HK1179958B

HK1179958B - Piperidine derivatives

Info

Publication number: HK1179958B
Application number: HK13107154.2A
Authority: HK
Inventors: 卡尔海因茨．博伊曼; 亚历山大．弗洛尔; 埃尔温．格奇; 卢克．格林; 西内塞．若利多; 亨纳．努斯特; 安雅．林贝格; 托马斯．吕贝斯; 安德鲁．托马斯
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2010-02-17
Filing date: 2011-02-14
Publication date: 2015-11-06

Description

Piperidine derivatives

The invention relates to compounds of formula I

Heteroaryl I is a five or six membered heteroaryl group, comprising 1 to 3 heteroatoms selected from O, S or N;

Heteroaryl II is a five or six membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, S or N, or is a two membered ring system comprising 1 to 4 heteroatoms selected from S, O or N, wherein at least one ring is aromatic in nature;

R¹is lower alkyl, lower alkoxy, lower alkyl substituted by halogen or halogen;

R²is halogen, lower alkyl, lower alkoxy, hydroxy, halogen-substituted lower alkyl, hydroxy-substituted lower alkyl or benzo [1, 3 ]]Dioxolyl, or

Is- (CHR)_p-phenyl, optionally substituted with: halogen, lower alkyl, lower alkoxy, S (O)₂-lower alkyl, cyano, nitro, halogen-substituted lower alkoxy, dimethylamino, - (CH)₂) p-NHC (O) O-lower alkyl or halogen substituted lower alkyl, and R is hydrogen, halogen, hydroxy or lower alkoxy, or

Is cycloalkenyl or cycloalkyl optionally substituted by lower alkyl substituted by hydroxy or halogen, or

Is a five or six membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S or N, optionally substituted by halogen, lower alkyl, lower alkoxy or dimethylamino, or

Is O-phenyl optionally substituted by halogen, or

Is heterocycloalkyl optionally substituted by halogen, hydroxy, lower alkyl substituted by halogen or C (O) O-lower alkyl;

R³Is hydrogen, lower alkyl, cyano or phenyl;

R⁴is 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, e.g.If o is 2 or 3 then R²May be the same or different;

or to pharmaceutically active acid addition salts thereof.

It has now been found that the compounds of formula I of the present invention are modulators of amyloid beta and, therefore, they may be useful in the treatment or prevention of diseases associated with the deposition of amyloid beta in the brain, especially Alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy (cerebral amyloid angiopathy), hereditary cerebral hemorrhage with amyloidosis (cardiac cerebral vascular with amyloidosis), Dutch-type (HCHWA-D), multi-infarct dementia (multi-infancement), dementia pugilistica (dementias), and Down syndrome (Down syndrome).

Alzheimer's Disease (AD) is the most common cause of senile dementia. Pathologically, AD is characterized by the deposition of amyloid in the brain in extracellular plaques and intracellular neurofibrillary tangles. Amyloid plaques are mainly composed of amyloid peptides (Α β peptides) derived from β -Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified, the most abundant of which are proteins of amino acid length 695, 751 and 770. They are all produced by differential splicing of a single gene. The a β peptides are derived from the same domain of APP.

A β peptides are produced from APP by the sequential action of two proteolytic enzymes, termed β -secretase and γ -secretase. The β -secretase enzyme first cleaves the extracellular domain of APP just outside the transmembrane domain (TM) to generate a C-terminal fragment of APP, which contains the TM and cytoplasmic domains (CTF β). CTF β is a substrate for γ -secretase, which cleaves at several adjacent positions within the TM to produce a β peptide as well as cytoplasmic fragments. The multiple proteolytic cleavages mediated by gamma-secretase produce a β peptides with different chain lengths, such as a β 38, a β 40 and a β 42. The latter is considered to be a more pathogenic amyloid peptide because of its strong tendency to form neurotoxic aggregates.

The beta-secretase enzyme is typically an aspartyl protease. Gamma-secretase has proteolytic activity and consists of several proteins, the exact composition of which is not fully known. However, presenilins are essential components of this activity and may represent a new group of atypical aspartyl proteases that cleave within the TM of their substrates and are themselves ubiquitous membrane proteins. Other essential components of gamma-secretase may be the foolin and the products of the aph1 and pen-2 genes. The substrates of the demonstrated gamma-secretases are proteins of the APP and Notch receptor family, however, gamma-secretases have relaxed substrate specificity and can also cleave other membrane proteins unrelated to APP and Notch.

Gamma-secretase activity is required for the production of a β peptides. This has been shown by genetic means, i.e., excision of the presenilin gene and low molecular weight inhibitory compounds. Since according to the amyloid hypothesis of AD, the production and deposition of a β is the ultimate cause of the disease, it is believed that selective and potent inhibitors of γ -secretase would be helpful in the prevention and treatment of AD.

An alternative approach to treatment is to modulate gamma-secretase activity, which results in a selective reduction in a β 42 production. This will result in an increase in shorter a β isoforms such as a β 38, a β 37, etc., which have a reduced ability to aggregate and form plaques and are less neurotoxic. Compounds that exhibit this effect in modulating gamma-secretase activity include certain nonsteroidal anti-inflammatory drugs (NSAIDs) and related analogs (Weggen et al, Nature, 414(2001) 212-16).

Accordingly, the compounds of the present invention will be useful in the treatment or prevention of diseases associated with the deposition of beta amyloid in the brain, particularly alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and down syndrome.

Various documents describe the current knowledge about the regulation of gamma-secretase, such as the following publications:

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

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

Takahashi et al, J.biol.chem. (J.Biochem.), 278(2003)18644-70

Beher et al, J.biol.chem. (journal of biochemistry) 279(2004)43419-26

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

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

Perretto et al, J.Med.chem. (journal of medicinal chemistry) 48(2005)5705-20

Clarke et al, J.biol.chem. (journal of biochemistry) 281(2006)31279-89

Stock et al, bioorg.Med.chem.Lett. (Bioorganic pharmaceutical chemical communication) 16(2006)2219-2223

Narlawawar et al, J.Med.chem. (journal of medicinal chemistry) 49(2006)7588-91

For compounds of formula I, the following definitions are used:

as used herein, the term "lower alkyl" refers to a saturated straight or branched chain group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, and the like. Preferred alkyl groups are those having 1 to 4 carbon atoms.

The term "halogen-substituted lower alkyl" as used herein refers to an alkyl group as described above wherein at least one hydrogen atom is substituted by halogen, e.g. CF₃、CHF₂、CH₂F、CH₂CF₃、CH₂CH₂CF₃、CF₂CHF₂、CH₂CF₂CF₃And the like.

The term "hydroxy-substituted lower alkyl" as used herein refers to an alkyl group as described above wherein at least one hydrogen atom is substituted with a hydroxy group, e.g. CH₂OH、CHCH₃OH or C (CH)₃)₂OH。

The term "lower alkoxy" as used herein refers to an alkyl group as described above, which is bonded via an O atom.

The term "halogen" refers to chlorine, iodine, fluorine and bromine.

The term "five or six membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, S or N" is selected from the group consisting of;

the term "two-membered ring system comprising 1 to 4 heteroatoms selected from S, O or N, wherein at least one ring is aromatic in nature" is selected from the group consisting of;

as used herein, the term "heterocycloalkyl" refers to an unsaturated or partially unsaturated ring containing heteroatoms such as O, S and N, said groups being selected from morpholinyl, dihydropyridinyl, dihydropyranyl, piperidinyl or 6-aza-spiro [2, 5] octyl.

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

The term "cycloalkenyl" refers to partially unsaturated alkyl rings having 3 to 6 carbon atoms, such as cyclohexenyl.

The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic or 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, methanesulfonic acid, p-toluenesulfonic acid and the like.

The invention relates to compounds of formula (I), to the use of said compounds for producing a medicament for treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down's syndrome, to the production thereof and to medicaments based on the compounds of formula (I) according to the invention.

Further objects of the invention are all forms of optically pure enantiomers, racemates or diastereomeric mixtures of compounds of formula I.

An embodiment of the invention are compounds of the formula I, wherein heteroaryl I isAnd heteroaryl II is a two-membered ring system comprising 1 to 4 heteroatoms, for example

[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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

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

[1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

[8- (2, 4-difluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

[8- (3, 4-difluoro-phenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

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

[8- (3, 4-difluoro-phenyl) -6-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

[1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] -amine

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

[8- (3, 4-difluoro-phenyl) -5-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

[1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] - [8- (3, 4, 5-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] -amine

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

[8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

[8- (3, 4-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

[8- (3, 4-difluoro-phenyl) -6-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

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

N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (3- (trifluoromethoxy) phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

8- (3-chlorophenyl) -N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-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] thiadiazol-5-yl) -piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (4- (trifluoromethoxy) 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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

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

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

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

(cis, rac) -N- (3-fluoro-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

(3S, 4R) -and (3R, 4S) -N- (3-fluoro-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

(cis, rac) - [ 3-fluoro-1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] - [8- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] -amine

(cis, rac) - [3, 4-difluoro-1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] - [8- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] -amine

N- (3, 3-difluoro-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

(4-fluorophenyl) (2- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-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-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine.

