound (230 mg; 30%) as a light brown oil.

MS ISP (m/e): 461,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.41 (s, 3H),1.47 (s, 9H), 1.55 (s, 3H), 1.50-1.70 (m, 2H), 1.95-2.10 (m, 2H), 2.80-3.00 (m, 2H), 3.85 (s, 2H), 3.90-4.10 (m, 3H), 4.50-4.55 (s, 1H), 4.95-5.05 (br s, 1H), 6.38 (s. 1H), 7.17-7.29 (m, 4H).

b) 2-[6-(4-Chloro-benzyl)-2-(piperidine-4-ylamino)-pyrimidine-4-yl]-propan-2-ol

To a solution of 4-[4-(4-chloro-benzyl)-6-(1-hydroxy-1-methyl-ethyl)-pyrimidine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (220 mg; 0,447 mmol) in dichloromethane (5 ml) was added at 0°C trifluoroacetic acid (365 ml, 4.77 mmol) and the mixture was stirred for 18 hours while giving you the opportunity to warm to ambient temperature. It was podslushivaet by adding 1 M aqueous solution of sodium carbonate (5 ml) and was extracted with dichloromethane (15 ml). Organics were washed with 1M aqueous sodium carbonate solution (15 ml) and dried over sodium sulfate. Concentration allowed us to obtain specified in the title compound (192 mg; 99%) as brown semi-solid substance.

MS ISP (m/e): of 361.2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.30-1.40 (m, 2H), 1.40 (s, 3H), 1.41 (s, 3H), 1.95-2.10 (m, 2H), 2.65-2.80 (m, 2H), 3.05-3.20 (m, 2H), 3.89 (s, 1H), 3.80-4.00 (m, 1H), 3.85 (s, 2H), 5.03 (br s, 1H), 5.29 (s, 1H), 6.35 (s, 1H), 7.18-7.29 (m, 4H).

C) 2-[6-(4-Chloro-benzyl)-2-(2'-methyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)-pyrimidine-4-yl]-propan-2-ol

A solution of 2-[6-(4-chloro-benzyl)-2-(piperidine-4-ylamino)-pyrimidine-4-yl]-propan-2-ol (76 mg, 0,19 mmol), 4-chloro-2-picoline (24 mg, 0,19 mmol) and triethylamine (53 ml, 0.38 mmol) in sulfolane (,76 ml) was stirred in a preheated oil bath at 150°C for 30 minutes. After adding an additional amount of 4-chloro-2-picoline (24 mg, 0,19 mmol) and triethylamine (53 ml, 0.38 mmol) the solution was stirred for 60 minutes at 150°C. It was diluted with ethyl acetate (15 ml), washed with 1 M aqueous sodium carbonate solution (20 ml), water (15 ml) and brine (15 ml). The combined aqueous layers were extracted with ethyl acetate (15 ml). The organic layer was dried over sodium sulfate. Concentration and purification by chromatography (SiO2; dichloro methane/methanol/triethylamine (95:4,5:0,5)) allowed us to obtain specified in the title compound (34 mg; 40%) as a whitish foam.

MS ISP (m/e): 452,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=1.41 (s, 3H), 1.42 (s, 3H), 1.45-1.60 (m, 2H), 2.05-2.20 (m, 2H), 2.46 (s, 3H), 2.95-3.10 (m, 2H), 3.75-3.90 (m, 2H), 3.86 (s, 2H), 4.00-4.10 (m, 1H), 4.50 (s'or, 1H), 5.02 (br s, 1H), 6.41 (s, 1H), 6.50-6.55 (m, 1H), 6.55-6.60 (m, 1H), 7.18-7.35 (m, 4H), 8.15 (d, 1H).

Example 36

(4-Benzyl-6-methyl-pyrimidine-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

(a) [1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-carbamino acid tert-butyl ester

The palladium acetate(II) (5.4 mg, 0,024 mmol) and 2-(dicyclohexylphosphino)-biphenyl (17,4 mg; 0,048 mmol) was stirred in a nitrogen atmosphere at room temperature in dioxane (1.7 ml) for 10 minutes. Was added tert-butylate sodium (44 mg; 0.33 mmol), BOC-4-aminopiperidine (61,3 mg; 0.3 mmol) and 5-chloro-3-methyl-[1,2,4]-Ty�diazol (44,4 mg; 0.33 mmol) and the reaction mixture was heated to 150°C for 30 minutes in a microwave oven. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient mixture of n-heptane/EtOAc from 9:1 to 1:1 (vol./about.) as eluent. Specified in the title compound was obtained as a yellow solid (39 mg; 44%).

MS ISP (m/e): 299,2 (43) [(M+H)+], 243,2 (100) [(M-isobutene+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=6.92 (br d, 1H), 3.72 (m, 2H), 3.03 (m, 1H), 3.25 (m, 2H), 2.27 (s, 3H), 1.83 (m, 2H), 1.44 (m, 2H), 1.38 (s, 9H).

b) 1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamine dihydrochloride

To a solution of [1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-carbamino acid tert-butyl ester (256 mg; 0,86 mmol) in CH2Cl2(8,6 ml) was added at room temperature under stirring a 2 m solution of HCl in diethyl ether (4.3 ml) and stirred at room temperature over night. The solvent was removed under reduced pressure. The crude product was twice treated with diethyl ether, obtaining mentioned in the title compound as a yellow semi-solid substances (260 mg; 100%).

MS ISP (m/e): 199,1 (100) [(M+H)+], 182,1 (52)./p>

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.26 (br s, 3H), 3.81 (m, 2H), 3.29-3.20 (m, 3H), 2.28 (s, 3H), 2.02 (m, 2H), 1.59 (m, 2H).

(c) (4-Benzyl-6-methyl-pyrimidine-2-yl)-[(R)-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-pyrrolidin-3-yl]-amine

A solution of 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamine dihydrochloride (54,2 mg; 0.2 mmol), 4-benzyl-2-chloro-6-methyl-pyrimidine (48,1 mg; 0.22 mmol) and N,N-diisopropylethylamine (120 ml, 0.7 mmol) in dioxane (0.6 ml) was heated at 200°C in the microwave for 1 hour. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc as eluent. Specified in the title compound was obtained as a yellow viscous oil (22 mg; 29%).

MS ISP (m/e): 381,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.32-7.21 (m, 5H), 6.26 (s, 1H), 5.27 (m, 1H), 4.13 (m, 1H), 3.86 (m, 4H), 3.33 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 2.13 (m, 2H), 1.62 (m, 2H).

Example 37

2-[2-[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

A solution of 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamine dihydrochloride (54,2 mg; 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol (69,7 mg; 0.22 mm�l) and N,N-diisopropylethylamine (120 μl; 0,7 mmol) in dioxane (2 ml) was heated at 200°C in a microwave for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel with a mixture of CH2Cl2/MeOH 19:1 (vol./about.) as eluent. Specified in the title compound was obtained as brown viscous oil (26 mg; 27%).

MS ISP (m/e): 479,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.12 (d, 2H), 7.73 (d, 2H), 7.08 (s, 1H), 5.21 (br d, 1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.90 (m, 2H), 3.38 (m, 2H), 2.43 (s, 3H), 2.23 (m, 2H), 1.70 (m, 2H), 1.55 (s, 6H).

Example 38

2-{6-(4-Chloro-phenyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol

In analogy to example 29 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamine (59,5 mg; 0.3 mmol) was brought into interaction with 2-[2-chloro-6-(4-chloro-phenyl)-pyrimidine-4-yl]-propan-2-olomu (85 mg; 0.3 mmol), receiving specified in the title compound (55 mg; 41%) as a whitish foam.

MS ISP (m/e): 445,2 (98) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.96 (d, 2H), 7.45 (d, 2H), 7.02 (s, 1H), 5.18 (d, 1H), 4.45 (s. 1H), 4.22 (br s, 1H), 3.92 (m, 2H), 3.38 (m, 2H), 2.43 (s, 3H), 2.24 (m, 2H), 1.70 (m, 2H), 1.54 (s, 6H).

Example 39

2-{6-(4-Chloro-benzyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol

a) 2-(2,6-Dichloro-pyrimidine-4-yl)-propan-2-ol

To mix up restwarmer-2,6-dichloro-pyrimidine-4-carboxylate (1.03 g; 5,0 mmol) in tetrahydrofuran (40 ml) was added at -75°C for 10 minutes 3M solution of chloride Metalmania in tetrahydrofuran (3,66 ml; 11.0 mmol). The solution was stirred at -78°C for 30 min, then was warmed to 0°C for 10 min and the stirring was continued for 2 h at 0°C. the Reaction was terminated by addition of a saturated solution of ammonium chloride (40 ml) and the mixture was extracted with ethyl acetate (100 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The remaining oil was purified by chromatography on silica gel using a mixture of heptane/0-20% ethyl acetate as eluent, receiving specified in the header connection (0,76 g; 73%) as a light yellow oil.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.53 (s, 1H), 2.85 (s, 1H), 1.58 (s, 6H).

(b) 2,4-Dichloro-6-(1-methyl-1-trimethylsilyloxy-ethyl)-pyrimidine

A mixture of 2-(2,6-dichloro-pyrimidine-4-yl)-propan-2-ol (1.04 g; 5.0 mmol) and N,O-bis(trimethyl-silyl)acetamide (1,49 ml; 6.0 mmol) was stirred at 100°C for 4 h. the Reaction mixture was cooled to 20°C and was purified by chromatography on silica gel using a mixture of heptane/0-10% ethyl acetate as eluent which allowed us to obtain specified in the title compound (1.16 g; 83%) as a colorless oil.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.60 (s, 1H), 1.57 (s, 6H), 0.21 (s, 9H).

C) 2-Chloro-4-(4-chloro-benzyl)-6-(1-�ethyl-1 trimethylsilyloxy-ethyl)-pyrimidine

To a solution of 2,4-dichloro-6-(1-methyl-1-trimethylsilyloxy-ethyl)-pyrimidine (5,02 g; 18,0 mmol) in THF (60 ml) was added Pd(TPP)4(0,83 g, to 0.72 mmol). The solution was purged with argon and then was added a 0.5 M solution of chloride of 4-chloro-Benzedrine in tetrahydrofuran (36 ml; 18,0 mmol) at 20°C for 1-3 minutes. The reaction mixture was heated to 50°C for 3 h in argon atmosphere. After cooling the mixture to 20°C was added a saturated aqueous solution of ammonium chloride (30 ml) for repayment of the reaction. The mixture was extracted with ethyl acetate (2×30 ml), organic layers were washed with brine (2×30 ml), dried over sodium sulfate and evaporated under reduced pressure. The remaining oil was purified by chromatography on silica gel using a mixture of heptane/0-30% ethyl acetate as eluent which allowed us to obtain specified in the title compound (4.72 in g; 71%) as a colorless oil.

MS ISP (m/e): of 369.0 (54) [(M+H)+].

d) 2-[2-Chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-ol

A solution of 2-chloro-4-(4-chloro-benzyl)-6-(1-methyl-1-trimethylsilyloxy-ethyl)-pyrimidine (3.69 g; 10.0 mmol) and toluene-4-sulfonic acid monohydrate (0.19 g; 1.0 mmol) in 90% aqueous tetrahydrofuran (40 ml) was stirred at 20°C for 2 h. the Solution was diluted with ethyl acetate and sequentially washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated under �eigendom pressure. The remaining oil was crystallizable from cyclohexane, receiving specified in the header connection (2,28 g; 77%) as a white solid.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31 (d, 2H), 7.21 (d, 2H), 7.18 (s, 1H), 4.07 (s, 2H), 3.12 (s, 1H), 1.51 (s, 6H).

(e) 2-{6-(4-Chloro-benzyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol

In analogy to example 29 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamine (65 mg; 0.33 mmol) was brought into interaction with 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-olomu (98 mg; 0.33 mmol), receiving specified in the title compound (55 mg; 36%) as a yellow foam.

MS ISP (m/e): 459,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.28 (d, 2H), 7.19 (d, 2H), 6.43 (s, 1H), 5.02 (d, 1H), 4.42 (s, 1H), 4.12 (br s, 1H), 3.88 (m, 2H), 3.87 (s, 2H), 3.32 (m, 2H), 2.42 (s, 3H), 2.16 (m, 2H), 1.62 (m, 2H), 1.43 (s, 6H).

Example 40

2-[2-[1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

a) 1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it O-benzyloxy

A solution of 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it (1.52 g; of 8.39 mmol), 0-benzylhydroxylamine hydrochloride (1.50 g; of 9.23 mmol) and ammonium acetate (1.62 g; 21,0 mmol) in MeOH (34,5 ml) was heated to a temperature of delegatie for 2 hours in a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by column chrom�the ture on silica gel, using a gradient from AcOEt to AcOEt/EtOH (9:1 (vol./about.)) as eluent and receiving specified in the title compound as a light yellow viscous oil (2.32 g; 96%).

MS ISP (m/e): 287,3 (35) [(M+H)+], 309,4 (10) [(M+Na)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.35 (m, 5H), 5.03 (s, 2H), 3.51 (sept, 4H), 2.64 (t, 2H), 2.37 (t, 2H), 2.33 (s, 3H).

b) 1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine

A solution of 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it O-benzyloxy (2.32 g; 8.1 mmol) in 7 m solution of NH3in MeOH (40,5 ml) were gidrirovanie in the hydrogen atmosphere in the presence of palladium on charcoal (10%; 464 mg). The catalyst was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure, obtaining specified in the header connection (1,61 g; 100%) as a yellow solid.

MS ISP (m/e): reached 183.1 (100) [(M+H)+], 166,2 (46) [(M-NH3+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=3.68 (m, 2H), 3.01 (m, 2H), 2.75 (m, 1H), 2.31 (s, 3H), 1.73 (m, 2H), 1.25 (m, 2H).

c) 2-[2-[1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol

A solution of 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine (36,5 mg; 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol (69,1 mg; 0.22 mmol) and N,N-diisopropylethylamine (52 μl; 0.3 mmol) in dioxane (2 ml) was heated at 160°C in a microwave oven for 5.5 hours. The reaction mixture was diluted with water and dvaid� was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with a mixture of EtOAc/EtOH 9:1 (vol./about.) as eluent. Specified in the title compound was obtained as white solid (29 mg; 31%).

MS ISP (m/e): 463,2 (100) [(M+H)+], 445,1 (32) [(M-H2O+H)+], 485,3 (11) [(M+Na)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.11 (d, 2H), 7.74 (d, 2H), 7.07 (s, 1H), 5.22 (m, 1H), 4.41 (m, 1H), 4.19 (m, 1H), 4.00 (m, 2H), 3.26 (m, 2H), 2.41 (s, 3H), 2.20 (m, 2H), 1.65 8m, 2H), 1.55 (s, 6H).

Example 41

(4-Benzyl-6-methyl-pyrimidine-2-yl)-[1-(3-bromo-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

A solution of (4-benzyl-6-methyl-pyrimidine-2-yl)-piperidine-4-yl-amine hydrochloride (125 mg; 0.39 mmol), 3-bromo-5-chloro-[1,2,4]thiadiazole (39 mg; 0,19 mmol) and N,N-diisopropylethylamine (66 µl; 0,39 mmol) in tetrahydrofuran (3 ml) was heated to 95°C for 4.5 hours. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as �luent. Specified in the title compound was obtained as a colorless oil (84 mg; 96%).

MS ISP (m/e): 447,2/445,2 (100/90) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31-7.23 (m, 5H), 6.27 (s, 1H), 4.92 (d, 1H), 4.12 (m, 1H), 3.86 (m, 4H), 3.39 (m, 2H), 2.26 (s, 3H), 2.17 (m, 2H), 1.60 (m, 2H).

Example 42

2-{6-(4-Chloro-benzyl)-2-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol

A solution of 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine (50 mg; 0.27 mmol), 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidine-4-yl]-propan-2-ol (81,5 mg; 0.27 mmol) and N,N-diisopropylethylamine (71 ml, 0.41 mmol) in dioxane (2.8 ml) was heated at 160°C in a microwave oven for 6 hours. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as eluent. Specified in the title compound was obtained as a colorless foam (31 mg; 26%).

MS ISP (m/e): 443,4/445,2 (100/29) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.28 (d, 2H), 7.19 (d, 2H), 6.41 (s, 1H), 5.04 (m, 1H), 4.03 (m, 1H), 3.96 (m, 2H), 3.87 (s, 2H), 3.20 (m, 2H), 2.40 (s, 3H), 2.22 (m, 2H),1.57(m,2H),1.42(s,6H).

Example 43

(4-Benzyl-6-methyl-PI�imidan-2-yl)-[1-(3-chloro-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

A solution of (4-benzyl-6-methyl-pyrimidine-2-yl)-piperidine-4-yl-amine hydrochloride (159 mg; 0.5 mmol), 3,5-dichloro-[1,2,4]thiadiazole (39 mg; 0.25 mmol) and N,N-diisopropylethylamine (85 μl; 0.5 mmol) in tetrahydrofuran (2 ml) was heated to 95°C for 4 hours in a nitrogen atmosphere. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using Et2O as eluent. Specified in the title compound was obtained as a colorless oil (52 mg; 52%).

MS ISP (m/e): 401,3/403,4 (100/45) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31-7.23 (m, 5H), 6.27 (s, 1H), 5.00 (d, 1H), 4.14 (m, 1H), 3.86 (s, 2H), 3.85 (m, 2H), 3.39 (m, 2H), 2.25 (s, 3H), 2.16 (m, 2H), 1.59 (m, 2H).

Example 44

(4-Benzyl-6-methyl-pyrimidine-2-yl)-[1-(3-methyl-[1,2,4]oxidiazol-5-yl)-piperidine-4-yl]-amine

a) 4-(4-Benzyl-6-methyl-pyrimidine-2-ylamino)-piperidine-1-carbonitrile

To a solution of (4-benzyl-6-methyl-pyrimidine-2-yl)-piperidine-4-yl-amine hydrochloride (255 mg; 0.8 mmol) in CH2Cl2(1.5 ml) was added at 0°C suspension of sodium hydrogen carbonate (202 mg; 2.49 mmol) in water (0.5 ml) and then within 1 minute, a solution of Bratianu (106 mg; 0.97 mmol) � CH 2Cl2(1 ml). The reaction mixture was stirred at 0°C for 45 minutes and then at room temperature overnight. The reaction mixture was diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3and saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as eluent. Specified in the title compound was obtained as a colorless oil (135 mg; 55%).

MS ISP (m/e): 308,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31-7.22 (m, 5H), 6.26 (s, 1H), 4.87 (d, 1H), 3.95 (m, 1H), 3.85 (s, 2H), 3.45 (dt, 2H), 3.18 (dt, 2H), 2.24 (s, 3H), 2.06 (m, 2H), 1.58 (ddt, 2H).

(b) (4-Benzyl-6-methyl-pyrimidine-2-yl)-N-(3-methyl-[1,2,4]oxidiazol-5-yl)-piperidine-4-yl]-amine

To a solution of 4-(4-benzyl-6-methyl-pyrimidine-2-ylamino)-piperidine-1-carbonitrile (135 mg; 0.44 mmol) and acetamidoxime (39 mg; 0.53 mmol) in EtOAc (1 ml) and THF (1 ml) was added over 10 minutes a solution of zinc chloride (73 mg; 0.53 mmol) in EtOAc (1 ml). After stirring at room temperature for 4 hours the reaction mixture was heated to a temperature of delegatie over night in a nitrogen atmosphere. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with cargoes or long goods.�enny aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of CH2Cl2/MeOH 19:1 (vol./about.) as eluent. Specified in the title compound was obtained as colorless resinous substance (98 mg; 61%).

MS ISP (m/e): 365,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.31-7.24 (m, 5H), 6.25 (s, 1H), 4.87 (d, 1H), 4.07 (m, 3H), 3.85 (s, 2H), 3.29 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 2.13 (m, 2H), 1.53 (m, 2H).

Example 45

5-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine

a) 6-(4-Fluoro-phenyl)-pyrazine-2-ylamine

Was prepared analogously to example 1d, based on 2-amino-6-chloropyrazine and 4-ferbinteanu acid. Specified in the title compound was obtained as a slightly brown solid (yield 91%).

MS ISP (m/e): RUR 190.3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.27 (s, 1H), 8.04 (dd, 2H), 7.84 (s, 1H), 7.30 (t, 2H), 6.52 (brs, 2H).

b) N-(6-(4-Fluoro-phenyl)-pyrazine-2-yl)-N'-ethoxycarbonyl-thiourea

Was prepared analogously to example 1E, on the basis of 6-(4-fluoro-phenyl)-pyrazine-2-ylamine. Specified in the title compound precipitated from the reaction mixture, was filtered and washed with n-heptane, dried and was obtained as white crystals (yield 80%).

MS ISP (m/e): 321,2 (100) [(M+H)+], 232,2 (34), 275,2 (25).

1H I�R (DMSO-D 6, 300 MHz): δ (mn-1)=12.18 (brs, 1H), 11.92 (brs, 1H), 9.56 (or s, 1H), 9.10 (s, 1H), 8.19 (dd, 2H), 7.40 (t, 2H), 4.25 (q, 2H), 1.28 (t, 3H).

c) 5-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrazine-2-ylamine

Was prepared analogously to example 1f, proceeding from N-(6-(4-fluoro-phenyl)-pyrazine-2-yl)-N'-ethoxycarbonyl-thiourea. The reaction mixture was diluted with water and the specified in the title compound was filtered and washed with a mixture of MeOH/Et2O (4:1) and then Et2O. the Product was purified column chromatography on silica gel using CH2Cl2/MeOH (about./about.=19:1) as eluent, obtaining mentioned in the title compound as white crystals (yield 73%).

MS ISP (m/e): 230,3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.83 (s, 1H), 8.19 (s, 1H), 8.12 (dd, 2H), 7.43 (t,2H), 6.54 (brs, 2H).

d) 5-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine

Was prepared analogously to example 1h, based on 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrazine-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 411,3 (67) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.87 (s, 1H), 8.12 (s, 1H), 8.01-7.96 (m, 2H), 7.29-7.23 (m, 2H), 4.78-4.76 (m, 1H), 4.07-3.88 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.27-2.22 (m, 2H), 1.74-1.61 (m, 2H).

Example 46

[8-(3,4-Debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, on the basis of 8-(3,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 428,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.32 (m, 1H), 7.96-7.88 (m, 1H), 7.72-7.67 (m, 1H), 7.52-7.49 (m, 1H), 7.31-7.22 (m, 1H), 6.93-6.88 (m, 1H), 4.56-4.53 (m, 1H), 3.98-3.89 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.31-2.24 (m, 2H), 1.70-1.61 (m, 2H).

Example 47

8-(3-Chloro-4-fluorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1h, based on 8-(3-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 444,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.32 (m, 1H), 8.11-8.07 (m, 1H), 7.88-7.83 (m, 1H), 7.51-7.49 (m, 1H), 7.28-7.22 (m, 1H), 6.93-6.88 (m, 1H), 4.54-4.51 (m, 1H), 4.00-3.88 (m, 3H). 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 2H), 1.74-1.61 (m, 2H).

Example 48

[8-(4-Chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

a) 5-Temporaril-pyridin-2-ylamine

To a solution of 5-bromo-pyridin-2-ylamine (2 g; for 11.55 mmol) and cyclopropylboronic acid (2,98 g; 34,68 mmol) in toluene (40 ml) and water (2 ml) there was added�if (K 3PO4(8,59 g; USD 40.46 mmol) in argon atmosphere. There was added Pd(OAc)2(259,52 mg; 1,16 mmol) and tricyclohexylphosphine (647,3 mg; 2.3 mmol) and stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and added water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (1.1 g; 71%).

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=7.73 (s, 1H), 7.04-7.02 (dd, J=8.48 & 2.04 Hz, 1H), 6.34 (d, J=8.48 & 2.04 Hz, 1H), 5.60 (s, 2H), 1.78-1.66 (m, 1H), 0.82-0.77 (m, 2H), 0.52-0.31 (m, 2H).

b) 3-Bromo-5-cyclopropyl-pyridine-2-ylamine

To a solution of 5-cyclopropyl-pyridine-2-Jamia (1.1 g; to 8.19 mmol) in anhydrous chloroform (100 ml) was added at room temperature bromine (0.42 ml; 8.2 mmol) in chloroform (11 ml) and stirred for 18 hours. Was added aqueous sodium thiosulfate solution, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a light yellow oil (1.0 g; 57%).

M ESI (electrospray ionization) (m/z): 213,0 [(M+H) +].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=7.77 (d, J=1.44 Hz, 1H), 7.39 (d, J=1.44 Hz, 1H), 5.9 (s, 2H), 1.79-1.74 (m, 1H), 0.85-0.80 (m, 2H), 0.59-0.55 (m, 2H).

c) N-(3-Bromo-5-cyclopropyl-pyridine-2-yl)-N'-ethoxycarbonyl-thiourea

To a solution of 3-bromo-5-cyclopropyl-pyridine-2-ylamine (1.0 g; 4,69 mmol) in anhydrous 1,4-dioxane (20 ml) was added ethoxycarbonylmethylene (0,55 ml; 5,16 mmol) in an argon atmosphere and stirred at room temperature for 6 hours. The solvent was evaporated and specified in the title compound was obtained as a light yellow oil (1.5 g; 98%).

MS ESI (m/z): 346,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=11.41 (s, 1H), 11.32 (s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 4.24-4.19 (q, J=7.08, 2H), 2.03-1.97 (m, 1H), 1.28-1.24 (t, J=7.12 Hz, 3H), 1.06-0.97 (m, 2H), 0.84-0.81 (m, 2H).

d) 8-Bromo-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

To a solution of N-(3-bromo-5-cyclopropyl-pyridine-2-yl)-N'-ethoxycarbonyl-thiourea (1.5 g; 4,36 mmol) in anhydrous methanol (20 ml) was added hydroxylamine hydrochloride (1.41 g; of 21.8 mmol) and diisopropylethylamine (12,14 ml; 13,08 mmol) in an argon atmosphere and stirred at room temperature for 6 hours. The methanol was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (910 mg; 82%).

MS ESI (m/z): 252,6 [(M+H)+].

1H YAM� (DMSO-D 6, 400 MHz): δ (mn-1)=8.41 (s, 1H), 7.48 (s, 1H), 6.12 (s, 2H), 1.99-1.90 (m,1H), 0.93-0.84 (m, 2H), 0.80-0.75 (m, 2H).

e) 8-(4-Chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

To a solution of 8-bromo-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (300 mg, 1,29 mmol) and 4-Chlorfenvinphos acid (463 mg; 2,96 mmol) in dioxane (15 ml) was added an aqueous solution of Na2CO3(2 M; 2 ml) and degassed with argon for 5 minutes. Added PdCl2(dpp)2·CH2Cl2(30,34 mg; 0.04 mmol) and stirred at 800C for 90 minutes. The reaction mixture was cooled to room temperature and added water (20 ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (252 mg; 75%).

MS ESI (m/z): 284,8 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=8.39 (s, 1H), 8.18 (d,2H), 7.54 (d, 2H), 7.45 (s, 1H), 2.05-2.01 (m, 1H), 0.97-0.92 (m, 2H), 0.84-0.82 (m, 2H).

f) 2-Bromo-8-(4-chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin

To a solution of tert-nitrite (0,18 ml; 1.05 mmol) in anhydrous acetonitrile (7 ml) was added copper bromide(II) (234 mg; 1.05 mmol) in an argon atmosphere and heated to 60°C for 0.1 hour. At 60°C was added 8-(4-chloro-phenyl-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200 mg; 0,7 mmol) in acetonitrile (5 ml). The reaction mixture was stirred at 75°C for 3 hours and then cooled to room temperature. Was added water (10 ml). The aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (150 mg; 61%).

MS ESI (m/z): 348,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=8.81 (s, 1H), 8.14 (d, J=8.52 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 2.12-2.10 (m, 1H), 1.03-0.93 (m, 4H).

(g) [8-(4-Chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

A solution of 2-bromo-8-(4-chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (50 mg; 0.14 mmol), 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine (see example a); 23 mg; 0.12 mmol) and sodium phenolate (21 mg; 0.2 mmol) in anhydrous 1,4-dioxane (3 ml) in a sealed tube purged with argon for 10 minutes. To the solution was added Pd2(dba)3·CHCl3(8 mg; 0.01 mmol) and xanthphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (2 mg) and stirred at 160°C for 15 hours. The reaction mixture was cooled to room temperature and added water (10 ml). The aqueous phase was extracted with ethyl acetate, the combined about�egy for organic phase was dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol as eluent. Specified in the title compound was obtained as a light brown solid (5 mg; 8%).

MS ESI (m/z): 460,0 [(M+H)+].

Example 49

2-{8-(4-Chloro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol

a) N-(6-Methyl-pyridin-2-yl)-acetamide

A solution of 6-methyl-pyridine-2-ylamine (50 g; 0,462 mol) in acetic anhydride (200 ml) was heated to 90°C for 90 minutes. The reaction mixture was cooled to room temperature and was evaporated. To the residue was added aqueous saturated solution of NaHCO3to pH 8. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and the solvent evaporated. Specified in the title compound was obtained as white solid (68 g; 98%).

MS ESI (m/e): 151,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=10.38 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.4 Hz, 1H), 2.38 (s, 3H), 2.06 (s, 3H).

b) 6-Acetylamino-pyridine-2-carboxylic acid

A solution of N-(6-methyl-pyridin-2-yl)-acetamide (South; 0,067 mmol) in water (100 ml) was heated to 75°C. Portions were added permanganate potassium (37 g, 233 mmol) at 75°C. After 4 hours at 75°C the reaction mixture was cooled to room temp�tours and the solid was filtered. The aqueous layer was evaporated to half of its original volume and acidified with using HCl (12 n) to pH 4-5. The precipitate was filtered and dried. Specified in the title compound was obtained as a whitish solid (4.5 g; 37%).

MS ESI (m/z): 181,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=13.0 (s, 1H), 10.78 (s, 1H), 8.26 (d, J=8.28 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.72 (d, J=7.1 Hz, 1H), 2.10 (s, 3H).

c) 6-Amino-pyridine-2-carboxylic acid methyl ester

A solution of 6-acetylamino-pyridine-2-carboxylic acid (16 g; 0,088 mol) in methanol solution of hydrogen chloride (4 n, 50 ml) was heated to a temperature of delegatie within 18 hours. The reaction mixture was cooled to room temperature and was evaporated. To the residue was added water and was podslushivaet solid NaHCO3. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and the solvent evaporated. Specified in the title compound was obtained as white solid (8 g; 59%).

MS ESI (m/z): 153,0 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=7.53 (t, J=7.52 Hz, 1H), 7.48 (d, J=7.28 Hz, 2H), 6.66 (d, J=8.04 Hz, 1H), 4.71 (s, 2H), 3.94 (s, 3H).

d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl ester

To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g; 66,0 mmol) in chloroform (450 ml) was added bromine (3.4 ml; 66,0 mmol) in CHCl3(100 ml) at room temp�the temperature and was stirred for 40 hours. The reaction mixture was diluted with CHCl3and washed with saturated solution of sodium thiosulfate and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a yellow solid (3.3 g; 22%).

MS ESI (m/e): 231,0 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.76 (d, J=7.88 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).

d) 6-Amino-3-bromo-pyridine-2-carboxylic acid methyl ester

At the stage (d) isomeric 6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester (3.0 g; 19%) was isolated as by-product.

MS ESI (m/e): 231,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.60 (d, J=8.72 Hz, 1H), 6.47 (d, J=7.88 Hz, 1H), 4.71 (s, 2H), 3.94 (s, 3H).

e) N-(3-Bromo-6-ethoxycarbonyl-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea

To a solution of 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (3.3 g; of 14.28 mmol) in anhydrous 1,4-dioxane (20 ml) was added ethoxycarbonylmethylene (1.8 ml; 15,7 mmol) in an argon atmosphere and stirred at room temperature for 16 hours. The solvent was evaporated and specified in the title compound was obtained as yellow solids (4,9 g; 95%).

MS ESI (m/e): 362,0 [(M+H)+].

1H NMR (DMSO-D6, 400 M�C): δ (mn -1)=1.54(s, 1H), 11.46 (s, 1H), 8.36 (d, J=8.16 Hz, 1H), 7.92 (d, J=8.16 Hz, 1H), 4.27-4.23 (m, 2H), 3.89 (s, 3H), 1.36-1.26 (m, 3H).

f) 2-Amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester

To a solution of N-(3-bromo-6-ethoxycarbonyl-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (2 g, 5,52 mmol) in anhydrous methanol (10 ml) was added hydroxylamine hydrochloride (1.92 g; 27,62 mmol) and diisopropylethylamine (2,98 ml; 16,57 mmol) in an argon atmosphere and stirred at room temperature for 4 hours. The solids were filtered off and to the residue was added methanol (40 ml). The reaction mixture was heated to a temperature of delegatie within 12 hours. The solvent was evaporated and specified in the title compound was obtained as a whitish solid (800 mg; 53%).

MS ESI (m/e): 270,8 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=7.66 (d, J=8.04 Hz, 1H), 7.43 (d, J=8.12 Hz, 1H), 4.9 (s, 2H), 4.02 (s, 3H).

q) 2-(2-Amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-propan-2-ol

To a solution of 2-amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (900 mg; 3,32 mmol) in tetrahydrofuran was added bromide Metalmania (1.4 M solution in a mixture of toluene/tetrahydrofuran; 75/25) (9,49 ml; 13,28 mmol) at -40°C and stirred at -30°C for 1 hour. The reaction mixture was warmed to room temperature and was quenched with a saturated aqueous solution of NH4Cl. The aqueous phase was extracted with etilize�atom, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a yellow solid (400 mg; 44%), which contained an admixture of 1-(2-amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-ethanone.

MS ESI (m/e): 273,2 [(M+H)+].

h) 2-[2-Amino-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-propan-2-ol

To a solution of 2-(2-amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-propan-2-ol (mixture of ketone) (120 mg; 0,443 mmol) and 4-chlorophenyl-Bronevoy acid (155 mg; 0,987 mmol) in dioxane (6 ml) was added an aqueous solution of Na2CO3(2 M 0,72 ml) and degassed with argon for 5 minutes. To the mixture was added PdCl2(dppf)2·CH2Cl2(30,34 mg; 0.04 mmol) and stirred at 90°C for 90 minutes. The reaction mixture was cooled to room temperature and added water (20 ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (65 mg; 48%), which contained an admixture of 1-[2-amino-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]PI�idin-5-yl]-ethanone.

S ESI (m/e): 273,2 [(M+H)+].

i) 2-[2-Bromo-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-propan-2-ol

To a solution of tert-nitrite (0.06 ml; 0.47 mmol) in anhydrous acetonitrile (5 ml) was added bromide, Cu(II) (105 mg; 0.47 mmol) in an argon atmosphere and heated to 60°C for 0.1 hour. At 60°C was added 2-[2-amino-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-propan-2-ol (mixture of alcohol and ketone) (90 mg; 0,32 mmol) in acetonitrile (5 ml) and stirred at 75°C for 3 hours. The reaction mixture was cooled to room temperature and added water (10 ml). The aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. Specified in the title compound was obtained as a whitish solid (20 mg; 48%).

MS ESI (m/e): 368,0 [(M+H)+].

k) 2-{8-(4-Chloro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol

A solution of 2-[2-bromo-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-propan-2-ol (42 mg; 0.11 mmol), 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine (18 mg; 0.1 mmol) and sodium phenolate (17 mg; 0.15 mmol) in anhydrous 1,4-dioxane (6 ml) in a sealed tube purged with argon for 10 minutes. To the solution was added Pd2(dba)3·CHCl3(Mg; 0,012 mmol) and xanthphos (2 mg) and degassing was continued for 5 minutes, then the reaction mixture was heated to 160°C for 15 hours. The reaction mixture was cooled to room temperature and added water (10 ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of dichloro methane/methanol as eluent. Specified in the title compound was obtained as white solid (7 mg; 13%).

MS ESI (m/e): 478,0 [(M+H)+].

Example 50

[6-Cyclopropyl-8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 48. Specified in the title compound was obtained as brown solid substance.

MS ESI (m/z): 444,3 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=8.46 (s, 1H), 8.36 (s, 1H), 8.19-8.16 (m, 2H), 7.45 (s, 1H), 7.31 (t, J=8.88 Hz, 2H), 6.73-6.69 (m, 2H), 4.3 (m, 2H), 3.10 (t, J=11.64 Hz, 2H), 2.5 (s, 3H), 2.04-1.99 (m, 3H), 1.44 (m, 2H), 0.97-0.93 (m, 2H), 0.85-0.83 (m, 2H).

Example 51

[8-(3-Chloro-4-fluoro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

To a solution of chloride dibutyrate (10 mg; 0.03 mmol) and 8-(3-chloro-4-fluoro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl�ina (obtained analogously to example 48A-e); 100 mg; 0.33 mmol) in anhydrous THF (1.5 ml) in an argon atmosphere was added 1-(b-methyl-pyrimidine-4-yl)-piperidine-4-it (example 93b); 63 mg; 0.33 mmol) and phenylsilane (0,016 ml; 0.4 mmol) and heated to 100°C in microwave oven for 40 minutes. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was purified by preparative HPLC (high performance liquid chromatography) (acetonitrile/H2About). Specified in the title compound was obtained as white solid (20 mg; 13%).

MS ESI (m/z): 477,8 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=8.5 (s, 1H), 8.34 (s, 1H), 7.6-7.55 (m, 2H), 7.34-7.3 (m, 1H), 7.17 (s, 1H), 6.71 (s, 1H), 6.63 (d, 1H), 4.24 (d, 2H), 3.08 (t, J=11.32 Hz, 2H), 2.23 (s, 3H), 2.00-1.94 (m, 3H), 1.4-1.32 (m, 2H), 0.94-0.9 (m, 2H), 0.77-0.75 (m, 2H).

Example 52

8-(2-Chloro-4-fluorophenyl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

1-(6-Methylpyrimidin-4-yl)piperidine-4-amine dihydrochloride (133 mg; 0.5 mmol) was suspended in dichloromethane (15 ml) and then was extracted with aqueous sodium hydroxide (2 M; 10 ml). The aqueous layer was extracted with dichloromethane (15 ml), organic layers were combined, dried over sodium sulfate and was evaporated carefully. After adding 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (180 mg; 0.55 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23,1 mg; 0.04 mmol), chloroform adduct of Tris(deben�iodination)diplegia(0) (21 mg; 0,02 mmol) and sodium phenolate (87 mg; 0.75 mmol) in anhydrous 1,4-dioxane (4 ml) the reaction mixture was stirred in argon atmosphere for 60 minutes at 130°C in a microwave oven. Concentrated and purification of the residue by chromatography (SiO2; heptane:ethyl acetate from 3:1 to 0:1) allowed us to obtain specified in the title compound as a yellow foam (97 mg; 44%).

MS ISP (m/e): 438,3 and 440,4 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (s, 1H), 8.36 (d, 1H), 7.50 (dd, 1H), 7.37 (d, 1H), 7.26 (dd, 1H), 7.10 (dt, 1H), 6.59 (dd, 1H), 6.39 (s, 1H), 4.53 (d, 1H), 4.35-4.20 (m, 2H), 3.98-3.75 (m, 1H), 3.17 (dt, 2H), 2.35 (s, 3H), 2.28-2.15 (m, 2H), 1.55-1.40 (m, 2H).

Example 53

8-(3,4-Differenl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 52, using 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 422,2 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (s, 1H), 8.33 (d, 1H), 7.92 (ddd, 1H), 7.70 (m, 1H), 7.50 (d, 1H), 7.35 (m, 1H), 6.89 (dd. 1H), 6.41 (s, 1H), 4.57 (d, 1H), 4.40-4.35 (m, 2H), 4.00-3.90 (m, 1H), 3.19 (dt, 2H), 2.37 (s, 3H), 2.28-2.15 (m, 2H), 1.60-1.40 (m, 2H).

Example 54

8-(3,4-Differenl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 52, using�UY 2-bromo-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 436,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.15 (d, 1H), 7.90 (add, 1H), 7.70 (m, 1H), 7.35 (s, 1H), 7.35 (m, 1H), 6.41 (s, 1H), 4.50 (d, 1H), 4.40-4.35 (m, 2H), 4.00-3.90 (m, 1H), 3.18 (dt, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.30-2.17 (m, 2H), 1.60-1.40 (m, 2H).

Example 55

8-(3,4-Differenl)-6-fluoro-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 52, using 2-bromo-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as an orange viscous oil.

MS ISP (m/e): 440,4 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (s, 1H), 8.30 (dd, 1H), 7.95 (ddd, 1H), 7.70 (m, 1H), 7.44 (dd, 1H), 7.35 (m, 1H), 6.41 (s, 1H), 4.55 (d, 1H), 4.40-4.35 (m, 2H), 4.00-3.90 (m, 1H), 3.18 (dt, 2H), 2.37 (s, 3H), 2.30-2.17 (m, 2H), 1.60-1.40 (m, 2H).

Example 56

8-(3,4-Differenl)-6-chloro-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 52, using 2-bromo-8-(3,4-differenl)-6-chloro-[1,2,4]triazolo[1,5-a]pyridine instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as an orange viscous oil.

MS ISP (m/e): 440,4 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=.51 (s, 1H), 8.37 (d, 1H), 7.90 (dt, 1H), 7.70 (m, 1H), 7.50 (d, 1H), 7.30 (m, 1H), 6.41 (s, 1H), 4.57 (d, 1H), 4.40-4.30 (m, 2H), 4.00-3.90 (m, 1H), 3.18 (dt, 2H), 2.37 (s, 3H), 2.30-2.17 (m, 2H), 1.60-1.40 (m, 2H).

Example 57

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-methylpyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) tert-Butyl-4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate

Was prepared analogously to example 52, using tert-butyl-4-aminopiperidin-1-carboxylate instead of 1-(6-methylpyrimidin-4-yl)piperidine-4-amine. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 446,3 and 448,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35 (d, 1H), 7.51 (dd, 1H), 7.37 (d, 1H), 7.28 (dd, 1H), 7.09 (ddd, 1H), 6.87 (dd, 1H), 4.49 (d, 1H), 4.05-3.90 (m, 2H), 3.82-3.70 (m, 1H), 2.98 (dt, 2H), 2.15-2.02 (m, 2H), 1.65-1.55 (m, 2H), 1.46 (s, 9H).

b) 8-(2-Chloro-4-fluorophenyl)-N-(piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of tert-butyl-4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate (810 mg; 1.82 mmol) in tetrahydrofuran (8 ml) and methanol (6 ml) was added a solution of hydrogen chloride (4.0 M in dioxane; 2.3 ml; 9.1 mmol). The reaction mixture was stirred for 1.5 hours at 60°C and then concentrated in vacuo. The residue was diluted with ethyl acetate (40 ml) and washed with aqueous sodium carbonate (1m; 30 ml), water (30 ml) and brine (30 ml). The aqueous layers were extracted with additional amount�PTO ethyl acetate (40 ml). The organics were combined, dried over magnesium sulfate and filtered. Concentrated allowed us to obtain specified in the title compound as a yellow foam (639 mg; 98%).

MS ISP (m/e): 346,2 and 348,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35 (d, 1H), 7.51 (dd, 1H), 7.37 (d, 1H), 7.28 (dd, 1H), 7.09 (ddd, 1H), 6.87 (dd, 1H), 4.54 (d, 1H), 3.70-3.65 (m, 1H), 3.25-3.10 (m, 2H), 2.80 (dt, 2H), 2.15-2.02 (m, 2H), 1.65-1.55 (m, 2H).

c) 8-(2-Chloro-4-fluorophenyl)-N-(1-(2-methylpyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 8-(2-chloro-4-fluorophenyl)-N-(piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (69 mg; 2 mmol), 4-bromo-2-methylpyridine (34 mg; 0.2 mmol) and N,N-diisopropylethylamine (40 mg; 0.3 mmol) in 1,4-dioxane (0.8 ml) was stirred for 30 minutes at 150°C in a microwave oven. Purification of the reaction mixture by chromatography (SiO2; heptane:ethyl acetate (1:1) to ethylacetoacetate ammonium (80:18:2)) allowed us to obtain specified in the title compound as a yellow semi-solid substances (21 mg; 24%).

MS ISP (m/e): 437,3 and 439,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35 (m, 2H), 7.50 (dd, 1H), 7.37 (dd, 1H), 7.26 (dd, 1H), 7.10 (dt, 1H), 6.86 (m, 1H), 6.55 (m, 1H), 5.30 (s, 1H), 4.53 (m, 1H), 3.90-3.80 (m, 1H), 3.75-3.60(m, 1H), 3.57 (m, 2H), 3.17 (dt, 2H), 2.46 (s, 3H), 2.30-2.10 (m, 2H), 1.55-1.40 (m, 2H).

Example 58

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Received an�logical example 57, using 4-bromo-2-chloropyridine instead of 4-bromo-2-methylpyridine. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 457,3; 459,3 and 461,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36 (d, 1H), 8.00 (d, 1H), 7.65 (d, 1H), 7.50 (dd, 1H), 7.37 (dd, 1H), 7.26 (dd, 1H), 7.10 (dt, 1H), 6.89 (dd, 1H), 6.66 (d, 1H), 6.59 (dd, 1H), 4.51 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 2H), 3.12 (dt, 2H), 2.21 (m, 2H), 1.55-1.40 (m, 2H).

Example 59

8-(2-Chloro-4-fluorophenyl)-N-(1-(5-fluoro-2-methylpyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 4-chloro-5-fluoro-2-methylpyridine instead of 4-bromo-2-methylpyridine. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 455,3 and 457,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35 (d, 1H), 8.08 (d, 1H), 7.65 (d, 1H), 7.50 (m, 1H), 7.37 (dd, 1H), 7.26 (dd, 1H), 6.89 (dd, 1H), 6.60 (dd, 1H), 4.65 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 2H), 3.12 (dt, 2H), 2.45 (s, 3H), 2.21 (m, 2H), 1.55-1.40 (m, 2H).

Example 60

8-(2-Chloro-4-fluorophenyl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 4-chloropyrimidine instead of 4-bromo-2-methylpyridine. Specified in the title compound was obtained as an orange semi-solid substances.

MS ISP (m/e): USD 424.2 and 426,1 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36 (d, 1H), 8.10 (d, 1H), 7.50 (dd, 1H), 739 (d, 1H), 7.28 (dd, 1H), 7.09 (ddd, 1H), 6.86 (dd, 1H), 6.33 (d, 1H), 4.54 (d, 1H), 4.40-4.35 (m, 2H), 3.95-3.85 (m, 1H), 3.17 (dt, 2H), 2.50 (s, 3H), 2.20 (m, 2H), 1.55-1.40 (m, 2H).

Example 61

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 4-chloro-2-methylpyrimidin instead of 4-bromo-2-methylpyridine. Specified in the title compound was obtained as a yellow semi-solid substances.

MS ISP (m/e): 438,3 and 440,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36 (d, 1H), 8.10 (d, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 7.28 (dd, 1H), 7.09 (ddd, 1H), 6.86 (dd, 1H), 6.33 (d, 1H), 4.54 (d, 1H), 4.40-4.35 (m, 2H), 3.95-3.85 (m, 1H), 3.17 (dt, 2H), 2.50 (s, 3H), 2.20 (m, 2H), 1.55-1.40 (m, 2H).

Example 62

8-(2-Chloro-4-fluorophenyl)-N-(1-(2,6-dimethylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 4-chloro-2,6-dimethylpyrimidin instead of 4-bromo-2-methylpyridine. Specified in the title compound was obtained as a yellow semi-solid substances.

MS ISP (m/e): 452,2 and 454,3 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.37 (d, 1H), 7.47 (dd, 1H), 7.39 (d, 1H), 7.28 (dd, 1H), 7.10 (ddd, 1H), 6.89 (dd, 1H), 6.22 (d, 1H), 4.38 (d, 1H), 4.45-4.35 (m, 2H), 3.95-3.85 (m, 1H), 3.15 (dt, 2H), 2.48 (s, 3H), 2.33 (s, 3H), 2.20 (m, 2H), 1.55-1.40 (m, 2H).

Example 63

8-(2-Chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 52, using 2-bromo-8-(2-chloro-4-fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 452,2 and 454,2 [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (s, 1H), 8.18 (s, 1H), 7.48 (dd, 1H), 7.7 (m, 1H), 7.23 (m, 1H), 7.08 (ddd, 1H), 6.39 (d, 1H), 4.45 (d, 1H), 4.35-4.25 (m, 2H), 3.95-3.85 (m, 1H), 3.15 (dt, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 2.18 (m, 2H), 1.55-1.40 (m, 2H).

Example 64

[8-(2-Chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 1a-f). Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 444,2/446,1 (100/30) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.35 (m, 1H), 7.52-7.47 (m, 1H), 7.40-7.37 (m, 1H), 7.29-7.26 (m, 1H), 7.13-7.06 (m, 1H), 6.93-6.88 (m, 1H), 4.74-4.71 (m, 1H), 3.92-3.85 (m, 3H), 3.40-3.30 (m, 2H), 2.41 (s, 3H), 2.27-2.21 (m, 2H), 1.72-1.58 (m, 2H).

Example 65

[8-(2,4-Debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 8-(2,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 1a-f). Specified in the header Conn�approval was obtained as white solids.

MS ISP (m/e): 428,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.85-7.77 (m, 1H), 7.50-7.47 (m, 1H), 7.04-6.87 (m, 3H), 4.60-4.57 (m, 1H), 3.90-3.86 (m, 3H), 3.39-3.29 (m, 2H), 2.41 (s, 3H), 2.27-2.21 (m, 2H), 1.70-1.57 (m, 2H).

Example 66

[8-(4-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea

3-Bromopyridin-2-amine (30 g, 168 mmol) and ethoxycarbonylmethylene (24.8 g; 21,3 ml, 185 mmol) was dissolved in dioxane (300 ml) and stirred at room temperature. After 4 hours was added an additional amount ethoxycarbonylmethylene (1 ml; 8.4 mmol). After 1 hour the solvent was evaporated and the residue was dried in high vacuum for 12 hours. Specified in the title compound was obtained as a light yellow solid (51,2 g; 100%) and used without purification in the next step.

MS ISP (m/e): 304,0/305,9 (100/73) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.41 (m, 1H) 7.99-7.96 (m, 1H), 7.11-7.07 (m, 1H), 4.32 (q, 2H), 1.36 (t, 3H).

b) 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Hydroxylamine (58,5 g, 842 mmol) and N,N-diisopropylethylamine (65,3 g; 86,3 ml, 505 mmol) was dissolved in methanol (200 ml) and ethanol (200 ml). Was added N-(3-bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51,2 g, 168 mmol) and the reaction mixture stirred at room temperature for 1 hour and �ATEM at 60°C for 3 hours. The white precipitate was filtered and triturated with water for 25 minutes, was filtered and triturated twice with diethyl ether. The solid is dried by joint evaporation with toluene and dried in vacuum. Specified in the title compound was obtained as white solid (27,9 g; 78%).

MS ISP (m/e): 213,0/215,1 (86/95) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).

c) 8-(4-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg; 2.35 mmol), 4-Chlorfenvinphos acid (757 mg; 4,69 mmol), dichlormethane adduct dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (153 mg; 0,188 mmol) and aqueous solution of Na2CO3(2 n; 2,35 ml; 4,69 mmol) in dioxane (10 ml) was stirred at 110°C for 2 hours. The reaction mixture was diluted with 2 n aqueous solution of sodium carbonate and was extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of pentane/diethyl ether as eluent. Specified in the title compound was obtained as white solid (572 mg; 99%).

MS ISP (m/e): 245,3/247,2 (100/38) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.30 (dd, 1H) 7.93-7.88 (m, 2H), 7.52-7.45 (m, 3H), 6.92 (t, 1H), 4.51 (bs, 2H).

d) 2-Bromo-8-(4-chloro-phenyl)-[12,4]triazolo[1,5-a]pyridin

A mixture of copper bromide(II) (150,6 mg; 0,674 mmol) and tert-nitrite (89 µl; 0,674 mmol) in acetonitrile (5 ml) was heated to 60°C and 8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (150 mg, 0,613 mmol) was added in small portions. Upon completion of addition the reaction mixture was heated to 75°C for 1 hour. Added additional amount of copper bromide(II) (150,6 mg; 0,674 mmol) and tert-nitrite (89 µl; 0,674 mmol) and the mixture was heated to 75°C for another hour. The reaction mixture was cooled to room temperature and added water. The aqueous phase three times were extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using a mixture of pentane/diethyl ether as eluent. Specified in the title compound was obtained as white solid (165 mg; 87%).

MS ISP (m/e): 308,0/310.0/312,1 (85/100/31) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.54-8.51 (m, 1H), 7.97-7.94 (m, 2H), 7.70-7.67 (m, 1H), 7.51-7.48 (m, 2H), 7.17-7.12 (m, 1H).

e) 1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine

1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine dihydrochloride (see example 36b); 2.3 g; 8.48 to mmol) was neutralized with 2 n NaOH. The aqueous layer three times was extracted with CH2Cl2and three times with ethyl acetate, the combined organic phases were dried over Na2SO4Phil�trevali and the solvents evaporated. The crude product was purified flash chromatography with CH2Cl2and MeOH column on Si-NH2(50 g). Specified in the title compound was isolated as a light yellow oil (1.2 g; 71%).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=3.89-3.84 (m, 2H), 3.24-3.14 (m, 2H), 3.02-2.93 (m, 1H), 2.40 (s, 3H), 1.95-1.89 (m, 2H), 1.51-1.38 (m, 2H).

(f) [8-(4-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

A suspension of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine (40 mg; 202 mmol), 2-bromo-8-(4-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (74,7 mg; 242 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9,34 mg; 16,1 mmol), chloroform adduct of Tris(dibenzylideneacetone)diplegia(0) (8,35 mg; 8,07 mmol) and sodium phenolate (35,1 mg; 303 μmol) in anhydrous dioxane (3 ml) were barbotirovany with argon for 5 minutes.The mixture was then subjected to microwave irradiation at 150°C for 60 minutes. The crude substance was purified flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a whitish foam (42 mg; 49%).

MS ISP (m/e): 426,1/428,3 (100/39) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.33-8.31 (m, 1H), 7.92-7.89 (m, 2H), 7.52-7.44 (m, 3H), 6.93-6.88 (m, 1H), 4.52-4.50 (m, 1H), 3.99-3.87 (m, 3H), 3.41-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.23 (m, 2H), 1.73-1.60 (m, 2H).

Example 67

[8-(3-Chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 458,2/460,2 (100/34) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.15-8.13 (m, 1H), 8.09-8.06 (m, 1H), 7.89-7.84 (m, 1H), 7.35 (m, 1H), 7.27-7.26 (m, 1H), 4.47-4.44 (m, 1H), 3.94-3.86 (m, 3H). 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.31-2.24 (m, 2H), 1.73-1.60 (m, 2H).

Example 68

[8-(2-Chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 458,2/460,2 (100/40) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.18 (m, 1H), 7.49-7.44 (m, 1H), 7.29-7.24 (m, 2H), 7.12-7.05 (m, 1H), 4.82-4.79 (m, 1H), 3.89-3.84 (m, 3H), 3.39-3.30 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.25-2.20 (m, 2H), 1.71-1.58 (m, 2H).

Example 69

[8-(3,4-Debtor-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a whitish solid substance.

MS ISP (m/e): 442,2 (100) [(M+H)+].

1H NMR (CDCb, 300 MHz): δ (mn-1)=8.14 (m, 1H), 7.94-7.87 (m, 1H), 7.72-7.67 (m, 1H), 7.35 (m, 1H), 7.28-7.24 (m, 1H), 4.47-4.44 (m, 1H), 3.94-3.87 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.29-2.22 (m, 2H), 1.72-1.60 (m, 2H).

Example 70

[8-(3,4-Debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]feast�DIN-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 432,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.16-7.07 (m, 1H), 7.00-6.93 (m, 1H), 6.91-6.87 (m, 1H), 4.12-4.02 (m, 4H), 3.87-3.68 (m, 3H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.31-1.91 (m, 6H), 1.64-1.51 (m, 2H).

Example 71

[8-(4-Fluoro-2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine F

Was prepared analogously to example 66. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 440,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.31-8.29 (m, 1H), 7.58-7.53 (m, 1H), 7.46-7.44 (m, 1H), 6.88-6.84 (m, 1H), 6.80-6.72 (m, 2H), 4.53-4.50 (m, 1H), 3.91-3.85 (m, 3H), 3.79 (s, 3H), 3.39-3.29 (m, 2H), 2.41 (s, 3H), 2.26-2.21 (m, 2H), 1.69-1.56 (m, 2H).

Example 72

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 478,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.29 (m, 2H), 8.20-8.15 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.29 (m, 1H), 6.96-6.91 (m, 1H), 4.66-4.63 (m, 1H), 3.96-3.89 (m, 3H), 3.41-3.31 (m, 2H), 2.42 (s, 3H), 2.30-2.25 (m, 2H), 1.75-1.62 (m, 2H).

Example 73

[8-(2,4-Debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 432,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.02-6.91 (m, 1H), 6.86-6.79 (m, 2H), 4.37-4.33 (m, 1H), 4.11-4.07 (m, 2H), 4.02-3.99 (m, 1H), 3.87-3.81 (m, 2H), 3.76-3.66 (m, 1H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.31-1.90 (m, 6H), 1.64-1.49 (m, 2H).

Example 74

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 482,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.44-7.41 (m, 1H), 7.36-7.30 (m, 1H), 7.22-7.13 (m, 1H), 4.18-4.08 (m, 3H), 4.03-4.00 (m, 1H), 3.88-3.67 (m, 3H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.35-1.90 (m, 6H), 1.65-1.50 (m, 2H).

Example 75

[8-(2-Fluoro-4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as orange solids.

MS ISP (m/e): 488,2 (100) [(M+H)+].

1H NMR (CDCl3), 300 MHz): δ (mn-1)=8.42-8.39 (m, 1H), 8.14-8.09 (m, 1H), 7.87-7.78 (m, 2H), 7.61-7.58 (m, 1H), 6.98-6.93 (m, 1H), 4.54-4.52 (m, 1H), 3.94-3.87 (m, 3H), 3.40-3.31 (m, 2H), 3.11 (s, 3H), 2.42 (s, 3H), 2.28-2.23 (m, 2H), 1.72-1.59 (m, 2H).

Example 76

[8-(2-Fluoro-4-methanesulfonyl-FeNi�)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as orange solids.

MS ISP (m/e): 478,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.40-8.37 (m, 1H), 8.01-7.96 (m, 1H), 7.56-7.54 (m, 2H), 7.50-7.47 (m, 1H), 6.96-6.91 (m, 1H), 4.56-4.53 (m, 1H), 3.93-3.87 (m, 3H), 3.40-3.31 (m, 2H), 2.41 (s, 3H), 2.28-2.23 (m, 2H), 1.72-1.59 (m, 2H).

Example 77

[8-(3,4-Debtor-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66, on the basis of 3-bromo-5-herperidin-2-amine instead of 3-bromopyridin-2-amine in step a). Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 446,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.30-8.29 (m, 1H), 8.01-7.93 (m, 1H), 7.74-7.69 (m, 1H), 7.45-7.42 (m, 1H), 7.33-7.24 (m, 1H), 4.54-4.51 (m, 1H), 3.94-3.89 (m, 3H), 3.41-3.31 (m, 2H), 2.42 (s, 3H), 2.28-2.23 (m, 2H), 1.73-1.60 (m, 2H).

Example 78

18-(2,4-Dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 460,2/462,2/464,1 (100/70/14) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.37-8.35 (m, 1H), 7.54 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.33 (m, 2H), 6.92-6.87 (m, 1H), 4.56-4.54 (m, 1H), 3.91-3.85 (m, 3H), 3.38-3.29 (m, 2H), 2.41 (s, 3H), 2.26-2.21 (m, 2H), 1.69-1.57 (m, 2H).

Example 7

[8-(2-Fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 482,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.38-7.33 (m, 2H), 7.19-7.14 (m, 1H), 4.46-4.41 (m, 1H), 4.16-4.09 (m, 3H), 3.87-3.81 (m, 2H), 3.76-3.67 (m, 1H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.36-1.95 (m, 6H), 1.65-1.50 (m, 2H).

Example 80

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as brown solid substance.

MS ISP (m/e): 446,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.35 (m, 1H), 7.61-7.48 (m, 2H), 7.14-7.05 (m, 1H), 6.94-6.89 (m, 1H), 4.55-4.53 (m, 1H), 3.93-3.86 (m, 3H), 3.40-3.30 (m, 2H), 2.41 (s, 3H), 2.28-2.21 (m, 2H), 1.72-1.62 (m, 2H).

Example 81

[8-(3,4-Debtor-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 8-(3,4-Debtor-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

A solution of 8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously to example 66A-C), based on 3-bromo-5-herperidin-2-amine; 237 mg; 897 mmol) in ethanol (8 ml) and HCl (25%� in water; 144 mg; 120 ml, 987 mmol) was gidrirovanie at 80°C and 80 bar (8×103kPa) for 18 hours in the presence of Pd/C (237 mg; 222 μmol). The catalyst was filtered, thoroughly washed with MeOH and the solvents evaporated. The crude substance was purified flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a white foam (76 mg; 32%).

MS ISP (m/e): 269,2 (100) [(M+H)+].

(b) [8-(3,4-Debtor-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

A solution of 8-(3,4-differenl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (74 mg; 276 µmol), 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (82 mg; 414 μmol) and isopropylate titanium(IV) (240 mg; 253 ml, 828 mmol) in dichloroethane (6 ml) was heated to 85°C for 12 hours. Added additional amount of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (54 mg; 276 µmol) and stirred at 85°C for the next two hours. The reaction mixture was cooled to 50°C, was added sodium borohydride (41,7 mg; 1.1 mmol) and ethanol (3 ml) and stirred at 50°C for one hour. The solvent was evaporated, the residue was extracted with 2 n solution of Na2CO3and ethyl acetate. The organics were combined, dried over Na2SO4, filtered and the solvent evaporated. The residue was purified by flash chromatography (�silicagel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and then preparative HPLC. Specified in the title compound was obtained as a light green foam (37,1 mg; 30%).

MS ISP (m/e): 450,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.14-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.93-6.91 (m, 1H), 5.32-5.27 & 5.20-5.15 (m, 1H), 4.36-4.33 (m, 1H), 4.31-4.29 (m, 1H), 4.26-4.23 (m, 1H), 4.18-4.16 (m, 1H), 3.86-3.83 (m, 2H), 3.75-3.67 (m, 1H). 3.33-3.27 (m, 2H), 2.63-2.43 (m, 2H), 2.40 (s, 3H), 2.20-2.16 (m, 2H), 1.64-1.52 (m, 2H).

Example 82

[8-(3,4-Debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 3-Bromo-6-(trifluoromethyl)pyridin-2-amine

A solution of 6-(trifluoromethyl)pyridin-2-amine (200 mg, 1,23 mmol) in dichloromethane (2,47 ml) was cooled to 0°C and slowly over 30 minutes was added bromine (197 mg; 63.4 per µl; 1,23 mmol). After 25 hours at 0°C the reaction mixture was extracted with saturated solution of Na2S2O3, water and brine, dried over Na2SO4and concentrated in vacuum. The crude substance was purified flash chromatography on silica gel using a mixture of CH2Cl2/MeOH (with 10% ammonia) as eluent. Specified in the title compound was obtained as white solid (711 mg; 24%).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.80-7.77 (m, 1H), 6.91-6.89 (m, 1H).

(b) [8-(3,4-Debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]�iadiza-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66, on the basis of 3-bromo-6-(trifluoromethyl)pyridin-2-amine instead of 3-bromopyridin-2-amine in step a). Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 496,3 (53) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.01-7.94 (m, 1H), 7.78-7.71 (m, 1H), 7.57-7.55 (m, 1H), 7.35-7.29 (m, 2H), 4.73-4.71 (m, 1H), 3.93-3.89 (m, 3H), 3.43-3.34 (m, 2H), 2.42 (s, 3H), 2.30-2.25 (m, 2H), 1.75-1.60 (m, 2H).

Example 83

[8-(2-Methyl-pyrimidine-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 408,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=9.28 (s, 2H), 8.38-8.36 (m, 1H), 7.58-7.56 (m, 1H), 6.96-6.93 (m, 1H), 4.59-4.57 (m, 1H), 3.99-3.89 (m, 3H), 3.39-3.32 (m, 2H), 2.81 (s, 3H), 2.42 (s, 3H), 2.28-2.24 (m, 2H), 1.72-1.62 (m, 2H).

Example 84

[8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 423,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.73 (m, 1H), 8.31-8.29 (m, 1H), 8.25-8.22 (m, 1H), 7.49-7.47 (m, 1H), 6.92-6.85 (m, 2H), 4.56-4.55 (m, 1H), 4.03-3.88 (m, 3H), 4.00 (s, 3H), 3.39-3.32 (m, 2H), 2.42 (s, 3H), 2.28-2.24 (m, 2H), 1.71-1.61 (m, H).

Example 85

[8-(2-Chloro-4-fluoro-phenyl)-11,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66a-d and f, using 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine (see example 40b) instead of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine in stage f. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 428,3/430,3 (100/41) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.35 (m, 1H), 7.53-7.48 (m, 1H), 7.40-7.37 (m, 1H), 7.29-7.26 (m, 1H), 7.13-7.07 (m, 1H), 6.91-6.87 (m, 1H), 4.53-4.50 (m, 1H), 3.97-3.80 (m, 3H), 3.27-3.18 (m, 2H), 2.39 (s, 3H), 2.24-2.19 (m, 2H), 1.66-1.53 (m, 2H).

Example 86

[8-(3-Chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66, on the basis of 3-bromo-5-herperidin-2-amine instead of 3-bromopyridin-2-amine in step a). Specified in the title compound was obtained as a whitish solid substance.

MS ISP (m/e): 462,2/464,3 (100/33) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.30-8.29 (m, 1H), 8.15-8.12 (m, 1H), 7.90-7.85 (m, 1H), 7.45-7.41 (m, 1H), 7.30-7.24 (m, 1H), 4.54-4.52 (m, 1H), 3.94-3.89 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.23 (m, 2H), 1.73-1.60 (m, 2H).

Example 87

N-(1-(3,4-Dichlorobenzyl)-1H-1,2,4-triazole-3-yl)-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine

Was prepared analogously to example�5. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 424,2/426,0 (100/66) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.73 (s, 1H), 7.46-7.43 (m, 1H), 7.35 (m, 1H), 7.10-7.07 (m, 1H), 5.09 (s. 2H), 4.14-4.11 (m, 1H), 3.89-3.70 (m, 3H), 3.34-3.25 (m, 2H), 2.41 (s, 3H), 2.21-2.16 (m, 2H), 1.65-1.52 (m, 2H).

Example 88

[8-(6-Fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a whitish foam.

MS ISP (m/e): 411,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.77-8.76 (m, 1H), 8.53-8.47 (m, 1H), 8.37-8.35 (m, 1H), 7.56-7.53 (m, 1H), 7.09-7.05 (m, 1H), 6.96-6.91 (m, 1H), 4.52-4.49 (m, 1H), 4.00-3.88 (m, 3H), 3.41-3.31 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 2H), 1.74-1.61 (m, 2H).

Example 89

[8-(2-Fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a brown oil.

MS ISP (m/e): 411,3 (81) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50-8.43 (m, 1H), 8.38-8.36 (m, 1H), 8.27-8.25 (m, 1H), 7.67-7.64 (m, 1H), 7.37-7.34 (m, 1H), 6.96-6.91 (m, 1H), 4.54-4.51 (m, 1H), 3.96-3.88 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.23 (m, 2H), 1.72-1.61 (m, 2H).

Example 90

[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

/p>

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 470,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.60 (m, 1H), 8.38-8.30 (m, 2H), 7.99-7.96 (m, 1H), 7.73-7.68 (m, 1H), 7.63.7.61 (m, 1H), 6.98-6.93 (m, 1H), 4.67-4.64 (m, 1H), 3.98-3.89 (m, 3H), 3.41-3.32 (m, 2H), 3.11 (s, 3H), 2.42 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.61(m,2H).

Example 91

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 446,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.33 (m, 1H), 7.76-7.70 (m, 2H), 7.52-7.49 (m, 1H), 6.94-6.89 (m, 1H), 4.57-4.54 (m, 1H), 3.97-3.89 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.30-2.25 (m, 2H), 1.74-1.61 (m, 2H).

Example 92

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 450,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=6.96-6.87 (m, 1H), 6.78-6.70 (m, 1H), 4.38-4.33 (m, 1H), 4.11-4.05 (m, 3H), 3.86-3.81 (m, 2H), 3.76-3.66 (m, 1H), 3.34-3.24 (m, 2H), 2.40 (s, 3H), 2.33-1.93 (m, 6H), 1.64-1.50 (m, 2H).

Example 93

[8-(2-Fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-Pipa�idin-4-yl]-amine

a) 8-(6-Methylpyrimidin-4-yl)-1,4-dioxa-8 azaspiro[4.5]Dean

A solution of 1,4-dioxa-8 azaspiro[4.5]Decan (3,04 g; 2,72 ml; of 21.2 mmol), 4-chloro-6-methylpyrimidine (3,00 g; 23.4 mmol) and N,N-diisopropylethylamine (4,12 g; the 5.56 ml, 31.8 mmol) in dioxane (50 ml) was heated to 140°C in microwave oven for 40 minutes. The reaction mixture was concentrated, then was purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH40H (9:1) in dichloromethane). Specified in the title compound was obtained as an orange oil (a 4.64 g; 93%).

MS ISP (m/e): 236,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52-8.51 (m, 1H), 6.42 (m, 1H), 4.01 (s, 4H), 3.83-3.79 (m, 4H), 2.45 (s, 3H), 1.79-1.75 (m, 4H).

b) 1-(6-Methylpyrimidin-4-yl)piperidine-4-it

To a solution of 8-(6-methylpyrimidin-4-yl)-1,4-dioxa-8 azaspiro[4.5]Decan (a 4.64 g; 19.7 mmol) in acetone (45 ml) was added 2 n HCl (180 g; 150 ml; 4,94 mol) and stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, then summed to pH 7 using a solution of NaHCO3. The aqueous phase was 4 times was extracted with CH2Cl2organic layers were combined, dried over Na2SO4and the solvent evaporated. Specified in the title compound was obtained as a light brown liquid (2.7 g; 72%).

MS ISP (m/e): 192,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.57 (m, 1H), 6.48 (m, 1H), 3.99-3.95(m, 4H), 2.57-2.53 (m, 4H), 2.41 (s, 3H).

(C) [8-(2-Fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 1-(6-methylpyrimidin-4-yl)piperidine-4-it and 8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 1d-g). Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 476,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (m, 1H), 7.38-7.32 (m, 2H), 7.19-7.14 (m, 1H), 6.38 (m, 1H), 4.46-4.42 (m, 1H), 4.30-4.24 (m, 2H), 4.13-3.95 (m, 3H), 3.78-3.69 (m, 1H), 3.17-3.08 (m, 2H), 2.35 (s, 3H), 2.38-2.29 (m, 1H), 2.18-1.93 (m, 5H), 1.50-1.35 (m, 2H).

Example 94

[8-(6-Fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

a) 1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-ylamine

1-(6-Methylpyrimidin-4-yl)piperidine-4-amine dihydrochloride (see example 30b; 2 g; 7,54 mmol) was neutralized with 2 n NaOH and CH2Cl2aqueous layers three times was extracted with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered and the solvent evaporated. Specified in the title compound was obtained as a brown oil (1.31 g; 90%).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (m, 1H), 6.39 (m, 1H), 4.35-4.31 (m, 2H), 3.02-2.93 (m, 3H), 2.35 (s, 3H), 1.94-1.89 (m, 2H), 1.37-1.29 (m, 4H).

(b) [8-(6-f�op-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl-amine

Was prepared analogously to example 66A-d and f. At the stage (f) 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine was used instead of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine. Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 405,5 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.77-8.76 (m, 1H), 8.54-8.47 (m, 2H), 8.38-8.35 (m, 1H), 7.55-7.52 (m, 1H), 7.08-7.05 (m, 1H), 6.95-6.91 (m, 1H), 6.41 (m, 1H), 4.53-4.51 (m, 1H), 4.37-4.33 (m, 2H), 4.02-3.92 (m, 1H), 3.23-3.14 (m, 2H), 2.37 (s, 3H), 2.27-2.22 (m, 2H), 1.59-1.46 (m, 2H).

Example 95

[8-(5-Chloro-thiophene-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 426,1/428,2 (90/36) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.26-8.23 (m, 1H), 7.76-7.74 (m, 1H), 7.56-7.53 (m, 1H), 6.97-6.96 (m, 1H), 6.86-6.81 (m, 1H), 6.42 (m, 1H), 4.61-4.58 (m, 1H), 4.37-4.33 (m, 2H), 4.03-3.94 (m, 1H), 3.24-3.15 (m, 2H), 2.37 (s, 3H), 2.29-2.23 (m, 2H), 1.61-1.48 (m, 2H).