Another embodiment of the present invention are the compounds of formula I, wherein heteroaryl I is And heteroaryl II is a group comprisingFive-or six-membered heteroaryl having 1 to 3 heteroatoms selected from O, S or N, e.g. the following compounds

[1- (3, 5-dichloro-benzyl) -1H- [1, 2, 4] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

[1- (3-chloro-benzyl) -1H- [1, 2, 4] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

2- [2- [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamino ] -6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -propan-2-ol

2- {6- (4-chloro-phenyl) -2- [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol or

2- {6- (4-chloro-benzyl) -2- [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol.

Another embodiment of the present invention are the compounds of formula I, wherein heteroaryl I isAnd heteroaryl II is a two-membered ring system comprising 1 to 4 heteroatoms, for example

[1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amines

[8- (2-chloro-4-fluoro-phenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl ]-amines

[8- (4-fluoro-3-trifluoromethyl-phenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

[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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

[1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]- [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-yl]-amines

[8- (2, 3-dichloro-phenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

[8- (3-chloro-phenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxazol-2-yl) -piperidin-4-yl]-amines

3- (2- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

3- (2- (1- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) piperidin-4-ylamino) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-8-yl) benzonitrile

N- (1- (5-methyl-1, 3, 4-) Oxadiazol-2-yl) piperidin-4-yl) -8- (3- (trifluoromethoxy) 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]]Oxadiazol-2-yl) -piperidin-4-yl]-an amine.

2- {8- (4-chloro-phenyl) -2- [1- (6-methyl-pyrimidin-4-yl) -piperidin-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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

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

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

8- (2-chloro-4-fluorophenyl) -N- (1- (2-methylpyrimidin-4-yl) piperidin-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) piperidin-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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

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

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

[8- (2-chloro-thiophen-3-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

[1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] - [8- (2, 3, 4-trifluoro-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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

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

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

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

[1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] - [8- (3, 4, 5-trifluoro-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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

3- {2- [1- (6-methyl-pyrimidin-4-yl) -piperidin-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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

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

4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

8- (3, 4-difluorophenyl) -N- (1- (6-methoxypyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

8- (3, 4-difluorophenyl) -N- (1- (pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

8- (3, 4-difluorophenyl) -6-methyl-N- (1- (pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

2- {8- (3, 4-difluoro-phenyl) -2- [1- (6-methyl-pyrimidin-4-yl) -piperidin-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) piperidin-4-yl) benzo [ d ] thiazol-2-amine

[4- (3, 4-difluoro-phenyl) -4, 5, 6, 7-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrimidin-2-yl ] - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

(cis, rac) - [8- (3, 4-difluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [ 3-fluoro-1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

(cis, rac) -N- (3-fluoro-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

2- {8- (3, 4-difluoro-phenyl) -2- [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamino ] - [1, 2, 4] triazolo [1, 5-a ] pyridin-5-yl } -propan-2-ol or

N- (3, 3-difluoro-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine.

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

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

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

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

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

8- (3, 4-difluorophenyl) -N- (1- (2-methoxypyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

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

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

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

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

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

8- (3, 4-difluorophenyl) -N- (1- (2-ethoxypyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

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

N- (1- (2-Chloropyridin-4-yl) piperidin-4-yl) -4- (3, 4-difluorophenyl) -6-methylbenzo [ d ] thiazol-2-amine

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

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

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

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

N- (1- (2-methoxypyridin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) -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-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-4-carbonitrile

(cis, rac) -N- (1- (2-chloropyridin-4-yl) -3-fluoropiperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

(cis, rac) -N- (3-fluoro-1- (2-methoxypyridin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

N- (1- (2-Chloropyridin-4-yl) -4-phenylpiperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

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

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

8- (2, 4-difluorophenyl) -N- (1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-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) piperidin-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 ] pyridin-2-ylamino) -1- (2- (trifluoromethyl) pyridin-4-yl) piperidine-4-carbonitrile.

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

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

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

6-chloro-8- (3, 4-difluorophenyl) -N- (1- (6-methylpyridazin-4-yl) piperidin-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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine.

An embodiment of the present invention are additional compounds of formula I-1

Wherein

Heteroaryl I is a five or six membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, S or N;

heteroaryl II is a five or six membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S or N, or is a two membered ring system containing 1 to 4 heteroatoms selected from S or N, wherein at least one ring is aromatic in nature;

R¹is lower alkyl or halogen;

R²is lower alkyl, hydroxy-substituted lower alkyl, or is- (CH)₂)_p-phenyl, optionally 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 a pharmaceutically active acid addition salt thereof.

The compounds of formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example, by a method comprising:

a) reacting a compound of formula 2

With a compound of formula 3

To produce a compound of formula I

Wherein X is halogen and the other groups have the meanings as described above, and,

if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt;

or

b) Reacting a compound of formula 6

With a compound of formula 7

To produce a compound of formula I

Wherein X is halogen and the other radicals have the meanings indicated above, or

c) Reacting a compound of formula 8

With a compound of formula 9

To produce a compound of formula I

Wherein the radicals have the meanings indicated above and R³Is hydrogen, and, in addition,

the compound obtained is converted, if necessary, into a pharmaceutically acceptable acid addition salt.

The preparation of the compounds of formula I of the present invention can be carried out in a continuous or convergent synthetic route. The synthesis of the compounds of the invention is shown in the following scheme. The techniques required to carry out the reaction and to purify the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and symbols used in the following description of the methods have the meanings given herein before.

In more detail, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence shown in the scheme, however, the sequence of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, the methods described in the examples, or methods known in the art.

Scheme 1

The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by coupling an amine of formula 2 with a halide of formula 3 (see scheme 1). The reaction can be accomplished using generally known procedures, such as displacement reactions under catalytic conditions (such as, for example, palladium (0) or copper (II) catalysis) or under thermal conditions or under basic conditions.

Scheme 2

Alternatively, halide 3 can be coupled under the above conditions with an amine of formula 4, the amine of formula 4 having a protecting group PG, e.g. Boc, on the piperidine nitrogen (see scheme 2). Following deprotection using, for example, trifluoroacetic acid, piperidine 6 may be coupled with a heteroaryl I halide of formula 7 to yield a compound of formula I.

Scheme 3

R³Is hydrogen;

alternatively, anilines of formula 9 can be used in reductive amination reactions with ketones of formula 8 or 10 (see scheme 3) to yield compound I directly or after cleavage of the protecting group PG of 5 followed by coupling with heteroaryl I halide 7 as described in scheme 2. Reductive amination can be accomplished by methods known to those skilled in the art of organic synthesis, for example by heating amines and ketones in a suitable solvent (e.g., toluene, dichloroethane, THF), possibly in the presence of an acid (e.g., acetic acid, tetraisopropyl orthotitanate), and reducing the intermediate imine with a suitable reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, hydrogen in the presence of palladium on charcoal).

Anilines of formula 9 that can be used as starting materials for the preparation of compounds of formula I can be prepared as described in the schemes below.

Scheme 4

Alternatively, the coupling of the aniline of formula 9 with the ketone of formula 8 or 10 can be achieved according to the aza-Wittig/reduction scheme (see scheme 4). The anilines of formula 9 can be first converted to their corresponding trialkylphosphazenes 11 by reaction with a trialkylhalophosphine (e.g. dichlorotrimethylphosphine, prepared by reaction of trimethylphosphine with hexachloroethane in THF or dichloromethane) and an organic amine base (e.g. triethylamine, diisopropylethylamine) in a suitable solvent (e.g. THF, dichloromethane). The ketone of formula 8 or 10 is then added to the reaction mixture containing the phosphazene 11 prepared in situ and the mixture is heated. The resulting imine/enamine 12 or 13 is then treated with a suitable reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, decaborane, borane-THF complex, hydrogen in the presence of palladium on charcoal) in a suitable solvent (THF, DCM, MeOH, and mixtures thereof) with or without acid catalysis (e.g., acetic acid) at ambient or elevated temperature to yield a compound of formula 5 or I (hydrogen for R3).

Scheme 5

A representsOr

Alternatively, the triazolopyridines of formula 5a may be constructed by: by conversion of the amine of formula 14 into its corresponding isothiocyanate 15 (e.g. by reaction with thiophosgene or 1, 1' -thiocarbonyldiimidazole in dichloromethane in the presence of an organic or aqueous inorganic base) and reaction with an amine of formula 4 (see scheme 5). The resulting thiourea 16 can be activated by alkylation with methyl iodide and subsequently cyclized to triazolopyridine 5a by intense heating (> 130 ℃) in a polar solvent such as dimethylacetamide in the presence of a suitably functionalized hydroxylamine derivative such as O- (trimethylsilyl) -hydroxylamine.

Scheme 6

D represents a carbocyclic ring, preferably

Triazolopyridines of formula 5b may be prepared by: the cyclic hydrazide 18 and isothiocyanate 19 (prepared by methods known to those skilled in the art) are first condensed to form thiourea 20 (see scheme 6). Activation of the thio group by alkylation (e.g., methyl iodide, in DMF, at elevated temperature) allows it to be displaced by azide (e.g., sodium azide, in DMF, at elevated temperature) to yield guanidinium azide 22. Staudinger reduction with trimethylphosphine gives the intermediate phosphazene 23, which, upon heating, cyclizes to give the triazolopyridine 5 b.

Scheme 7

A representsOrAnd X represents Cl or Br.

Anilines 9a (see scheme 7) in which the heteroaryl group II is a cyclic triazole moiety can be constructed from the corresponding amino derivative 14, the amino derivative 14 being either commercially available or can be obtained from the corresponding halide 24 by palladium catalyzed Suzuki coupling with a boronic acid or boronic ester (e.g. pinacol ester). The amine 14 may be reacted with ethoxycarbonyl isothiocyanate to produce a thiourea derivative 25, the thiourea derivative 25 undergoing a cyclization reaction upon treatment with hydroxylamine in the presence of a base under the release of carbon dioxide to produce a cyclic triazole 9a (as described, for example, by m. nettekoven et al, Synthesis 2003, 11, 1649-1652).

Scheme 8

Alternatively, the order of the steps in scheme 7 may be changed (see scheme 8). The halide 24 (which is commercially available or can be synthesized by methods known in the art) can be reacted with ethoxycarbonyl isothiocyanate followed by treatment with hydroxylamine to produce the cyclic triazole 28. These halides can then be subjected to, for example, palladium-catalyzed Suzuki coupling with boronic acids or copper (I) -catalyzed coupling with phenols (e.g. according to d.maiti et al JOC 2010, 75, 1791-.

Scheme 9

A isOrB isOr

Compound 9a can be hydrogenated using palladium on carbon as a catalyst to produce the corresponding partially saturated compound 9b (see scheme 9). Depending on the nature of ring a, the reaction may require elevated temperatures or hydrogen pressures or the presence of an acid (e.g., HCl). Alternatively, compound 9a may be reduced with a metal such as magnesium in an alcohol solution (e.g., ethanol) with or without activation of the metal (e.g., activation with a catalytic amount of iodine).

If ring B of compound 9B contains an NH group, this may be modified, for example by reductive amination with an aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride to give an alkylated amine, acylation with an anhydride or acid chloride in the presence of a base to give an amide, reaction with a sulfonyl chloride to give a sulfonamide, reaction with carbonyldiimidazole or triphosgene and an alcohol or amine to give a carbamate or urea, respectively.

To accomplish these modifications, it may be desirable to protect the amino group on the triazole 9a prior to the hydrogenation step, for example by protection with a Boc group, which may be introduced, for example, using Boc anhydride and which may be removed after hydrogenation and modification with, for example, trifluoroacetic acid.

Scheme 10

Introduction of an amine substituent (R) in position 8 of triazolopyridine 9c ²RR 'N) (R and R' are preferably methyl) (see scheme 10) can be achieved by: by treating 3-bromo-2-nitropyridine with an amine RR' NH in a polar solvent (e.g., DMSO) in the presence of a base (e.g., potassium carbonate), a catalyst (e.g., TBAI), at ambient or higher temperatures. Reduction of the nitro group with a metal, metal salt or hydrogen in the presence of a catalyst (e.g., palladium on charcoal) produces aminopyridine 14c, which pyridine 14c can be converted to the corresponding aminotriazole derivative 9c according to scheme 7.

Scheme 11

R and R' are lower alkyl;

8-alkyl or 8-cycloalkyl substituted triazolopyridines can be obtained by directed ortho-metallation of suitable protected aminopyridines (e.g. pivaloyl derivatives) by means of bis-deprotonation with n-butyllithium (scheme 11). The resulting dianion is reacted at low temperature with an aldehyde or ketone to produce 3-carbinolpyridine derivatives 30 or 32. The pivaloyl directing substituent may be removed under basic conditions at elevated temperature using, for example, potassium hydroxide. If the alpha hydrogen atom next to the alcohol is available, dehydration can occur to produce the corresponding olefin 34. The obtained aminopyridine 31, 33 or 34 can be converted to the corresponding aminotriazole derivative 9d, 9e or 9f according to scheme 7.

Scheme 12

R²' is phenyl optionally substituted by halogen or lower alkyl.

Aminotriazoles of the general formula 9g can be prepared starting from the mandelate derivative 35 (see scheme 12). Allylation and subsequent ozonolysis of the double bond yields aldehyde 37, which aldehyde 37 forms hydrazone 38 upon treatment with Boc-protected hydrazine. Catalytic hydrogenation in the presence of nickel produces compound 39. Heating in water results in lactamization and deprotection (similar to j.w.nilsson et al j.med.chem.2003, 46, 3985-. The hydrazide 40 undergoes a cyclization reaction with cyanamide by first heating under acidic conditions followed by heating under basic conditions (analogous to WO2010/098487, preparative examples 2-7) to give 9g of aniline.

Scheme 13

The amine 41 may be acylated with N-cyanobiphenoxyiminocarbonate (see scheme 13) and alkylated with a suitably protected 3-halo-propanol (e.g. bromo-alcohol protected with THP ether) in the presence of a base (e.g. potassium carbonate) in a polar solvent (e.g. DMF) at ambient temperature or higher. After deprotection of the alcohol, compound 44 is cyclized, e.g., under Mitsunobo conditions or with tetrabromomethane and triphenylphosphine, to give amine 9 h.

Scheme 14

3-bromo-5-nitro-4H- [1, 2, 4] triazole can be alkylated with a suitably protected bromo-alcohol (e.g. with tert-butyldimethylsilyl) in the presence of a base (e.g. potassium carbonate). Deprotection of the protected alcohol 45 may result in spontaneous cyclization of the free alcohol on the bromide or may be base catalyzed to yield the bicyclic derivative 46. Reduction of the nitro group with a metal catalyst (e.g., palladium on charcoal) or a metal salt or metal catalyst produces the amine 9i (see scheme 14).

Scheme 15

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

aniline 9k (see scheme 15) in which heteroaryl II is a substituted triazole or pyrazole moiety can be deprotonated, for example by 47 or 48 with sodium hydride in DMF and subsequently with Q-R²By alkylation of (a). Q represents a leaving group (e.g., Cl, Br, I, tosylate, mesylate). The nitro compound 49 may be reduced to the amine 9k using well known methods, for example catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal or by metal reduction, for example using stannous chloride in HCl or by hydrazine in the presence of palladium on charcoal.

Starting materials 47, 48 are commercially available or can be readily prepared by methods known to those skilled in the art of organic synthesis. Examples of 47 are, but are not limited to, 1H- [1, 2, 4] triazol-3-ylamine and 1H-pyrazol-3-ylamine. Examples of 48 are, but not limited to, 4-nitro-1H-pyrazole.

Scheme 16

C represents a carbocyclic ring, preferably

Aniline 9l (see scheme 16) where heteroaryl II is a cyclic thiazole can be prepared by condensation of α -bromoketone 50 with thiourea (e.g. by heating in a suitable solvent such as ethanol). Alpha-bromoketones are commercially available or can be readily prepared by methods known to those skilled in the art of organic synthesis, for example by reaction of the appropriate ketone with bromine in chloroform.

The halide of formula 3, which can be used as starting material for the preparation of the compound of formula I, can be prepared as described in the scheme below.

Scheme 17

Halotriazole 3 can be prepared from aniline 9 (see scheme 17) via formation of the corresponding diazonium salt and subsequent decomposition in the presence of a halide source such as copper (I) halide or hydrogen halide (X ═ chlorine or bromine).

Scheme 18

Anilines of the general formula 9m or the corresponding bromides 3m with a 2-propan-2-ol group in the 5-position of triazolopyridine (see scheme 18) can be prepared by: 2-amino-triazolopyridines 53 were produced starting from ester 51 by bromination in chloroform, followed by cyclization as described in scheme 8. Ester 53 can then be treated with methyl magnesium bromide to produce tertiary alcohol 54. The bromide is converted, for example by a Suzuki reaction, to give the aniline 9m or after a Sandmeyer reaction to give the bromide 3 m. Starting material 51 is commercially available or may be synthesized by methods known in the art, for example for R ═ Me, 51 may be prepared from the corresponding bromide by reaction with trimethylboroxine in the presence of a palladium catalyst.

Scheme 19

R²’、R²"and R²"' is lower alkyl, hydroxy-substituted lower alkyl, - (CH)₂)_p-phenyl, optionally substituted by halogen, lower alkyl or lower alkyl substituted by halogen.

The halide 3a in which heteroaryl II is a pyrimidine (see scheme 19) can be prepared as described, for example, in k.baumann et al, WO 2009103652: dichloro-derivative 56 is produced by reduction of trichloro-pyrimidine 55, for example by treatment with zinc (zink) in aqueous ammonia at 0 ℃. Subsequently, the 4-chloro substituent of 56 may be substituted in a nucleophilic substitution reaction (e.g., with a Grignard reagent R²' MgX, e.g. benzylmagnesium chloride, in tetrahydrofuran at-80 to +20 ℃) or by displacement reactions assisted by metal catalysts (e.g. using palladium acetate, 2- (dicyclohexylphosphino-biphenyl, tetrahydrofuran, microwave oven, 30min, 200 ℃). Alternatively, one of the reactive chlorine atoms of 55 is first replaced by a group R²' substitution followed by a second chloro substituent in intermediate 57 by group R²"' substitution, thereby producing 3 a.