Example 96

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 472,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.37-8.30 (m, 2H), 8.22-8.18 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.29 (m, 1H), 6.95-6.0 (m, 1H), 6.42 (m, 1H), 4.53-4.50 (m, 1H), 4.38-4.34 (m, 2H), 4.02-3.92 (m, 1H), 3.23-3.13 (m, 2H), 2.37 (s, 3H), 2.29-2.23 (m, 2H), 1.60-1.47 (m, 2H).

Example 97

[8-(6-Dimethylamino-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 430,5 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.74 (m, 1H), 8.52 (m, 1H), 8.26-8.17 (m, 2H), 7.46-7.43 (m, 1H), 6.88-6.84 (m, 1H), 6.64-6.61 (m, 1H), 6.41 (m, 1H), 4.46-4.43 (m, 1H), 4.36-4.31 (m, 2H), 4.03-3.94 (m, 1H), 3.24-3.15 (m, 2H), 3.15 (s, 6H), 2.38 (s, 3H), 2.27-2.22 (m, 2H), 1.59-1.46 (m, 2H).

Example 98

[8-(2-Chloro-thiophene-3-yl)-11,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 426,1/428,3 (100/44) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.35-8.32 (m, 1H), 7.76-7.64 (m, 1H), 7.50-7.48 (m, 1H), 7.23-7.21 (m, 1H), 6.92-6.87 (m, 1H), 6.41 (m, 1H), 4.55-4.52 (m, 1H), 4.34-4.30 (m, 2H), 4.00-3.90 (m, 1H), 3.23-3.14 (m, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 2H), 1.57-1.44(m, 2H).

Example 99

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 93. Specified in the title compound was obtained as a light yellow�Oh foam.

MS ISP (m/e): 476,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (m, 1H), 7.43-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.18-7.14 (m, 1H), 6.38 (m, 1H), 4.29-4.25 (m, 2H), 4.17-4.09 (m, 3H), 4.01-3.99 (m, 1H), 3.77-3.69 (m, 1H), 3.17-3.10 (m, 2H), 2.36 (s, 3H), 2.37-2.28 (m, 1H), 2.18-1.89 (m, 5H), 1.49-1.37 (m, 2H).

Example 100

[8-(3,4-Debtor-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66a-d and f, using 3-bromo-5-(trifluoromethyl)pyridin-2-amine instead of 3-bromopyridin-2-amine in step a) and 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine (see example a) instead of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine in stage f). Specified in the title compound was obtained as a brown foam.

MS ISP (m/e): 490,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.66 (m, 1H), 8.52 (m, 1H), 7.99-7.93 (m, 1H), 7.74-7.70 (m, 1H), 7.64 (m, 1H), 7.33-7.29 (m, 1H), 6.42 (m, 1H), 4.69-4.67 (m, 1H), 4.37-4.34 (m, 2H), 4.00-3.93 (m, 1H), 3.22-3.15 (m, 2H), 2.37 (s, 3H), 2.26-2.22 (m, 2H), 1.59-1.49 (m, 2H).

Example 101

[8-(3,4-Debtor-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66 using 3-bromo-5-(trifluoromethyl)pyridin-2-amine instead of 3-bromopyridin-2-amine in step a). Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 496,3 (100) [(M+H)+].

1H NMR (CDCl , 300 MHz): δ (mn-1)=8.65 (m, 1H), 7.98-7.93 (m, 1H), 7.73-7.69 (m, 1H), 7.65 (m, 1H), 7.34-7.27 (m, 1H), 4.69-4.67 (m, 1H), 3.98-3.90 (m, 3H), 3.40-3.33 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.73-1.64 (m, 2H).

Example 102

[1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 440,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.38-8.36 (m, 1H), 7.61-7.55 (m, 1H), 7.50-7.48 (m, 1H), 7.14-7.05 (m, 1H), 6.93-6.86 (m, 1H), 6.41 (m, 1H), 4.51-4.49 (m, 1H), 4.35-4.30 (m, 2H), 3.99-3.89 (m, 1H), 3.23-3.13 (m, 2H), 2.37 (s, 3H), 2.26-2.20 (m, 2H), 1.57-1.45 (m, 2H).

Example 103

[8-(2-Fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as brown solid substance.

MS ISP (m/e): 405,3 (15) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1) 8.51-8.44 (m, 2H), 8.39-8.36 (m, 1H), 8.26-8.24 (m, 1H), 7.66-7.63 (m, 1H), 7.36-7.33 (m, 1H), 6.95-6.90 (m, 1H), 6.41 (m, 1H), 4.57-4.54 (m, 1H), 4.35-4.31 (m, 2H), 4.00-3.90 (m, 1H), 3.22-3.13 (m, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 2H), 1.58-1.45 (m, 2H).

Example 104

[8-(2,6-Dimethoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as yellow�oil.

MS ISP (m/e): 447,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (m, 1H), 8.28-8.26 (m, 1H), 8.08-8.05 (m, 1H), 7.62-7.59 (m, 1H), 6.88-6.83 (m, 1H), 6.46-6.43 (m, 1H), 6.40 (m, 1H), 4.51-4.48 (m, 1H), 4.33-4.29 (m, 2H), 3.98-3.91 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.22-3.13 (m, 2H), 2.36 (s, 3H), 2.25-2.19 (m, 2H), 1.56-1.43 (m, 2H).

Example 105

[8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 417,4 (35) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.73 (m, 1H), 8.51 (m, 1H), 8.32-8.30 (m, 1H), 8.26-8.23 (m, 1H), 7.49-7.46 (m, 1H), 6.92-6.85 (m, 2H), 6.41 (m, 1H), 4.52-4.49 (m, 1H), 4.36-4.31 (m, 2H), 4.02-3.96 (m, 1H), 4.00 (s, 3H), 3.23-3.14 (m, 2H), 2.36 (s, 3H), 2.26-2.21 (m, 2H), 1.58-1.45 (m, 2H).

Example 106

[8-(3,4-Debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 93. Specified in the title compound was obtained as a light yellow oil.

MS ISP (m/e): to 426.2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (m, 1H), 7.15-7.07 (m, 1H), 6.99-6.93 (m, 1H), 6.91-6.87 (m, 1H), 6.38 (m, 1H), 4.29-4.24 (m, 2H), 4.12-4.04 (m, 4H), 3.78-3.68 (m, 1H), 3.17-3.09 (m, 2H), 2.35 (s, 3H), 2.30-2.25 (m, 1H), 2.17-1.88 (m, 5H), 1.50-1.35 (m, 2H).

Example 107

[8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 407,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.73-8.72 (m, 1H), 8.32-8.29 (m, 1H), 8.26-8.22 (m, 1H), 7.49-7.46 (m, 1H), 6.92-6.85 (m, 2H), 4.51-4.49 (m, 1H), 4.01-3.93 (m, 3H), 4.00 (s, 3H), 3.28-3.19 (m, 2H), 2.40 (s, 3H), 2.26-2.21 (m, 2H), 1.68-1.55 (m, 2H).

Example 108

[8-(6-Fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as brown solid substance.

MS ISP (m/e): 395,2 (51) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.76-8.75 (m, 1H), 8.53-8.47 (m, 1H), 8.37-8.35 (m, 1H), 7.55-7.52 (m, 1H), 7.09-7.05 (m, 1H), 6.95-6.91 (m, 1H), 4.58-4.55 (m, 1H), 4.01-3.83 (m, 3H), 3.28-3.19 (m, 2H), 2.40 (s, 3H), 2.26-2.21 (m, 2H), 1.68-1.56 (m, 2H).

Example 109

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 462,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.34 (m, 1H), 8.32-8.29 (m, 1H), 8.21-8.16 (m, 1H), 7.55-7.52 (m, 1H), 7.35-7.29 (m, 1H), 6.95-6.90 (m, 1H), 4.57-4.54 (m, 1H), 4.01-3.81 (m, 3H), 3.28-3.19 (m, 2H), 2.40 (s, 3H), 2.28-2.22 (m, 2H), 1.70-1.57 (m, 2H).

Example 110

[8-(3-Chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]PI�idin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66a-d and f on the basis of 3-bromo-5-herperidin-2-amine instead of 3-bromopyridin-2-amine in step a) and using 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine (see example 40b) instead of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine in stage f). Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 446,1/448,1 (100/35) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.30-8.28 (m, 1H), 8.15-8.12 (m, 1H), 7.90-7.85 (m, 1H), 7.44-7.41 (m, 1H), 7.30-7.24 (m, 1H), 4.55-4.53 (m, 1H), 3.99-3.81 (m, 3H), 3.28-3.19 (m, 2H), 2.40 (s, 3H), 2.26-2.20 (m, 2H), 1.69-1.56 (m, 2H).

Example 111

[8-(3-Chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66a-d and f on the basis of 3-bromo-5-herperidin-2-amine instead of 3-bromopyridin-2-amine in step a) and using 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine (see example a) instead of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-amine in stage f). Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 456,3/458,3 (100/34) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.31-8.29 (m, 1H), 8.15-8.12 (m, 1H), 7.90-7.85 (m, 1H), 7.45-7.41 (m, 1H), 7.30-7.24 (m, 1H), 6.41 (m, 1H), 4.53-4.51 (m, 1H), 4.37-4.33 (m, 2H), 3.99-3.89 (m, 1H), 3.23-3.14 (m, 2H), 2.37 (s, 3H), 2.27-2.21 (m, 2H), 1.59-1.46 (m, 2H).

Example 112

[8-(4-Fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4 triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-it (see example 25b) and 8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 1d-g). Specified in the title compound was obtained as brown solid substance.

MS ISP (m/e): 466,3 (71) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.43-7.41 (m, 1H), 7.36-7.31 (m, 1H), 7.19-7.13 (m, 1H), 4.17-4.02 (m, 4H), 3.93-3.87 (m, 2H), 3.70-3.58 (m, 1H), 3.23-3.13 (m, 2H), 2.38 (s, 3H), 2.35-2.26 (m, 1H), 2.16-1.90 (m, 5H), 1.60-1.49 (m, 2H).

Example 113

[8-(2-Methyl-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a light yellow oil.

MS ISP (m/e): 401,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.73-8.60 (m, 1H), 8.52 (m, 1H), 8.39-8.37 (m, 1H), 7.80 (m, 1H), 7.72-7.70 (m, 1H), 7.63-7.61 (m, 1H), 6.95-6.90 (m, 1H), 6.41 (m, 1H), 4.63-4.61 (m, 1H), 4.36-4.32 (m, 2H), 4.02-3.93 (m, 1H), 3.24-3.14 (m, 2H), 2.65 (s, 3H), 2.37 (s, 3H), 2.27-2.22 (m, 2H), 1.60-1.47 (m, 2H).

Examples 114 and 115

[8-(3,4-Debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 8-(3,4-Debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 66, step a, the outcome� of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (see example 82A) at the stage. Specified in the title compound was obtained as a whitish solid substance.

MS ISP (m/e): 315,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.97-7.90 (m, 1H), 7.76-7.70 (m, 1H), 7.57-7.55 (m, 1H), 7.36-7.30 (m, 2H), 4.75 (bs, 2H).

b) 8-(3,4-Debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 81A, using 8-(3,4-debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. Specified in the title compound was obtained as a racemic mixture of diastereomers as a white solid.

MS ISP (m/e): 319,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.19-7.10 (m, 1H), 7.02-6.96 (m, 1H), 6.93-6.89 (m, 1H), 4.72-4.67 (m, 1H), 4.18 (bs, 2H), 4.12-4.07 (m, 1H), 2.47-2.39 (m, 1H), 2.29-2.12 (m, 3H).

c) 2-Bromo-8-(3,4-debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin

Was prepared analogously to example 66d, using 8-(3,4-debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. Specified in the title compound was obtained as a racemic mixture of diastereomers as a yellow oil.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.20-7.11 (m, 1H), 7.01-6.94 (m, 1H), 6.91-6.87 (m, 1H), 4.92-4.86 (m, 1H), 4.22-4.17 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.19 (m, 3H).

(d) [8-(3,4-Debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to n�the emer 66f, using 2-bromo-8-(3,4-debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine. Both diastereoisomer was shared by preparative HPLC (without establishing the configuration of diastereomers).

Example 114: diastereoisomer A (rat). Retention time 3.13 minutes (Gemini NX; 3 µm; 50×4.6 mm). A white solid substance.

MS ISP (m/e): 499,9 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.18-7.09 (m, 1H), 6.95-6.89 (m, 1H), 6.86-6.82 (m, 1H), 4.74-4.68 (m, 1H), 4.20-4.15 (m, 2H), 3.90-3.70 (m, 3H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.47-2.13 (m, 5H), 1.99-1.89 (m, 1H), 1.66-1.46 (m, 2H).

Example 115: diastereoisomer B (rat). Retention time 3,57 minutes (Gemini NX; 3 µm; 50×4.6 mm). A white solid substance.

MS ISP (m/e): 500,0 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.18-7.09 (m, 1H), 7.02-6.95 (m, 1H), 6.93-6.88 (m, 1H), 4.74-4.67 (m, 1H), 4.22-4.14 (m, 1H), 4.12-4.03 (m, 1H), 3.88-3.67 (m, 3H), 3.34-3.27 (m, 2H), 2.40 (s, 3H), 2.46-2.12 (m, 6H), 1.66-1.48 (m, 2H).

Examples 116 and 117

[8-(3,4-Debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 8-(3,4-Debtor-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 66A-C, based on 3-bromo-5-trifluoromethyl-pyridine-2-ylamine. Specified in the header connection received light gray solid.

MS ISP (m/e): 315,1 (84) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)8.63 (m, 1H), 7.98-7.91 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.64 (m, 1H), 7.36-7.30 (m, 1H), 4.67 (bs, 2H).

b) 8-(3,4-Debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

To a solution of 8-(3,4-differenl)-6-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg; 1,59 mmol) and magnesium (309 mg; 12.7 mmol) in methanol (80 ml) and THF (40 ml) was added iodine (2 mg; of 7.88 mmol), stirred for 10 minutes at room temperature, treated with ultrasound for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and dried over Na2SO4then was filtered, washed thoroughly with THF and the solvent evaporated. The crude substance was purified flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a racemic mixture of diastereomers as a white solid (324 mg; 64%).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.21-7.12 (m, 1H), 7.10-7.03 (m, 1H), 7.01-6.96 (m, 1H), 4.38-4.32 (m, 1H), 4.15 (br, 2H), 4.13-4.04 (m, 2H), 3.06-2.93 (m, 1H), 2.57-2.50 (m, 1H), 2.04-1.91 (m, 1H).

c) [8-(3,4-Debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 8-(3,4-debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. CIS - and TRANS-isomers were separated preparative HPLC.

Example 116: (6R,8R)/(6S,8S)-racemate. Time�of eriane 3.2 minutes (Gemini NX; 3 mm; 50×4.6 mm). White foam.

MS ISP (m/e): 500,0 (100) [(M+H)+].

1H NMR (CDCl3, 600 MHz): 6 (mn-1)=7.18-7.15 (m, 1H), 7.08-7.05 (m, 1H), 7.00-6.98 (m, 1H), 4.40-4.37 (m, 1H), 4.12-4.04 (m, 3H), 3.85-3.82 (m, 2H), 3.71-3.66 (m, 1H), 3.32-3.27 (m, 2H), 3.03-2.97 (m, 1H), 2.55-2.52 (m, 1H), 2.40 (s, 3H), 2.18-2.15 (m, 2H), 2.02-1.95 (m, 1H), 1.61-1.52 (m, 2H).

Example 117: (6R,8S)/(6S,8R)-racemate. Retention time of 3.4 minutes (Gemini NX; 3 µm; 50×4.6 mm). White foam.

MS ISP (m/e): 500,0 (100) [(M+H)+].

1H NMR (CDCl3, 600 MHz): δ (mn-1)=7.19-7.13 (m, 1H), 6.91-6.86 (m, 1H), 6.81 (m, 1H), 4.39-4.33 (m, 2H), 4.19-4.04 (m, 2H), 3.88-3.84 (m, 2H), 3.73 (m, 1H), 3.34-3.27 (m, 2H), 2.94 (m, 1H), 2.41 (s, 3H), 2.32-2.18 (m, 4H), 1.62-1.57 (m, 2H).

Example 118

[1-(5-Methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 430,0 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.35 (m, 1H), 7.60-7.52 (m, 1H), 7.50-7.47 (m, 1H), 7.13-7.05 (m, 1H), 6.93-6.88 (m, 1H), 4.57 (m, 1H), 3.98-3.92 (m, 2H), 3.87-3.83 (m, 1H), 3.28-3.19 (m, 2H), 2.39 (s, 3H), 2.25-2.19 (m, 2H), 1.64-1.55 (m, 2H).

Example 119

[8-(3,4-Dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a light brown oil.

MS ISP (m/e): 454,3/456,3 (100/78) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (m�n -1)=8.51 (m, 1H), 8.35-8.33 (m, 1H), 8.15 (m,1H), 7.86-7.82 (m, 1H), 7.56-7.51 (m, 2H), 6.92-6.88 (m, 1H), 6.41 (m, 1H), 4.55-4.52 (m, 1H), 4.37-4.32 (m, 2H), 4.01-3.92 (m, 1H), 3.23-3.14 (m, 2H), 2.37 (s, 3H), 2.27-2.22 (m, 2H), 1.57-1.47 (m, 2H).

Example 120

[1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 440,3 (75) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52-8.51 (m, 1H), 8.36-8.34 (m, 1H), 7.76-7.71 (m, 2H), 7.51-7.49 (m, 1H), 6.93-6.88 (m, 1H), 6.42 (m, 1H), 4.57-4.54 (m, 1H), 4.37-4.33 (m, 2H), 4.02-3.92 (m, 1H), 3.24-3.14 (m, 2H), 2.37 (s, 3H), 2.28-2.22 (m, 2H), 1.60-1.47 (m, 2H).

Example 121

[8-(2-Fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): of 405.4 (59) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.42-8.40 (m, 1H), 8.34-8.32 (m, 1H), 7.84-7.82 (m, 1H), 7.73 (m, 1H), 7.69-7.66 (m, 1H), 6.97-6.92 (m, 1H), 6.42 (m, 1H), 4.59-4.56 (m, 1H), 4.37-4.33 (m, 2H), 4.03-3.92 (m, 1H), 3.23-3.15 (m, 2H), 2.37 (s, 3H), 2.28-2.22 (m, 2H), 1.60-1.49 (m, 2H).

Example 122

[8-(2-Fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

a) 8-Phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see 66b); 500 mg; 2.35 mmol), phenol (442 mg; 4,69 mmol), copper iodide(I) (44,7 mg; 235 mmol), picolinic acid (57.8 mg, 469 mmol) and tribasic potassium phosphate (1,49 g; to 7.04 mmol) in DMSO (10 ml) was heated to 120°C. After 12 hours was added an additional amount of phenol (442 mg; 4,69 mmol), copper iodide(I) (44,7 mg; 235 mmol), picolinic acid (57.8 mg, 469 mmol) and tribasic potassium phosphate (1,49 g; to 7.04 mmol) and stirred at 120°C for 18 hours. To the reaction mixture were added water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent evaporated. The crude substance was purified by prep. HPLC. Specified in the title compound was obtained as a whitish solid (200 mg; 38%).

MS ISP (m/e): of 227.2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.10-8.07 (m, 1H), 7.42-7.37 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.11 (2H), 6.78-6.67 (m, 2H), 4.53 (bs, 2H).

(b) [8-(2-Fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

A solution of 8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (80 mg; 354 µmol), 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b); 101 mg; 530 μmol) and isopropylate titanium(IV) (302 mg; 314 ml, 1.06 mmol) in 1,2-dichloroethane (5 ml) was heated to 85°C for 12 hours. Added additional amount of isopropylate titanium(IV) (302 mg; 314 ml, 1.06 mmol) and the mixture was stirred at 85°C teche�their next 8 hours. The reaction mixture was cooled to 50°C, was added NaBH4(53.5 mg, of 1.41 mmol) and ethanol (3 ml) and the reaction mixture was stirred at 50°C for one hour. The solvent was evaporated, the residue was extracted with 2 n solution of Na2CO3and ethyl acetate. The organics were combined, dried over Na2SO4, filtered and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as white solid (27 mg; 19%).

MS ISP (m/e): RUR 402.4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.11-8.09 (m, 1H), 7.42-7.37 (m, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m, 2H), 6.75-6.64 (m, 2H), 6.41 (m, 1H), 4.51-4.48 (m, 1H), 4.35-4.31 (m, 2H), 4.05-3.96 (m, 1H), 3.21-3.13 (m, 2H), 2.36 (s, 3H), 2.26-2.22 (m, 2H), 1.57-1.45 (m, 2H).

Example 123

18-(3-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as an orange foam.

MS ISP (m/e): 420,3/422,3 (100/38) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.35-8.32 (m, 1H), 7.99 (m, 1H), 7.87-7.84 (m, 1H), 7.53-7.51 (m, 1H), 7.45-7.36 (m, 2H), 6.92-6.87 (m, 1H), 6.41 (m, 1H), 4.54-4.51 (m, 1H), 4.36-4.31 (m, 2H), 4.02-3.92 (m, 1H), 3.23-3.14 (m, 2H), 2.36 (s, 3H), 2.27-2.22 (m, 2H), 1.56-1.47 (m, 2H).

Example 124

3-{2-[1-(6-Methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile

Was prepared analogously to example 94. Specified in the title compound was obtained as an orange foam.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.37-8.36 (m, 1H), 8.22-8.19 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.53 (m, 2H), 6.95-6.91 (m, 1H), 6.41 (m, 1H), 4.55-4.53 (m, 1H), 4.37-4.32 (m, 2H), 4.01-3.92 (m, 1H), 3.23-3.15 (m, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 2H), 1.60-1.48 (m, 2H).

Example 125

[8-(4-tert-Butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as an orange foam.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.31-8.29 (m, 1H), 7.88-7.85 (m, 2H), 7.53-7.49 (m, 3H), 6.90-6.85 (m, 1H), 6.40 (m, 1H), 4.52-4.49 (m, 1H), 4.34-4.29 (m, 2H), 3.99-3.95 (m, 1H), 3.23-3.15 (m, 2H), 2.36 (s, 3H), 2.26-2.21 (m, 2H), 1.55-1.45 (m, 2H), 1.35 (s, 9H).

Example 126

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine

Was prepared analogously to example 122, using 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (see example 1C) at the stage (b). Specified in the title compound was obtained as white solids.

MS ISP (m/e): 408,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.10-8.08 (m, 1H), 7.42-7.37 (m, 2H). 7.23-7.18 (m, 1H), 7.14-7.12 (m, 2H), 6.75-6.65 (m, 2H), 4.52-4.49 (m, 1H), 4.04-3.95 (m, 1H), 3.91-3.87 (m, 2H), 3.39-3.30 (m, 2H), 2.42 (s, 3H), 2.28-2.23 (m, 2H), 1.72-1.60 (m, 2H).

Example 127

N-(1-(2-Chloropyrid�n-4-yl)piperidine-4-yl)-8-(5-herperidin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66 using 1-(2-chloropyridin-4-yl)piperidine-4-amine dihydrochloride (see example 169b) at the stage (e). Specified in the title compound was obtained as a light yellow oil.

MS ISP (m/e): 424,2/426,3 (100/27) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.93-8.87 (m, 1H), 8.58-8.57 (m, 1H), 8.39-8.35 (m, 2H), 8.05-8.02 (m, 1H), 7.57-7.50 (m, 1H), 7.01-6.95 (m, 1H), 6.70-6.69 (m. 1H), 6.62-6.59 (m, 1H), 4.56-4.53 (m, 1H), 4.02-3.93 (m, 1H), 3.88-3.83 (m, 2H), 3.20-3.11 (m, 2H), 2.30-2.26 (m, 2H), 1.69-1.57 (m, 2H).

Example 128

8-(3,5-Bis(trifluoromethyl)phenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 127. Specified in the title compound was obtained as orange solids.

MS ISP (m/e): 541,3/543,3 (100/39) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.56 (m, 2H), 8.41-8.38 (m, 1H), 8.04-8.02 (m, 1H), 7.90 (m, 1H), 7.66-7.64 (m, 1H), 6.99-6.94 (m, 1H), 6.69 (m, 1H), 6.62-6.59 (m, 1H), 4.59-4.56 (m, 1H), 4.00-3.92 (m, 1H), 3.89-3.84 (m, 2H), 3.17-3.08 (m, 2H), 2.31-2.25 (m,2H), 1.65-1.60 (m,2H).

Example 129

4-(2-(1-(2-Chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile

Was prepared analogously to example 127. Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 430,3/432,3 (100/35) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.39-8.36 (m, 1H), 8.13-8.10 (m, 2H), 8.03-8.01 (m, 1H), 7.79-7.76 (m, 2H), 7.59-7.56 (m, 1H), 6.97-6.92 (m, 1H), 6.68 (m, 1H), 6.61-6.58 (m, 1H), 4.57-4.55 (m, 1H), 3.99-3.91 (m, 1H), 3.86-3.81 (m, 2H), 3.18-3.09 (m, 2H), 2.28-2.22 (m, 2H), 1.66-1.55 (m, 2H).

Example 130

[8-(2,3-Dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 444,2/446,1 (100/49) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.39-8.37 (m, 1H), 7.55-7.52 (m, 1H), 7.41-7.36 (m, 2H), 7.33-7.28 (m, 1H), 6.92-6.88 (m, 1H), 4.53-4.50 (m, 1H), 3.97-3.90 (m, 2H), 3.88-3.78 (m. 1H), 3.27-3.18 (m, 2H), 2.39 (s, 3H), 2.24-2.19 (m, 2H), 1.65-1.53 (m, 2H).

Example 131

[8-(3-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 94. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 438,2/440,3 (100/37) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.37-8.34 (m, 1H), 7.83-7.77 (m, 1H), 7.51-7.49 (m, 1H), 7.28-7.22 (m, 2H), 6.92-6.87 (m, 1H), 6.40 (m, 1H), 4.51-4.49 (m, 1H), 4.34-4.28 (m, 2H), 3.99-3.88 (m, 1H), 3.22-3.13 (m, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 2H), 1.57-1.46 (m, 2H).

Example 132

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 127. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 435,3/437,3 (100/31) [(M+N)+].

1H NMR CDCl 3, 300 MHz): δ (mn-1)=8.33-8.30 (m, 1H), 8.03-8.01 (m, 1H), 7.56-7.49 (m, 3H), 7.43-7.37 (m, 1H), 6.97-6.93 (m, 1H), 6.92-6.87 (m, 1H), 6.68-6.67 (m, 1H), 6.61-6.58 (m, 1H), 4.54-4.52 (m, 1H), 3.99-3.91 (m, 1H), 3.87 (s, 3H), 3.85-3.79 (m, 2H), 3.18-3.09 (m, 2H), 2.28-2.22 (m, 2H), 1.65-1.53 (m, 2H).

Example 133

8-(3-Chlorophenoxy)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 122, using 1-(2-chloropyridin-4-yl)piperidine-4-it (see example 232b) on stage b). Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 454,8 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.17-8.15 (m, 1H), 8.03-8.01 (m, 1H), 7.33-7.28 (m, 1H), 7.18-7.15 (m, 1H), 7.09-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.90-6.88 (m, 1H), 6.77-6.72 (m, 1H), 6.68-6.67 (m, 1H), 6.61-6.58 (m, 1H), 5.12-5.10 (m, 1H), 3.98-3.89 (m, 1H), 3.83-3.79 (m, 2H), 3.19-3.10 (m, 2H), 2.25-2.19 (m, 2H), 1.67-1.55 (m, 2H).

Example 134

(2'-Chloro-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-[8-(4-triptoreline-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 127. Specified in the title compound was obtained as a whitish solid substance.

MS ISP (m/e): 489,2/491,2 (100/42) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.33 (m, 1H), 8.04-8.02 (m, 1H), 7.96-7.93 (m, 2H), 7.52-7.50 (m, 1H), 7.35-7.32 (m, 2H), 6.95-6.91 (m, 1H), 6.68 (m, 1H), 6.62-6.59 (m, 1H), 4.94-4.91 (m, 1H), 3.98-3.90 (m, 1H), 3.86-3.79 (m, 2H), 3.21-3.12 (m, 2H), 2.27-2.22 (m, 2H), 1.68-1.55 (m, 2H).

Example 135

3-(2-(1-(2-Chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]feast�DIN-8-yl)benzonitrile

Was prepared analogously to example 127. Specified in the title compound was obtained as light yellow solids.

MS ISP (m/e): 430,3/432,4 (100/31) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.36 (m, 2H), 8.22-8.19 (m, 1H), 8.03-8.01 (m, 1H), 7.70-7.67 (m, 1H), 7.62-7.54 (m, 2H), 6.96-6.91 (m, 1H), 6.69-6.68 (m, 1H), 6.61-6.59 (m, 1H), 4.59-4.56 (m, 1H), 4.00-3.90 (m, 1H), 3.86-3.82 (m, 2H), 3.19-3.10 (m, 2H), 2.28-2.23 (m, 2H), 1.64-1.55 (m, 2H).

Example 136

[8-(4-Chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 126. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 442,3/444,2 (100/44) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.13-8.11 (m, 1H), 7.36-7.33 (m, 2H), 7.07-7.04 (m, 2H), 6.80-6.77 (m, 1H), 6.72-6.67 (m, 1H), 4.54-4.51 (m, 1H), 4.01-3.87 (m, 3H), 3.39-3.29 (m, 2H), 2.42 (s, 3H), 2.27-2.22 (m, 2H), 1.71-1.62 (m, 2H).

Example 137

4-(2-(1-(6-Methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile

Was prepared analogously to example 94. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 411,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.39-8.37 (m, 1H), 8.13-8.11 (m, 2H), 7.79-7.76 (m, 2H), 7.59-7.50 (m, 1H), 6.96-6.91 (m, 1H), 6.41 (m, 1H), 4.58-4.55 (m, 1H), 4.36-4.32 (m, 2H), 4.01-3.92 (m, 1H), 3.23-3.14 (m, 2H), 2.37 (s, 3H), 2.27-2.21 (m, 2H), 1.58-1.46 (m, 2H).

Example 138

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 476,2 (56)[(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.93-7.89 (m, 2H), 7.57-7.51 (m, 2H), 7.25 (m, 1H), 6.94-6.90 (m, 1H), 4.55-4.53 (m, 1H), 4.01-3.89 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.30-2.25 (m, 2H), 1.74-1.62 (m, 2H).

Example 139

8-(2,3-Dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 460,2/462,2/464,2 (100/71/13) [(M+H)+].

1H NMR (CDCb, 300 MHz): δ (mn-1)=8.39-8.37 (m, 1H), 7.56-7.52 (m, 1H), 7.40-7.36 (m, 2H), 7.33-7.28 (m, 1H), 6.93-6.88 (m, 1H), 4.57-4.54 (m, 1H), 3.95-3.84 (m, 3H), 3.39-3.30 (m, 2H), 2.41 (s, 3H), 2.27-2.21 (m, 2H), 1.70-1.61 (m, 2H).

Example 140

8-(3,4-Dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 460,3/462,2 (100/68) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 8.15-8.14 (m, 1H), 7.85-7.82 (m. 1H), 7.56-7.51 (m, 2H), 6.93-6.89 (m, 1H), 4.58-4.55 (m, 1H), 3.99-3.89 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m,2H), 1.74-1.64 (m, 2H).

Example 141

8-(3-Chlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 426,2/428,3 (100/42) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.32 (m, 1H), 7.99 (m, 1H), 7.87-7.84 (m, 1H), 7.54-7.51 (m, 1H), 7.45-7.36 (m, 2H), 6.93-6.88 (m, 1H), 4.56-4.53 (m, 1H). 4.00-3.88 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 2H), 1.74-1.61 (m, 2H).

Example 142

[8-(3-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a light brown oil.

MS ISP (m/e): 410,2/412,3 (100/33) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.32 (m, 1H), 7.99 (m,1H), 7.87-7.84 (m, 1H), 7.54-7.51 (m, 1H), 7.42-7.36 (m, 2H), 6.92-6.88 (m, 1H), 4.55-4.53 (m, 1H), 4.00-3.81 (m, 3H), 3.29-3.20 (m, 2H), 2.40 (s, 3H), 2.27-2.22 (m, 2H), 1.69-1.57 (m, 2H).

Example 143

[8-(3,4-Debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

a) 8-(3,4-Differenl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously to example 66A-C); 500 mg; 2.03 mmol) in methanol (60 ml) and THF (30 ml) was added magnesium (395 m�; The 16.2 mmol) and iodine (3 mg). After 1.5 hours at room temperature was added an additional amount of magnesium (395 mg; 16,2 mmol) and the reaction mixture was stirred at 50°C for 1 hour. Once again I added magnesium (148 mg; 6,09 mmol) and stirred at room temperature for 4 hours. The solvent was evaporated, the residue was dissolved in THF and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (silica gel; 100 g; 0% to 15% MeOH/NH3(9:1) to dichloromethane; 45 minutes). Specified in the title compound was obtained as white solid (226 mg; 45%).

MS ISP (m/e): 251,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.16-7.07 (m, 1H), 7.01-6.94 (m, 1H), 6.91-6.87 (m, 1H), 4.12-4.05 (m, 5H), 2.33-2.24 (m, 1H), 2.20-1.86 (m, 3H).

(b) [8-(3,4-Debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

A solution of 1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-it (79,6 mg; 440 mmol) and 8-(3,4-differenl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (110 mg; 440 mmol) in toluene (5 ml) and acetic acid (280 ml) was heated to a temperature of delegatie in the trap Dean-stark.

The reaction mixture was cooled to room temperature, was added ethanol (3 ml), then sodium borohydride (66,5 mg; 61,9 µl; 1,76 mmol). The reaction mixture was stirred at 50°C for 3 hours. Added additional Koli�the degree of sodium borohydride (66,5 mg; 61,9 ml, of 1.76 mmol) and stirred at 50°C for 3 hours. To the reaction mixture were added water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 100 g; 0% to 15% MeOH in dichloromethane; 40 minutes). Specified in the title compound was obtained as white solid (32,8 mg; 18%).

MS ISP (m/e): 416,3 (69) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.16-7.07 (m, 1H), 7.00-6.93 (m, 1H), 6.91-6.87 (m, 1H), 4.12-4.01 (m, 4H), 3.93-3.87 (m, 2H), 3.72-3.60 (m, 1H), 3.23-3.13 (m, 2H), 2.38 (s, 3H), 2.32-2.23 (m, 1H), 2.18-1.88 (m, 5H), 1.58-1.48 (m, 2H).

Example 144

3-(2-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile

Was prepared analogously to example 66. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 417,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.36 (m, 2H), 8.22-8.19 (m, 1H), 7.71-7.67 (m, 1H), 7.62-7.54 (m, 2H), 6.97-6.92 (m, 1H), 4.56-4.54 (m, 1H), 4.00-3.89 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.30-2.25 (m, 2H), 1.74-1.62 (m, 2H).

Example 145

18-(3,4-Dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as yellow solids.

MS ISP (m/e): 444,3/446,2 (100/54) (M+H) +].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.32 (m, 1H), 8.15 (m, 1H), 7.85-7.82 (m, 1H), 7.56-7.51 (m, 2H), 6.92-6.88 (m, 1H), 4.59-4.57 (m, 1H), 3.99-3.83 (m, 3H), 3.28-3.20 (m, 2H), 2.40 (s, 3H), 2.26-2.22 (m, 2H), 1.69-1.57 (m, 2H).

Example 146

[8-(5-Dimethylamino-2-nitro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow oil.

MS ISP (m/e): 480,3 (80) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.33-8.31 (m, 1H), 8.18-8.14 (m, 1H), 7.33-7.31 (m, 1H), 6.90-6.85 (m, 1H), 6.70-6.66 (m, 1H), 6.54-6.53 (m, 1H), 4.49-4.47 (m, 1H), 3.87-3.84 (m, 3H), 3.37-3.28 (m, 2H), 3.10 (s, 6H), 2.41 (s, 3H), 2.23-2.18 (m, 2H), 1.66-1.53 (m, 2H).

Example 147

[8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 528,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.56 (s, 2H), 8.40-8.38 (m, 1H), 7.90 (m, 1H), 7.66-7.64 (m, 1H), 6.99-6.94 (m. 1H), 4.58-4.55 (m. 1H), 4.00-3.91 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.32-2.27 (m, 2H), 1.76-1.63 (m, 2H).