Scheme 20

R²Is- (CH)₂)_p-phenyl, optionally substituted by halogen, lower alkyl or lower alkyl substituted by halogen.

The halide 3b (see scheme 20) in which heteroaryl II is pyrimidine can be prepared from methyl 2, 6-dichloro-pyrimidine-4-carboxylate by reaction with, for example, methyl magnesium chloride in THF at-78 ℃ to 0 ℃ which reaction produces 2- (2, 6-dichloro-pyrimidin-4-yl) -propan-2-ol. The chloride in the 4-position of 2- (2, 6-dichloro-pyrimidin-4-yl) -propan-2-ol may be substituted by a substituent R ²By substitution, e.g. in Suzuki coupling reactions, with aryl/heteroaryl boronic acids/esters R²-B(OH/OR’)₂In the presence of a palladium catalyst and a base (e.g. sodium carbonate) in, for example, dimethoxyethane as solvent, thereby producing chloride 3 b. Alternatively, the 4-chloro substituent may be reacted with the organozinc chloride R in the presence of a palladium catalyst²ZnCl (e.g., benzylzinc chloride) reacts to produce chloride 3 b. To achieve these modifications, it may be necessary to protect the alcohol group of 2- (2, 6-dichloro-pyrimidin-4-yl) -propan-2-ol prior to the second step, for example by protection with a trimethylsilyl group which may be introduced, for example, with bis (trimethylsilyl) acetamide and which may be removed after modification in THF/water using, for example, p-TsOH.

Scheme 21

The ketone 10d can be prepared by: according to a.a. calabrese et al, US20050176772, starting from dimethyl 3-oxoglutarate, dimethylation with methyl iodide followed by cyclization with benzylamine and formaldehyde. Ester hydrolysis and decarboxylation occur in refluxing aqueous HCl to produce ketone 10 d. The exchange of protecting groups from the benzyl group to the boc group can be achieved by hydrogenation in the presence of boc anhydride to yield ketone 10e (see scheme 21). The ketone 10e may be subjected to an aza-wittig/reduction scheme with an amine of formula 9, as described in scheme 4.

The ketones of formula 8, which can be used as starting materials for the preparation of compounds of formula I, can be prepared as described in the following schemes.

Scheme 22

The ketone 8a (see scheme 22) in which heteroaryl I is 3-methyl- [1, 2, 4] thiadiazole can be prepared starting from 5-chloro-3-methyl- [1, 2, 4] thiadiazole, 5-chloro-3-methyl- [1, 2, 4] thiadiazole being obtained by condensation of acetamidine with perchloromethylmercaptan in the presence of sodium hydroxide. The chloride may be coupled with 1, 4-dioxa-8-azaspiro (4, 5) decane in the presence of a palladium catalyst and a base such as sodium tert-butoxide. Acid (e.g., HCl) catalyzed cleavage of the ketal then produces ketone 8 a.

Scheme 23

Wherein heteroaryl I is [1, 3, 4]]The ketone 8b of oxadiazoles (see scheme 23) may be substituted by 5-methyl- [1, 3, 4%]Diazol-2-ylamine is prepared by base-catalyzed condensation with acrylates. Decarboxylation of ketone 8b can be achieved by: in the case of allyl esters, the deallylation is effected by palladium (0) -catalyzed allylation in the presence of a trapping agent, such as formic acid or an amine. In alkoxy estersIn the case of (b), standard decarboxylation methods may be used.

The amines of formula 2, which can be used as starting materials for the preparation of compounds of formula I, can be prepared as described in the following schemes.

Scheme 24

The ketone 8 can be readily converted to the amine 2 via reductive amination using ammonia or hydroxylamine or other suitable amine precursors (see scheme 24).

Scheme 25

Wherein heteroaryl I is [1, 2, 4]]The amine 2a of oxadiazole (see scheme 25) can be prepared by: the deprotection yields the amine 2a after deprotection by reaction with cyanogen bromide starting with an N-Boc protected aminopiperidine followed by cyclization with an acetamide oxime in the presence of a Lewis acid such as zinc (II) chloride.

Scheme 26

The amines 2b (see scheme 26) in which heteroaryl I is 3-methyl- [1, 2, 4] thiadiazole can be prepared, for example, by: the Boc protecting group was cleaved off by palladium catalyzed coupling of 5-chloro-3-methyl- [1, 2, 4] thiadiazole to piperidin-4-yl-carbamic acid tert-butyl ester and subsequent cleavage in the presence of acid. Alternatively, the amine 2b can be prepared from Boc-protected aminopiperidine: by reaction with an isothiocyanate source such as benzoyl isothiocyanate, a metal isothiocyanate, thiophosgene or an activated thiourea derivative to produce the corresponding thiourea derivative. Condensation with 1, 1-dimethoxy-ethyl) -dimethyl-amine and subsequent cyclization with hydroxylamine-O-sulfonic acid in the presence of a base such as pyridine yields the amine 2b after deprotection.

The amines of formulae 4a and 4b and the ketones of formulae 10a, 10b, 10c (which may preferably be present as hydrates thereof, depending on the nature of the ketone) which can be used as starting materials for the preparation of the compounds of formula I can be prepared as described in the following schemes.

Scheme 27

The α -fluorination of the N-protected 4-piperidones can be effected, for example, by: following the procedure of m.van Niel et al j.med.chem.1999, 42, 2987-2104, by reaction of the corresponding silyl enol ether with an electrophilic fluorinating agent such as a fluorine reagent (selectifluor). Reductive amination of ketone 10a with benzylamine and sodium triacetoxyborohydride predominantly affords the cis isomer of 4-amino-3-fluoropiperidine (. about.5: 1 cis: trans ratio). The two isomers can be separated by silica gel chromatography. The benzyl group is cleaved, e.g., by hydrogenation, to yield the amine 4a (see scheme 27).

Scheme 28

Difluoro derivatives 10b, 10c, and 4b can be prepared starting from 3-benzylamino-propionic acid esters (see scheme 28). Reaction with formaldehyde and benzotriazole followed by a Reformatsky-type reaction affords the corresponding acyclic difluoro derivative (as described by o.bezencon et al WO 2005040120). Diekmann cyclisation can be effected, for example, by using potassium tert-butoxide in NMP. Hydrolysis and decarboxylation of the ester by heating in aqueous HCl provides the hydrate of 3, 3-difluoropiperidone 10 c. The exchange of the protecting groups from the benzyl group to the boc group can be achieved by hydrogenation in the presence of a boc anhydride. Reductive amination using benzylamine and, for example, sodium borohydride, followed by cleavage of the benzyl group, yields 3, 3-difluoro-4-aminopiperidine 4 b.

Scheme 29

R¹Is Cl R¹Is OMe or OEt

When treated with a suitable sodium salt (NaOMe or NaOEt), respectively, in a suitable alcohol solvent such as methanol or ethanol, wherein R is¹Compounds of formula Ia which are halogens such as Cl can be converted to where R¹Compounds of formula Ib which are alkoxy groups (e.g., OMe, OEt) (see scheme 29).

Scheme 30

Wherein R is³Compounds of formula Ic which are cyano can be prepared by: by reacting a compound of formula 8 with a compound of formula 9 in the presence of a cyanating agent, such as trimethylsilyl cyanide, in the presence of acetic acid (see scheme 30).

Scheme 31

R³Is phenyl or methyl

The compounds of the formula Id can be prepared by reaction of compounds of the formula Ic with Grignard reagents in suitable solvents such as THF (see scheme 31).

Scheme 32

The compound of formula Ie may be prepared starting 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 to form the corresponding amide. The amide can be converted to an amine upon treatment with 1, 3-dibromo-5, 5-dimethylhydantoin in potassium hydroxide and sodium sulfite. Cleavage of the Boc protecting group affords 4-methyl-piperidin-4-ylamine, which in turn can be converted to compound 2c upon reaction 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 an isothiocyanate by reaction with 1, 1' -thiocarbonyldiphyridin-2 (1H) -one in a suitable solvent such as DCM. Treatment with aqueous ammonia provided the corresponding thiourea. Treatment with methyl iodide in a suitable solvent such as ethanol gives methylisothiourea which undergoes a cyclisation reaction with (3-chloropropyl) -phenyl-acetic acid of formula 58 in the presence of EDCI, HOBt, DIPEA and hydrazine to give compounds of the general formula Ie.

The compounds were studied according to the tests given below.

Description of the Gamma-secretase assay

Cellular gamma-secretase assay

Human glioma H4 cells overexpressing human APP at 30,000 cells/well/200 μ L were plated in 96-well plates in IMDM medium containing 10% FCS, 0.2mg/L Hygromycin (Hygromycin) B and at 37 deg.C, 5% CO before addition of test compound₂The culture was carried out for 2 hours.