Example 148

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(4-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the header connection�Uchali in the form of a light yellow foam.

MS ISP (m/e): 476,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.32 (m, 1H), 8.01-7.98 (m, 2H), 7.53-7.50 (m, 1H), 7.35-7.32 (m, 2H), 6.94-6.89 (m, 1H), 4.54-4.51 (m, 1H), 4.00-3.88 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.73-1.60 (m, 2H).

Example 149

3-(2-(1-(5-Methyl-1,3,4-oxadiazol-2-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile

Was prepared analogously to example 85. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 401,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.36 (m, 2H), 8.23-8.19 (m, 1H), 7.70-7.67 (m, 1H), 7.62-7.52 (m, 2H), 6.96-6.91 (m, 1H), 4.55-4.52 (m, 1H), 4.01-3.83 (m, 3H), 3.29-3.20 (m, 2H), 2.40 (s, 3H), 2.27-2.22 (m, 2H), 1.70-1.61 (m, 2H).

Example 150

N-(1-(5-Methyl-1,3,4-oxadiazol-2-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 460,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.93-7.90 (m, 2H), 7.56-7.49 (m, 2H), 7.24 (m, 1H), 6.94-6.89 (m, 1H), 4.53-4.50 (m, 1H), 4.01-3.84 (m, 3H), 3.28-3.19 (m, 2H), 2.40 (s, 3H), 2.28-2.22 (m, 2H), 1.69-1.56 (m, 2H).

Example 151

[8-(3-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as same�the foam.

MS ISP (m/e): 422,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.32-8.30 (m, 1H), 7.55-7.49 (m, 3H), 7.43-7.37 (m, 1H), 6.97-6.93 (m, 1H), 6.92-6.87 (m, 1H), 4.55-4.52 (m, 1H), 4.00-3.86 (m, 3H), 3.87 (s, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.73-1.60 (m, 2H).

Example 152

[8-(3-Chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 2-Bromo-8-(3-chlorphenoxy)-[1,2,4]triazolo[1,5-a]pyridin

The copper bromide(II) (365 mg; 1,63 mmol) and tert-butyl nitrite (168 mg; 195 µl; 1,63 mmol) was dissolved in acetonitrile (8.0 ml) and heated to 60°C. 8-(3-Chlorphenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained as in example 122A); 387 mg; 1,48 mmol) was added in small portions, heated to 75°C and stirred for 2 hours.

To the reaction mixture were added water and the aqueous phase was extracted with methylene chloride. The combined organic layers were dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (silica gel; 70 g; 0% to 100% ethyl acetate in toluene; 35 minutes). Specified in the title compound was obtained as a light red solid (142 mg; 30%).

MS ISP (m/e): 324,2/326,1 (77/100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.32 (m, 1H), 7.38-7.33 (m, 1H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.03 (m, 1H), 6.96-6.90 (m, 2H).

(b) [8-(3-Chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-yl]-amine

Was prepared analogously to example 66f, using 2-bromo-8-(3-chlorphenoxy)-[1,2,4]triazolo[1,5-a]pyridine. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 442,3/444,3 (100/40) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.17-8.14 (m, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.09-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.88-6.85 (m, 1H), 6.75-6.70 (m, 1H), 4.62-4.60 (m, 1H), 4.00-3.86 (m, 3H), 3.38-3.29 (m, 2H), 2.41 (s, 3H), 2.27-2.22 (m, 2H), 1.72-1.59 (m, 2H).

Example 153

N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 143, using 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 444,3 (64) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (m, 1H), 6.96-6.87 (m, 1H), 6.78-6.70 (m, 1H), 6.38 (m, 1H), 4.38-4.34 (m, 1H), 4.30-4.24 (m, 2H), 4.12-4.07 (m, 2H), 4.01-3.98 (m, 1H), 3.79-3.67 (m, 1H), 3.17-3.08 (m, 2H), 2.35 (s, 3H), 2.32-2.25 (m, 1H), 2.18-1.91 (m,5H), 1.50-1.35 (m, 2H).

Example 154

[8-(3-Chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66f, using 2-bromo-8-(3-chlorphenoxy)-[1,2,4]triazolo[1,5-a]pyridine (see example 152a) and 1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-ylamine (see example 40b). Specified in the title compound was obtained as yellow oil.

MS ISP (m/e): 426,1 (59) (M+H) +].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.16-8.14 (m, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.09-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.88-6.85 (m, 1H), 6.75-6.70 (m, 1H), 4.58-4.55 (m, 1H), 3.98-3.85 (m, 3H), 3.26-3.17 (m, 2H), 2.39 (s, 3H), 2.24-2.19 (m, 2H), 1.67-1.54 (m, 2H).

Example 155

[8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 85. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 512,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.57 (m, 2H), 8.40-8.39 (m, 1H), 7.91 (m, 1H), 7.66-7.64 (m, 1H), 6.99-6.94 (m, 1H), 4.58-4.56 (m, 1H), 4.03-3.85 (m, 3H), 3.27-3.19 (m, 2H), 2.41 (s, 3H), 2.29-2.25 (m, 2H), 1.71-1.64 (m, 2H).

Example 156

[8-(5-Chloro-2-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 444,3/446,2 (100/27) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.37-8.34 (m, 1H), 7.86-7.83 (m, 1H), 7.54-7.50 (m, 1H), 7.37-7.32 (m, 1H), 7.18-7.12 (m, 1H), 6.93-6.88 (m, 1H), 4.55-4.52 (m, 1H), 3.98-3.87 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.72-1.59 (m, 2H).

Example 157

[8-(3-Dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 1-(6-methylpyrimidin-4-yl)PI�uridin-4-it (see example 93b) and 6-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 66A-C). Specified in the title compound was obtained as a white foam. MS ISP (m/e): 429,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (m, 1H), 8.31-8.29 (m, 1H), 7.54-7.52 (m, 1H), 7.37-7.32 (m, 2H), 7.23-7.21 (m, 1H), 6.90-6.85 (m, 1H), 6.81-6.78 (m, 1H), 6.41 (m, 1H), 4.50-4.47 (m, 1H), 4.35-4.31 (m, 2H), 4.04-3.93 (m, 1H), 3.77-3.73 (m, 2H), 3.21-3.13 (m, 2H), 3.01 (s, 6H), 2.36 (s, 3H), 2.27-2.22 (m, 2H).

Example 158

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(6-methylpyridine-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 407,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=9.01-9.00 (m, 1H), 8.34-8.32 (m, 1H), 8.28-8.24 (m, 1H), 7.55-7.53 (m, 1H), 7.30-7.26 (m, 1H), 6.94-6.90 (m, 1H), 4.52-4.49 (m, 1H), 4.01-3.88 (m, 3H), 3.40-3.31 (m, 2H), 2.62 (s, 3H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.73-1.61 (m, 2H).

Example 159

7-Methoxy-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-4-phenylbenzo[d]thiazol-2-amine

a) 2-Chloro-7-methoxy-4-phenylbenzo[d]thiazole

A solution of copper chloride(II) (78,7 mg; 585 μmol) and tert-nitrite (67,1 mg; 77.6 per ml, 585 mmol) in acetonitrile (5 ml) was heated to 60°C. 7-Methoxy-4-phenylbenzo[d]thiazol-2-amine (100 mg, 390 μmol) was added in small portions. Upon completion of addition the reaction mixture was heated to 60°C for t�ex hours. The reaction mixture was cooled to room temperature, was added water and was extracted with diethyl ether. The organics were combined, dried over sodium sulfate, filtered and the solvents evaporated under reduced pressure, obtaining specified in the title compound as a light brown oil (100 mg; 93%).

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.72 (d, 2H), 7.65 (d, 1H), 7.49 (t, 2H), 7.39 (t, 1H), 7.25 (d, 1H), 4.02 (s, 3H).

b) 7-Methoxy-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-4-phenylbenzo[d]thiazol-2-amine

A solution of 2-chloro-7-methoxy-4-phenylbenzo[d]thiazole (100 mg; 363 mmol), 1-(6-methylpyrimidin-4-yl)piperidine-4-amine dihydrochloride (115 mg; 435 mmol) and substrate Hunya (187 mg; 253 µl; 1,45 mmol) in dioxane (2 ml) was heated to 160°C in a microwave for 30 minutes. Was added N-methyl-2-pyrrolidinone (0.5 ml) and the reaction mixture was heated to 200°C in a microwave for 2 hours. Added water and the reaction mixture was twice extracted with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was evaporated in vacuum and the residue was purified column chromatography on silica gel, using a gradient from dichloromethane to a mixture of dichloro methane/methanol 9:1 (vol./about.) as eluent, obtaining mentioned in the title compound in the form of light�about brown solid (40 mg; 25%).

MS ISP (m/e): RR 432.4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 7.77 (d, 2H), 7.43-7.29 (m, 4H), 6.72 (d, 1 H), 6.39 (s, 1 H), 5.53 (br s, 1 H), 4.31 (br d, 2H), 3.98 (s, 3H), 3.79 (m, 1 H), 3.10 (m, 2H), 2.36 (s, 3H), 2.20 (br d, 2H), 1.50 (m, 2H).

Example 160

N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-8-morpholino-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 4-(2-Nitropyridine-3-yl)morpholine

To a solution of 3-bromo-2-nitropyridine (207 mg; 1 mmol) in DMSO (2 ml) at room temperature under stirring and in a nitrogen atmosphere was added morpholine (95,8 mg; 95.8 per μl; 1.1 mmol), the iodide of tetrabutylammonium (18,5 mg; 50,0 mmol) and potassium carbonate (152 mg; 1.1 mmol). The reaction mixture was stirred at 80°C overnight. Added water and the aqueous phase was twice extracted with diethyl ether. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as yellow oil (57 mg; 27%) after column chromatography on silica gel using a gradient mixture of heptane/ethyl acetate 4:1 to 1:1 (vol./about.) as eluent.

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.45 (d, 1H), 7.96 (d, 1H), 7.71 (dd, 1H), 3.67 (t, 4H), 3.00 (t, 4H).

b) 3-Morpholinopropan-2-amine

To a solution of 4-(2-nitropyridine-3-yl)morpholine (155 mg; 741 μmol) in �dilacerate was added Pd/C (10%; 15.5 mg, 146 μmol) and the reaction mixture was gidrirovanie in an atmosphere of hydrogen for 3 hours at room temperature. The catalyst was filtered off, washed with ethyl acetate and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as purple solid (128 mg; 96%).

MS ISP (m/e): 180,1 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.66 (d, 1H), 7.14 (d, 1H), 6.54 (dd, 1H), 5.59 (br s, 2H), 3.75 (t, 4H), 2.79 (t, 4H).

c) 8-Morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 1e-f, based on 3-morpholinopropan-2-amine. The crude product was purified column chromatography on silica gel, using ethyl acetate as eluent. Specified in the title compound was obtained as a light brown solid (yield 85% over 2 stages).

MS ISP (m/e): 220,2 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.10 (d, 1H), 6.76 (t, 1H), 6.68 (d, 1H), 5.92 (br s, 2H), 3.77 (t, 4H), 3.38 (t, 4H).

d) N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-8-morpholino-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1h, based on 8-morpholine-4-yl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as white solid (yield 34%) after column chromatography on silica gel using a gradient� from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 395,2 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.36 (s, 1H), 8.18 (d, 1H), 6.77-6.71 (m, 3H), 6.60 (d, 1H), 4.27 (br d, 2H), 3.77 (br s, 5H), 3.39 (br s, 4H), 3.10 (t, 2H), 2.25 (s, 3H), 1.97 (br d, 2H), 1.42 (br q, 2H).

Example 161

tert-Butyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

a) 8-Bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 1e-f, based on 2-amino-3-bromo-5-methylpyridine. The crude product was purified by crystallization from hot EtOAc. Most of the product was insoluble and to precipitate during processing. This substance was filtered, washed with water and CH2Cl2, dried and combined with the rest of the substance. Specified in the title compound was obtained as white solid (yield 73% over two steps).

MS ISP (m/e): 227,1/229,2 (100/84) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.43 (s, 1H), 7.63 (s, 1H), 6.13 (br s, 2H), 2.27 (s, 3H).

b) tert-Butyl-4-(2-amino-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (1.14 g; 5 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2,39 g; 7.5 mmol), dichlormethane adduct dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (204 mg; 250 �KMOL) and water solution PA 2CO3(2 n; 12.5 ml; 25 mmol) in dioxane (50 ml) was stirred at 110°C over night. The reaction mixture was diluted with water and was extracted with twice tO. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, using tO as eluent. After stirring with diethyl ether, filtration and drying were receiving specified in the title compound as a light yellow crystalline solid (1,54 g; 93%).

MS ISP (m/e): 330,1 (100) [(M+H)+], 274,1 (87), 230,3 (23), 201,3 (20).

c) tert-Butyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Was prepared analogously to example 1h, based on tert-butyl-4-(2-amino-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate and 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as pale-yellow solids (yield 32%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 505,3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.37 (s, 2H), 7.26 (br s, 2H), 6.74 (s, 1H), 6.60 (d, 1H) 4.28 (br d, 2H), 4.07 (br s, 2H), 3.79 (br m, 1H), 3.56 (t, 2H), 3.11 (t, 2H), 2.57 (br s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.97 (br d, 2H), 1.43 (br s, 11H).

Example 162

8-Cyclohexenyl-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 8-Cyclohexenyl-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 160b, on the basis of 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Specified in the title compound was obtained as a light brown solid (yield 63%) after column chromatography on silica gel, using ethyl acetate as eluent.

MS ISP (m/e): 229,3 (100) [(M+H)+].

b) 8-Cyclohexenyl-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1h, based on 8-cyclohexenyl-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as a yellow viscous oil (yield 17%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 404,6 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.00 (s, 1H). 7.12 (s, 1H), 7.04 (t, 1H), 6.41 (s, 1H), 4.43-4.29 (m, 2H), 3.95 (m, 1H), .21 (t, 2H), 2.54 (br s, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 2.28 (m, 2H), 1.83 (m, 2H), 1.45-1.78 (m, 6H).

Example 163

tert-Butyl-3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl

(a) [3-(2-Amino-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-carbamino acid tert-butyl ester

Was prepared analogously to example 160b, on the basis of 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 3-((tert-butoxycarbonylamino)methyl)-phenylboronic acid. Specified in the title compound was obtained as a whitish solid (yield 99%) after precipitation from diethyl ether.

MS ISP (m/e): 354,4 (80) [(M+H)+], 298,4 (100), 237,2 (99).

b) tert-Butyl-3-(2-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl

A solution of copper bromide(II) (213 mg; 955 mmol) and mpem-nitrite (109 mg; 127 µl; 955 mmol) in acetonitrile (3.2 ml) was heated to 60°C. was Added tert-butyl-3-(2-amino-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzyl-carbamate (225 mg; 637 mmol) in small portions. Upon completion of addition the reaction mixture was heated to 75°C for two hours. The reaction mixture was cooled to room temperature, was added water and was extracted with methylene chloride. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvents evaporated under reduced �the force, receiving specified in the title compound as a light yellow solid (114 mg; 43%) after column chromatography on silica gel using a gradient from heptane to a mixture of heptane/ethyl acetate 1:1 (vol./about.) as eluent.

MS ISP (m/e): 417,2/419,1 (75/87) [(M+N)+], 361,1/363,0 (94/100).

c) tert-Butyl-3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl

A solution of 1-(6-methylpyrimidin~4-yl)piperidine-4-amine (52.5 mg, 273 mmol), tert-butyl-3-(2-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl (114 mg; 273 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.6 mg, 21.9 mmol), chloroform adduct of Tris(dibenzylideneacetone)diplegia(0) (11.3 mg, 10.9 μmol) and sodium phenolate (50,1 mg; 410 μmol) in dioxane (Almost degassed three times and the reaction was carried out at 140°C. in a nitrogen atmosphere in a microwave oven for 1 hour. Specified in the title compound was obtained as a light yellow solid (46 mg; 32%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 529,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.13 (s, 1H), 7.85 (d, 1H), 7.82 (s, 1H), 7.42 (t, 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.41 (s, 1H), 4.92 (brs, 1H), 4.47 (d, 1H), 4.40-4.25 (m, 4H), 3.95 (m, 1H), 3.19 (t, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.25 (br d, 2H), 1.701.46 (m, 2H), 1.46 (s, 9H).

Example 164

Ethyl-3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl

a) 8-(3-(Aminomethyl)phenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride

To a solution of tert-butyl-3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl (46 mg; 87,0 mmol) in methylene chloride (1 ml) was added 2 M HCl solution in ether (500 µl). The suspension was stirred at room temperature over night. The solvent was decanted and the residue three times triturated with diethyl ether. Specified in the title compound was dried under reduced pressure, and was obtained as a yellow solid (39 mg; 89%).

MS ISP (m/e): 429,3 (100) [(M+H)+], 412,4 (57).

b) Ethyl-3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamoyl

To a suspension of 8-(3-(aminomethyl)phenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (37 mg; of 73.8 mmol) in dichloromethane (0.75 ml) was added N,N-diisopropylethylamine (38,1 mg; 51,5 ml, 295 mmol). To the resulting yellow solution was added ethylchloride (8,99 mg; to 7.89 µl; of 81.2 μmol) and the reaction mixture was stirred at room temperature over night. Specified in the header connection�ie was obtained as a light yellow solid (35 mg; 95%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 501,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.13 (s, 1H), 7.83 (br s, 2H), 7.44 (t, 1 H), 7.36 (s, 1 H), 7.33 (d, 1 H), 6.41 (s, 1 H), 5.08 (br m, 1 H), 4.53 (br d, 1 H), 4.44 (d, 2H), 4.32 (br d, 2H), 4.15 (q, 2H), 3.96 (m, 1H), 3.69 (m, 1H), 3.20 (t, 2H), 3.10 (m, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 2.22 (brd, 2H), 1.25 (t, 3H).

Example 165

Ethyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

a) 6-Methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(1,2,3,6-tetrahydropiridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 164a, based on tert-butyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Since the product is not precipitated from the reaction mixture, it was diluted with water and twice extracted with methylene chloride. The aqueous layer was podslushivaet 1 n aqueous solution of sodium hydroxide and 4 times was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and the solvent evaporated, getting mentioned in the title compound as a yellow solid (194 mg; 77%).

MS ISP (m/e): 405.5 (53) [(M+H)+], 76,4 (100).

b) Ethyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Was prepared analogously to example 164b, based on 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(1,2,3,6-tetrahydropiridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and ethylchloride. Specified in the title compound was obtained as pale-yellow solids (yield 36%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 477,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.04 (s, 1H), 7.18 (Ih s, 1H), 7.11(s, 1H), 6.41 (s, 1H), 4.41 (br d, 1H), 4.22-4.15 (m, 4H), 3.96 (m, 1H), 3.73 (t, 1H), 3.17 (t, 2H), 2.64 (br s, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.21 (br d, 2H), 1.50 (m, 2H), 1.31-1.25 (m, 5H).

Example 166

Isopropyl-4-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Was prepared analogously to example 164b, based on 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(1,2,3,6-tetrahydropiridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and isopropylcarbamate. Specified in the title compound was obtained as a colorless solid (yield 32%) after column chromatography on silica gel using a gradient from methylene chloride to CME�and methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 491,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.04 (s, 1H), 7.16 (br s, 1H), 7.11 (s, 1H), 6.41 (s, 1H), 4.97 (sept, 1H), 4.39 (d, 1H), 4.31 (br d, 2H), 4.21 (br s, 2H), 3.96 (m, 1H), 3.72 (t, 1H), 3.18 (t, 2H), 2.63 (br s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21 (br d, 2H), 1.53 (m, 2H), 1.26 (d, 6H).

Example 167

N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine Serie-2-amine

a) (3-Bromo-3-Phenylpropoxy)(tert-butyl)dimethylsilane

A suspension of tert-butultimately(3 phenylpropoxy)silane (2.22 g; to 8.86 mmol), N-bromosuccinimide (1.58 g; to 8.86 mmol) and benzoyl peroxide (66,4 mg; 266 mmol) in carbon tetrachloride (17,8 ml) was heated to a temperature of delegatie for 3 hours. The reaction mixture was filtered, the residue washed with carbon tetrachloride and the solvent evaporated. Added water and the reaction mixture was twice extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a light yellow oil (1.63 g; 55%) after column chromatography on silica gel using a mixture of heptane/ethyl acetate 19:1 (vol./about.) as eluent.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.42-7.26 (m, 5H), 5.42 (dd, 1H), 3.76 (m, 1H), 3.68 (m, 1H), 2.48 (m, 1H), 2.8 (m, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).

b) 5-Bromo-1-(3-(tert-butyldimethylsilyloxy)-1-phenylpropyl)-3-nitro-1H-1,2,4-triazole

A solution of (3-bromo-3-phenylpropoxy)(tert-butyl)dimethylsilane (934 mg; 2,84 mmol) in acetonitrile (27 ml) was stirred at room temperature in a nitrogen atmosphere with sodium iodide (425 mg; 2,84 mmol) for 15 minutes. Was added potassium carbonate (560 mg; from 4.05 mmol) and the reaction mixture was heated to 60°C. At this temperature within 30 minutes was added 5-bromo-3-nitro-1H-1,2,4-triazole (532 mg; 2.7 mmol) dissolved in acetonitrile (5.3 ml). The reaction mixture was stirred for 2 hours at 85°C. water was Added and the aqueous phase was twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a colorless viscous oil (510 mg; 42%) after column chromatography on silica gel using a gradient from heptane to a mixture of heptane/ethyl acetate 4:1 (vol./about.) as eluent.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.42-7.36 (m, 5H), 5.91 (dd, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 2.72 (m, 1H), 2.39 (m, 1H), 0.91 (s, 9H), 0.00 (s, 6H).

c) 2-Nitro-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine Serie

To a solution of 5-bromo-1-(3-(tert-butyldimethylsilyloxy)-1-phenylpropyl)-3-nitro-1H-1,2,4-triazole� (510 mg; 1,16 mmol) in tetrahydrofuran (11.6 ml) was added in a nitrogen atmosphere at room temperature a 1 M solution of fluoride of tetrabutylammonium in tetrahydrofuran (3,47 ml; 3,47 mmol). The yellow solution was stirred at room temperature over night. Added water and the aqueous phase was twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a light yellow solid (174 mg; 61%) after column chromatography on silica gel using a gradient of heptane/ethyl acetate 4:1 to 1:1 (vol./about.) as eluent.

MS ISP (m/e): 247,2 (100) [(M+H)+], 264,1 (36).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.42-7.38 (m, 3H), 7.09 (d, 2H), 5.61 (t, 1H), 4.56 (m, 2H), 2.77 (m, 1H), 2.42 (m, 1H).

d) 7-Phenyl-6,7-dihydro-5H-[1,2,4]triazole[5,1-b][1,3]oxazine Serie-2-ylamine

To a solution of 2-nitro-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine Serie (174 mg; 707 mmol) in ethyl acetate (7 ml) was added 10% Pd on coal (17,4 mg; 164 mmol). The reaction mixture was gidrirovanie at room temperature in hydrogen atmosphere overnight. The catalyst was filtered and washed with ethyl acetate. Specified in the title compound was obtained as white solid (143,3 mg; 94%) after TRANS�of masiania with diethyl ether.

MS ISP (m/e): 217,3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.39-7.29 (m, 3H), 7.16 (d, 2H), 5.22 (t, 1H), 5.15 (brs, 2H), 4.35 (m, 1H), 4.21 (m, 1H), 2.50 (m, 1H), 2.15 (m, 1H).

e) N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine Serie-2-amine

Was prepared analogously to example 1h, on the basis of 7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine Serie-2-amine and 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as pale-yellow solids (yield 17%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 392,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (s, 1H), 7.38-7.31 (m, 3H), 7.12 (d, 2H), 6.37 (s, 1H), 4.44-4.20 (m, 4H), 3.97 (brd, 1H), 4.25 (m, 1H), 3.09 (m, 1H), 2.65 (m, 1H), 2.34 (s, 3H), 2.25-2.10 (m, 3H), 1.41 (m, 2H).

Example 168

8-(3,6-Dihydro-2H-Piran-4-yl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 8-(3,6-Dihydro-2H-Piran-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 160b, on the basis of 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and 2-(3,6-dihydro-2H-Piran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Specified in the title compound was obtained as a light brown solid (yield 55%) after the number�night chromatography on silica gel, using ethyl acetate as eluent.

MS ISP (m/e): 231,2 (50) [(M+H)+], 201,2 (100) [(M-CH2CO+H)+].

b) 8-(3,6-Dihydro-2H-Piran-4-yl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1h, on the basis of 8-(3,6-dihydro-2H-Piran-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b). Specified in the title compound was obtained as yellow oil (yield 5%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 406,5 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.51 (s, 1H), 8.04 (s, 1H), 7.34 (s, 1H), 7.13 (s, 1H), 6.41 (s, 1H), 4.42 (brs, 2H), 4.34 (brd, 2H), 3.98 (t, 2H), 3.96 (m, 1H), 3.17 (t, 2H), 2.61 (br s, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.21 (br d, 2H), 1.52 (br d, 2H).

Example 169

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) tert-Butyl-1-(2-chloropyridin-4-yl)piperidine-4-ylcarbamate

To a mixture of 2-chloro-4-herperidin (1.00 g; and 7.60 mmol) and BOC-4-aminopiperidine (1,98 g; a 9.09 mmol) in NMP (10 ml) was added DIPEA (of 1.86 ml; 10.6 mmol). Turbid solution for 6 minutes barbotirovany argon, then the reaction mixture was heated in a microwave oven for 2×30 minutes to 150°C. the Mixture then was poured into water and was extracted with et�the etate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 50 g; 0 to 50% ethyl acetate in heptane) allowed us to obtain specified in the title compound (1.47 g; 62%) as a white solid.

MS ISP (m/e): 312,1 [(M+H)+].

b) 1-(2-Chloropyridin-4-yl)piperidine-4-amine dihydrochloride

To a solution of tert-butyl-1-(2-chloropyridin-4-yl)piperidine-4-ylcarbamate (1.00 g; 3,21 mmol) in dichloromethane (16 ml) was added HCl (2 M in diethyl ether; 8,02 ml; 16,0 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. The mixture is then filtered, the white precipitate was washed with dichloromethane and diethyl ether and dried, which allowed us to obtain specified in the title compound (913 mg; 99%) as a white solid.

MS ISP (m/e): 212,1/214,1 [(M+H)+].

c) N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A suspension of 1-(2-chloropyridin-4-yl)piperidine-4-amine dihydrochloride (142 mg; 0.50 mmol) in dichloromethane was washed with 2 n NaOH, the aqueous layer was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate and evaporated. The remainder, representing the free base, was dissolved in dioxane (4 ml) was added 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (obtained analogously to example 66a-d) (170 mg; 0,5 mmol�), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg; 8 mol%), chloroform complex Tris(dibenzylideneacetone)diplegia (21 mg; 4 mol%) and sodium phenolate (87 mg; 0.75 mmol), the reaction mixture was barbotirovany of Hypertension for 5 minutes and then irradiated at 130°C in microwave oven for 1 hour. The crude substance was purified flash chromatography (silica-NH2; 20 g; 0 to 100% ethyl acetate in heptane). Specified in the title compound was obtained as a yellow solid (103 mg; 47%).

MS ISP (m/e): 232,1 [(M+H)+].

Example 170

8-(3,4-Differenl)-N-(1-(6-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 169, using 1-(6-methoxypyridine-4-yl)piperidine-4-amine (122 mg; 0.43 mmol) instead of 1-(2-chloropyridin-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a light yellow foam (90 mg; 47%).

MS ISP (m/e): 438,3 [(M+H)+].

Example 171

8-(2-Chloro-4-fluorophenyl)-N-(1-(6-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 170, using 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (180 mg; 0.55 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (71 mg;31%).

MS ISP (m/e): 454,2 [(M+H)sup> +].

Example 172

8-(2-Chloro-4-fluorophenyl)-N-(1-(6-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 171 by using 1-(6-ethoxypyridine-4-yl)piperidine-4-amine (100 mg; 0.34 mmol) instead of 1-(6-methoxypyridine-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a light yellow foam (78 mg; 49%).

MS ISP (m/e): 468,3/470,3 [(M+H)+].

Example 173

8-(3,4-Differenl)-N-(1-(6-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 172, using 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (116 mg; 0,37 mmol) instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (71 mg; 46%).

MS ISP (m/e): 452,2 [(M+H)+].

Example 174

8-(3,4-Differenl)-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) tert-Butyl-1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-ylcarbamate

To a mixture of 4-chloro-6-(trifluoromethyl)pyrimidine (0,82 g; 4,49 mmol) and BOC-4-aminopiperidine (1.17 g; 5,84 mmol) in NMP (5,7 ml) was added DIPEA (1,10 ml; 6,29 mmol), after 30 minutes the mixture was poured into water and was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate filtered and evaporated. Purification by chromatography (silica gel; 70 g; 0 to 50% ethyl acetate in heptane) allowed us to obtain specified in the title compound (1.43 g; 92%) as a white solid.

MS ISP (m/e): 347,2 [(M+H)+].

b) 1-(6-(Trifluoromethyl)pyrimidine-4-yl)piperidine-4-anindividual

To a solution of tert-butyl-1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-ylcarbamate (1.42 g; 4.1 mmol) in dichloromethane (20 ml) was added HCl (2 M in diethyl ether; 10,2 ml; 20.5 mmol) and the reaction mixture stirred at room temperature for 18 hours. The mixture was filtered, the white precipitate was washed with dichloromethane and diethyl ether and dried, which allowed us to obtain specified in the title compound (1,27 g; 97%) as a white solid.

MS ISP (m/e): 247,2 [(M+H)+].

C) 8-(3,4-Differenl)-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 173, using 1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-amine dihydrochloride (116 mg; 0,37 mmol) instead of 1-(6-ethoxypyridine-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a whitish foam (93 mg; 49%).

MS ISP (m/e): 476,2 [(M+H)+].

Example 175

8-(2-Chloro-4-fluorophenyl)-6-methyl-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C using the 2-�rum-8-(2-chloro-4-fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (150 mg; 0,44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (103 mg; 51%).

MS ISP (m/e): 506,2/508,3 [(M+H)+].

Example 176

8-(2-Chloro-4-fluorophenyl)-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (144 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (88 mg; 45%).

MS ISP (m/e): m/e=492,2/494,2 [(M+H)+].

Example 177

8-(3,4-Differenl)-6-methyl-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 174 using 2-bromo-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (143 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (89 mg; 46%).

MS ISP (m/e): m/e=490,2 [(M+H)+].

Example 178

8-(3,4-Differenl)-6-fluoro-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine (144 mg; 0,44 m�ol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (50 mg; 25%).

MS ISP (m/e): m/e=494,2 [(M+H)+].

Example 179

6-Chloro-8-(3,4-differenl)-N-(1-(6-(trifluoromethyl)pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-6-chloro-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (152 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (63 mg; 31%).

MS ISP (m/e): 510,3/512,3 [(M+H)+].

Example 180

8-(3,4-Differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) tert-Butyl-1-(6-methylpyridazin-4-yl)piperidine-4-ylcarbamate

To a mixture of 5-chloro-3-methylpyridine (1.3 g; 10.1 mmol) and BOC-4-aminopiperidine (2,63 g, 13,1 mmol) in NMP (13 ml) was added DIPEA (2,47 ml; 14.2 mmol). Turbid solution for δ minutes barbotirovany argon, then the reaction mixture was heated in a microwave oven for 30 minutes to 150°C. the Mixture then was poured into water and was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 50 g; 50 to 100% ethyl acetate in heptane) allowed us to obtain specified in the title compound (2.18 g; 74%) as a whitish solid�th substance.

MS ISP (m/e): 293,2 [(M+H)+].

b) 1-(6-Methylpyridazin-4-yl)piperidine-4-amine dihydrochloride

To a solution of tert-butyl-1-(6-methylpyridazin-4-yl)piperidine-4-ylcarbamate (2.14 g; 7,32 mmol) in dichloromethane (36 ml) was added HCl (2 M in diethyl ether; 18,3 ml, 36.6 mmol) and the reaction mixture stirred at room temperature for 24 hours. The mixture is then filtered, the white precipitate was washed with dichloromethane and diethyl ether and dried, which allowed us to obtain specified in the title compound (2.35 g; 82%) as a white solid.

MS ISP (m/e): 193,2 [(M+H)+].

c) 8-(3,4-Differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 173, using 1-(6-methylpyridazin-4-yl)piperidine-4-amine dihydrochloride (14 mg; 0,053 mmol) instead of 1-(6-ethoxypyridine-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a yellow foam (10 mg; 45%).

MS ISP (m/e): 422,3 [(M+H)+].

Example 181

8-(3,4-Differenl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 173, using 1-(2-methoxypyridine-4-yl)piperidine-4-amine dihydrochloride (101 mg; 0.36 mmol) instead of 1-(6-ethoxypyridine-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a whitish foam (66 mg; 42%).

MS ISP (m/e): 437,2 [(M+H)+ ].

Example 182

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 181, using 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (129 mg; 0.4 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (57 mg; 35%).

MS ISP (m/e): 453,2/455,3 [(M+H)+].

Example 183

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (143 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (73 mg; 40%).

MS ISP (m/e): 455,3 [(M+H)+].

Example 184

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 169, using 2-bromo-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine (145 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish solid (36 mg; 20%).

MS ISP (m/e): 459,2/461,2 [(M+H)+].

Example 185

8-(2-Chloro-4-f�arvanil)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (150 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (82 mg; 43%).

MS ISP (m/e): 471,4/473,2 [(M+H)+].

Example 186

6-Chloro-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-6-chloro-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (152 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (25 mg; 13%).

MS ISP (m/e): 475,1/477,1 [(M+H)+].

Example 187

8-(3,4-Differenl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 1-(Pyrimidine-4-yl)piperidine-4-amine

To a solution of (1-pyrimidine-4-yl-piperidine-4-yl)-carbamino acid mpem-butyl ester (1.00 g; 3,59 mmol) in dichloromethane (16 ml) was added HCl (2 M in diethyl ether; 8,98 ml; 18,0 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was then diluted with NaOH (2 n) at 0°C and was extracted with dichloromethane. The combined organic extracts are then dried over sodium sulfate and filter�Lee, which allowed us to obtain specified in the title compound (511 mg; 80%) as a light yellow solid substance.

MS ISP (m/e): 179,2 [(M+H)+].

b) 8-(3,4-Differenl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 1-(pyrimidine-4-yl)piperidine-4-amine (71 mg; 0.4 mmol) instead of 1-(2-chloropyridin-4-yl)piperidine-4-amine dihydrochloride.

Specified in the title compound was obtained as a white foam (63 mg; 39%).

MS ISP (m/e): to 408.4(M+H)+].

Example 188

8-(3,4-Differenl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 187b, using 2-bromo-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (130 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a white foam (60 mg; 36%).

MS ISP (m/e): 422,2 [(M+H)+].

Example 189

8-(2-Chloro-4-fluorophenyl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 187b, using 2-bromo-8-(2-chloro-4-fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (136 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a white foam (63 mg; 36%).

MS ISP (m/e): 438,2 [(M+H)+].

Example 190

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 1-(2-Chloropyrimidine-4-yl)piperidine-4-amine dihydrochloride

To a solution of 1-(2-chloro-pyrimidine-4-yl)-piperidine-4-yl)-carbamino acid tert-butyl ester (1.00 g; 3,20 mmol) in dichloromethane (18 ml) was added HCl (2m in diethyl ether and 8.0 ml; 16,0 mmol) and the reaction mixture stirred at room temperature for 18 hours. The mixture is then filtered, the white precipitate was washed with dichloromethane and diethyl ether and dried, which allowed us to obtain specified in the title compound (0.95 g; 99%) as a white solid.

MS ISP (m/e): 213,1/to 215, 4 [(M+H)+].

b) 8-(2-Chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 171 by using 1-(2-chloropyrimidine-4-yl)piperidine-4-amine dihydrochloride (286 mg; 1.0 mmol) instead of 1-(6-methoxypyridine-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a white foam (133 mg; 29%).

MS ISP (m/e): 458,3/460,2[(M+H)+].

Example 191

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-6,8-bis(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 2-bromo-6,8-bis(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (186 mg; 0.44 mmol) instead of 2-bromo-8-(34-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (24 mg; 11%).

MS ISP (m/e): 553,3 [(M+H)+].

Example 192

8-(2-Chloro-4-ethoxyphenyl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 58) (46 mg; 0.10 mmol) in tO (1 ml) was added a solution of sodium ethoxide (21% in ethanol; 56 ál; 0.15 mmol) and the reaction mixture was stirred in an argon atmosphere in a sealed tube at 60°C for 16 h. After cooling to room temperature the mixture was heated in a microwave oven to 150°C for 45 minutes and then was added a solution of sodium ethoxide (21% in ethanol; 56 ál; 0.15 mmol) and the mixture was heated to 150°C for 30 minutes in a microwave oven. The mixture then was evaporated, diluted with water and was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 20 g; 0 to 100% ethyl acetate in heptane) allowed us to obtain specified in the title compound (17 mg; 35%) as a white foam.

MS ISP (m/e): 493,3/495,4 [(M+H)+].

Example 193

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To dissolve�8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 190b) (71 mg; 0,155 mmol) in MeOH (1.5 ml) was added a solution of sodium methylate (30% in MeOH; 35 µl; 0,186 mmol) and the reaction mixture was stirred in a sealed vial in an argon atmosphere at 60°C for 18 hours and then heated in a microwave oven to 150°C for 30 minutes. The mixture then was evaporated.

Purification by chromatography (silica gel; 20 g; 0 to 100% methanol in dichloromethane) allowed us to obtain specified in the title compound (33 mg; 47%) as a light yellow foam.

MS ISP (m/e): 454,3/456,2 [(M+H)+].

Example 194

8-(2-Chloro-4-methoxyphenyl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 190b) (71 mg; 0,155 mmol) in MeOH (1.5 ml) was added a solution of sodium methylate (30% in MeOH; 35 µl; 0,186 mmol) and the reaction mixture was stirred in a sealed vial in an argon atmosphere at 60°C for 18 hours and then heated in a microwave oven to 150°C for 30 minutes. The mixture then was evaporated.

Purification by chromatography (silica gel; 20 g; 0 to 100% methanol in dichloromethane) allowed us to obtain specified in the title compound (5 mg; 7%) as a light yellow foam.

MS ISP (m/e): 466,3/468,3 [(M+H)+].

Example 195

N-(1-(2-Chloropyrimidine-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]t�Iesolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 190b, using 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (311 mg; 1.0 mmol) instead of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish solid (149 mg; 34%).

MS ISP (m/e): 442,2/444,3 [(M+H)+].

Example 196

8-(3,4-Differenl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example s) (88 mg; 0.20 mmol) in tO (1 ml) was added a solution of sodium ethoxide (21% in ethanol; 75 μl; 0.2 mmol) and the reaction mixture was heated in a microwave oven to 150°C for 30 minutes. Added an additional solution of sodium ethoxide (21% in ethanol; 75 μl; 0.2 mmol) and the mixture was heated to 150°C in the next 30 minutes. The mixture then was evaporated. Purification by chromatography (silica gel; 20 g; 0 to 100% methanol in dichloromethane) allowed us to obtain specified in the title compound (3 mg; 3%) as a colorless resin.

MS ISP (m/e): 451,3 [(M+H)+].

Example 197

8-(4-Ethoxy-3-fluorophenyl)-N-(1-(pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[,2,4]triazolo[1,5-a]pyridin-2-amine (example s) (88 mg; 0.20 mmol) in tO (1 ml) was added a solution of sodium ethoxide (21% in ethanol; 75 μl; 0.2 mmol) and the reaction mixture was heated in a microwave oven to 150°C for 30 minutes, then was added a solution of sodium ethoxide (21% in ethanol; 75 μl; 0.2 mmol) and the mixture was heated to 150°C in the next 30 minutes. The mixture then was evaporated.

Purification by chromatography (silica gel; 20 g; 0 to 100% methanol in dichloromethane) allowed us to obtain specified in the title compound (7 mg; 8%) as a whitish foam.

MS ISP (m/e): 433,5 [(M+H)+].

Example 198

8-(3,4-Differenl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 195) (88 mg; 0,155 mmol) in MeOH (2.0 ml) was added a solution of sodium methylate (30% in MeOH; 41 μl; 0,22 mmol) and the reaction mixture was heated in a microwave at 120°C for 2 h. the Mixture then was evaporated. Purification by chromatography (silica gel; 20 g; 0 to 100% methanol in dichloromethane) allowed us to obtain specified in the title compound (71 mg; 81%) as a white foam.

MS ISP (m/e): 438,3 [(M+H)+].

Example 199

2-{8-(3,4-Debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol

Received similar�icno example 49. Specified in the title compound was obtained as light yellow solids.

MS ESI (m/z): 498,0 [(M+H)+].

Example 200

8-(3,4-Differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) tert-Butyl-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-ylcarbamate

To a mixture of 4-iodo-2-(trifluoromethyl)pyridine (356 mg; 1.3 mmol) and BOC-4-aminopiperidine (340 mg; 1.7 mmol) in NMP (2.6 ml) was added DIPEA (319 μl; 1,83 mmol). The cloudy solution was barbotirovany argon for δ minutes, then the reaction mixture was heated in a microwave oven for 3×30 minutes to 150°C. the Mixture then was poured into water and was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 50 g; 0 to 100% ethyl acetate in heptane) allowed us to obtain specified in the title compound (343 mg; 76%) as a white solid.

MS ISP (m/e): 346,2 [(M+H)+].

b) 1-(2-(Trifluoromethyl)pyridin-4-yl)piperidine-4-amine

To a solution of tert-butyl-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-ylcarbamate (314 mg; 0.91 mmol) in dichloromethane (4.5 ml) was added HCl (2 M in diethyl ether; 2,27 ml; 4,55 mmol) and the reaction mixture was stirred at room temperature for 18 h. the Mixture was then filtered, the white precipitate was washed with dichloromethane and diethyl � dried, which allowed us to obtain specified in the title compound (201 mg; 90%) as a whitish solid substance.

MS ISP (m/e): 246,2 [(M+H)+].

c) 8-(3,4-Differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-amine (70 mg; 0.29 mmol) instead of 1-(2-chloropyridin-4-yl)piperidine-4-lindegaard.

Specified in the title compound was obtained as a white foam (72 mg; 53%).

MS ISP (m/e): 475,2 [(M+H)+].

Example 201

8-(2-Chloro-4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (93 mg; 0.29 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (78 mg; 56%).

MS ISP (m/e): to 491.2(M+H)+].

Example 202

8-(3,4-Differenl)-6-fluoro-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 180C, using 2-bromo-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine (145 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (87 mg; 45%).

MS ISP (m/e): 440,3 [(M+H)+].

Example 203

8-(3,4-Differenl)-6-methyl-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 180C, using 2-bromo-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (143 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (96 mg; 50%).

MS ISP (m/e): 436,3 [(M+H)+].

Example 204

8-(2-Chloro-4-fluorophenyl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 180C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (144 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (73 mg; 38%).

MS ISP (m/e): 438,1 [(M+H)+].

Example 205

6-Chloro-8-(3,4-differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 180C, using 2-bromo-6-chloro-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (152 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (100 mg; 50%).

MS ISP (m/e): 456,2 [(M+H)+].

Example 206

8-(chlor-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 180C, using 2-bromo-6-chloro-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (150 mg; 0.44 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (96 mg; 48%).

MS ISP (m/e): 452,1 [(M+H)+].

Example 207

4-(3-Chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine

a) tert-Butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate

To a suspension of 4-bromo-6-methylbenzo[d]thiazol-2-amine (1.0 g; 4,32 mmol) in dichloromethane (30 ml) was added di-tert-butyl-dicarbonate (1.0 g; 4.75 mmol), then 4-dimethylaminopyridine (0.6 g; 4.75 mmol) and the mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane, was added Amberiite® IR120, the mixture was filtered through glass wool and concentrated, obtaining specified in the title compound as an orange powder (1.3 g; 89%).

MS ISP (m/e): 343,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=12.01 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 2.39 (s, 3H), 1.49 (s, 9H).

b) 4-(3-Chloro-4-fluorophenyl)-6-methylbenzo[d]thiazol-2-amine

To a mixture of tert-butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate (0.6 g; 1.75 mmol), 3-chloro-4-ftorhinolonovy acid (0.5 g; 2,62 mmol), palladium acetate(II) (0.08 g; 0.35 mmol), triphenylphosphine (0.3 g; 1.05 mmol) was added degassed dio�San (10 ml) and degassed 1 M aqueous sodium carbonate (5,24 ml; 5,24 mmol). The mixture was heated to 100°C for 16 hours in an argon atmosphere and then was diluted with ethyl acetate, washed with water, brine and concentrated. The rest of pererestorani in trifluoroacetic acid (2 ml) and stirred for 15 minutes. The solvent was evaporated, the residue pererestorani in dichloromethane, washed with saturated sodium bicarbonate, dried with sodium sulfate and concentrated. The product was purified column chromatography on silica gel using a mixture of n-heptane:ethyl acetate (about./about.=9:1-4:1) as eluent, obtaining mentioned in the title compound as a white solid (0.4 g; 80%).

MS ISP (m/e): 293,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.82 (dd, 1H), 7.64-7.59 (m, 1H), 7.41 (brs, 1H), 7.20 (t, 1H), 7.15 (brs, 1H), 5.24 (brs, 2H), 2.44 (s, 3H).

c) 2-Bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole

To an ice cold mixture of copper bromide(II) (0.18 g; 0.8 mmol) and tert-nitrite (0,11 ml; 0.9 mmol) in acetonitrile (10 ml) was added solid 4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazol-2-amine (0.2 g; 0.7 mmol). The ice bath was then removed and the reaction mixture was allowed to warm to room temperature for 0.5 hours. The reaction mixture was diluted with dichloromethane, washed with 1 M hydrochloric acid, dried with sodium sulfate and concentrated, obtaining specified in the title compound as a light yellow solid (0,24 �; 99%).

MS ISP (m/e): 356,0 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.81 (dd, 1H), 7.70-7.65 (m, 1H), 7.59 (brs, 1H), 7.30 (brs, 1H), 7.24 (t, 1H), 2.52 (s, 3H).

d) 4-(3-Chloro-4-fluorophenyl)-N-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine

To a solution of 2-bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole (0.06 g; 0.2 mmol) in dimethylacetamide (1 ml) was added 1-(2-chloropyridin-4-yl)piperidine-4-amine dihydrochloride (0.05 g; 0.2 mmol), then triethylamine (70 μl; 0.5 mmol) and the mixture was heated to 175°C for 1 h in the microwave. The reaction mixture was then diluted with dichloromethane, washed with water, brine, dried with sodium sulfate and concentrated. The product was purified preparative HPLC, receiving specified in the title compound as a light yellow solid (0.02 g; 24%).

MS ISP (m/e): 487,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.06-7.98 (m, 2H), 7.65-7.61 (m, 1H), 7.41 (brs, 1H), 7.19 (apt, 2H), 6.67 (brs, 1H), 6.60 (d, 1H), 5.21 (brs, 1H), 3.93-3.82 (m, 3H), 3.10 (t, 2H), 2.44 (s, 3H), 2.02 (d, 2H), 1.71-1.55 (m, 4H).

Example 208

4-(3-Chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)benzo[d]thiazol-2-amine

Was prepared analogously to example 207d on the basis of 2-bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole and 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamine dihydrochloride. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 468,2 [(M+H)sup> +].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.90 (d, 1H), 7.62-7.45 (m, 2H), 7.40 (brt, 1H), 7.34 (brs, 1H), 7.14-7.08 (m, 2H), 6.36 (brs, 1H), 4.32 (d, 2H), 3.88-3.78 (m, 1H), 3.12 (t, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 2.20 (d, 2H), 1.49 (q, 2H).

Example 209

4-(3,4-Differenl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)benzo[d]thiazol-2-amine

Was prepared analogously to example 207b-C), then 208, based on tert-butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate and 3,4-diftorhinolonom acid.

Specified in the title compound was obtained as white solids.

MS ISP (m/e): 452,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.77-7.63 (m, 2H), 7.50-7.43 (m, 2H), 7.40 (s, 1H), 7.23-7.15 (m, 2H), 6.44 (brs, 1H), 4.38 (d, 2H), 3.96-3.87 (m, 1H), 3.27 (t, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.27 (d, 2H), 1.62 (q, 2H).

Example 210

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-4-(3,4-differenl)-6-methylbenzo[d]thiazol-2-amine

Was prepared analogously to example 207b-d, based on tert-butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate and 3,4-diftorhinolonom acid. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 470,8 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.03 (d, 1H), 7.79-7.72 (m, 2H), 7.51-7.47 (m, 1H), 7.41 (brs, 1H), 7.24-7.16 (m, 2H), 6.68 (brs, 1H), 6.60 (d, 1H), 5.23 (brs, 1H), 3.91-3.81 (m, 3H), 3.10 (t, 2H), 2.44 (s, 3H), 2.27 (d, 2H), 1.62 (q, 2H).

Example 211

4-(2-Chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)PIP�ridin-4-yl)benzo[d]thiazol-2-amine

Was prepared analogously to example 207b, 208 then, based on tert-butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate and 2-chloro-4-ftorhinolonovy acid. Specified in the title compound was obtained as white solids.

MS ISP (m/e): 468,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.51 (s, 1H), 7.45 (brs, 1H), 7.39 (dd, 1H), 7.23 (dd, 1H), 7.09-7.02 (m, 2H), 6.39 (brs, 1H), 5.32 (brs, 1H), 4.31 (d, 2H), 3.76-3.68 (m, 1H), 3.12 (t, 2H), 2.44 (s, 3H), 2.37 (s, 3H), 2.20 (d, 2H), 1.52 (q, 2H).

Example 212

4-(2-Chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine

Was prepared analogously to example 207b-d, based on tert-butyl-4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate and 2-chloro-4-ftorhinolonovy acid. Specified in the title compound was obtained as white solids.

MS ISP(m/e): 487,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.02 (d, 1H), 7.45 (brs,1H), 7.39 (brt, 1H), 7.23 (dd, 1H), 7.07-7.01 (m, 2H), 6.66 (brs, 1H), 6.58 (dd, 1H), 5.22 (brs, 1H), 3.80 (d, 2H), 3.76-3.68 (m, 1H), 3.07 (t, 2H), 2.44 (s, 3H), 2.22 (d, 2H), 1.59 (q, 2H).

Example 213

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(4-foreperiod-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 2-Nitropyridine-3-yl triftormetilfullerenov

To an ice cold solution of 2-nitropyridine-3-ol (10.0 g; 71 mmol) and triethylamine (14,9 ml; 107 mmol) in methylene chloride (150 ml) drop� added triftormetilfullerenov anhydride (14.5 ml; 86 mmol) and the mixture was stirred for 2 hours. Added water and the mixture was extracted with methylene chloride. The organic phase was dried with sodium sulfate and the solvent evaporated in vacuum. The residue was purified by column chromatography on silica gel using a mixture of n-heptane/ethyl acetate (vol./about. from 2:8 to 3:7) as eluent. Specified in the title compound was obtained as a light brown liquid (18,4 g; 95%).

MS ISP (m/e): 273,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.65 (dd, 1H), 8.00 (dd, 1H), 7.80 (dd, 1H).

b) 3-(4-Foreperiod-1-yl)-2-nitropyridine

To a solution of 4-foreveryday hydrochloride (1,54 g; 11 mmol) and triethylamine (4.5 ml; 33 mmol) in dimethylacetamide (30 ml) was added 2-nitropyridine-3-yl triftormetilfullerenov (3,00 g; 11 mmol) and the mixture was heated to 110°C for 1 hour. Added water and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried with sodium sulfate. The solvent was evaporated under vacuum and the product was used without further purification. Specified in the title compound was obtained as a yellow oil (2.22 g; 89%).

MS ISP (m/e): 226,0 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.10 (dd, 1H), 7.55 (dd, 1H), 7.47 (dd, 1H), 4.95-4.75 (m, 1H), 3.25-3.17 (m, 2H), 3.07-3.00 (m, 2H), 2.10-1.95 (m, 4H).

c) 3-(4-Foreperiod-1-yl)pyridin-2-amine

To a solution of 3-(4-foreperiod-1-yl)-2-nitropyridine (2.0 g; 8,9 mmol) in meth�Nola (25 ml) was added a large spoonful of Raney Nickel and the mixture was stirred under hydrogen atmosphere for 5 hours. The reaction mixture was then filtered through Hyflo filter and the solvent was evaporated in vacuum, which allowed to obtain the product, used without any further purification. Specified in the title compound was obtained as a dark brown solid (1.7 g; 100%).

MS ISP (m/e): 196,2 [(M+H)+].

d) N-(3-(4-Foreperiod-1-yl)-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea

Was prepared analogously to example 1E, based on 3-(4-foreperiod-1-yl)pyridin-2-amine. The residue was purified by column chromatography on silica gel using a mixture of n-heptane/ethyl acetate (vol./about. from 1:1 to 3:7) as eluent, which allowed us to obtain specified in the title compound as a yellow solid (yield 73%).

MS ISP (m/e): 327,1 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=12.0 (brs, 1H), 11.3 (bs, 1H), 8.13 (dd, 1H), 7.60 (dd, 1H), 7.34 (dd, 1H), 4.95-4.75 (m, 1H), 4.22 (q, 2H), 3.01 (t, 2H), 2.87-2.80 (m, 2H), 2.07-1.81 (m, 4H), 1.26 (t, 3H).

e) 5-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

Was prepared analogously to example 1f, proceeding from N-(3-(4-foreperiod-1-yl)-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea, which allowed us to obtain specified in the title compound without any further purification as a pale yellow solid (yield 100%).

MS ISP (m/e): 236,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.95 (dd, 1H), 6.74-6.75 (m, 2H), 4.97-4.79 (m, 1H), 4.40 (brs, 2H), 3.54-3.43 (m, 4H), 2.87-2.80 (m, 2H), 221-2.02 (m, 4H).

f) N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(4-foreperiod-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1h, based on 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine and 1-(2-chloropyridin-4-yl)piperidine-4-it, which allowed us to obtain specified in the title compound as a colorless resin (yield 7%).

MS ISP (m/e): 430,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.02 (dd, 1H), 7.98 (dd, 1H), 6.75-6.66 (m, 3H), 6.60 (dd, 1H), 5.01-4.79 (m, 2H), 3.95-3.86 (m, 1H), 3.85-3.78 (m, 2H), 3.52-3.37 (m, 4H), 3.14 (t, 2H), 2.27-2.00 (m, 6H), 1.68-1.56 (m, 2H).

Example 214

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(4-(trifluoromethyl)piperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 213, based on 2-nitropyridine-3-yl triftormetilfullerenov (example 213b) and 4-triftormetilfullerenov hydrochloride. The residue was purified by preparative HPLC, which allowed us to obtain specified in the title compound as a colorless resin (yield 37%).

MS ISP (m/e): 430,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.02 (dd, 1H), 7.98 (dd, 1H), 6.75-6.66 (m, 3H), 6.60 (dd, 1H), 5.01-4.79 (m, 2H), 3.95-3.86 (m, 1H), 3.85-3.78 (m, 2H), 3.52-3.37 (m, 4H), 3.14 (t, 2H), 2.27-2.00 (m, 6H), 1.68-1.56 (m, 2H).

Example 215

(S)-6-(2-(1-(2-Chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-6-azaspiro[2.5]Octan-4-ol

Was prepared analogously to example 213, based on 2-nitropyridine-3-and�and triftormetilfullerenov (example 213b) and (S)-6-azaspiro[2.5]Octan-4-ol hydrochloride (US 2009/23713 A1). The residue was purified by preparative HPLC, which allowed us to obtain specified in the title compound as a colorless resin (yield 30%).

MS ISP (m/e): 454,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.01 (d, 1H), 7.95 (dd, 1H), 6.75-6.70 (m, 2H), 6.66 (d, 1H), 6.58 (dd, 1H), 5.05 (bs, 1H), 4.03 (dd, 1H), 3.93-3.76 (m, 3H), 3.60 (d, 1H), 3.19-3.04 (m, 5H), 2.44 (td, 1H), 2.22 (d, 2H), 1.60 (qd, 2H), 0.98 (dt, 1H), 0.73-0.66 (m, 1H), 0.47-0.37 (m, 3H).

Example 216

N-(1-(2-Chloropyridin-4-yl)piperidine-4-yl)-8-(4,4-deformability-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 213, based on 2-nitropyridine-3-yl triftormetilfullerenov (example 213b) and 4,4-deformability hydrochloride. The residue was purified by preparative HPLC, which allowed us to obtain specified in the title compound as a colorless resin (yield 37%).

MS ISP (m/e): 488,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.05-8.0 (m, 2H), 6.80-6.74 (m, 2H), 6.68 (d, 1H), 6.61 (dd, 1H), 5.82 (brs, 1H), 3.94-3.85 (m, 1H), 3.80 (dt, 2H), 3.42 (t, 4H), 3.18 (dd, 2H), 2.29-2.17 (m, 6H), 1.71-1.60 (m, 2H).

Example 217

8-(2-Chloro-4-fluorophenyl)-2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol

a) Methyl-2-(2-chloro-4-fluorophenyl)pent-4-ENOAT

To the cooled (-78°C) solution hexamethyldisilazide lithium (27,1 ml; 1 M in THF; 27,1 mmol) in THF (30 ml) was added methyl-2-(2-chloro-4-fluorophenyl)acetate (5 g; 24,7 mmol) in THF (10 ml). After stirring for 0.5 hours, added allylbromide (2.4 ml; 27,1 mmol) in one portion, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature (0.5 hours). The reaction mixture was diluted with ethyl acetate, washed with water, brine, the organic phase was dried with sodium sulfate and the solvent evaporated in vacuum. The residue was purified by column chromatography on silica gel using a mixture of n-heptane/ethyl acetate (vol./about. from 1:0 to 9:1) as eluent. Specified in the title compound was obtained as a colourless liquid (6.0 g; 100%).

MS ISP (m/e): 264,3 [(M+Na)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.36 (dd, 1H), 7.13 (dd, 1H), 6.97 (td, 1H), 5.77-5.67 (m, 1H), 5.05 (d, 1H), 5.01 (d, 1H), 4.20 (t, 1H), 3.68 (s, 3H), 2.83-2.74 (m, 1H), 2.54-2.46 (qn, 1H).

b) Methyl 2-(2-chloro-4-fluorophenyl)-3-(oxirane-2-yl)propanoate

To chilled in ice to a solution of methyl 2-(2-chloro-4-fluorophenyl)pent-4-enoate (6.0 g; 24,7 mmol) in methylene chloride (50 ml) was added meta-chloroperbenzoic acid (6.7 g; 70% purity; to 27.2 mmol). Cooling bath was removed and the reaction mixture was stirred for 16 hours. The reaction mixture was filtered, the filtrate was washed several times with 1 n sodium hydroxide, dried with sodium sulfate and the solvent evaporated in vacuum. The residue was purified by column chromatography on silica gel using a mixture of n-heptane/ethyl acetate (vol./about. from 1:9 to 2:8) as eluent. Specified in the headers�ke compound was obtained as a colourless liquid (5.1 g; 80%).

MS ISP (m/e): 259,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.37-7.30 (m, 1H), 7.17-7.13 (m, 1H), 7.02-6.96 (m, 1H), 4.34-4.28 (m, 1H), 3.70 (s, 3H), 3.01-2.96 (m, 0.5 H), 2.86-2.80 (m, 0.5 H), 2.76 (t, 0.5 H), 2.70 (t, 0.5 H), 2.51 (dd, 0.5 H), 2.41 (dd, 0.5 H), 2.37 (dt, 0.5 H), 2.25 (dt, 0.5 H), 2.06 (dt, 0.5 H), 1.85 (dt, 0.5 H).

c) tert-Butyl(3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-ylcarbamate

To a solution of methyl 2-(2-chloro-4-fluorophenyl)-3-(oxirane-2-yl)propanoate (4,56 g; 17,6 mmol) in 2-propanol (20 ml) was added tert-butyl-carbazate (2.3 g; 17,6 mmol) and the reaction mixture was heated to a temperature of delegatie for 16 hours. Then the reaction mixture was concentrated to dryness, pererestorani in toluene (20 ml) was added 1,5,7-diazobicyclo(4.4.0)Dec-5-ene (0.6 g; 4.4 mmol) and the mixture was heated to a temperature of delegatie for 3 hours. The reaction mixture then was diluted with ethyl acetate, washed with 1 n HCl, dried with sodium sulfate and the solvent evaporated in vacuum. The residue is recrystallized from hot ethyl acetate, which allowed us to obtain specified in the title compound as a colorless solid (1.7 g; 26%). Uterine fluid contained TRANS-isomer.

MS ISP (m/e): 359,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.23 (dd, 1H), 7.12 (dd, 1H), 6.98 (td, 1H), 6.90 (br, 1H), 4.39-4.35 (t, 2H), 4.05 (dd, 1H), 3.67 (d, 1H), 2.32-2.27 (m, 1H), 2.17-2.05 (m, 1H), 1.48 (s, 9H).

(d) (3SR,5SR)-1-Amino-3-(2-chloro-4-fluorophenyl)-5-hydroxypiperidine-2-he

To tert-butyl(3SR,5SR)3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-ylcarbamate (1,67 g; The 4.7 mmol) was added HCl (10 ml; 4 n in dioxane) and the reaction mixture was stirred for 1 hour. Then the reaction mixture was concentrated to dryness, pererestorani in dichloromethane, washed with sodium bicarbonate, dried with sodium sulfate and the solvent was evaporated in vacuo, which allowed us to obtain specified in the title compound as a light yellow crystalline solid (1.11 g; 92%).

MS ISP (m/e): 259,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.19-7.12 (m, 2H), 6.99-6.94 (m, 1H), 4.36-4.30 (m, 2H), 3.89 (dd, 1H), 3.62 (dd, 1H), 2.23-2.17 (m, 2H).

e) tert-Butyl-4-(3-((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-yl)touraid)piperidine-1-carboxylate

To a solution of (3SR,5SR)-1-amino-3-(2-chloro-4-fluorophenyl)-5-hydroxypiperidine-2-one (0.8 g; 2.9 mmol) in dimethylacetamide (1 ml) was added 4-isothiocyanatobenzene-1-carboxylic acid tert-butyl ester (0.8 g; 3.2 mmol; US 2006/14958 A1) and the reaction mixture was stirred for 2 hours at 80°C. the Reaction mixture was diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent evaporated in vacuum. The product was triturated from dichloromethane by adding heptane, which allowed us to obtain specified in the title compound as colorless powder (1.2 g; 83%).

MS ISP (m/e): 501,2 [(M+H)+].

1H NMR (DMSO-D6, 400 MHz): δ (mn-1)=7.45-40 (m, 2H), 7.20 (td, 1H), 4.30-4.15 (m, 4H), 3.92-3.79 (m, 3H), .93-2.82 (m, 2H), 2.16-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.41 (s, 9H), 1.37-1.27 (m, 2H).

f) tert-Butyl-4-(((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1 elimino)(methylthio)methylamino)piperidine-1-carboxylate

To a solution of tert-butyl-4-(3-((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-yl)touraid)piperidine-1-carboxylate (1.2 g; 2.4 mmol) in DMF (5 ml) was added itmean (0.2 ml; 3.6 mmol) and the reaction mixture was heated to 90°C for 15 minutes. The reaction mixture was evaporated to dryness, pererestorani in stillette, washed with saturated sodium bicarbonate, water, brine, dried with sodium sulfate and the solvent evaporated in vacuum. Specified in the title compound, a mixture of geometric isomers, was used crude in the next stage (1.2 g; 99%).

MS ISP (m/e): 515,2 [(M+H)+].

g) tert-Butyl-4-(8-(2-chloro-4-fluorophenyl)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate

To a solution of tert-butyl-4-(((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1 elimino)(methylthio)methylamino)piperidine-1-carboxylate (1.1 g; 2.1 mmol) in DMF (5.5 ml) was added sodium azide (0.2 g; 3.2 mmol) and the reaction mixture was heated to 100°C for 48 hours. Then the reaction mixture was concentrated to dryness, pererestorani in ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent evaporated. The rest of pererestorani in THF, is added�and trimethylphosphine (2.1 ml; 1 M in toluene; 2.1 mmol) and the reaction mixture was heated to 160°C in a microwave oven for 12 hours. Then the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/MeOH (about./about. from 1:0 to 9:1) as eluent. Specified in the title compound was obtained as a light yellow foam (0.2 g; 20%) as an inseparable mixture (1:1) of diastereomers.

MS ISP (m/e): 466,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.15-7.06 (m, 2H), 6.97-6.93 (m, 1H), 4.77-3.53 (m, 8H), 2.95-2.89 (m, 2H), 2.55-2.36 (m, 1H), 2.03-1.99 (m, 2H), 1.45 (s, 9H), 1.37-1.27 (m, 2H).

h) 8-(2-Chloro-4-fluoro-phenyl)-2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol

To tert-butyl-4-(8-(2-chloro-4-fluorophenyl)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate (0.05 g; 0.1 mmol) was added HCl (3 ml; 4 n in dioxane) and the reaction mixture was stirred for 0.5 hours. Then the reaction mixture was concentrated to dryness, the residue pererestorani in dimethylacetamide (0.5 ml) was added triethylamine until the mixture became alkaline, was then added 2-chloro-4-herperidin (0.04 g; 0.3 mmol) and the mixture was heated to 80°C for 1 hour. The reaction mixture was evaporated to dryness, pererestorani in ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried with sodium sulfate and solvent� evaporated in vacuum. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/MeOH (about./about. from 1:0 to 95:5) as eluent. Specified in the title compound was obtained as a light yellow resin (0.04 g; 76%), an inseparable mixture (1:1) of diastereomers.

MS ISP (m/e): 477,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=7.98 (d, 1H), 7.15-7.06 (m, 2H), 6.98-6.92 (m, 1H), 6.64 (d, 1H), 6.56 (dd, 1H), 4.78-3.65 (m, 8H), 3.12-3.03 (m, 2H), 2.56-2.38 (m, 1H), 2.20-2.12 (m, 2H), 1.55-1.43 (m, 2H).

Example 218

8-(3-tert-Butylphenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1, stage P, on the basis of 1-(2-chloropyridin-4-yl)piperidine-4-it (see example 232b) and 8-(3-tert-butylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. The latter compound can be obtained analogously to example 1, stage (d-f on the basis of 2-amino-6-bromo-pyridine and 3-tert-butylaniline acid (EP 2243785 A1). Specified in the title compound was obtained as a colorless foam.

MS ISP (m/e): 461,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.30 (dd, 1H), 8.02-7.99 (m, 2H), 7.75 (dt, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 2H), 6.90 (t, 1H), 6.68 (d, 1H), 6.60 (dd, 1H), 4.52 (d, 1H), 4.01-3.91 (m, 1H), 3.84 (dt, 2H), 3.12 (td, 2H), 2.30-2.22 (m, 2H), 1.63-1.55 (m, 2H), 1.39 (s, 9H).

Example 219

[4-(3,4-Debtor-phenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

a) Z)-Phenyl-N'-cyano-N-(3.4-differenl)carbamimidoyl To a solution of 3,4-diferencia (646 mg; δ mmol) in isopropanol (10 ml) was added biphenyl cyanocarbonimidate (1.19 g; δ mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered, washed with isopropanol and dried under reduced pressure, obtaining specified in the title compound as a white solid (1.18 g; 86%).

MS ISP (m/e): of 274.1 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H).

b) (Z)-Phenyl-N'-cyano-N-(3,4-differenl)-N-(3-(tetrahydro-2H-Piran-2-yloxy)propyl)carbamimidoyl

To a solution of (Z)-phenyl-N'-cyano-N-(3,4-differenl)carbanilide (286 mg; 1.05 mmol) and 2-(3-bromopropane)tetrahydro-2H-PYRAN (369 mg; 277 µl; 1,57 mmol) in DMF (10.5 ml) was added at room temperature in a nitrogen atmosphere potassium carbonate (289 mg; 2,09 mmol). The suspension was heated to 85°C over night. Added additional amount of 2-(3-bromopropane)tetrahydro-2H-PYRAN (140 μl; 0.8 mmol) and potassium carbonate (145 mg; 1.05 mmol) and the reaction mixture was heated for δ hours to 85°C. water was Added and the reaction mixture was twice extracted with diethyl ether. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a light yellow elm�wow oil (202 mg; 46%) after column chromatography on silica gel using a gradient mixture of heptane/ethyl acetate 4:1 to 1:1 (vol./about.) as eluent.

MS ISP (m/e): 332,1 (100) [(M-THP+H)+], 416,3 (5) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.38 (t, 2H), 7.26-7.16 (m, 3H), 7.05 (m, 3H), 4.52 (t, 1H), 3.97 (t, 2H), 3.85 (m, 2H), 3.48 (m, 2H), 2.00 (pent, 2H), 1.79 (m, 1H), 1.68 (m, 1H), 1.55 (m, 4H).

c) N3-(3,4-Differenl)-N3-(3-(tetrahydro-2H-Piran-2-yloxy)propyl)-4H-1,2,4-triazole-3,5-diamine

To a solution of (Z)-phenyl-N'-cyano-N-(3,4-differenl)-N-(3-(tetrahydro-2H-Piran-2-yloxy)propyl)carbanilide (73 mg; 176 mmol) in methanol (0.5 ml) was added hydrazine hydrate (25% in water; 35,2 mg; 34,8 ml, 176 mmol). The reaction mixture was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel, using a mixture methylene chloride/methanol 19:1 (vol./about.) as eluent. Specified in the title compound was obtained as light yellow viscous oil (46 mg; 74%).

MS ISP (m/e): 354,2 (25) [(M+H)+], 270,3 (100) [(M-THP+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.56 (m, 1H), 7.26 (q, 1H), 7.16 (m, 1H), 5.96 (br s, 2H), 4.49 (t, 1H), 3.87 (m, 2H), 3.37 (m, 2H), 1.84 (m, 2H), 1.74 (m, 1H), 1.62 (m, 2H), 1.45 (m, 4H).

d) 3-((5-Amino-4H-1,2,4-triazole-3-yl)(3,4-differenl)amino)propan-1-ol

To a solution of N3-(3,4-differenl)-N3-(3-(tetrahydro-2H-Piran-2-yloxy)propyl)-4H-1,2,4-triazole-3,5-diamine (43 mg; mol) in methanol (1 ml) was added 2 n the aqueous solution of hydrogen chloride. The solution was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was transferred into a saturated aqueous solution of sodium hydrogen carbonate. It was twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure, obtaining specified in the title compound as a white solid (34 mg; Quant.) without further purification.

MS ISP (m/e): 270,3 (100) [(M+H)+].

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=7.56 (m, 1H), 7.26 (q, 1H), 7.15 (m, 1H), 6.00 (br s, 2H), 4.67 (t, 1H), 3.87 (t, 1H), 3.42 (q, 2H), 1.71 (t, 2H).

e) 4-(3,4-Differenl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-ylamine

To a solution of 3-((5-amino-4H-1,2,4-triazole-3-yl)(3,4-differenl)amino)propan-1-ol (31 mg; 115 mmol) in tetrahydrofuran (1,15 ml) was added at 0°C in an atmosphere of nitrogen triphenylphosphine (45,3 mg; 173 μmol). The reaction mixture was stirred for 15 minutes and then was added DEAD (diethylazodicarboxylate) (31,0 mg; 28,2 ml, 173 mmol). The reaction mixture was stirred for 30 minutes at 0°C and then at room temperature overnight. The same technique herself reproduced with additional quantities�m triphenylphosphine (45,3 mg; 173 mmol) and DEAD (31,0 mg; 28,2 ml, 173 mmol). Added water and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a colorless solid (14 mg; 48%) after column chromatography on silica gel, using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent.

MS ISP (m/e): 252,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.82 (m, 1H), 7.41-7.33 (m, 2H), 4.00 (t, 2H), 3.93 (bs, 2H), 3.72 (t, 2H), 2.30 (pent, 2H).

f) 4-(3,4-Differenl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine

To a solution of 4-(3,4-differenl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine (41 mg; 163 mmol) in tetrahydrofuran (1 ml) was added in a nitrogen atmosphere hexachlorethane (61,0 mg; 245 mmol), triethylamine (49.5 mg, 68.2 per ml, 490 mmol) and 1 M solution of trimethylphosphine in toluene (245 ml, 245 mmol). The suspension was stirred for 30 minutes at room temperature. Was added 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b); 46,8 mg; 245 μmol) dissolved in tetrahydrofuran (0.5 ml), and the yellow slurry heater�Ali to 150°C for 30 minutes. Was added a 1M solution of a complex of borane-tetrahydrofuran in methylene chloride (490 ml, 490 mmol) and the reaction mixture was heated to 100°C for one hour. The reaction mixture was diluted with water and was extracted with twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent evaporated. Specified in the title compound was obtained as a colorless solid (14 mg; 20%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (vol./about.) as eluent, and after subsequent purification preparative HPCL

MS ISP (m/e): 427,3 (100) [(M+H)+], 176,3 (81).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (s, 1H), 7.38 (m, 1H), 7.14-7.09 (m, 2H), 6.38 (s, 1H), 4.30 (br d, 2H), 4.03 (t, 2H), 3.91 (d, 1H), 3.73 (t, 2H), 3.71 (m, 1H), 3.14 (mt, 2H), 2.35 (s, 3H), 2.32 (m, 2H), 2.15 (br d, 2H), 1.41 (mq, 2H).