The compounds to be tested were dissolved in 100% Me₂In SO, 10mM stock solution was obtained. Typically, 12. mu.L of these solutions are further dissolved in 1000. mu.L of IMDM medium (w/o FCS). Followed byA1: 1 dilution of (A) produced a ten point dose response curve. 100 μ L of each dilution was added to the cells in a 96-well plate. A suitable control using only the carrier and reference compound was applied to the assay. Me₂The final concentration of SO was 0.4%.

At 37 ℃ 5% CO₂After 22 hours of incubation, 50 μ L of the supernatant was transferred to a round bottom 96 well polypropylene plate for detection of a β 42. mu.L of assay buffer (50mM Tris/Cl, pH 7.4, 60mM NaCl, 0.5% BSA, 1% TWEEN 20) was added to the wells followed by 100. mu.L of detection antibody (Ruthenized BAP 150.0625. mu.g/mL in assay buffer). 50 μ L of pre-mixed capture antibody (biotinylated 6E10 antibody, 1 μ g/mL) and streptavidin-coated magnetic beads (Dynal M-280, 0.125mg/mL) were pre-incubated for 1 hour at room temperature before addition to the assay plate. Assay plates were incubated on a shaker at room temperature for 3 hours and finally read in a Bioveris M8 Analyser according to the manufacturer's instructions (Bioveris).

Toxicity of the compounds was monitored by cell viability testing of cells treated with the compounds using a colorimetric assay (CellTiter 96TM AQ assay, Promega) according to the manufacturer's instructions. Briefly, after 50. mu.L of cell culture supernatant for detection of A.beta.42 was removed, 20. mu.L of 1x MTS/PES solution was added to the cells and 5% CO at 37 deg.C₂Incubate for 30 minutes. The optical density at 490nm was then recorded.

IC for A β 42 secretion inhibition was calculated by non-linear regression fitting analysis using XLFit 4.0 software (IDBS)₅₀The value is obtained.

Preferred compounds show IC₅₀< 0.5 (. mu.M). The data for inhibition of a β 42 secretion for all compounds are described in the following table:

the compounds of formula I and pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The 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, it can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

Pharmaceutical formulations may be prepared by processing a compound of formula I with a pharmaceutically inert inorganic or organic carrier. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, and processes for their preparation, which comprise bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers, are also an object of the present invention.

According to the present invention, the compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of diseases based on inhibition of a β 42 secretion, such as alzheimer's disease.

The dosage can vary within wide limits and will of course be adjusted to the individual requirements in each particular case. In the case of oral administration, the daily dose for an adult may vary from about 0.01mg of the compound of formula I to about 1000mg of the compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered in a single dose or divided into several doses, and furthermore, when it is considered necessary, the upper limit may be exceeded.

Tablet formulation (Wet granulation)

The preparation method comprises the following steps:

1. mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Fill into suitable capsules.

Example 1

The preparation method comprises the following steps:

1. items 1, 2, 3 and 4 were mixed and granulated with pure water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add item 5 and mix for 3 minutes; tabletting on a suitable tabletting machine.

Capsule preparation

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

Perchloromethanethiol (12g, 0.063mol) was added to a suspension of acetamidine hydrochloride (7g, 0.07mol) in dichloromethane (75mL) at room temperature under argon. After cooling to-10 ℃ a solution of sodium hydroxide (14g, 0.348mol) in water (22.5mL) was added slowly. The reaction mixture was stirred at 0 ℃ for 12 hours. Water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was purified by short path vacuum distillation (75 ℃, 30mbar) to give the title compound as a colourless liquid.

¹H NMR(CDCl₃，300MHz)：□(ppm)＝2.64(s，3H)。

b)8- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -1, 4-dioxa-8-aza-spiro [4.5] decane

To palladium (II) acetate (180mg, 0.001mmol) and 2- (dicyclohexylphosphino) biphenyl (572mg, 0.002mmol) in bisTo a pre-stirred solution in an alkane (10mL) (10 min at room temperature) was added 1, 4-dioxa-8-azaspiro (4, 5) decane (1.3mL, 10mmol), 5-chloro-3-methyl- [1, 2, 4%]Thiadiazole (1.48g, 11mmol) and sodium tert-butoxide (1.47g, 15mmol) were heated with a microwave at 130 ℃ for 15 minutes. The reaction mixture was diluted with half-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 silica gel chromatography using ethyl acetate as eluent. The title compound was obtained as a pale yellow solid (1.87g, 77%).

MS ISP(m/e)：242.4(23)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-one

To 8- (3-methyl- [1, 2, 4)]Thiadiazol-5-yl) -1, 4-dioxa-8-aza-spiro [4.5]A solution of decane (1.75g, 7mmol) in acetone (15mL) was added 2N aqueous HCl (50mL) and stirred at 50 ℃ for 3 h. The reaction mixture was cooled to 0 ℃ and saturated NaHCO was added dropwise₃The aqueous solution was brought to pH 7. The aqueous phase was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was evaporated to yield the title compound as a light brown solid (1.29g, 90%).

MS ISP(m/e)：198.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝3.88-3.84(m，4H)，2.64-2.60(m，4H)，2.44(s，3H)。

d)3- (4-fluoro-phenyl) -pyridin-2-ylamine

2-amino-3-bromopyridine (2.0g, 11.2mmol), 4-fluorophenylboronic acid (3.23g, 22.4mmol), dichloro [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloromethane adduct (733mg, 0.001mmol) and Na₂CO₃In a solution of (2N, 11.2mL, 22.4mmol) in (B)The mixture in alkane (30mL) was heated to 110 ℃ for 2 hours. The reaction mixture was diluted with water and 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 n-heptane/diethyl ether as eluent. The title compound was obtained as a pale yellow solid (1.95g, 92%).

MS ISP(m/e)：189.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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) -pyridin-2-ylamine (200mg, 1.06mmol) in bisA solution in an alkane (10mL) was added ethoxycarbonyl isothiocyanate (141. mu.L, 1.17mmol) and stirred at room temperature for 12 h. The solvent was evaporated and the residue was used for the next step without purification. The title compound was obtained as a pale yellow solid (340mg, 100%).

MS ISP(m/e)：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 (370mg, 5.32mmol) and N, N-diisopropylethylamine (543. mu.L, 3.19mmol) in MeOH (2mL) and EtOH (2mL) was added a solution of N- (3- (4-fluoro-phenyl) -pyridin-2-yl) -N' -ethoxycarbonyl-thiourea (340mg, 1.06mmol) in MeOH (2mL) and EtOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then at 60 ℃ for 3 hours. The solvent was evaporated and saturated NaHCO ₃The aqueous solution was added to the residue. Using CH as the aqueous phase₂Cl₂After extraction, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using dichloromethane/methanol (10% ammonia) as eluent. The title compound was obtained as a white solid (205mg, 84%).

MS ISP(m/e)：229.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] in EtOH (10mL) and aqueous HCl (25%, 162 □ L, 1.12mmol) in the presence of palladium on charcoal (10%, 232mg, 0.22mmol) at 50bar and 50 deg.C]Triazolo [1, 5-a]Pyridin-2-ylamine (232mg, 1.02mmol) was hydrogenated for 18 hours. The catalyst was filtered off, washed thoroughly with EtOH and the solvent was removed from the combined filtrates. Saturated NaHCO₃The aqueous solution was added to the residue. Using CH as the aqueous phase₂Cl₂The combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using dichloromethane/methanol (10% ammonia) as eluent. The title compound was obtained as a white solid (174mg, 74%).

MS ISP(m/e)：233.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

To 8- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] in an argon atmosphere]Triazolo [1, 5-a]Pyridin-2-ylamine (60mg, 0.258mmol) and 1- (3-methyl- [1, 2, 4]]A solution of thiadiazol-5-yl) -piperidin-4-one (76mg, 0.387mmol) in dry dichloroethane (3mL) was added tetraisopropyl orthotitanate (236. mu.L, 0.775mmol) and heated to 85 ℃ for 12 hours. The reaction mixture was cooled to room temperature, sodium borohydride (20mg, 0.517mmol) and ethanol (1.5mL) were added and stirred at room temperature for 3 hours and at 50 ℃ for 30 minutes. The reaction mixture was cooled to room temperature and evaporated. Mixing Na₂CO₃To the residue was added an aqueous solution of (2M). 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 dichloromethane/methanol (10% ammonia) as eluent. The title compound was obtained as a white solid (28.8mg, 27%).

MS ISP(m/e)：414.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

Prepared in analogy to example 1 step h) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 8- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (example 1 f). The title compound was obtained as a white solid (yield 28%).

MS ISP(m/e)：410.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step h) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 5- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-g), starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid (yield 30%).

MS ISP(m/e)：414.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

Prepared in analogy to example 1, step h) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 5- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-f), starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid.

MS ISP(m/e)：410.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

a)1- (3, 5-dichloro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine

3-amino-1, 2, 4-triazole (420mg, 5.0mmol) was dissolved in DMF (3mL) under argon, sodium hydride (55%, 218mg, 5.0mmol) was added in small portions at room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ℃, 3, 5-dichlorobenzyl chloride (977mg, 5.0mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto water and the aqueous phase was extracted with ethyl acetate. The combined organic phases are in Na₂SO₄Dry above, filter, evaporate the solvent and purify the residue by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (357mg, 29%).