Example 220

N-(1-(2-Methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 8-(2-Methoxypyridine-4-yl)-1,4-dioxa-8 azaspiro[4,5]Dean

A solution of palladium acetate(II) (62.5 mg; 279 μmol) and 2-(DICYCLOHEXYL-phosphino)biphenyl (201 mg; 557 µmol) in dioxane (1.5 ml) was stirred under argon atmosphere at room temperature for 10 minutes, then was added to a solution of 4-chlor-methoxypyridine (500 mg; 3,48 mmol), 1,4-dioxa-8 azaspiro[4.5]Decan (499 mg; 446 ml, 3.48 mmol) and tert-butylate sodium (502 mg; with 5.22 mmol) in dioxane (1.5 ml), degassed and the reaction mixture was barbotirovany argon for δ minutes. The reaction mixture was heated in a microwave oven to 130°C for 30 minutes.

The reaction mixture was filtered through Dicalite, to the filtrate was added water and the aqueous phase three times were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 70 g; 80% to 100% ethyl acetate in heptane). Specified in the title compound was obtained as a brown oil (700 mg; 80%).

MS ISP (m/e): 251,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.88-7.86 (m, 1H), 6.41-6.39 (m, 1H), 6.07-6.06 (m, 1H), 3.99 (s, 4H), 3.89 (s, 3H), 3.47-3.43 (m, 4H), 1.77-1.74 (m, 4H).

b) N-(1-(2-Methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 93b-C, using 8-(2-methoxypyridine-4-yl)-1,4-dioxa-8 azaspiro[4.5]decane. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 459,4 (83) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.88-7.86 (m, 1H), 6.96-6.87 (m, 1H), 6.77-6.70 (m, 1H), 6.40-6.37 (m, 1H), 6.06-6.05 (m, 1H), 4.38-4.34 (m, 1H), 4.11-4.07 (m, 2H), 4.01-3.98 (m, 1H), 3.89 (s, 3H), 3.77-3.62 (m. 3H), 3.07-2.98 (m, 2H), 2.33-2.24 (m, 1H), 2.16-1.90 (m, 5H), 1.56-1.42 (m, 2H).

PR�measures 221

[8-(2-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 426,1/428,2 (100/47) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.35 (m, 1H), 7.54-7.49 (m, 2H), 7.42-7.35 (m, 3H), 6.93-6.88 (m, 1H), 4.63-4.60 (m, 1H), 3.94-3.85 (m, 3H), 3.39-3.30 (m, 2H), 2.41 (s, 3H), 2.27-2.22 (m, 2H), 1.70-1.61 (m, 2H).

Example 222

[8-(3-Dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (see example 1C) and 8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 66A-C). Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 435,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.30-8.28 (m, 1H), 7.55-7.52 (m, 1H), 7.36-7.32 (m, 2H), 7.22 (m, 1H), 6.91-6.86 (m, 1H), 6.80-6.78 (m, 1H), 4.57-4.54 (m, 1H), 4.00-3.87 (m, 3H), 3.38-3.30 (m, 2H), 3.01 (s, 6H), 2.42 (s, 3H), 2.29-2.23 (m, 2H), 1.72-1.62 (m, 2H).

Example 223

[8-(2-Fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 411,2 (100) (M+H) +].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.43-8.40 (m, 1H), 8.34-8.32 (m, 1H), 7.84-7,81 (m, 1H),7.73(m, 1H), 7.70-7.67 (m, 1H), 6.98-6.94 (m, 1H), 4.62-4.60 (m, 1H), 4.01-3.90 (m, 3H), 3.42-3.32 (m, 2H), 2.42 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.66 (m, 2H).

Example 224

[8-(3,5-Bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 93. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 526,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.49 (m, 1H), 7.79 (s, 1H), 7.65 (s, 2H), 6.38 (m, 1H), 4.28-4.23 (m, 3H), 4.16-4.00 (m, 3H), 3.79-3.68 (m, 1H), 3.17-3.07 (m, 2H), 2.35 (s, 3H), 2.41-2.32 (m, 1H), 2.17-1.92 (m, 5H), 1.51-1.34 (m, 2H).

Example 225

(8-Benzo[1,3]dioxol-5-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66. Specified in the title compound was obtained as a yellow foam.

MS ISP (m/e): 436,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.29-8.27 (m, 1H), 7.49 (m, 1H), 7.46-7.41 (m, 2H), 6.94-6.91 (m, 1H), 6.89-6.85 (m, 1H), 6.02 (s, 2H), 4.51-4.49 (m, 1H), 4.00-3.88 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.29-2.24 (m, 2H), 1.72-1.59 (m, 2H).

Example 226

[8-(2-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) (8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-and�)-piperidine-4-yl]-amine

To a suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see example 66b), (80 mg; 376 μmol) and hexachlorethane (133 mg; 563 mmol) in an argon atmosphere in anhydrous THF (3 ml) was added triethylamine (114 mg; 157 µl; 1,13 mmol), then trimethylphosphine (1 M in THF; 563 ml, 563 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then was added 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (88,9 mg; 451 mmol) and the mixture was heated in a microwave oven to 150°C for 30 minutes. Added additional amount of 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (40 mg; 188 μmol) and heated to 150°C for 30 minutes. To the reaction mixture was added NaBH4(56,8 mg; 1.5 mmol) and EtOH (2.0 ml) and heated to 65°C for 1 hour. Added additional amount of NaBH4 (56,8 mg; 1.5 mmol) and stirred at 65°C in the next hour. Added additional amount of NaBH4(56,8 mg; 1.5 mmol) and the reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was extracted with CH2Cl2and water, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated.

The residue was purified by flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a white foam (140 mg; 95%).

MS ISP (m/e): 394,1/395,9 (100/98) [(M+H)+].

1H �Mr (CDCl 3, 300 MHz): δ (mn-1)=8.30-8.27 (m, 1H), 7.62-7.59 (m, 1H), 6.73-6.69 (m, 1H), 4.61-4.59 (m, 1H), 3.98-3.87 (m, 3H), 3.40-3.31 (m, 2H), 2.42 (s, 3H), 2.27-2.22 (m, 2H), 1.73-1.59 (m, 2H).

(b) [8-(2-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 66, using (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine and 2-chloro-5-(trifluoromethyl)-phenylboronic acid. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 494,3/496,2 (100/41) [(M+N)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.41-8.38 (m, 1H), 7.81 (m, 1H), 7.67-7.60 (m, 2H), 7.44-7.41 (m, 1H), 6.95-6.90 (m, 1H), 4.55-4.52 (m, 1H), 3.92-3.85 (m, 3H), 3.39-3.29 (m, 2H), 2.41 (s, 3H), 2.28-2.22 (m, 2H), 1.72-1.59 (m, 2H).

Example 227

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(6-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine

Was prepared analogously to example 66, based on 5-bromopyridin-2-amine in step a). Specified in the title compound was obtained as orange solids.

MS ISP (m/e): 392,2 (40) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.53 (m, 1H), 7.67-7.63 (m, 1H), 7.57-7.40 (m, 6H), 4.50-4.47 (m, 1H), 4.03-3.89 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.31-2.25 (m, 2H), 1.74-1.61 (m, 2H).

Example 228

[8-(3,5-Bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2'-methoxy-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amine

Was prepared analogously to example 220. Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 541,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.90-7.88 (m, 1H), 7.81 (s, 1H), 7.63 (s, 2H), 6.42-6.39 (m, 1H), 6.05-6.04 (m, 1H), 4.27-4.22 (m, 1H), 4.16-4.12 (m, 2H), 3.90 (s, 3H), 3.78-3.65 (m, 3H), 3.12-3.02 (m, 2H), 2.40-2.33 (m, 1H), 2.21-1.92 (m, 5H), 1.61-1.46 (m, 2H).

Example 229

[8-(3,5-Bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 532,0 (57) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.80 (m, 1H), 7.64 (m, 2H), 4.32 (br, 1H), 4.27-4.23 (m, 1H), 4.16-4.12 (m, 2H), 3.87-3.81 (m, 2H), 3.76-3.67 (m, 1H), 3.35-3.25 (m, 2H), 2.40 (s, 3H), 2.38-2.33 (m, 1H), 2.19-1.91 (m, 5H), 1.67-1.52 (m, 2H).

Example 230

[8-(4-Dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 1h, using 1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-it (see example 1C) and 8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (obtained analogously to example 66A-C). Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 435,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.23-8.21 (m, 1H), 7.91-7.88 (m, 2H), 7.48-7.45 (m, 1H), 6.88-6.81 (m, 3H), .52-4.49 (m, 1H), 3.98-3.87 (m, 3H), 3.41-3.32 (m, 2H), 3.01 (s, 6H), 2.42 (s, 3H), 2.30-2.24 (m, 2H), 1.73-1.60 (m, 2H).

Example 231

4-(8-(3,4-Differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(6-methylpyrimidin-4-yl)piperidine-4-carbonitrile F

To a solution of 1-(6-methylpyrimidin-4-yl)piperidine-4-it (see example 93b); 100 mg; 0,523 mmol) and 8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (129 mg; 0,523 mmol) in Acoh was added dropwise trimethylsilylacetamide (196 μl; 1,57 mmol) and the resulting mixture was stirred at room temperature for 88 hours. The mixture was then poured into NaOH (6 M, 6 ml) and stirred for 10 minutes. The precipitate is then filtered and dried. Purification by chromatography (silica gel; 20 g; 30 to 100% ethyl acetate in heptane) allowed us to obtain specified in the title compound (20 mg; 9%) as a yellow solid.

MS ISP (m/e): 447,4 [(M+H)+].

Example 232

1-(2-Chloropyridin-4-yl)-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-4-carbonitrile

a) 8-(2-Chloropyridin-4-yl)-1,4-dioxa-8 azaspiro[4.5]Dean

To a solution of 1,4-dioxa-8 azaspiro[4.5]Decan (895 µl; 6,98 mmol) and 2-chloro-4-herperidin (1.01 g; to 7.68 mmol) in dioxane (15 ml) was added N,N-diisopropylethylamine (1,83 ml; 10.5 mmol). The reaction mixture was barbotirovany argon for δ minutes, then it was heated to 120°C in microwave oven for 3 hours. After pariani�, purification by chromatography (silica gel; 20 g; from 30% to 10% ethyl acetate in heptane) received specified in the title compound (1.3 g; 73%) as a yellow solid.

MS ISP (m/e): 255,3 [(M+H)+].

b) 1-(2-Chloropyridin-4-yl)piperidine-4-it

To a solution of 8-(2-chloropyridin-4-yl)-1,4-dioxa-8 azaspiro[4.5]Decan (1.26 g; 4.95 mmol) in acetone (11 ml) was added HCl (2 n; 39,6 ml, 79.1 mmol) and the resulting mixture was stirred at 50°C for 2 hours, then cooled to room temperature. pH summed up to ~8 by adding solid sodium bicarbonate, and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated, receiving specified in the header of the product (1.03 g; 99%) as a white solid.

MS ISP (m/e): 211,1 [(M+H)+].

c) 1-(2-Chloropyridin-4-yl)-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-4-carbonitrile

Was prepared analogously to example 231, using 1-(2-chloropyridin-4-yl)piperidine-4-it (150 mg; 0.44 mmol) instead of 1-(6-methylpyrimidin-4-yl)piperidine-4-it.

Specified in the title compound was obtained as a light yellow solid (31 mg; 14%).

MS ISP (m/e): 466,3 [(M+H)+].

Example 233

8-(3,4-Differenl)-N-((3S,4R)-3-methoxy-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) (3S,4R)-tert-Butyl-4-(8-(3,4-d�fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3-methoxypiperidine-1-carboxylate

Was prepared analogously to example C, using (3S,4R)-4-amino-1-BOC-3-methoxy-pyridine (100 mg; 0.43 mmol) instead of 1-(2-chloropyridin-4-yl)piperidine-4-amine.

Specified in the title compound was obtained as a yellow resin (40 mg; 20%).

MS ISP (m/e): 460,3 [(M+H)+].

b) 8-(3,4-Differenl)-N-(3S,4R)-3-methoxypiperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride

To a solution of (3S,4R)-tert-butyl-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-3-methoxypiperidine-1-carboxylate (37 mg; of 80.5 mmol) in dichloromethane (1 ml) was added HCl (2 M in diethyl ether; 201 ml, 403 mmol) and the reaction mixture stirred at room temperature for 18 hours. The mixture then was filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried, which allowed us to obtain specified in the title compound (32 mg; 92%) as a whitish solid substance.

MS ISP (m/e): to 360.2 [(M+H)+].

c) 8-(3,4-Differenl)-N-((3S,4R)-3-methoxy-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

8-(3,4-Differenl)-N-((3S,4R)-3-methoxypiperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (28 mg; for 64.8 mmol) was extracted with a mixture of dichloromethane/2 M NaOH. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was dissolved in dioxane (0.5 ml) and to this solution was added 4-chloro-6-methylpyrimidin (9,2 mg; 71,2 μmol) and DIPEA (17,0 MK�; 97,2 mmol). The solution for δ minutes barbotirovany with argon and then heated in a microwave at 130°C for 2×30 minutes. After evaporation, purification by chromatography (silica gel; 10 g; 0 to 10% methanol in dichloromethane) received specified in the title compound (18 mg; 62%) as a whitish foam.

MS ISP (m/e): 452,3 [(M+H)+].

Example 234

8-(3,4-Differenl)-N-(4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(6-methylpyrimidin-4-yl)piperidine-4-carbonitrile (Example 231) (50 mg, 112 μmol) in THF (2 ml) dropwise at 0°C was added the bromide Metalmania (1.4 M in a mixture of toluene:THF; 240 ml, 336 mmol), the resulting mixture was allowed to warm to room temperature and stirred for 3 hours. Then, the mixture was quenched with a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 10 g; 0 to 10% methanol in dichloromethane) allowed us to obtain specified in the title compound (9 mg; 19%) as a light yellow solid substance.

MS ISP (m/e): 436,3 [(M+H)+].

Example 235

8-(3,4-Differenl)-N-(4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p�ridin-2-amine

a) tert-Butyl-4-carbamoyl-4-demerol-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)-4-demerol-4-carboxylic acid (2.85 g; 11.7 mmol) in DMF (57 ml) was added CDI (2,28 g, 14,1 mmol). The mixture was stirred at 60°C for 30 minutes, then cooled to room temperature. Caution was added ammonium hydroxide (18,2 ml, 117 mmol) and stirring was continued for 1 hour. The mixture then was evaporated, yielding a colorless oil. It was extracted with ethyl acetate, the organic layer was washed with HCl (1 M), water, sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. The residue was transferred into toluene, then hexane was added and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with hexane and dried, obtaining specified in the title compound (2.55 g; 90%) as a white solid.

MS ISP (m/e): 243,3 [(M+H)+].

b) tert-Butyl-4-amino-4-demerol-1-carboxylate To a suspension of tert-butyl-4-carbamoyl-4-demerol-1-carboxylate (2,52 g; 10.4 mmol) in acetonitrile (7.6 ml) and water (23,4 ml) was added KOH (2,63 g; for 46.8 mmol) at 0°C. Then, in one portion was added 1,3-dibrom-5,5-dimethylhydantoin (1.64 g; 5,72 mmol) at 0°C and after stirring at 0°C for 30 minutes the solution was allowed to warm to room temperature ipermediali for 1 hour. Was added sodium sulfite (131 mg; 1.04 mmol) and the mixture was stirred for 15 minutes at room temperature, was then added ethyl acetate and the reaction mixture was cooled to 10°C. was Added K2PO4(2,34 g; 11.0 mmol) and the mixture was heated to room temperature and was extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, was filtered and was evaporated, getting mentioned in the title compound (2.1 g; 94%) as a colorless oil.

MS ISP (m/e): 215,3 [(M+H)+].

C) 4-Demerol-4-amine bis(4-methylbenzenesulfonate)

A solution of tert-butyl-4-amino-4-demerol-1-carboxylate (1,96 g; 9,15 mmole) in MeOH (15,2 mmol) was added dropwise during 30 minutes to a solution of n-toluensulfonate acid monohydrate (4,00 g, 21,0 mmol) in 2-propanol (7,9 ml) at 60°C. the Reaction mixture was then heated to 60°C for 16 h. After cooling to 0°C the precipitate was filtered, washed with 2-propanol and dried, obtaining specified in the title compound (3.91 g; 93%) as a white solid.

MS ISP (m/e): shall be 115.1 [(M+H)+].

a) 4-Methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-amine

To a mixture of 4-Demerol-4-amine bis(4-methylbenzenesulfonate) (3.91 g; 8,53 mmol) and 4-chloro-6-methylpyrimidine (1.10 g; 8,53 mmol) in NMP (35 ml) was added K2PO4(3.12 g; a 17.9 mmol) and the reaction mixture was stirred at 80°C for 18 hours.

Last� cooling to room temperature, added 0.5 M aqueous K2PO4and the mixture was twice extracted with dichloromethane. The combined organic layers twice was extracted with HCl (1 n). The combined aqueous layers were podslushivaet using NaOH (6 n), and was twice extracted with dichloromethane, the organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 70 g; 0 to 100% ethyl acetate in heptane, then 0 to 50% methanol in ethyl acetate containing 10% triethylamine) allowed us to obtain specified in the title compound (1,09 g; 62%) as a light yellow semi-solid substances.

MS ISP (m/e): 207,2 [(M+H)+].

e) 4-(4-Isothiocyanato-4-demerol-1-yl)-6-methylpyrimidin

To a solution of 4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-amine (1,09 g, 5,28 mmol) in dichloromethane (17,2 ml) was added 1,1'-thiocarbonyldiimidazole-2(1H)-he (1.84 g; a 7.92 mmol) and the reaction mixture stirred at room temperature for 16 hours. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel; 3×70 g; 50 to 100% ethyl acetate in heptane) allowed us to obtain specified in the title compound (1.2 g; 91%) as a light yellow solid substance.

MS ISP (m/e): 249,1 [(M+H)+].

f) 1-(4-Methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)thiourea

A solution of 4-(4-isothiocyanato-4-demerol-1-yl)-6-methylpyrimidin�to (1.18 g; 0.53 mmol) in ammonia (7 M in MeOH; 13,6 ml; 95,0 mmol) was stirred in a sealed vial at room temperature for 3 h and then was heated at 50°C for 18 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel; 50 g; 0 to 20% methanol in dichloromethane) allowed us to obtain specified in the title compound (1.2 g; 100%) as a white foam.

MS ISP (m/e): to 266.2 [(M+H)+].

g1) Methyl-4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-ylcarbamate hydroiodide

To a solution of 1-(4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)thiourea (1.28 g; 4.82 mmol) in EtOH (11,7 ml) was added MeI (332 μl; 5,31 mmol) and the reaction mixture was stirred in argon atmosphere at 75°C for 3 hours. The reaction mixture was then evaporated and the residue (white foam) was stirred in diethyl ether (15 ml) at room temperature for 1 hour. The solid is then washed with diethyl ether and dried, which allowed us to obtain specified in the title compound (1.89 g; 96%) as a white solid.

MS ISP (m/e): RUR 190.3 [(M+H)+].

q2) 5-Chloro-2-(3,4-differenl)pentanoic acid

To a solution of 3,4-dipertanyakan acid (5,00 g, 29,0 mmol) in THF (58 ml) dropwise at 0°C was added NaHMDS (1 M in THF; to 58.1 ml; to 58.1 mmol). The reaction mixture was then stirred at 0°C for 20 min, then, dropwise, at 0°C was added 1-chloro-3�propan (3,12 ml; 29,0 mmol) and the reaction mixture stirred at room temperature for 16 hours. The mixture was then quenched with water (3 ml) with cooling in an ice bath and evaporated. To the residue was added NaOH (1 n, 150 ml) and the resulting solution was extracted with diethyl ether (2×100 ml). The aqueous layer was acidified with using HCl (1 n; 200 ml) and was extracted with diethyl ether (2×100 ml). The combined organic layers are then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 2×50 g; 0 to 50% ethyl acetate in heptane) allowed us to obtain specified in the title compound (2,02 g; 28%) as a light yellow oil.

MS ISP (m/e): 247,0/249,1 [(M-N)-].

h) 8-(3,4-Differenl)-N-(4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of methyl 4-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-ylcarbamate of hydroiodide (1.85 g; of 4.54 mmol) containing 5-chloro-2-(3,4-differenl)pentanoic acid (1.24 g; 5.00 mmol), EDC (0,87 g; of 4.54 mmol) and 1-hydroxybenzotriazole hydrate (1,39 g, 9.08 mmol) in DMF (22,3 ml) was added DIPEA (1,98 ml; 11,4 mmol) and the reaction mixture stirred at room temperature for 18 hours. Then was added hydrazine monohydrate (0,57 ml; 18,2 mmol) and the reaction mixture was stirred at 70°C for 5 h. the Reaction mixture then was poured into water, and was twice extracted with atilas�tat, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 2×50 g; 0 to 20% methanol in dichloromethane) allowed us to obtain specified in the title compound (14 mg; 1%) as a light red foam

MS ISP (m/e): 440,3 [(M+H)+].

Example 236

N-(1-(2-Chloropyridin-4-yl)-4-demerol-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 234, using 1-(2-chloropyridin-4-yl)-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-4-carbonitrile (18 mg; 36 μmol) instead of 4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(6-methylpyrimidin-4-yl)the piperidine-4-carbonitrile.

Specified in the title compound was obtained as a whitish solid (2.5 mg; 14%).

MS ISP (m/e): 455,2 [(M+H)+].

Example 237

8-(3,4-Differenl)-N-(2-methyl-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example C, using 4-chloro-6-methylpyrimidin instead of 4-bromo-2-methylpyridine and 8-(3,4-differenl)-N-(2-demerol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine instead of 8-(2-chloro-4-fluorophenyl)-N-(piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

Specified in the title compound was obtained as a light brown foam.

MS ISP (m/e): 43,3 [(M+H) +].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (s, 1H), 8.32 (s, 1H), 7.95 (m, 1H), 7.70 (m, 1H), 7.50 (d, 1H), 7.23 (m, 1H), 6.89 (dd, 1H), 6.33 (s, 1H), 4.70 (d, 1H), 4.50 (m, 1H), 4.30 (m, 1H), 4.00 (m, 1H), 3.35-3.25 (m, 2H), 2.60 (m, 1H), 2.40 (s, 3H), 2.10-2.00 (m, 2H), 1.34 (d, 3H).

Example 238

(CIS, RAC)-N-(3-Fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 4-Trimethylsilyloxy-3.6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

tert-Butyl-4-oxopiperidine-1-carboxylate (10 g; of 48.7 mmol) was dissolved in anhydrous DMF (12.0 ml). Was added in an argon atmosphere trimethylsilane (6,35 g; 7,39 ml; 58,4 mmol) and triethylamine (11,8 g; 16,2 ml, 117 mmol) and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, was added a saturated solution of NaHCO3and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (added 1 drop of Et3N during the preparation of the column (silica gel; 100 g; from 0% to 100% pentane in Et2O; 45 minutes). Specified in the title compound was obtained as a colourless liquid (13.2 g; 99%).

MS ISP (m/e): 272,2/216,3 (41/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=4.80 (m, 1H), 3.88-3.87 (m, 2H), 3.55-3.51 (m, 2H), 2.11 (m, 2H), 1.47 (s, 9H), 0.20 (s, 9H).

b) tert-Butyl-3-fluoro-4-oxopiperidine-1-carboxylate

4 Trimethylsilyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13.2 g; to 48.6 mmol) was dissolved in acetonitrile (250 ml). Was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (19.0 g; of 53.5 mmol) and the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added brine, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 100 g; from 0% to 100% EtOAc in heptane). Specified in the title compound was obtained as white solid (5,66 g; 53%).

MS ISP (m/e): 161,2 (100) [(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=4.94-4.73 (m, 1H), 4.47 (m, 1H), 4.22-4.16 (m, 1H), 3.29-3.20 (m, 2H), 2.64-2.52 (m, 2H), 1.50 (s, 9H).

c) (CIS, RAC)-tert-Butyl-4-(benzylamino)-3-foreperiod-1-carboxylate

A mixture of tert-butyl-3-fluoro-4-oxopiperidine-1-carboxylate (1,255 g; 5.78% was established mmol), triacetoxyborohydride sodium (1.89 g; 8,67 mmol) and benzylamine (681 mg; 695 µl; 6,35 mmol) in 1,2-dichloroethane (15 ml) was maintained at room temperature for 3 hours. To the reaction mixture were added an aqueous solution of sodium carbonate (2 M) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and dissolve�spruce evaporated. The residue was purified by flash chromatography (silica gel; 100 g; from 0% to 100% EtOAc in heptane). Specified in the title compound was obtained as yellow oil (982 mg; 55%), in addition received TRANS-isomer (yellow oil; 200 mg; 11%).

MS ISP (m/e): 309,3/253,2 (50/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.35-7.27 (m, 5H), 4.85-4.67 ('or, 1H), 4.33 br, 1H), 4.11 (br, 1H), 3.87 (s, 2H), 3.04-2.88 (m, 1H), 2.78-2.64 (m, 2H), 1.77-1.50 (m, 3H), 1.46 (s, 9H).

(d) (CIS, RAC)-4-Amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

A suspension of (CIS)-tert-butyl-4-(benzylamino)-3-foreperiod-1-carboxylate, Pd/C (102 mg; the 95.5 mmol) in MeOH (20 ml) were gidrirovanie at room temperature for 6 hours. The catalyst was filtered, thoroughly washed with MeOH and the solvents evaporated. Specified in the title compound was obtained as a light yellow foam (690 mg; 99%).

MS ISP (m/e): 219,2/163,3 (3/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=4.63-4.47 (br, 1H), 4.31 (br, 1H), 4.07 (br, 1H), 3.08-2.79 (m, 3H), 1.77-1.63 (m, 2H), 1.49 (bs, 2H), 1.46 (s, 9H).

(e) (CIS, RAC)-tert-Butyl-3-fluoro-4-(8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate

A suspension of CIS-tert-butyl-4-amino-3-foreperiod-1-carboxylate (350 mg; 1.6 mmol), 2-bromo-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridine (obtained analogously to example 66a-d); 579 mg; 1,76 mmol), chloroform adduct of Tris(dibenzylideneacetone)dipal�Diya(0) (66,4 mg; For 64.1 mmol), phenolate sodium (279 mg; 2,41 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74,2 mg; 128 mmol) in anhydrous dioxane (12 ml) were barbotirovany with argon for 5 minutes, then heated to 150°C for 60 minutes. The crude substance was purified flash chromatography (silica gel; 100 g; from 0% to 100% EtOAc in heptane). Specified in the title compound was obtained as a light yellow oil (231 mg; 31%).

MS ISP (m/e): 466,3/410,3 (58/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.62-7.54 (m, 1H), 7.51-7.49 (m, 1H), 7.14-7.05 (m, 1H), 6.94-6.89 (m, 1H), 4.93-4.76 (br, 1H), 4.86-4.83 (m, 1H), 4.45 (br, 1H), 4.26 (br, 1H), 4.02-3.83 (m, 1H), 3.15-2.79 (m, 2H), 1.97-1.91 (m, 1H), 1.88-1.74 (m, 1H), 1.47 (s, 9H).

(f) (CIS, RAC)-N-(3-foreperiod-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of (CIS)-tert-butyl-3-fluoro-4-(8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate (462 mg; 993 μmol) in CH2Cl2(10 ml) at 0°C was added TFA (792 mg; 535 µl; to 6.95 mmol) and stirred at room temperature for 18 hours. The reaction mixture was extracted with saturated solution of NaHCO3and ethyl acetate, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The product was twice evaporated together with the toluene. Specified in the title compound was obtained as a light yellow foam (363 mg; 100%).

The crude product is used�Ali the next step without further purification.

MS ISP (m/e): 366,2/346,1 (58/100) [(M+H)+/(M-HF)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.48 (m, 1H), 7.14-7.05 (m, 1H), 6.93-6.88 (m, 1H), 4.88 (bs, 1H), 4.85-4.72 (br, 1H), 4.01-3.81 (m, 1H), 3.41-3.33 (m, 1H), 3.19-3.13 (m, 1H), 2.95-2.70 (m, 2H), 1.99-1.94 (m, 1H), 1.74-1.65 (m, 1H), 1.60 (s, 1H).

(g) (CIS, RAC)-N-(3-Fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Degassed solution of 2-(dicyclohexylphosphino)biphenyl (9,21 mg; 26,3 mmol) and palladium acetate(II) (2,95 mg; 13,1 mmol) in dioxane (2 ml) was stirred for 10 minutes at room temperature, was then added to a solution of (CIS)-N-(3-foreperiod-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (60 mg; 164 mmol), 5-chloro-3-methyl-1,2,4-thiadiazole (24.3 mg, 181 μmol) and tert-butylate sodium (23,7 mg; 246 μmol) in dioxane (2 ml). The solution was barbotirovany with argon for 5 minutes, then heated to 140°C in microwave oven for 30 minutes. Added additional amount of degassed solution of 2-(dicyclohexylphosphino)-biphenyl (9,21 mg; 26,3 mmol) and palladium acetate(II) (2,95 mg; 13,1 mmol) in dioxane (2 ml), then 5-chloro-3-methyl-1,2,4-thiadiazole (24.3 mg, 181 μmol) and heated to 140°C for 30 minutes and further to 150°C for 30 minutes. The reaction mixture was directly purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Wook�specified in the title compound was obtained as a light yellow foam (19,7 mg; 26%).

MS ISP (m/e): 464,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.34 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.50 (m, 1H), 7.15-7.05 (m, 1H), 6.96-6.91 (m, 1H), 5.08-4.92 (m, 1H), 4.88-4.85 (m, 1H), 4.40-4.32 (m, 1H), 4.17-3.93 (m, 2H), 3.53-3.29 (m, 1H), 3.19-3.13 (m, 1H), 2.42 (s, 3H), 2.10-2.00 (m, 2H).

Examples 239 and 240

(3S,4R)- and (3R,4S)-N-(3-Fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

As a result of separation of racemic (CIS)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 238; 52 mg) chiral HPLC (Choralpak AD) using a mixture of isopropanol/n-heptane (2:3) as eluent received both enantiomer (without establishing the absolute configuration of enantiomers).

Example 239: enantiomer 1(-), retention time 15,76 minutes (19 mg).

Example 240: enantiomer 2(+), retention time 26,72 minutes (16 mg).

Example 241

(CIS, RAC)-[3-Fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 238. Specified in the title compound was obtained as a light yellow oil.

MS ISP (m/e): of 428.0 (100) [(M+H)+].

1P NMR (CDCl3, 300 MHz): δ (mn-1)=8.31-8.29 (m, 1H), 7.97-7.92 (m, 2H), 7.52-7.49 (m, 1H), 7.21-7.15 (m, 2H), 6.94-6.90 (m, 1H), 5.11-4.94 (m, 1H), 4.91-4.88 (m, 1H), 4.41-4.32 (m, 1H), 4.21-3.95 (m, H), 3.54-3.31 (m, 2H), 2.42 (s, 3H), 2.11-2.02 (m, 2H).

Example 242

(CIS, RAC)-[8-(3,4-Debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine

A solution of 8-(3,4-differenl)-N-(CIS-3-foreperiod-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained as in example 238a-f); 60,0 mg; 173 mmol), 4-chloro-6-methylpyrimidine (24,4 mg; 190 mmol) and N,N-Diisopropylamine (33,5 mg; 44,1 ml, 259 mmol) in dioxane (4 ml) was heated to 150°C in microwave oven for 2 hours. The reaction mixture was directly purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as an orange foam (52 mg; 69%).

MS ISP (m/e): 440,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.53 (m, 1H), 8.33-8.31 (m, 1H), 7.96-7.89 (m, 1H), 7.74-7.68 (m, 1H), 7.53-7.50 (m, 1H), 7.32-7.23 (m, 1H), 6.95-6.90 (m, 1H), 6.46 (m, 1H), 5.11-4.94 (m, 1H), 4.89-4.86 (m, 2H), 4.60-4.55 (m, 1H), 4.21-4.02 (m, 1H), 3.29-3.02 (m, 2H), 2.38 (s, 3H), 2.13-2.08 (m, 1H), 1.97-1.83 (m, 1H).

Example 243

(CIS, RAC)-[3,4-Debtor-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

Was prepared analogously to example 238. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): to 446.1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.33-8.30 (m, 1H), 7.95-7.88 (m, 1H), 7.72-7.68 (m, 1H), 7.53-7.50 (m, 1H), 7.32-7.23 (m, 1H, 6.95-6.91 (m, 1H), 5.11-4.95 (m, 1H), 4.92-4.89 (m, 1H), 4.41-4.33 (m, 1H), 4.21-3.95 (m, 2H), 3.55-3.31 (m, 2H), 2.42 (s, 3H), 2.12-2.03 (m, 2H).

Example 244

(CIS, RAC)-N-(1-(2-Chloropyridin-4-yl)-3-foreperiod-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a mixture of 8-(3,4-differenl)-N-(CIS-3-foreperiod-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained as in example 238a-f); 60 mg; 173 μmol) and 2-chloro-4-herperidin (22,7 mg; 173 μmol) in NMP (3 ml) was added DIPEA (31,3 mg; 42,2 ml, 242 mmol). The cloudy solution was barbotirovany with argon for 5 minutes, then heated to 150°C in a microwave for 60 minutes. Added additional amount of 2-chloro-4-herperidin (22,7 mg; 173 μmol) and DIPEA (31,3 mg; 42,2 ml, 242 mmol) and heated to 150°C for 30 minutes. The reaction mixture was poured into H2O, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a white foam (26 mg; 33%).

MS ISP (m/e): 459,4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.33-8.30 (m, 1H), 8.05-8.03 (m, 1H), 7.95-7.89 (m, 1H), 7.73-7.68 (m, 1H), 7.53-7.51 (m, 1H), 7.32-7.23 (m, 1H), 6.95-6.90 (m, 1H), 6.72-6.71 (m, 1H), 6.64-6.61 (m, 1H), 5.11-4.95 (m, 1H), 4.90-4.86 (m, 1H), 4.29-3.95 (m, 3H), 3.32-3.06 (m, 2H), 2.14-1.94 (m, 2H).

Example 245

p> (CIS, RAC)-N-(3-Fluoro-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 242. Specified in the title compound was obtained as an orange foam.

MS ISP (m/e): of 458.4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.52 (m, 1H), 8.37-8.34 (m, 1H), 7.62-7.54 (m, 1H), 7.52-7.49 (m, 1H), 7.15-7.05 (m, 1H), 6.95-6.91 (m, 1H), 6.45 (m, 1H), 5.08-4.92 (m, 1H), 4.89-4.84 (m, 2H), 4.58-4.53 (m, 1H), 4.18-4.00 (m, 1H), 3.27-3.00 (m, 2H), 2.37 (s, 3H), 2.11-2.06 (m, 1H), 1.94-1.80 (m, 1H).

Example 246

(CIS, RAC)-N-(3-Fluoro-1-(2-methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Degassed solution of 2-(dicyclohexylphosphino)biphenyl (9,21 mg; 26,3 mmol) and palladium acetate(II) (2,95 mg; 13,1 mmol) in dioxane (2 ml) was stirred for 10 minutes at room temperature, was then added to a solution of (CIS, RAC)-N-(3-foreperiod-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (60 mg; 164 mmol), 4-chloro-2-methoxypyridine (see example T); 25.9 mg, 181 μmol) and tert-butylate sodium (23,7 mg; 246 μmol) in dioxane (2 ml). The solution was barbotirovany with argon for 5 minutes, then heated to 140°C in microwave oven for 30 minutes. Added additional amount of degassed solution of 2-(dicyclohexylphosphino)biphenyl (9,21 mg; 26,3 mmol) and palladium acetate(II) (2,95 mg; 13,1 mmol�) in dioxane (2 ml), then 4-chloro-2-methoxypyridine (25.9 mg, 181 μmol) and heated to 140°C in a microwave oven within the next 30 minutes. The reaction mixture was directly purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and then preparative HPLC. Specified in the title compound was obtained as a whitish foam (25 mg; 32%).