MS ISP(m/e)：243.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3, 5-dichloro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a white solid (yield 27%).

MS ISP(m/e)：424.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (4-methyl-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a white solid.

MS ISP(m/e)：370.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-fluoro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a colorless oil.

MS ISP(m/e)：374.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] - [1- (3-trifluoromethyl-benzyl) -1H- [1, 2, 4] triazol-3-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-trifluoromethyl-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a white solid.

MS ISP(m/e)：424.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (4-fluoro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a white solid.

MS ISP(m/e)：374.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (4-chloro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a white solid.

MS ISP(m/e)：390.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] - [1- (3, 4, 5-trifluoro-benzyl) -1H- [1, 2, 4] triazol-3-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3, 4, 5-trifluoro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a yellow solid.

MS ISP(m/e)：410.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-chloro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a yellow solid.

MS ISP(m/e)：390.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-chloro-benzyl) -1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a colorless oil.

MS ISP(m/e)：390.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

3-Aminopyrazole (506mg, 5.8mmol) was dissolved in DMF under an argon atmosphereTo (2mL) was added sodium hydride (55%, 241mg, 5.5mmol) in small portions at room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ℃, 2, 4-dichlorobenzyl chloride (1100mg, 5.5mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto water and the aqueous phase was extracted with ethyl acetate. The combined organic phases are in Na₂SO₄Dry above, filter, evaporate the solvent and purify the residue by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (700mg, 52%).

MS ISP(m/e)：242.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (2, 4-dichloro-benzyl) -1H-oxazol-3-ylamine. The title compound was obtained as a colorless oil (yield 56%).

MS ISP(m/e)：423.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1 step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (4-fluoro-benzyl) -1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil.

MS ISP(m/e)：373.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1 step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (4-chloro-benzyl) -1H-pyrazol-3-ylamine. The title compound was obtained as a white solid (yield 70%).

MS ISP(m/e)：389.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

[1- (3-chloro-benzyl) -1H-pyrazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1 step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-chloro-benzyl) -1H-pyrazol-3-ylamine. The title compound was obtained as a white solid.

MS ISP(m/e)：389.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-trifluoro-benzyl) -1H-pyrazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1, step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3, 4, 5-trifluoro-benzyl) -1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil (yield 42%).

MS ISP(m/e)：409.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1 step H) starting from 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (example 1c) and 1- (3-fluoro-benzyl) -1H-pyrazol-3-ylamine. The title compound was obtained as a yellow oil (yield 73%).

MS ISP(m/e)：373.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

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

Prepared in analogy to example 1 step H) starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1- (2, 4-dichloro-phenyl) -5-methyl-1H- [1, 2, 4] triazol-3-ylamine. The title compound was obtained as a light yellow solid (yield ═ 34%).

MS ISP(m/e)：426.1(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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] triazol-3-yl ] -piperidin-4-yl-amine hydrochloride

Reacting 4- [1- (2, 4-dichloro-phenyl) -5-methyl-1H- [1, 2, 4]Triazol-3-ylamino]Tert-butyl-piperidine-1-carboxylate (120mg, 0.28mmol) was dissolved in bis saturated with HCl gasAlkane (2 ml). The mixture was stirred at room temperature overnight, concentrated and the residue triturated with diethyl ether to give the title compound as a brownish solid (57mg, 56%).

MS ISP(m/e)：326.1(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝9.22(s broad，1H)，9.00(sbroad，1H)，8.82(s broad，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] triazol-3-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1 step b)) starting from [1- (2, 4-dichloro-phenyl) -5-methyl-1H- [1, 2, 4] triazol-3-yl ] -piperidin-4-yl-amine hydrochloride and 5-chloro-3-methyl- [1, 2, 4] thiadiazole (example 1 step a)). The title compound was obtained as a light yellow solid (yield 10%).

MS ISP(m/e)：424.1/426.0(100/72)[(M+H)⁺]。

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

Example 21

[1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

a) 2-bromo-6-phenyl-cyclohexanone

To 2-phenyl-cyclohexanone (10.0g, 57mmol) in CHCl at-10 deg.C₃(20mL) bromine (9.6g, 3.1mL, 60mmol) in CHCl was added₃(10mL) and the reaction mixture was warmed to 0 ℃. After 2 hours, the solvent was evaporated, methanol (30mL) was added to the residue, cooled to 0 ℃, stirred for 30 minutes and the white solid was filtered off to give the title compound as a white solid (5.48g, 38%).

MS ISP(m/e)：253.0/255.1(31/32)[(M+H)⁺]，270.1/272.1(100/95)[(M+NH₄)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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 (4.32g, 17mmol) and thiourea (1.18g, 16mmol) in EtOH (150mL) was heated to reflux for 12 hours. The solvent was evaporated, diethyl ether was added to the residue and stirred at room temperature for 1 hour, the solid was filtered off and washed with diethyl ether. The solid was dissolved in ethyl acetate and the organic phase was washed three times with sodium carbonate solution. The organic phase was dried over sodium sulfate and the solvent was evaporated to give the title compound as a white solid (3.46g, 88%).

MS ISP(m/e)：231.1[(M+H)⁺]。

¹H NMR(DMSO-D₆300 MHz): □ (ppm, 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 (1.15mg, 5mmol) in dichloroethane (15mL) was added 1-Boc-4-piperidone (1.57g, 7.5mmol) and tetraisopropyl orthotitanate (4.44mL, 15mmol) with stirring at room temperature. The reaction was stirred overnight at 85 ℃ in a sealed tube. Ethanol (15mL) and sodium borohydride (378mg, 10mmol) were added at room temperature and the reaction was stirred at 85 ℃ for 4.5 h. Water was added, the reaction stirred for 30 minutes and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. Water was added and the reaction was extracted twice 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 gradient from n-heptane/EtOAc 9: 1 to 1: 1(v/v) as eluent to give the title compound as a pale yellow viscous oil (1.58g, 76%).

MS ISP(m/e)：414.4(100)[(M+H)⁺]358.3(34) [ (M-isobutene + H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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) -piperidin-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 (1.575g, 3.8mmol) in dichloromethane (13.8mL) was added a 2M HCl solution in diethyl ether (6.9 mL). The reaction was stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated with diethyl ether and evaporated. The title compound was obtained as a pale yellow solid (1.32g, 90%).

MS ISP(m/e)：314.2(100)[(M+H)⁺]，231.2(34)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

(4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -piperidin-4-yl-amine dihydrochloride (77.3mg, 0.2mmol) was suspended in tetrahydrofuran (2 mL). N, N-diisopropylethylamine (110 □ l, 0.64mmol) was added at 0 ℃ under nitrogen and stirring at room temperature. To the yellow solution was added 4-chloro-6-methylpyrimidine (28.9mg, 0.22mmol) and the reaction was stirred at room temperature overnight. The reaction was heated to reflux overnight and then heated to 200 ℃ with N-methylpyrrolidone in a microwave oven for 30 minutes. Water was added and the reaction was extracted twice 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(v/v) as eluent. The title compound was obtained as a pale yellow solid (55mg, 68%).

MS ISP(m/e)：406.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

(4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -piperidin-4-yl-amine dihydrochloride (115.9mg, 0.3mmol) was dissolved in N-methylpyrrolidinone (3 mL). N, N-diisopropylethylamine (165 □ l, 0.96mmol) and 4-chloro-2-methylpyrimidine (44.7mg, 0.33mmol) were added under nitrogen and stirring at room temperature. The reaction was heated to 200 ℃ in a microwave oven for 30 minutes. Water was added and the reaction was extracted twice 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(v/v) as eluent. The title compound was obtained as a pale yellow viscous oil (34mg, 28%).

MS ISP(m/e)：406.4(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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

Palladium (II) acetate (3.6mg, 0.016mmol) and 2- (dicyclohexylphosphino) biphenyl (11.6mg, 0.032mmol) in bis (N-cyclohexylphosphino) at room temperature under nitrogenIn an alkane (1.8mL) for 10 minutes. Sodium tert-butoxide (29mg, 0.3mmol), (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -piperidin-4-yl-amine dihydrochloride (77.3mg, 0.2mmol), N, N-diisopropylethylamine (69 □ L, 0.4mmol) and 5-chloro-3-methyl- [1, 2, 4mmol) were added ]Thiadiazole (29.6 mg; 0.22mmol) and the reaction heated to 200 ℃ in a microwave oven for 30 minutes. The reaction was diluted with water and extracted 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 heptane/EtOAc 4: 1 to 1: 4(v/v) as eluent. The title compound was obtained as a white solid (55mg,67％)。

MS ISP(m/e)：412.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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] thiadiazol-2-yl) -piperidin-4-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

Palladium (II) acetate (3.6mg, 0.016mmol) and 2- (dicyclohexylphosphino) biphenyl (11.6mg, 0.032mmol) in bis (N-cyclohexylphosphino) at room temperature under nitrogenIn an alkane (1.8mL) for 10 minutes. Sodium tert-butoxide (29mg, 0.3mmol), (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -piperidin-4-yl-amine dihydrochloride (77.3mg, 0.2mmol), N-diisopropylethylamine (69 □ L, 0.4mmol) and 2-bromo-5-methyl-1, 3, 4-thiadiazole (40.2 mg; 0.22mmol) were added and the reaction was heated to 200 ℃ in a microwave oven for 30 minutes. The reaction was diluted with water and extracted 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 EtOAc as eluent. The title compound was obtained as a yellow solid (23mg, 28%).

MS ISP(m/e)：412.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-yl]- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amines

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

5-methyl-1, 3, 4-substituted benzene under stirring and nitrogen at room temperatureA solution of oxadiazol-2-ylamine (198.2mg, 2mmol) and allyl acrylate (851 □ L, 6mmol) in N-methylpyrrolidone (4mL) was added potassium tert-butoxide (359.1mg, 3.2 mmol). The reaction was stirred overnight. To the resulting suspension was added tetrahydrofuran and the title compound was filtered off, washed with tetrahydrofuran, dried and obtained as white solid crystalline title compound (255mg, 42%).

MS ISP(m/e)：266.1(84)[(M-K+H)⁺]，208.2(100)。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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). The potassium salt of the ester (163mg, 0.54mmol) was dissolved in a small amount of 25% aqueous HCl and the solvent was removed under reduced pressure. The residue was evaporated twice with toluene/tetrahydrofuran. The residue was suspended in tetrahydrofuran (0.26 mL). To a solution of triethylamine (263 □ L, 1.88mmol) and formic acid (42 □ L, 1.08mmol) in tetrahydrofuran (0.51mL) was added, under nitrogen and stirring, a solution of palladium (II) acetate (3.0mg, 0.013mmol) and triphenylphosphine (7.3mg, 0.027mmol) in tetrahydrofuran (0.77 mL). After stirring at room temperature for 5 minutes, the prepared catalyst solution was added to the suspension. The reaction was stirred at room temperature for 1 hour, poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow viscous oil (54mg, 55%).

MS ISP(m/e)：279.1(100)[(M+H)⁺]，182.1(36)，222.1(21)。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝3.72(t，4H)，2.47(t，4H)，2.35(s，3H)。

b)1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-ones

Reacting 4-hydroxy-1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -1, 2, 5, 6-tetrahydro-pyridine-3-carboxylic acid allyl ester

c) [1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-yl]- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amines

To 4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl at room temperature under stirringA solution of amine (46mg, 0.2mmol) in dichloroethane (0.6mL) was added 1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-one (50mg, 0.28mmol) and tetraisopropyl orthotitanate (178 □ L, 0.6 mmol). The reaction was stirred overnight at 90 ℃ under nitrogen in a sealed tube. Ethanol (0.6mL) and sodium borohydride (15mg, 0.4mmol) were added at room temperature and the reaction was stirred at 85 ℃ for 4.5 h. Water was added, the reaction stirred for 30 minutes and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. Water was added and the reaction was extracted twice 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. Use of CH on silica gel by column chromatography₂Cl₂The residue was purified twice with a gradient of/MeOH 19: 1(v/v) followed by AcOEt to AcOEt/EtOH 1: 9(v/v) as eluent to give the title compound as a pale yellow viscous oil (28mg, 35%).

MS ISP(m/e)：396.1(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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 ]]Triazol-3-yl]- [1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-one (91mg, 0.5mmol) and 1- (3-chloro-benzyl) -1H- [1, 2, 4]A solution of triazol-3-ylamine (104mg, 0.5mmol) in dry toluene (8mL) and acetic acid (0.4mL) was heated under reflux in a Dean-Stark trap for 12 hours. The reaction mixture was cooled to room temperature, ethanol (5mL) was added followed by sodium borohydride (19mg, 0.5mmol) and stirred at room temperature overnight. The reaction mixture was extracted with water and ethyl acetate, and the organic layers were combined and washed with Na₂SO₄Dry, filter and evaporate the solvent. The residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (91mg, 49%).

MS ISP(m/e)：374.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - (3, 4, 5, 6-tetrahydro-2H- [1, 4' ] bipyridinyl-4-yl) -amine dihydrochloride

To a solution of 4-benzyl-2-chloro-6-methyl-pyrimidine (WO 2009103652; 70mg, 0.32mmol) and 4- (4-aminopiperidino) pyridine dihydrochloride (ABCR; 80mg, 0.32mmol) in waterTo the suspension in alkane (2mL) was added potassium carbonate (885mg, 6.4mmol), palladium (II) acetate (3mg, 0.013mmol), and 2- (dicyclohexylphosphino) biphenyl (11mg, 0.031 mmol). The reaction mixture was refluxed overnight, concentrated, hydrolyzed and extracted with ethyl acetate. Chromatography on Si-Amine (silica, 10g) using cyclohexane/ethyl acetate as eluent yielded a gummy solid, which was dissolved in dioxane In an alkane and with several drops of a bis saturated with HCl gasAlkane treatment gave the title compound (70mg, 51%) as a light yellow solid.

MS ISP(m/e)：360.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (2-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

a) [1- (2-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -carbamic acid tert-butyl ester

Boc-4-aminopiperidine (715.3mg, 3.5mmol), 4-chloro-2-methylpyrimidine (521mg, 3.85mmol) and N, N-diisopropylethylamine (899 □ L, 5.25mmol) in bisThe suspension in alkane (14mL) was heated to 150 ℃ for 30 minutes in a microwave. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as white crystals after stirring the crude product with diethyl ether and drying (649.5mg, 64%).

MS ISP(m/e)：293.2(100)[(M+H)⁺]237.1(37) [ (M-isobutene + H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride

To [1- (2-methyl-pyrimidin-4-yl) -piperidin-4-yl ] at room temperature with stirring]-carbamic acid tert-butyl ester (818.7mg, 2.8mmol) in CH₂Cl₂(14mL) A2M HCl solution in diethyl ether (7mL) was added and stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated twice with diethyl ether. The solvent was removed under reduced pressure to obtain the title compound (869mg, 100%) as a pale brown solid

MS ISP(m/e)：193.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (2-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

A solution of 1- (2-methyl-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride (53mg, 0.2mmol), 4-benzyl-2-chloro-6-methylpyrimidine (48.1mg, 0.22mmol), and N, N-diisopropylethylamine (120L, 0.7mmol) in N-methyl-pyrrolidone (1mL) was heated in a microwave oven at 200 ℃ for 1 hour. The reaction was diluted with water and extracted 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 AcOEt/EtOH 9: 1(v/v) as eluent. The title compound was obtained as a pale yellow solid (16mg, 21%).

MS ISP(m/e)：375.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-ylamino ] -6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -propan-2-ol

Palladium (II) acetate (2.7mg, 0.012mmol) and 2- (dicyclohexylphosphino) biphenyl (8.4mg, 0.024mmol) in bisThe mixture in alkane (1mL) was stirred at 20 ℃ for 10 minutes under argon atmosphere. The resulting catalyst solution was added to potassium carbonate (692mg, 5.0mmol), 1- (2-methyl-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride (80mg, 0.3mmol), and 2- [ 2-chloro-6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ]-propan-2-ol (95mg, 0.3mmol) in bisSuspension in alkane (1.7mL). The reaction mixture was heated to 170 ℃ in a microwave oven for 30 minutes. The reaction mixture was cooled, diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Use of CH on silica gel by column chromatography₂Cl₂The crude product was purified with 0-10% MeOH as eluent. The title compound was obtained as a pale yellow solid (9mg, 6%).

MS ISP(m/e)：473.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(br 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-pyrimidin-4-yl) -piperidin-4-ylamino ] -6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -propan-2-ol

a) [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -carbamic acid tert-butyl ester

Boc-4-aminopiperidine (613mg, 3mmol), 4-chloro-6-methylpyrimidine (433mg, 3.3mmol) and N, N-diisopropylethylamine (771 □ L, 4.5mmol) were added to diThe suspension in alkane (12mL) was heated to 150 ℃ for 30 minutes in a microwave. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. A gradient from AcOEt to AcOEt/EtOH 9: 1 was applied by column chromatography on silica gelThe crude product was purified for eluent. The title compound was obtained as a pale yellow solid (693mg, 79%).

MS ISP(m/e)：293.2(100)[(M+H)⁺]237.1(58) [ (M-isobutene + H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride

To [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] at room temperature with stirring]-carbamic acid tert-butyl ester (686mg, 2.3mmol) in CH₂Cl₂(12mL) A2M HCl solution in diethyl ether (6mL) was added and stirred at room temperature overnight. Filtering off the precipitate with CH₂Cl₂And diethyl ether and dried to give the title compound (610mg, 98%) as a pale yellow solid

MS ISP(m/e)：193.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆300 MHz): □ (ppm) ═ 8.77(s, 1H), 8.42(br s, 2H), 7.20(s, 1H), 3.45(m under water peak, 3H), 2.42(s, 3H), 2.08(m, 2H), 1.59(m, 2H).

c)2- [2- [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamino ] -6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -propan-2-ol

A solution of 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride (53mg, 0.2mmol), 2- [ 2-chloro-6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -propan-2-ol (69.7mg, 0.22mmol)) and N, N-diisopropylethylamine (120 □ L, 0.7mmol) in N-methyl-pyrrolidone (1mL) was heated in a microwave oven at 160 ℃ for 5 hours. The reaction was diluted with water and extracted 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(v/v) as eluent. The title compound was obtained as a white solid (36mg, 38%).