MS ISP (m/e): 473,6 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.38-8.36 (m, 1H), 7.93-7.91 (m, 1H), 7.51-7.44 (m, 2H), 7.14-7.05 (m, 1H), 6.98-6.93 (m, 1H), 6.46-6.43 (m, 1H), 6.10-6.09 (m, 1H), 5.60-5.57 (m, 1H), 5.08-4.92 (m, 1H), 4.25-3.95 (m, 3H), 3.91 (s, 3H), 3.29-3.02 (m, 2H), 2.10-1.92 (m, 2H).

Example 247

N-(3,3-Debtor-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 3-(Benzotriazole-1-ylmethyl-benzyl-amino)-propionic acid ethyl ester

To a solution of 1H-benzo[e][1,2,3]triazole (5,46 g; 45,8 mmol) in MeOH (32 ml) at 0°C was added ethyl-3-(benzylamino)propanoate (10 g; 45,8 mmol) and aqueous formaldehyde (36%; 4,56 ml; to 59.6 mmol). The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent was evaporated and the residue was purified by flash chromatography using flash module (flash pack) (330 g) using a gradient mixture of EtOAc/heptane (5-50%) for 40 minutes. Specified in the title compound was obtained as a colorless oil (12,62 g; 81%).

b) Ethyl-3-(benzyl(3-e�hydroxy-3-oxopropyl)amino)-2,2-debtorrent

To a suspension aktivirovannoi zinc dust (4.13 g; 63.2 mmol) in anhydrous THF (100 ml) in an argon atmosphere was added TMS-CI (trimethylsilane) (3.60 g; a 4.24 ml; 33,2 mmol). After 10 minutes was slowly added ethyl-bromodifluoroacetate (7,05 g; 4,49 ml; to 34.7 mmol) while the temperature was maintained below 30°C (cooling in water bath). Then was added a solution of 3-(benzotriazole-1-ylmethyl-benzyl-amino)-propionic acid ethyl ester (10,69 g, of 31.6 mmol) in anhydrous THF (100 ml). Temperature (exothermic reaction) was maintained in the range of 20-25°C using a water bath. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 5% aqueous solution of NaHCO3and filtered through Dicalite. The filtrate three times were extracted with ethyl acetate. The organic layers were washed with water and 1 n HCl, then dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel; 100 g; 0% to 50% EtOAc in heptane) to obtain specified in the title compound as colorless liquid (10,78 g; 99%).

MS ISP (m/e): 344,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.34-7.22 (m, 5H), 4.32-4.25 (q, 2H), 4.12-4.05 (q, 2H), 3.75 (s, 2H), 3.21-3.13 (t, 2H), 2.93-2.88 (t, 2H), 2.45-2.40 (t, 2H), 1.34-1.29 (t, 3H), 1.24-1.20 (t, 3H).

c) Ethyl 1-benzyl-5,5-debtor-4-oxopiperidine-3-carboxylate

To a solution of ethyl-3-(benzyl(3-ethoxy-3-oxopropyl)amino)-2,2-�of ofcorporate (10,78 g; Of 31.4 mmol) in NMP (100 ml) at 0°C was added tert-butylate potassium (5,64 g; a 50.2 mmol) and the reaction mixture stirred at room temperature for 2 days. The reaction mixture was cooled to 0°C was added an aqueous solution of NH4Cl. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography using a gradient mixture of EtOAc/heptane 0-70% in 40 minutes, receiving specified in the title compound as a white solid (5,56 g; 60%).

MS ISP (m/e): 298,4/316,2 (19/100) [(M+H)+/(M+H2O)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=11.59 (s, 1H), 7.38-7.27 (m, 5H), 4.30-4.23 (q, 2H), 3.71 (s, 2H), 3.32-3.29 (m, 2H), 2.98-2.90 (m, 2H), 1.33-1.28 (t, 3H).

(d) 1-Benzyl-3,3-deformability-4,4-diol

A solution of ethyl 1-benzyl-5,5-debtor-4-oxopiperidin-3-carboxyla (4,272 g; 14.4 mmol) in 3 n HCl (175 ml) was heated at reflux for 14 hours. The reaction mixture was cooled to room temperature, then was added solid NaHCO3to pH 8 and three times were extracted with ethyl acetate, the combined organic layers were dried over Na2SO4and the solvents evaporated. Specified in the title compound was obtained as white solid (3.5 g; 100%).

MS ISP (m/e): 244,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.33-7.30 (m, 5H), 3.62 (s, 2H), 2.85-2.77 (m, 4H), 2.62-2.58 (m, 2H), 1.99-.96 (m, 2H).

e) tert-Butyl-3,3-debtor-4,4-dihydroxypyridine-1-carboxylate

A suspension of 1-benzyl-3,3-deformability-4,4-diol (3.5 g; 14.4 mmol), di-tert-butyl-dicarbonate (3,45 g; 3,64 ml; 15,8 mmol) and palladium on charcoal (10%; 459 mg; 432 mmol) in ethanol (75 ml) were gidrirovanie at room temperature over night. The catalyst was filtered, thoroughly washed with MeOH and the solvent evaporated, getting mentioned in the title compound as a light yellow oil (4.3 g; 100%; purity 85%).

MS (ISN) m/e): 294,3/312,2 (46/100) [(M-H2O+AcO)-/(M+AcO)-].

f) 4-Benzylamino-3,3-debtor-piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl-3,3-debtor-4,4-dihydroxypyridine-1-carboxylate (1 g; 3,36 mmol) and benzylamine (539 mg; 550 μl; of 5.03 mmol) in anhydrous toluene (70 ml) was heated to a temperature of delegatie using the apparatus of the Dean-stark within 12 hours. Added additional amount of benzylamine (20 ml, 185 mmol) and heated to a temperature of delegatie using the apparatus of the Dean-stark within the next 12 hours. Drove about 50 ml of toluene, the residue was cooled to 55°C, was added ethanol (35 ml) and NaBH4(508 mg; 13.4 mmol) and the reaction mixture was stirred at 55°C for 2 hours. Added additional amount of NaBH4(508 mg; 13.4 mmol) and stirred in the next hour. Added another� number of NaBH 4(508 mg; 13.4 mmol). After 2 hours the reaction mixture was concentrated, then added a 2 n solution of Na2COs, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and the solvents evaporated. The residue was purified by flash chromatography (70 g; 0% to 100% EtOAc in hexano). Specified in the title compound was obtained as a colorless oil (875 mg; 80%).

MS ISP (m/e): 327,3/271,3 (18/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.34-7.24 (m, 5H), 4.03 (b, 1H), 3.92 (s, 2H), 3.77 (b, 1H), 3.39-3.25 (m, 1H), 3.15-3.07 (m, 1H), 3.03-2.91 (m, 1H), 1.92-1.86 (m, 1H), 1.67-1.60 (m, 1H), 1.55 (b, 1H), 1.46 (s, 9H).

g) 4-Amino-3,3-debtor-piperidine-1-carboxylic acid tert-butyl ester

A suspension of 4-benzylamino-3,3-debtor-piperidine-1-carboxylic acid tert-butyl ester (830 mg; 2.54 mmol), Pd/C (81,2 mg; is 76.3 mmol) in MeOH (30 ml) were gidrirovanie at room temperature for 14 hours. The catalyst was filtered, thoroughly washed with MeOH and the solvents evaporated. Specified in the title compound was obtained as a colorless oil (601 mg; 100%).

MS ISP (m/e): to 181.1 (61) [(M-tBu)+].

(h) 3,3-Debtor-4-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

A suspension of 4-amino-3,3-debtor-piperidine-1-carboxylic acid tert-butyl ester (90 mg; 381 mmol), 2-bromo-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridi�a (obtained analogously to example 66a-d); 162 mg; 495 mmol), chloroform adduct of Tris(dibenzylideneacetone)diplegia(0) (15.8 mg, 15.2 μmol), phenolate sodium (65,2 mg; 533 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17,6 mg; 30,5 mmol) in anhydrous dioxane (5.0 ml) was barbotirovany with argon for 5 minutes, then heated to 160°C in a microwave for 60 minutes. The catalyst was filtered off, washed with CH2Cl2and the solvents evaporated. The residue was purified by flash chromatography (silica gel; 70 g; 0% to 100% EtOAc in heptane). Specified in the title compound was obtained as an orange solid (27 mg; 15%).

MS ISP (m/e): 484,2/428,2 (45/100) [(M+H)+/(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.33 (m, 1H), 7.64-7.55 (m, 1H), 7.52-7.49 (m, 1H), 7.15-7.05 (m, 1H), 6.94-6.90 (m, 1H), 4.82-4.78 (d, 1H), 4.48-4.11 (m, 3H), 3.23-2.91 (m, 2H), 2.17-2.12 (m, 1H), 1.80-1.60 (m, 1H), 1.48 (s, 9H).

i) N-(3,3-Deformability-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 3,3-debtor-4-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110 mg; 228 μmol) in CH2Cl2(4 ml) at 0°C was added TFA (182 mg; 123 µl; 1,59 mmol) and stirred at room temperature for 18 hours. Added additional amount of TFA (182 mg; 123 µl; 1,59 mmol) and stirred at 50°C for 6 hours. The reaction mixture was extracted with saturated solution of NaHCO3and et�the etate, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The product of four times was evaporated together with toluene. Specified in the title compound was obtained as a light yellow foam (87 mg; 100%).

MS ISP (m/e): 384,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.34 (m, 1H), 7.64-7.56 (m, 1H), 7.51-7.49 (m, 1H), 7.15-7.06 (m, 1H), 6.94-6.90 (m, 1H), 4.87-4.84 (d, 1H), 4.33-4.16 (m, 1H), 3.35-3.25 (m, 1H), 3.14-3.09 (m, 1H), 2.99-2.72 (m, 2H), 2.25-2.18 (m, 1H), 1.66-1.61 (m, 2H).

j) N-(3,3-Debtor-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Degassed solution of 2-(dicyclohexylphosphino)biphenyl (12,7 mg; 36,3 mmol) and palladium acetate(II) (4,08 mg; 18,2 mmol) in dioxane (2 ml) was stirred for 10 minutes at room temperature, then was added a solution of N-(3,3-deformability-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (87 mg; 227 mmol), 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and tert-butylate sodium (32.7 mg, 340 μmol) in dioxane (2 ml). The solution was barbotirovany with argon for 5 minutes, then heated to 150°C in a microwave for 60 minutes. Once again I added a degassed solution of 2-(dicyclohexylphosphino)biphenyl (12,7 mg; 36,3 mmol) and palladium acetate(II) (4,08 mg; 18,2 mmol) in dioxane (2 ml), was then added 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and heated to 150°C in microwave pechev the next 60 minutes. Once again I added a degassed solution of 2-(dicyclohexylphosphino)biphenyl (12,7 mg; 36,3 mmol) and palladium acetate(II) (4,08 mg; 18,2 mmol) in dioxane (2 ml), was then added 5-chloro-3-methyl-1,2,4-thiadiazole (30.5 mg, 227 μmol) and heated to 150°C in a microwave oven within the next 60 minutes. The crude substance was purified flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and then preparative HPLC. Specified in the title compound was obtained as a white foam (42 mg; 38%).

MS ISP (m/e): 482,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.37-8.35 (m, 1H), 7.62-7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.15-7.06 (m, 1H), 6.97-6.92 (m, 1H), 4.87-4.84 (d, 1H), 4.46-4.32 (m, 2H), 3.90-3.85 (m, 1H), 3.60-3.37 (m, 2H), 2.42 (s, 3H), 2.34-2.27 (m, 1H), 2.04-1.90 (m, 1H).

Example 248

N-(1-(2-Chloropyridin-4-yl)-4-phenylpiperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 236 using bromide vinylmania (1 M in THF; 0,625 ml; of 0.625 mmol) in place of bromide Metalmania.

Specified in the title compound was obtained as a whitish solid (21 mg; 20%) after purification using HPLC.

MS ISP (m/e): 517,2 [(M+H)+].

Example 249

8-(3,4-Differenl)-N-(1-(6-methylpyrimidin-4-yl)-4-phenylpiperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 234, using bromide vinylmania (1 M � THF; Of 0.625 ml; of 0.625 mmol) in place of bromide Metalmania.

Specified in the title compound was obtained as white solid (27 mg; 27%) after purification using HPLC.

MS ISP (m/e): 498,3 [(M+H)+].

Example 250

2-{8-(4-Fluoro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol

Was prepared analogously to example 49. Specified in the title compound was obtained as a whitish solid substance.

MS ESI (m/z): 462,0 [(M+H)+].

1H NMR (DMSO, 400 MHz): δ (mn-1)=8.36 (s, 1H), 8.15-8.11 (m, 2H), 7.75 (d, J=7.84 Hz, 1H), 7.32 (t, J=8.88 Hz, 2H), 7.13 (d, J=7.84 Hz, 1H), 6.87 (d, J=7.36 Hz, 1H), 6.74(8, 1H), 5.81 (s, 1H), 4.28 (d, J=12.52 Hz, 2H), 3.16 (t, J=11.28 Hz, 2H), 2.25 (s, 3H), 2.01 (d, J=2.49 Hz, 2H), 1.72 (s, 6H), 1.54-1.46 (m, 2H).

Example 251

2-{8-(3,4-Debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol

Was prepared analogously to example 49. Specified in the title compound was obtained as a whitish solid substance.

MS ESI (m/z): 480,0 [(M+H)+].

Example 252

8-(2-Chloro-4-fluorophenyl)-6-methyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (102 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]Tria�olo[1,5-a]pyridine.

Specified in the title compound was obtained as a light yellow foam (88 mg; 58%).

MS ISP (m/e): 505,3/507,2 [(M+H)+].

Example 253

N-(1-(2-(Trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridine (98 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (72 mg; 49%).

MS ISP (m/e): 499,3 [(M+H)+].

Example 254

8-(2,4-Differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-8-(2,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine (93 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (81 mg; 57%).

MS ISP (m/e): to 475.3(M+H)+].

Example 255

6-Chloro-8(2-chloro-4-fluorophenyl)-N-(1-(2-trifluoromethyl)pyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-6-chloro-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (108 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound floor�Chali as a yellow foam (50 mg; 32%).

MS ISP (m/e): 525,2/527,1 [(M+H)+].

Example 256

8-(3,5-Bis(trifluoromethyl)phenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200, using 8-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-[1,2,4]triazolo[1,5-a]pyridine (123 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a yellow foam (94 mg; 54%).

MS ISP (m/e): 575,2 [(M+H)+].

Example 257

8-(2-Chloro-4-fluorophenyl)-6-fluoro-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 200C, using 2-bromo-8-(2-chloro-4-fluorophenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine (103 mg; 0.3 mmol) instead of 2-bromo-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine.

Specified in the title compound was obtained as a whitish foam (61 mg; 40%).

MS ISP (m/e): 509,2/511,2 [(M+H)+].

Example 258

4-Chloro-3-(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile

Was prepared analogously to example 226. Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 451,2/453,2 (100/35) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.42-8.39 (m, 1H), 7.86 (m, 1H), 7.65 (m, 2H), 7.44-7.41 (m, 1H), 6.96-6.91 (m, 1H), 4.64-4.61 (m, 1H), 3.92-3.85 (m, 3H), 3.40-3.3 (m, 2H), 2.41 (s, 3H), 2.27-2.22 (m, 2H), 1.72-1.59 (m, 2H).

Example 259

(3,4-Differenl)-N-((3RS,4SR)-3-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

(CIS, RAC)-8-(3,4-Differenl)-N-(3-foreperiod-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained as in example 238a-f) was brought into interaction with 4-iodo-2-(trifluoromethyl)pyridine in analogy to example 242, which allowed us to obtain specified in the title compound as a light brown foam (yield 35%).

MS ISP (m/e): 493,2 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.36 (d, 1H), 8.32 (d, 1H), 7.96-7.90 (m, 1H), 7.73-7.68 (m, 1H), 7.52 (d, 1H), 7.32-7.23 (m, 1H), 7.07 (d, 1H), 6.93 (t, 1H), 6.81 (dd, 1H), 5.06 (d, 1H), 4.88 (d, 1H), 4.33 (tt, 1H), 4.21-4.02 (m, 2H), 3.29 (dd, 1H), 3.16 (td, 1H), 2.18-2.11 (m, 1H), 1.98 (qd, 1H).

Example 260

[1-(3-Methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(6-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine

To a mixture of (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine (obtained analogously to example a) using 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine, which was obtained analogously to example 66A-b) (78 mg; 198 mmol), phenol (37.2 mg; Of 34.8 ml, 396 mmol), copper iodide(1) (1,77 mg; 19,8 mmol), picolinic acid (4,87 mg; 39,6 mmol) and tribasic potassium phosphate (126 mg; 593 mmol) was added DMSO (1 ml) and heated to 120°C for 12 hours. Added�if an additional amount of phenol (37.2 mg; Of 34.8 ml, 396 mmol), picolinic acid (4,87 mg; 396 mmol), copper iodide(I) (1,77 mg; 19,8 mmol) and tribasic potassium phosphate (126 mg; 593 mmol) in DMSO (1 ml) and stirred at 120°C in the next 16 hours. To the reaction mixture were added water and the aqueous phase three times were extracted with ethyl acetate. The combined organic phases were dried over Na2SO4and the solvent evaporated. The residue was purified by flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) to dichloromethane; 45 minutes) and then preparative HPLC. Specified in the title compound was obtained as a whitish foam (15 mg; 18%).

MS ISP (m/e): 408,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.12-8.11 (m, 1H), 7.39-7.34 (m, 3H), 7.28-7.24 (m, 1H), 7.17-7.12 (m, 1H), 7.02-7.00 (m, 2H), 4.41-4.39 (m, 1H), 3.93-3.88 (m, 3H), 3.38-3.29 (m, 2H), 2.42 (s, 3H), 2.28-2.23 (m, 2H), 1.72-1.58 (m, 2H).

Example 261

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) (7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

To a suspension of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously to example 66A-b, proceeding from 4-bromo-pyridine-2-ylamine) (250 mg, 1,17 mmol) and hexachloroethane (333 mg; 1.41 mmol) in an argon atmosphere in anhydrous THF (12.5 ml) was added triethylamine (356 mg; 491 μl; 3,52 mmol) and the mixture was heated to 50°C for 10 minutes. Added trimethylol�Jn (1 M in THF; Of 1.41 ml, 1.41 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then was added 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (278 mg; 1.41 mmol) and the mixture was heated in a microwave oven to 150°C for 30 minutes. To the reaction mixture was added a solution of decaborane (143 mg; 153 µl; 1,17 mmol) in anhydrous methanol (3 ml) and stirred at room temperature for 3 hours. Added additional amount of decaborane (34,4 mg; 36,6 ml, 282 mmol) in anhydrous methanol (1,00 ml). The reaction mixture was heated to 60°C for 12 hours. Added additional amount of decaborane (17 mg) dissolved in methanol (1 ml), and heated to 70°C for 3 hours. Was added an aqueous solution of NaHCO3and the aqueous phase was extracted with CH2Cl2organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a whitish solid (300 mg; 65%).

MS ISP (m/e): 394,0/396,0 (96/100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.16-8.14 (m, 1H), 7.56 (m, 1H), 6.94-6.91 (m, 1H), 4.49-4.46 (m, 1H), 3.93-3.87 (m, 3H), 3.39-3.30 (m, 2H), 2.42 (s, 3H), 2.27-2.22 (m, 2H), 1.72-1.60 (m, 2H).

b) N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Received Ana�ogino example 66c) from (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine and phenylboronic acid. Specified in the title compound was obtained as a whitish foam.

MS ISP (m/e): 392,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.35-8.33 (m, 1H), 7.56-7.60 (m, 3H), 7.52-7.44 (m, 3H), 7.10-7.07 (m, 1H), 4.55-4.52 (m, 1H), 3.99-3.90 (m, 3H), 3.41-3.32 (m, 2H), 2.42 (s, 3H), 2.31-2.25 (m, 2H), 1.74-1.60 (m, 2H).

Examples 262 and 263

(4-Fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol and

{8-[(4-fluoro-phenyl)-methoxy-methyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) N-{3-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridin-2-yl)pivalate

To a solution of N-(pyridin-2-yl)palamida (1.84 g; 10 mmol) in tetrahydrofuran (100 ml) was added at -78°C in a nitrogen atmosphere a 1.6 M butyllithium in hexane (13.1 per ml; 21 mmol). The reaction is slightly exothermic and appears yellow staining. The reaction mixture is heated to 0°C for 15 minutes and stirred at 0°C for 2 hours. Formed a white suspension. The reaction mixture was cooled to -78°C was added 4-forbindelse (1.52 g; 1,29 ml; 12.0 mmol) in tetrahydrofuran (6,55 ml). The reaction mixture was warmed to room temperature overnight, yielding an orange suspension. Was added a saturated aqueous solution of ammonium chloride and the reaction mixture was twice extracted with ethyl acetate and once with methylene chloride. Volun�inannie organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Specified in the title compound was obtained as a yellow viscous oil (1,058 g; 35%) after purification column chromatography on silica gel using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as eluent.

MS ISP (m/e): 303,1 (100) [(M+H)+].

(b) (2-Amino-pyridin-3-yl)-(4-fluoro-phenyl)-methanol

To a solution of N-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-pyridin-2-yl}palamida (890 mg, to 2.94 mmol) in ethanol (44 ml) was added 2 n aqueous sodium hydroxide solution (of 7.36 ml; 14.7 mmol). The reaction mixture was heated to 100°C for 5 hours. Added water and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure, obtaining specified in the title compound as a light yellow solid (548 mg; 85%) without further purification.

MS ISP (m/e): 219,2 (61) [(M+H)+], 201,2 (100) [(M-H2O+H)+].

(c) (2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-fluoro-phenyl)-methanol

Was prepared analogously to example 1e-f, based on (2-amino-pyridin-3-yl)-(4-fluoro-phenyl)-methanol. After pouring the contents of the reaction mixture into water, rinsing, and drying has been specified in W�head compound as white solids (yield 63% over 2 stages).

MS ISP (m/e): 259,1 (19) [(M+H)+], 241,2 (100).

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.42 (d, 1H), 7.52 (d, 1H), 7.46 (dd, 2H), 6.89 (t, 2H), 6.08 (m, 2H), 6.02 (br s, 2H).

(d) (4-Fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol and {8-[(4-fluoro-phenyl)-methoxy-methyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Was prepared analogously to example 219f, proceeding from (2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)(4-fluorophenyl)methanol and 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it. As a reducing agent used 1 EQ. decaborane in methanol at 50°C over night. The crude product was purified column chromatography on silica gel, using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as eluent, receiving eluruumist first {8-[(4-fluoro-phenyl)-methoxy-methyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine (yield 4%) as a colorless oil.

MS ISP (m/e): 454,3 (100) [(M+H)+], 422,2 (98), 241,2 (98).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.22 (d, 1H), 7.48 (m, 3H), 7.00 (t, 2H), 6.83 (t, 1H), 5.76 (br s, 1H), 4.52 (m, 1H), 3.89 (m, 3H), 3.43 (s, 3H), 3.35 (br t, 2H), 2.42 (s, 3H), 2.23 (br d, 2H), 1.64 (m, 2H).

(4-Fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol was elyuirovaniya second and was then purified preparative HPCL. Specified in the header soy�the coalescing was obtained as white solid (yield 42%).

MS ISP (m/e): 440,2 (100) [(M+H)+], 422,1 (69).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.50 (d, 1H), 7.55 (d, 1H), 7.46 (dd, 2H), 7.11 (t, 2H), 6.91 (t, 1H), 6.75 (d,1H), 6.10 (brs,1H), 6.07 (brs, 1H), 3.77 (m, 3H), 3.32 (m, 2H), 2.28 (s, 3H), 2.00 (br d, 2H), 1.57 (m, 2H).

Example 264

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-C][1,4]oxazine Serie-2-amine

a) (2-Oxo-ethoxy)-phenylacetic acid methyl ester

Allyloxy-phenylacetic acid methyl ester (described in EJOC 2000, 3145-3163; 3 g; 14.5 mmol) was dissolved in dichloromethane (300 ml) and cooled to -75°C. the Solution was barbotirovany O3for 6 hours until the solution became blue. The solution was barbotirovany argon for 1 hour, then the reaction mixture was added dimethyl sulfide (9,04 g; 10,8 ml; 145 mmol) and kept at room temperature for 12 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography using SiO2-flash module (50 g) and a gradient of 10-100% EtOAc in heptane for 60 minutes, obtaining specified in the title compound as a light yellow oil (2.72 g; 90%).

1H NMR (CDCl3, 300 MHz): δ (mn-1)=9.75 (s, 1H), 7.47-7.36 (m, 5H), 5.03 (s, 1H), 4.13 (s, 2H), 3.74 (s, 3H).

b) tert-Butyl-2-(2-(2-methoxy-2-oxo-1-phenylethane)ethyliden)hydrazine-carboxylate

(2-Oxo-ethoxy)-phenylacetic acid methyl ester (2.7 g; 13,0 mmol) and tert-butyl-carbazate (1,75 g, 13,0 mmol) was dissolved in �oluwole (290 ml) and heated to 65°C over night.

The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography (silica gel; 100 g; from 0% to 100% EtOAc in heptane for 60 minutes), receiving specified in the title compound as a yellow viscous oil (2,81 g; 67%).

MS ISP (m/e): 323,3 (42) [(M+H)+], 267,1 (100) [(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.85 (bs, 1H), 7.44-7.34 (m, 5H), 4.94 (s, 1H), 4.23-4.21 (m, 2H), 3.71 (s, 3H), 1.50 (s, 9H).

c) tert-Butyl-2-(2-(2-methoxy-2-oxo-1-phenylethane)ethyl)hydrazine-carboxylate

tert-Butyl-2-(2-(2-methoxy-2-oxo-1-phenylethane)ethyliden)hydrazine-carboxylate (4.7 g; 14.6 mmol) in MeOH (175 ml) were gidrirovanie at a pressure of 3.5 bar (350 kPa) and 30°C for 20 hours in a vessel Parra in the presence of Raney Nickel (4,69 g; at 37.2 mmol). The reaction mixture was filtered and washed with MeOH. The solvent was evaporated, getting mentioned in the title compound as brown oil (4.5 g; 95%) which was used crude in the next reaction.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.47-7.33 (m, 5H), 6.30 (bs, 1H), 4.93 (s, 1H), 4.20 (bs, 1H), 3.72 (s, 3H), 3.70-3.57 (m, 2H), 3.12-3.07 (m, 2H), 1.46 (s, 9H).

d) 4-Amino-2-phenylmorpholine-3-one

tert-Butyl-2-(2-(2-methoxy-2-oxo-1-phenylethane)ethyl)hydrazine-carboxylate (390 mg; 1.2 mmol) in water (85 ml) was heated to 95°C for 12 h. the Reaction mixture was extracted with dichloromethane, the organics were combined, dried over Na2SO4and the solvent evaporated, receiving specified�OE in the title compound as a light yellow oil (183 mg; 79%).

MS ISP (m/e): 193,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.45-7.33 (m, 5H), 5.24 (s, 1H), 4.54 (bs, 2H), 4.12-4.05 (m, 1H), 3.99-3.91 (m, 1H), 3.83-3.75 (m, 1H), 3.65-3.58 (m, 1H).

e) 8-Phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-C][1,4]oxazine Serie-2-amine

4-Amino-2-phenylmorpholine-3-one (175 mg; 910 mmol) and cyanamide (230 mg; 179 ml, 5.46 mmol) was dissolved in ethanol (4 ml). Was added p-toluensulfonate acid monohydrate (260 mg; 209 ml, 1.37 mmol) and the mixture was heated at reflux (80°C) for 24 hours.

After cooling to room temperature was added triethylamine (461 mg; 634 μl; 4,55 mmol) and the mixture was heated at reflux (80°C) for 3 days.

The reaction mixture was extracted with saturated sodium bicarbonate solution and EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and the solvent evaporated. The residue was purified by chromatography using NH2-flash module (10 g) and the gradient of 0-15% MeOH/NH3(9:1) in dichloromethane, obtaining specified in the title compound as a whitish solid (41 mg; 21%).

MS ISP (m/e): 217,3 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.40-7.37 (m, 5H), 5.75 (s, 1H), 4.31-4.16 (m, 2H), 4.13-4.06 (m, 4H).

f) N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-C][1,4]oxazine Serie-2-amine

Was prepared analogously to example a using 8-phenyl-6,8-dihydro-5H-[12,4]triazolo[5,1-C][1,4]oxazine Serie-2-amine and 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it (see example 1d). Specified in the title compound was obtained as a white foam.

MS ISP (m/e): 398,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=7.42-7.37 (m, 5H), 5.76 (s, 1H), 4.30-4.08 (m, 5H), 3.87-3.83 (m, 2H), 3.78-3.67 (m, 1H), 3.35-3.26 (m, 2H), 2.40 (s, 3H), 2.22-2.16 (m, 2H), 1.64-1.53 (m, 2H).

Example 265

N-(1-(6-Methylpyrimidin-4-yl)piperidine-4-yl)-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-C][1,4]oxazine Serie-2-amine

Was prepared analogously to example 264, using 1-(6-methyl-pyrimidine-4-yl)-piperidine-4-it (see example 93b) in stage f). Specified in the title compound was obtained as a light yellow foam.

MS ISP (m/e): 392,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.43 (s, 1H), 7.41-7.36 (m, 5H), 6.41 (s, 1H), 5.75 (s, 1H), 4.33-4.19 (m, 4H), 4.14-4.07 (m, 3H), 3.82-3.71 (m, 1H), 3.23-3.15 (m, 2H), 2.37 (s, 3H), 2.21-2.16 (m, 2H), 1.54-1.47 (m, 2H).

Examples 266 and 267

N-((3R,4S,5S)-3,5-Dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and

N-((3S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) (3S,5R)-3,5-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

A suspension of (3R,5S)-1-benzyl-3,5-dimethylpiperidin-4-it (obtained according to A. A. Calabrese et al., US 20050176772, preparatory example 12-14) (2.08 g; 9,57 mmol), di-tert-butyl-dicarbonate (2.3 g; 2,42 ml; 105 mmol) and palladium on charcoal (10%; 306 mg; 287 μmol) in ethanol (47,5 ml) were gidrirovanie at room temperature for 12 hours. The catalyst was filtered, thoroughly washed with MeOH and the solvent evaporated, getting mentioned in the title compound as a white solid (2,38 g).

MS ISP (m/e): of 172.2 (100) [(M-tBu)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=4.36 (bs, 2H), 2.70-2.51 (m, 4H), 1.50 (s, 9H), 1.03-1.01 (d, 6H).

b) 3,5-Dimethyl-4-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously to example 66A-C) (300 mg, to 1.14 mmol) and hexachloroethane (296 mg; 1.25 mmol) in anhydrous THF (8 ml) was added triethylamine (287 mg; 396 ál; 2,84 mmol) in an argon atmosphere, then added trimethylphosphine (1 M in THF; 1.25 ml; 1.25 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then was added (3R,5S)-tert-butyl-3,5-dimethyl-4-oxopiperidin-1-carboxylate (315 mg; 1.25 mmol) and the mixture was heated to 150°C in microwave oven for 3 hours. To the reaction mixture was added a solution of decaborane (139 mg; 148 ml, to 1.14 mmol) in MeOH (3 ml) and stirred at 50°C for 2 hours. Added additional amount of decaborane (139 mg; 148 ml, to 1.14 mmol) in MeOH (3 ml) and stirred at 50°C for 2 hours. The reaction mixture was poured into water and ek�was tragically dichloromethane. The organics were combined, dried over Na2SO4and evaporated. The residue was purified by flash chromatography using SiO2-flash module (70 g) and a gradient of 0-100% EtOAc in heptane over 35 min, receiving specified in the title compound as a whitish foam (208 mg; 39%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 476,2/420,2/376,3 (13/40/62) [(M+H)+/(M-tBu)+/(M-Boc)+].

c) 3,5-Dimethyl-piperidine-4-yl)-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine

To a solution of tert-butyl-3,5-dimethyl-4-(8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-1-carboxylate (200 mg; 421 mmol) in CH2Cl2(5 ml) was added trifluoroacetic acid (336 mg; 227 µl; to 2.94 mmol) at 0°C and then stirred at room temperature for 18 hours. Added additional amount of trifluoroacetic acid at 0°C (336 mg; 227 µl; to 2.94 mmol) and stirred at room temperature for 2 hours. To the reaction mixture was added a saturated solution of NaHCO3and the aqueous phase was extracted with EtOAc. The organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The product was evaporated together with toluene. Specified in the title compound was isolated as a white solid (106 mg; 67%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 376,5 (100) [(M+H)+].

d) N-((3R,4S,5S)-3,5-Dimethyl-1-(3-methyl-1,2,4-t�diazol-5-yl)piperidine-4-yl)-8-(2.3.4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and N-((3S,5S)-3.5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Degassed solution of 2-(dicyclohexylphosphino)biphenyl (14,9 mg; and 42.6 mmol) and palladium acetate(II) (4,78 mg; 21,3 mmol) in dioxane (2 ml) was stirred for 10 minutes at room temperature, was then added to a solution of N-(3,5-dimethylpiperidin-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (100 mg, 266 μmol), 5-chloro-3-methyl-1,2,4-thiadiazole (39,4 mg; 293 mmol) and tert-butylate sodium (38.4 mg, 400 μmol) in dioxane (2 ml). The solution was barbotirovany with argon for 5 minutes, then heated to 150°C in microwave oven for 30 minutes. The crude substance was purified flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and again was purified flash chromatography (silica gel; 20 g; 0-100% EtOAc in heptane) to obtain:

the compound of Example 266: N-((3R,4S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine in the form of a whitish solid (45 mg; 36%).

MS ISP (m/e): 474,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.34-8.31 (m, 1H), 7.62-7.55 (m, 1H), 7.49-7.47 (m, 1H), 7.15-7.06 (m, 1H), 6.92-6.88 (m, 1H), 4.59-4.56 (d, 1H), 4.24-4.19 (dt, 1H), 3.67-3.61 (m, 2H), 2.95-2.86 (m, 2H), 2.42 (s, 3H), 2.20-2.11 (m, 2H), 1.03-1.00 (d, 6H), and

the compound of Example 267: N-((3S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine in the form of whitish foam (23 mg; 18%).

MS ISP (m/e): 474,2 (100) [(M+H)+].

1 H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.34 (m, 1H), 7.61-7.53 (m, 1H), 7.50-7.47 (m, 1H), 7.15-7.05 (m, 1H), 6.93-6.88 (m, 1H), 4.57-4.54 (d, 1H), 3.97-3.91 (m, 1H), 3.76-3.68 (m, 1H), 3.56-3.55 (m, 2H), 3.01-2.93 (m, 1H), 2.54-2.48 (m, 1H), 2.40 (s, 3H), 2.09-1.99 (m, 1H), 1.09-1.07 (d, 3H), 1.02-1.00 (d, 3H).

Example 268

T-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-7-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was obtained in analogy to example 260, using (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine (see example a) instead of (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine. Specified in the title compound was obtained as a whitish foam.

MS ISP (m/e): to 408.4 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.21-8.18 (m, 1H), 7.45-7.40 (m, 2H), 7.28-7.23 (m, 1H), 7.13-7.10 (m, 2H), 6.69-6.68 (m, 1H), 6.63-6.60 (m, 1H), 4.59-4.56 (m, 1H), 3.91-3.87 (m, 3H), 3.38-3.28 (m, 2H), 2.41 (s, 3H), 2.26-2.20 (m, 2H), 1.71-1.58 (m, 2H).

Examples 269 and 270 and 271

(3SR,4SR)-, (3R,4S)- and (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

a) 4-[8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

To a suspension of 8-(3,5-bis(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously approx�ru 66A-C) (80 mg; 231 μmol) and hexachlorethane (65.6 mg; 277 mmol) in an argon atmosphere in anhydrous THF (4 ml) was added triethylamine (70,1 mg; 96,6 µl; 693 mmol), then trimethylphosphine (1 M in THF; 277 ml, 277 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then was added tert-butyl-3-fluoro-4-oxopiperidine-1-carboxylate (example 238b); 60,2 mg; 277 mmol) and the mixture was heated to 150°C for 30 minutes in a microwave oven. To the reaction mixture was added a solution of decaborane (28,2 mg; 30,0 ml, 231 mmol) in anhydrous methanol (1 ml) and stirred at room temperature for 3 hours. To the reaction mixture were added an aqueous solution of NaHCO3the aqueous phase was extracted with CH2Cl2organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a whitish foam (107 mg; 85%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 548,3/492,2 (33/100) [(M+H)+/(M-tBu)+].

b) 8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-fluoro-piperidine-4-yl)-amine

To a solution of 4-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (180 mg; 329 mmol) in CH2Cl2(3 ml) at 0°C was added three�torakusu acid (262 mg; 177 ml, 2.3 mmol) and then stirred at room temperature for 18 hours. Added additional amount of trifluoroacetic acid (262 mg; 177 ml, 2.3 mmol) and stirred at 40°C for 6 hours. To the reaction mixture were added saturated aqueous solution of NaHCO3and the aqueous phase was extracted with ethyl acetate, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The product was twice evaporated together with the toluene. Specified in the title compound was obtained as a light yellow foam (142 mg; 96%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 448,2/428,2 (32/100) [(M+H)+/(M-HF)+].

c) [8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

Degassed solution of palladium acetate(II) (2,73 mg; 12,2 mmol) and 2-(dicyclohexylphosphino)biphenyl (8,52 mg; 24,3 mmol) in dioxane (1 ml) was stirred for 10 minutes at room temperature, was then added to a solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-foreperiod-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (68 mg; 152 mmol), 5-chloro-3-methyl-1,2,4-thiadiazole (24,5 mg; 182 mmol) and tert-butylate sodium (21,9 mg; 228 μmol) in dioxane (2 ml). The solution was barbotirovany with argon for 5 minutes, then heated to 150°C in microwave oven for 45 minutes. Again this was added a degassed solution �of cetate palladium(O) (3.1 mg; 13,8 mmol) and 2-(dicyclohexylphosphino)biphenyl (9,69 mg; 27,6 mmol) in dioxane (1 ml), was then added 5-chloro-3-methyl-1,2,4-thiadiazole (24,5 mg; 182 mmol) and was heated for the next 45 minutes to 150°C. the Crude substance was purified flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a colorless oil (30 mg; 36%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 546,7 (100) [(M+H)+].

(d) (3SR,4SR)-, (3R,4S)- and (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine

A mixture of CIS - and TRANS-isomers were separated using supercritical fluid chromatography (SFC) on a column Chiralpak AD-H using ethanol and CO2as eluent and receiving TRANS-isomer in the form of a racemate (example 269), and two CIS-enantiomer (example 270 and 271) without establishing the absolute configuration of these enantiomers.

Example 269: (3SR,4SR)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine.

Retention time: 4,00/4,33 minutes.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.42-8.39 (m, 1H), 7.91 (s, 1H), 7.68-7.66 (m, 1H), 7.02-6.97 (m, 1H), 4.88-4.66 (m, 1H), 4.79-4.77 (m, 1H), 4.23-4.02 (m, 2H), 3.78-3.68 (m, 1H), 3.59-3.44 (m, 2H), 2.60-1.80 (m, 2H), 2.43 (s, 3H).

Example 270: (3R,4S)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-IU�yl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine or enantiomer.

Retention time: 5,06 minutes.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.40-8.38 (m, 1H), 7.91 (s, 1H), 7.69-7.66 (m, 1H), 7.02-6.97 (m, 1H), 5.11-4.98 (m, 1H), 4.93-4.90 (m, 1H), 4.44-3.96 (m, 3H), 3.53-3.30 (m, 2H), 2.43 (s, 3H), 2.15-2.06 (m, 2H).

Example 271: (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine or enantiomer.

Retention time: 6,33 minutes.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.40-8.37 (m, 1H), 7.91 (s, 1H), 7.68-7.66 (m, 1H), 7.02-6.97 (m, 1H), 5.14-4.98 (m, 1H), 4.93-4.90 (m, 1H), 4.44-3.97 (m, 3H), 3.53-3.30 (m, 2H), 2.43 (s, 3H), 2.15-2.06 (m, 2H).

Examples 272 and 273 and 274

(3SR,4SR)-, (3R,4S)- and (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

(a) [8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

A solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-foreperiod-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 269b); 68 mg; 152 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (32,2 mg; 198 μmol) and diisopropylethylamine (39,3 mg; and 53.1 ml, 304 mmol) in anhydrous dioxane (2 ml) stirred at 70°C for 12 hours and then at 110°C for 1 hour. Added additional amount of diisopropylethylamine (39,3 mg; and 53.1 ml, 304 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazol� (32,2 mg; 198 μmol) and heated to 110°C in the next hour. The solvent was evaporated and the residue was directly purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a colorless oil (46 mg; 57%) as a mixture of CIS - and TRANS-isomers.

MS ISP (m/e): 530,1/510,3 (100/27) [(M+H)+/(M-HF)+].

(b) (3SR,4SR)-, (3R,4S)- and (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine

A mixture of CIS - and TRANS-isomers were separated using supercritical fluid chromatography (SFC) on a column Chiralpak AD-H using ethanol and CO2as eluent and receiving TRANS-isomer in the form of a racemate (example 272) and two CIS-enantiomer (example 273 and 274) without establishing the absolute configuration of these enantiomers.

Example 272: (3SR,4SR)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine.

Retention time: 4,11/4,37 minutes.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.42-8.38 (m, 1H), 7.91 (s, 1H), 7.68-7.65 (m, 1H), 7.01-6.96 (m, 1H), 5.11-4.64 (m, 2H), 4.40-4.01 (m, 2H), 3.86-3.71 (m, 1H), 3.49-3.15 (m, 2H), 2.57-1.77 (m, 2H), 2.41 (s, 3H).

Example 273: (3R,4S)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine.

Retention time: 5,72 minutes.

1H YAM� (CDCl 3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.40-8.37 (m, 1H), 7.91 (s, 1H), 7.68-7.65 (m, 1H), 7.01-6.96 (m, 1H), 5.11-4.94 (m, 1H), 4.93-4.90 (m, 1H), 4.40-3.98 (m, 3H), 3.41-3.14 (m, 2H), 2.41 (s, 3H), 2.11-2.04 (m, 2H).

Example 274: (3S,4R)-[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine.

Retention time: 8,18 minutes.

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 2H), 8.40-8.37 (m, 1H), 7.91 (s, 1H), 7.68-7.65 (m, 1H), 7.01-6.96 (m, 1H), 5.11-4.94 (m, 1H), 4.92-4.89 (m, 1H), 4.40-3.98 (m, 3H), 3.41-3.14 (m, 2H), 2.41 (s, 3H), 2.11-2.04 (m, 2H).

Example 275

N-(3,3-Debtor-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 3,3-Debtor-4-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

To a suspension of 8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (obtained analogously to example 66A-C); 200 mg; 757 μmol) and hexachlorethane (215 mg; 908 mmol) in an argon atmosphere in anhydrous THF (10 ml) was added triethylamine (230 mg; 317 ml, 2.27 mmol), then added trimethylphosphine (1 M in THF; 908 ml, 908 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then was added tert-butyl-3,3-debtor-4,4-dihydroxypyridine-1-carboxylate (see example e); 230 mg; 908 mmol) and the mixture was heated to 150°C in microwave oven for 30 minutes. To the reaction mixture was added a solution of DECA�Oran (92,5 mg; Of 98.4 ál; 757 μmol) in MeOH (1 ml), then stirred at room temperature for 12 hours. Again added a solution of decaborane (92,5 mg; 98,4 µl; 757 μmol) in MeOH (5 ml) and heated to 70°C for 18 hours. To the reaction mixture were added an aqueous solution of NaHCO3the aqueous phase was extracted with CH2Cl2organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), it was provided 85 mg of the intermediate imina, namely 3,3-debtor-4-[(E)-8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-elimina]-piperidine-1-carboxylic acid tert-butyl ester, which was dissolved in anhydrous MeOH (3 ml). Added decaborane (21.6 mg; 23,0 ml, 177 mmol) and heated to 70°C for 30 minutes. To the reaction mixture were added an aqueous solution of NaHCO3the aqueous phase was extracted with CH2Cl2organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified (together with the fractions of the first crude product chromatography) flash chromatography (silica gel; 50 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), obtaining specified in the title compound as a white foam (300 mg; 82%).

MS ISP (m/e): 484,3/428,1/384,2 (13/100/41) [(M+H)+/(M-tBu)+/(M-Boc)+].

<> b) N-(3,3-Deformability-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 3,3-debtor-4-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110 mg; 228 μmol) in CH2Cl2(4 ml) at 0°C was added TFA (182 mg; 123 ml, 1.59 mmol) and stirred at room temperature for 18 hours. Added additional amount of TFA (182 mg; 123 µl; 1,59 mmol) and stirred at 50°C for 6 hours. The reaction mixture was extracted with saturated solution of NaHCO3and ethyl acetate, the organics were combined, dried over Na2SO4, filtered and the solvents evaporated. The product of four times was evaporated together with toluene. Specified in the title compound was obtained as a light yellow foam (87 mg; 100%).

MS ISP (m/e): 384,2 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.36-8.34 (m, 1H), 7.64-7.56 (m, 1H), 7.51-7.49 (m, 1H), 7.15-7.06 (m, 1H), 6.94-6.90 (m, 1H), 4.87-4.84 (d, 1H), 4.33-4.16 (m, 1H), 3.35-3.25 (m, 1H), 3.14-3.09 (m, 1H), 2.99-2.72 (m, 2H), 2.25-2.18 (m, 1H), 1.66-1.61 (m, 2H).

C) N-(3,3-Debtor-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A solution of N-(3,3-deformability-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (75 mg; 196 mmol), 4-chloro-6-methylpyrimidine (27,7 mg; 215 mmol) and N,N-diisopropylethylamine (37,9 mg; 49,9 ml, 293 mmol) in dioxane (4 ml) was heated to 150°C in �mikrovolnovoi oven for 1 hour. Added additional amount of 4-chloro-6-methylpyrimidine (27,7 mg; 215 mmol) and N,N-diisopropylethylamine (37,9 mg; 49,9 ml, 293 mmol) and heated to 150°C in a microwave oven in the next hour. Added additional amount of 4-chloro-6-methylpyrimidine (27,7 mg; 215 mmol) and N,N-diisopropylethylamine (37,9 mg; 49,9 ml, 293 mmol) and heated to 110°C for 12 hours. The crude substance was purified directly flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was obtained as a light yellow foam (25 mg; 22%).

MS ISP (m/e): 476,1 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.55 (s, 1H), 8.37-8.35 (m, 1H), 7.62-7.55 (m, 1H), 7.53-7.50 (m, 1H), 7.15-7.06 (m, 1H), 6.96-6.91 (m, 1H), 6.47 (s, 1H), 4.94-4.91 (d, 1H), 4.85-4.75 (m, 1H), 4.48-4.32 (m, 2H), 3.39-3.11 (m, 2H), 2.39 (s, 3H), 2.30-2.25 (m, 1H), 1.84-1.76 (m, 1H).

Example 276

N-(3,3-Debtor-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A solution of N-(3,3-deformability-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see example 275b); 75 mg; 196 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (41.5 mg, 254 μmol) and diisopropylethylamine (50,6 mg; of 68.3 ml, 391 mmol) in anhydrous dioxane (4 ml) was stirred at 110°C for 3 hours. Added additional amount of diisopropylethylamine (50,6 mg; of 68.3 ml, 391 mmol) and 2-bromo-5-methyl�-1,3,4-oxadiazole (41,5 mg; 254 μmol) and heated to 110°C for 12 hours. The solvent was evaporated and the residue was purified by flash chromatography (silica gel; 70 g; 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). Specified in the title compound was as a white foam (36 mg; 40%).

MS ISP (m/e): 466,0 (100) [(M+H)+].

1H NMR (CDCl3, 300 MHz): δ (mn-1)=8.37-8.34 (m, 1H), 7.63-7.55 (m, 1H), 7.53-7.50 (m, 1H), 7.15-7.06 (m, 1H), 6.96-6.91 (m, 1H), 4.83-4.80 (m, 1H), 4.43-4.17 (m, 2H), 4.14-4.07 (m, 1H), 3.48-3.23 (m, 2H), 2.41 (s, 3H), 2.31-2.24 (m, 1H), 2.03-1.89 (m, 1H).

Example 277

4-(8-(2-Chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-carbonitrile

To a suspension of 8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 0,19 mmol) and hexachloroethane (54 mg, 0,226 mmol) in THF (1.5 ml) was added triethylamine (79 μl; 0,57 mmol), then added trimethylphosphine (1 M in THF; 0,226 ml; 0,23 mmol) and the resulting mixture was stirred in argon atmosphere for 30 min. Then added the ketone, 1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-it (46 mg; 0,19 mmol) and the mixture was heated in a microwave at 120°C for 30 minutes. Was then added to the cyanide of trimethylsilyl (48 ml, 0.38 mmol), was then added MeOH (1.5 ml) and acetic acid (44 ml, 0.75 mmol) and the mixture was heated to 70°C for 24 hours. After cooling to room temperature the mixture was evaporated, the residue was extracted with dichlo�methane and washed with saturated sodium bicarbonate solution. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel; 50 g; 0 to 20% ethyl acetate in heptane) allowed us to obtain specified in the title compound (20 mg; 21%) as a white foam.

MS ISP (m/e): 516,2 [(M+H)+].

Example 278

N-((3RS,4SR)-3-Fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

(CIS, RAC)-N-(3-Foreperiod-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 238f) was brought into interaction with 4-iodo-2-(trifluoromethyl)pyridine in analogy to example 242, which allowed us to obtain specified in the title compound as a whitish foam (yield 33%).

MS ISP (m/e): 511,1 [(M+H)+].

1H NMR (CDCl3, 400 MHz): δ (mn-1)=8.36 (d, 2H), 7.60-7.51 (m, 2H), 7.14-7.05 (m, 2H), 6.94 (t, 1H), 6.80 (dd, 1H), 5.04 (d, 1H), 4.88 (d, 1H), 4.31 (tt, 1H), 4.17-4.02 (m, 2H), 3.27 (dd, 1H), 3.14 (td, 1H), 2.16-2.09 (m, 1H), 1.96 (qd, 1H).

Example 279

8-(2-Chloro-4-fluorophenyl)-N-(4-methyl-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 234, using 4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-carbonitrile (100 mg, 0,19 mmol) instead of 4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(6-methylpyrimidin-4-yl)piperidin�-4-carbonitrile.

Specified in the title compound was obtained as a white foam (25 mg; 26%).

MS ISP (m/e): to 505.2(M+H)+].

Example 280

8-(2-Chloro-4-fluorophenyl)-N-(4-phenyl-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 279 using bromide vinylmania (1 M in THF; 0,582 ml; 0,582 mmol) instead of bromide Metalmania.

Specified in the title compound was obtained as a white foam (19 mg; 17%).

MS ISP (m/e): 567,2 [(M+H)+].

Example 281

N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(4-(trifluoromethyl)cyclohex-1-enyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

a) 1-(2-Aminopyridin-3-yl)-4-(trifluoromethyl)cyclohexanol and 3-(4-trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine

Was prepared analogously to example 262, step a-b, proceeding from N-(pyridin-2-yl)palamida and 4-(trifluoromethyl)cyclohexanone. 3-(4-Trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine was obtained after column chromatography on silica gel, using a gradient from CH2Cl2to CH2Cl2/MeOH 19:1 (vol./about.) as eluent, in the form of white solids (yield 26% over 2 stages).

MS ISP (m/e): 243,3 (100) [(M+H)+], 226,3 (14).

1-(2-Aminopyridin-3-yl)-4-(trifluoromethyl)cyclohexanol, the second-eluted, was obtained as white solid (yield 15% over 2 stages).

MS ISP (m/e): 261,1 (100) [(M+H)+/sup> ], 243,3 (52).

b) 8-(4-(Trifluoromethyl)cyclohex-1-enyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 1e-f, based on 3-(4-trifluoromethyl-cyclohex-1-enyl)-pyridine-2-ylamine. Specified in the title compound was obtained as white solid (yield 84% over 2 stages) after column chromatography on silica gel using ethyl acetate as eluent.

MS ISP (m/e): 283,1 (100) [(M+H)+].

c) N-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(4-(trifluoromethyl)cyclohex-1-enyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Was prepared analogously to example 219f, based on 8-(4-(trifluoromethyl)-cyclohex-1-enyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it. As a reducing agent used 4 equivalent of sodium borohydride in ethanol at 70°With during the night. Specified in the title compound was obtained after column chromatography on silica gel, using ethyl acetate as eluent, as a pale yellow solid (yield 44%).

MS ISP (m/e): 464,2 (100) [(M+H)+], 243,2 (26).

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.51 (d, 1H), 7.38 (d, 2H), 7.29 (or s, 1H), 6.88 (t, 1H), 6.79 (d, 1H), 3.78 (m, 3H), 3.33 (m, 2H), 2.79-2.45 (m, 4H), 2.31 (m, 1H), 2.28 (s, 3H), 2.20-1.99 (m, 3H), 1.59 (m, 3H).

Example 282

1-(2-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-4-(trifluoromethyl)cyclohexanol

a) 1-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-4-(trifluoromethyl)-cyclohexanol

Was prepared analogously to example 1e-f, based on 1-(2-aminopyridin-3-yl)-4-(trifluoromethyl)cyclohexanol. Specified in the title compound was obtained as white solid (yield 81% over 2 stages) after column chromatography on silica gel using ethyl acetate as eluent.

MS ISP (m/e): 301,2 (40) [(M+H)+], 283,1 (100).

b) 1-(2-(1-(3-Methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-4-(trifluoromethyl)cyclohexanol

Was prepared analogously to example 219f, based on 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-4-(trifluoromethyl)cyclohexanol and 1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-it. As a reducing agent used 4 equivalent of sodium borohydride in ethanol at 70°With during the night. Specified in the title compound was obtained after column chromatography on silica gel using ethyl acetate as the eluent, in the form of a white solid (yield 46%).

MS ISP (m/e): 482,3 (100) [(M+H)+], 464,2 (29), 243,2 (37).

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.51 (d, 1H), 7.56 (d, 2H), 6.91 (t, 1H), 6.68 (d, 1H), 5.28 (s, 1H), 3.77 (m, 3H), 3.33 (m, 2H), 2.68-2.42 (m, 4H), 2.28 (s, 3H), 2.05 (m, 2H), 1.75 (m, 4H), 1.61 (m, 3H).

Example 283

8-(Fluoro(4-fluorophenyl)methyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of (4-fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (72 mg; 164 mmol) in dichloromethane (0,82 ml) was added under an atmosphere of nitrogen TRIFLUORIDE, diethylaminoethyl (DAST) (58,7 mg; 48,1 ml, 328 mmol). The reaction mixture became yellow and was stirred at room temperature for 3 hours. Added water and the reaction mixture was twice extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Specified in the title compound was obtained as white solid (20,1 mg; 27%) after purification column chromatography on silica gel using ethyl acetate as eluent.

MS ISP (m/e): 442,4 (44) [(M+H)+], 422,1 (100).

1H NMR (DMSO-D6, 300 MHz): δ (mn-1)=8.29 (d, 1H), 7.49-7.43 (m, 3H), 7.06 (t, 2H), 6.90 (d, J=44.7 Hz, 1H), 6.85 (t, 1H), 4.49 (d, 1H), 3.89 (m, 3H), 3.35 (br t, 2H), 2.42 (s, 3H), 2.22 (brd, 2H), 1.65 (m, 2H).

1. The compound of the formula I

where
hetaryl I is a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N, and which is selected from the group consisting of

hetaryl II is a five - or six-membered heteroaryl groups�, containing 1-3 heteroatom as defined above for I hetaryl, or represents a bicyclic ring system containing 1-4 heteroatom selected from S, O or N, where at least one ring is aromatic in nature, and which is selected from the group consisting of

R1represents C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl, substituted by halogen, or halogen;
R2represents halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl, substituted by halogen, C1-7-alkyl, substituted by hydroxy or benzo[1,3]dioxole, or
represents -(R)p-phenyl, possibly substituted by halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted by halogen, dimethylamino, -(CH2)p-NHC(O)O-(C1-7-alkyl or C1-7-alkyl, substituted by halogen, and R represents hydrogen, halogen, hydroxy or C1-7-alkoxy, or represents C6-cycloalkenyl or C3-6-cycloalkyl, possibly substituted by hydroxy or C1-7-alkyl, substituted by halogen, or
represents a five - or six-membered heteroaryl group containing 1-3 heteroatom selected from O, S or N, as defined above, which probably replaced halogeno�, C1-7-alkyl, C1-7-alkoxy or dimethylamino,
or is O-phenyl, possibly substituted by halogen, or represents a 6-membered heteroseksualci containing 1-2 heteroatom selected from N and O, possibly substituted by halogen, hydroxy, C1-7-alkyl, substituted by halogen, or C(O)O-(C1-7-alkyl or represents azaspiro[2.5]octanol;
R3represents hydrogen, C1-7-alkyl, cyano or phenyl;
R4represents C1-7-alkoxy, C1-7-alkyl or halogen;
p is 0 or 1;
n is 0, 1 or 2; if n is 2, then R4may be the same or different;
m is 0, 1 or 2; if m is 2, then R1may be the same or different;
o is 0, 1, 2 or 3; when o is 2 or 3, then R2may be the same or different;
or its pharmaceutically active salts accession acid, except pyridin-4-yl-(3,4,5,6-tetrahydro-2H[1,4']bipyridinyl-4-yl)-amine, (5-chloro-6-ethyl-pyrimidine-4-yl)-(1-pyrimidine-2-yl-piperidine-4-yl)-amine and 6-chloro-N-[1-[5-(1-methylethyl)-2-pyrimidinyl]-4-piperidinyl]-4-pyrimidinamine.

2. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a bicyclic ring system containing 1-4 heteroatom as defined in claim 1.

3. The compound of formula I according to claim 2, wherein e�and connections are a
[8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine,
[8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-�l)-piperidine-4-yl]-amine,
[8-(2,4-debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-fluoro-4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[8-(3,4-debtor-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(6-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-Piperi�in-4-yl]-amine,
[8-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[8-(3,4-debtor-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine,
N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2,3-dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3-chlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
[8-(5-dimethylamino-2-nitro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazo�about[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
N-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(4-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
[8-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1 -(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1 -(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(5-chloro-2-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
(8-benzo[1,3]dioxol-5-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(3,5-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
(CIS,RAC)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
(3S,4R)- and (3R,4S)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
(CIS,RAC)-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
(CIS,RAC)-[3,4-debtor-1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
N-(3,3-debtor-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
4-chloro-3-(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,
(4-fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol or
N-((3S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

4. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a five - or six-membered heteroaryl group containing 1-3 heteroatom as defined in claim 1.

5. The compound of formula I according to claim 4, wherein these compounds are
[1-(3,5-dichloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
[1-(3-chloro-benzyl)-1H-[1,2,4]triazole-3-yl]-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-yl]-amine,
2-[2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-yl]-propan-2-ol,
2-{6-(4-chloro-phenyl)-2-[1-(3-methyl-[1,2,4]thiadiazole-5-yl)-piperidine-4-ylamino]-pyrimidine-4-yl}-propan-2-ol or

6. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a bicyclic ring system containing 1-4 heteroatom as defined in claim 1.

7. The compound of formula I according to claim 1, wherein these compounds are
[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine,
[8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[8-(2,3-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
3-(2-(1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,
[8-(3,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine,
3-(2-(1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,
N-(1-(5-methyl,3,4-oxadiazol-2-yl)piperidine-4-yl)-8-(3-(triptoreline)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine or
[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(5-methyl-[1,3,4]oxidiazol-2-yl)-piperidine-4-yl]-amine.

8. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a bicyclic ring system containing 1-4 heteroatom as defined in claim 1.

9. The compound of formula I according to claim 1, wherein these compounds are
2-{8-(4-chloro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,
8-(2-chloro-4-fluorophenyl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-6-fluoro-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(2-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
[8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(6-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(2-chloro-thiophene-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(2,3,4-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(3,4-debtor-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(3,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-[8-(3,4,5-Cryptor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
[8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
3-{2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzonitrile,
[8-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
[8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
tert-butyl-4-(6-methyl-2-(1-(6-methylpyr�idin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate,
8-(3,4-differenl)-N-(1-(6-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(6-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(pyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
2-{8-(3,4-debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,
4-(3-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidine-4-yl)benzo[d]thiazol-2-amine,
[4-(3,4-debtor-phenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-yl]-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
(CIS,RAC)-[8-(3,4-debtor-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(6-methyl-pyrimidine-4-yl)-piperidine-4-yl]-amine,
(CIS,RAC)-N-(3-fluoro-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
2-{8-(4-fluoro-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)-piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol,
2-{8-(3,4-debtor-phenyl)-2-[1-(6-methyl-pyrimidine-4-yl)piperidine-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-propan-2-ol or
N-(3,3-debtor-1-(6-methylpyrimidin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

10. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a bicyclic ring system containing 1-4 heteroatom as defined in claim 1.

11. The compound of formula I according to claim 10, wherein these compounds are
8-(2-chloro-4-fluorophenyl)-N-(1-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,5-bis(trifluoromethyl)phenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3-chlorophenoxy)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
(2'-chloro-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-[8-(4-triptoreline-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine,
3-(2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
6-chloro-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6,8-bis(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-ethoxyphenyl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(2-ethoxypyridine-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
4-(3-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-4-(3,4-differenl)-6-methylbenzo[d]thiazol-2-amine,
4-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-6-methylbenzo[d]thiazol-2-amine,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(4-foreperiod-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(2-chloropyridin-4-yl)piperidine-4-yl)-8-(4,4-deformability-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-2-(1-(2-chloropyridin-4-yl)piperidine-4-ylamino)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,
N-(1-(2-methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-am�n
[8-(3,5-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2'-methoxy-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amine,
1-(2-chloropyridin-4-yl)-4-(8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)piperidine-4-carbonitrile,
(CIS,RAC)-N-(1-(2-chloropyridin-4-yl)-3-foreperiod-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
(CIS,RAC)-N-(3-fluoro-1-(2-methoxypyridine-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(2-chloropyridin-4-yl)-4-phenylpiperidine-4-yl)-8-(3,4-differenl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-8-(2,3,4-tryptophanyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2,4-differenl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,5-bis(trifluoromethyl)phenyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine or
4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-carbonitrile.

12. The compound of formula I according to claim 1, wherein hetaryl I is aand hetaryl II is a bicyclic ring system containing 1-4 heteroatom as defined in claim 1.

13. The compound of formula I according to claim 12, and these �couplers are
8-(3,4-differenl)-6-fluoro-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(3,4-differenl)-6-methyl-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
8-(2-chloro-4-fluorophenyl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine,
6-chloro-8-(3,4-differenl)-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine or
8-(2-chloro-4-fluorophenyl)-6-methyl-N-(1-(6-methylpyridazin-4-yl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

14. A method for producing a compound of formula I, which is defined in any one of claims. 1-13, including:
(a) bringing into interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

where X represents a halogen, and other groups have the meanings described in claim 1, and,
if desired, the conversion of the compounds in pharmaceutically acceptable salt accession acid;
or
(b) bringing in the interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

where X represents a halogen, and other groups have the meanings described above, or
(C) is shown� in the interaction of a compound of formula

with a compound of the formula

to produce a compound of the formula

where groups have the meanings described above, a R3represents hydrogen, and,
if desired, the conversion of the compounds in pharmaceutically acceptable salt accession acid.

15. A medicament having inhibitory secretion β42 activity containing one or more compounds according to any one of claims. 1-13 and pharmaceutically acceptable excipient.

16. Medicament according to claim 15 for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome.

17. Use of a compound according to any one of claims. 1-13 for the manufacture of medicaments for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome, are associated with the activity of β-amyloid.

18. The compound according to any one of claims. 1-13 for use as therapeutically active substances with inhibiting the secretion β42 activity.

19. The use of soy�of inane according to any one of claims. 1-13 for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome, are associated with the activity of β-amyloid.

20. The compound according to any one of claims. 1-13 for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome, are associated with the activity of β-amyloid.

21. A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), multi-infarct dementia, dementia boxers or down syndrome, are associated with the activity of β-amyloid, comprising administering an effective amount of the compound defined in any one of claims. 1-13.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 5,5-condensed heteroarylene compounds IIIB, where U2, V1, V2 and W1 are selected from O, N, NH, S or CR3a; U1, W2, X1 and X2 represent C or N; R1 and R2 represents hydrogen, -C(O)CH(NR1bR1c)R1a, -C(O)CH(N(R1c)C(O)OR1b)R1a or -C(O)OR1a; R3a represents hydrogen or R3; R3 represents halogen or -C(O)OR1a; L1 and L2 are such as given in invention formula, each Z1 and Z2 represents bond or -O-; each Rla, R1b and R1c represents hydrogen, C1-6 alkyl or C6-14 aryl; or Rlb and Rlc together with N atom, which they are bound to, form 5-6-membered heterocyclyl; q, r, s, t and u equal 1. Invention also relates to pharmaceutical compositions, containing 5,5-condensed heteroarylene compounds, and methods of treating or preventing HCV infection.

EFFECT: 5,5-condensed heteroarylene derivatives, possessing inhibiting activity with respect to hepatitis C virus.

43 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of obtaining fluorescent catecholamines selected from dopamine and adrenalin, and their metabolites, selected from homovanillic and vanillin-mandelic acids, by a method of derivation. The compounds can be used as highly sensitive and selective markers for the determination of various diseases. The method of derivation includes oxidation of the initial compounds and their interaction with amines that form condensed structures in a medium of the CAPS-buffer solution or glycin - KOH 0.2 mM hydrogen peroxide in the presence of horseradish peroxidase as a catalyst. The process in preferably carried out in a 0.1 M buffer solution with the concentration of horseradish peroxidase 0.01-1 mcM; concentration of hydrogen peroxide - 100 mcM, amine concentration - 0.1-33 mM; concentration of catecholamines and metabolites - 0.03-1 mcM.

EFFECT: method is simple and producible as it does not require higher temperature and is realised in a water solution.

2 cl, 2 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a number of substituted dihydrobenzocycloalkyloxymethyl oxazolpyrimidinone of formula

wherein n represents 1, 2 or 3; R1 represents hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl and propyl; R2 is specified in a group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, 1,1-difluoropropyl, methoxymethyl and 2-fluoroethoxymethyl; R3 and R4 represent (C1-C4)alkyl; and R5 and R6 are identical or different and are independently specified in a group consisting of hydrogen, halogen, (C1-C4)alkyl and (C1-C4)alkoxy. The invention also refers to specific compounds specified in cl.8 of the patent claim, to compounds of formula

a pharmaceutical composition and the use of the declared compounds.

EFFECT: dihydrobenzocycloalkyl-oxymethyloxazolpyrimidinone as metabotropic glutamate receptor mGluR2 modulators.

14 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to nitroimidazoxazine derivatives of formula , wherein X represents O, OCH2, OCH2CH=CH or OCH2C≡C; Y represents a group of any of formulas IIa-IIc, wherein means an attachment point to X, and Z in formulas

represents CH2, CH=CH, C≡C or a direct bond; the numbers 2, 3 and 4 are positions of a terminal ring having R1 as a substitute; the terminal ring of formula I comprises C, CH or one nitrogen atom in each position, and each of R1 and R2 in formulas I and IIa represents one or two substitutes found in any accessible position of the ring and independently represents H, F, Cl, CF3, OCF2H, OCF3 or combinations thereof. Besides, the invention refers to a pharmaceutical compound based on a compound of formula I, a method of treating a microbial infection, specific compounds.

EFFECT: there are prepared new compound effective in treating the microbial infections, including in treating the diseases caused by Mycobacterium tuberculosis.

8 cl, 28 dwg, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to nitroimidazooxazine derivatives of general formula I, where n equals 1, V and W independently denote H or CH3, and one of X and Y is H and the other is one of the formulae and , where formula IIa includes a single ring labelled at position 3 and position 4 and containing R1 as a substitute, and formula IIb includes a first ring labelled at position 3 and position 4 and containing as substitutes both R2 and a terminal ring, labelled at position 4 and containing R1 as a substitute, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb include C, CH, or N at each ring position, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb independently contain no more than two nitrogen atoms; Z in formulae IIa and IIb is CH2 or a direct bond, R1 is independently any one or two of H, F, C1, CF3, OCF3 or OCH2Ph, and R2 is H. The invention also relates to a pharmaceutical composition based on the compound of formula I, a method of preventing and treating a microbial infection based on use of the compound of formula , and specific nitroimidazooxazine derivatives.

EFFECT: obtaining novel compounds with useful biological activity.

7 cl, 21 dwg, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt. The invention also refers to pharmaceutical compositions containing the above citrate, and methods for using citrate in treating several conditions.

EFFECT: what is prepared is the new 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene salt and the pharmaceutical compositions on the basis thereof which can find application in medicine for treating a proliferative disorder.

17 cl, 30 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 5,5-condensed heteroarylene compounds IIIB, where U2, V1, V2 and W1 are selected from O, N, NH, S or CR3a; U1, W2, X1 and X2 represent C or N; R1 and R2 represents hydrogen, -C(O)CH(NR1bR1c)R1a, -C(O)CH(N(R1c)C(O)OR1b)R1a or -C(O)OR1a; R3a represents hydrogen or R3; R3 represents halogen or -C(O)OR1a; L1 and L2 are such as given in invention formula, each Z1 and Z2 represents bond or -O-; each Rla, R1b and R1c represents hydrogen, C1-6 alkyl or C6-14 aryl; or Rlb and Rlc together with N atom, which they are bound to, form 5-6-membered heterocyclyl; q, r, s, t and u equal 1. Invention also relates to pharmaceutical compositions, containing 5,5-condensed heteroarylene compounds, and methods of treating or preventing HCV infection.

EFFECT: 5,5-condensed heteroarylene derivatives, possessing inhibiting activity with respect to hepatitis C virus.

43 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a formula compound. The method includes a stage of binding a formula compound with a formula compound in the presence of a base with the formation of the formula (I) compound. In formula (I) stereochemical configurations in the positions, marked with asterisks, are relative; Rb represents hydrogen; R00 represents a C1-10 aliphatic group or a C6-14 aryl group, including one-three rings; Rd, Re, Re', Rf, Rh, Rh', Rk represent hydrogen; Rg represents chlorine, fluorine, iodine or bromine; Rm represents a protective hydroxyl group; values of radicals Ra, R*, Rc are given in the invention formula. In formulas (II) and (III) Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rk and Rm are such as determined in formula (I) and R1 represents -CH2CHO. The invention also relates to methods of obtaining compounds of formulae (V), (VI), (VId) and to a compound of the structural formula (IIa). Structural formulae of compounds (V), (VI), (VId), (IIa) are given in the invention formula.

EFFECT: method makes it possible to carry out synthesis in a regioselective way and use the obtained product without purification.

15 cl, 1 tbl, 26 ex

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention describes a method of producing and a method of purifying dialkyl pemetrexed of formula (I) , having antifolate action. The compound can be used to treat non-small-cell cancer and, coupled with cisplatin, to treat malignant pleural mesothelioma of the lungs. The method includes reacting a carboxylic acid of formula (II) with a diester of glutamic acid of formula (III) or an acid-addition salt thereof. The process is carried out in the presence of a substituted triphenyl phosphate of formula (IV) , a base and a solvent. In formulae (I) and (III) each R1 and R2 independently represents alkyl groups. In formula (IV) X, Y and Z assume values given in the claim.

EFFECT: use of safe, mild, cheap, non-oxidising and easy to handle triphenyl phosphate simplifies the process and enables to obtain, for example, diethyl pemetrexed with purity higher than 99%.

14 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .

EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.

13 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chemical compounds of general formula I wherein LA, LB, LC, cycle A, cycle B, RA, RB, RC, RD, RE and RF have the values specified in the patent claim. The compounds of formula (I) are protein kinase inhibitors.

EFFECT: invention refers to pharmaceutical compositions containing the above compounds, as well as to using the above compounds for treating and/or preventing the diseases related to aberrant protein kinase activity, particularly oncological diseases.

10 cl, 14 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which possess an inhibiting activity with respect to anti-apoptotic Bcl-2 proteins. The invention also relates to a pharmaceutical composition, containing the said compounds, and to a method of treating urinary bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, hepatocellular cancer, lymphoblast leukosis, follicular lymphoma, lymphoid malignant diseases of a T-cell or B-cell origin, melanoma, myelogenous leukaemia, myeloma, oral cavity cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer.

EFFECT: obtaining the compounds, possessing the inhibiting activity with respect to anti-apoptotic Bcl-2 proteins.

4 cl, 5 tbl, 405 ex

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