MS ISP(m/e)：473.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol

To a solution of 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride (53mg, 0.2mmol) and N, N-diisopropylethylamine (120 □ L, 0.7mmol) in N-methyl-pyrrolidone (0.5mL) was added 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl]-propan-2-ol (65.4mg, 0.22mmol)) in bisSolution in alkane (1.5 mL). The reaction was heated in a microwave oven at 160 ℃ for 5 hours. The reaction was diluted with water and extracted 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(v/v) as eluent. The title compound was obtained as a white solid (27mg, 30%).

MS ISP(m/e)：453.3/455.2(100/39)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) -amine

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

2-chloro-4, 6-dimethylpyrimidine (5.00g, 0.035mol), 4-amino-1-Boc-piperidine (7.023g, 0.035mol), sodium tert-butoxide (5.055g, 0.53mol) in dioxane under an argon atmosphere Palladium (II) acetate (0.630g, 0.003mol) and 2- (dicyclohexylphosphino) biphenyl (1.966g, 0.006mmol) were added to a mixture in an alkane (120 mL). The reaction mixture was stirred at 130 ℃ for 5 hours. Diluted with ethyl acetate (400mL) and washed with aqueous sodium carbonate (1M, 200mL), water (200mL) and brine (150 mL). The combined aqueous layers were extracted with ethyl acetate (400mL) and the combined organic layers were dried over sodium sulfate. Concentration and passage chromatography (SiO)₂Purification of n-heptane/ethyl acetate 2: 1 to 1: 1) gave the title compound as an orange oil (5.44g, 51%).

MS ISP(m/e)：307.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) -piperidin-4-yl-amines

To a solution of 4- (4, 6-dimethyl-pyrimidin-2-ylamino) -piperidine-1-carboxylic acid tert-butyl ester in THF (50mL) at 0 deg.C was added hydrochloric acid (4M in bis44.3mL in alkane) and the reaction mixture was stirred at ambient temperature for 22 hours. The resulting suspension was filtered and dried. The residue was diluted with water (160mL) and washed with ethyl acetate (130 mL). To the aqueous layer were added ethyl acetate (160mL) and sodium carbonate (28.5g) and extracted with ethyl acetate (160 mL). Drying of the combined organic layers over sodium sulfate yielded the title compound as a pale yellow solid (2.15g, 59%).

MS ISP(m/e)：207.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝1.30-1.45(m，2H)，1.60(s br，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-pyrimidin-2-yl) -amine

To a solution of 4, 6-dimethyl-pyrimidin-2-yl) -piperidin-4-yl-amine (100mg, 0.49mmol) in DMF (1.0mL) was added 2-chloro-4-fluoropyridine (57 μ L, 0.63mmol) and N, N-diisopropylethylamine (117 μ L, 0.68 mmol). The reaction mixture was heated to 150 ℃ for 30 minutes in a microwave oven under argon atmosphere. It was diluted with ethyl acetate (15mL) and washed with water (15mL) and brine (10 mL). The aqueous layer was extracted with ethyl acetate (15mL) and the combined organic layers were dried over sodium sulfate. By chromatography (SiO)₂Purification of heptane/ethyl acetate/methanol 100: 0 to 0: 90: 10) gave the title compound as a white solid (121mg, 79%).

MS ISP(m/e)：318.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

In analogy to the procedure described for the synthesis of example 32 (step c), the title compound (4, 6-dimethyl-pyrimidin-2-yl) - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine was prepared from 4, 6-dimethyl-pyrimidin-2-yl) -piperidin-4-yl-amine using 4-chloro-6-methylpyrimidine instead of 2-chloro-4-fluoropyridine and obtained as a colorless oil.

MS ISP(m/e)：299.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝1.40-1.52(m，2H)，2.10-2.20(m，2H)，2.29(s，6H)，2.36(s，3H)，3.10-3.25(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) -pyrimidin-4-yl ] -propan-2-ol

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

A mixture of 2, 5-dimethyl-1-oxo-pyridin-4-ol bromide (5.00g, 22.7mmol) in phosphorus oxychloride (4.15mL, 45.5mmol) was stirred at 130 ℃ for 3 hours. After cooling to ambient temperature, it was carefully poured onto an aqueous sodium carbonate solution (1M, 100 mL). After stirring for 15 minutes t-butyl methyl ether (50mL) was added and the resulting mixture was stirred at ambient temperature for 18 hours. The aqueous layer was separated and extracted with t-butyl methyl ether (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield a brown oil. Further extraction of the aqueous layer in bulk with ethyl acetate (50mL) and drying over sodium sulfate yielded the title compound as a white solid (1.32g, 41%).

MS ISP(m/e)：157.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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 (200mg, 1.41mmol), Boc-4-aminopiperidine (311mg, 1.55mmol) and N, N-diisopropylethylamine (484. mu.L, 2.82mmol) in sulfolane (1mL) was heated in a microwave oven to 160 ℃ for 30 minutes followed by 220 ℃ for 30 minutes. After addition of aqueous hydrochloric acid (25% in water, 0.5mL) the mixture was stirred at ambient temperature for 18 h. It was treated with ammonia in methanol and concentrated. By chromatography (SiO) ₂Purification of dichloromethane/methanol/ammonia 95: 4.5: 0.5 to 90: 9: 1) gave the title compound as a light brown oil (99mg, 40%).

MS ISP(m/e)：206.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝1.45-1.60(m，2H)，1.63(s br，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) -pyrimidin-4-yl ] -propan-2-ol

To 2 ', 5' -dimethyl-3, 4, 5, 6-tetrahydro-2H- [1, 4 'under argon atmosphere']Bipyridin-4-ylamine (143mg, 0.48mmol), 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl]-propan-2-ol (99mg, 0.48mmol), finely ground potassium carbonate (100mg, 0.72mmol) in bisPalladium (II) acetate (5mg, 0.02mmol) and 2- (dicyclohexylphosphino) biphenyl (17mg, 0.05mmol) were added to a mixture in an alkane (2mL) and the reaction mixture was heated at 150 ℃ for 30 minutes. Concentration and passage chromatography (SiO)₂Purification of n-heptane/ethyl acetate/(ethyl acetate/triethylamine: 95: 5) 50: 0 to 0: 80: 20) gave the title compound as a light brown foam (67mg, 30%).

MS EI(m/e)：466.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(s br，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) -pyrimidin-4-yl ] -propan-2-ol

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

To 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl under argon]Propan-2-ol (500mg, 1.68mmol), 4-amino-1-Boc-piperidine (404mg, 2.02mmol), sodium tert-butoxide (243mg, 2.52mmol) in bisA mixture in an alkane (2.5mL) was added palladium (II) acetate (30mg, 0.14mmol) and 2- (dicyclohexylphosphino) biphenyl (94mg, 0.27mmol) and the reaction mixture was heated to 150 ℃ for 30 minutes in a microwave oven. It was diluted with ethyl acetate (15mL) and washed with water (15mL) and brine (15 mL). The aqueous layer was extracted with ethyl acetate (15mL) and dried over sodium sulfate. By chromatography (SiO)₂Purification of heptane: ethyl acetate 80: 20 to 60: 40) gave the title compound as a light brown oil (230mg, 30%).

MS ISP(m/e)：461.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(s br，1H)，6.38(s，1H)，7.17-7.29(m，4H)

b)2- [6- (4-chloro-benzyl) -2- (piperidin-4-ylamino) -pyrimidin-4-yl ] -propan-2-ol

To a solution of 4- [4- (4-chloro-benzyl) -6- (1-hydroxy-1-methyl-ethyl) -pyrimidin-2-ylamino ] -piperidine-1-carboxylic acid tert-butyl ester (220mg, 0.447mmol) in dichloromethane (5mL) was added trifluoroacetic acid (365 μ L, 4.77mmol) at 0 ℃ and the mixture was stirred for 18 hours while allowing it to warm to ambient temperature. It was basified by addition of 1M aqueous sodium carbonate (5mL) and extracted with dichloromethane (15 mL). The organic layer was washed with 1M aqueous sodium carbonate (15mL) and dried over sodium sulfate. Concentration yielded the title compound as a brown semi-solid (192mg, 99%).

MS ISP(m/e)：361.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(s br，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) -pyrimidin-4-yl ] -propan-2-ol

Reacting 2- [6- (4-chloro-benzyl) -2- (piperidin-4-ylamino) -pyrimidin-4-yl]A solution of-propan-2-ol (76mg, 0.19mmol), 4-chloro-2-picoline (24mg, 0.19mmol) and triethylamine (53 μ L, 0.38mmol) in sulfolane (0.76mL) was stirred in a pre-heated oil bath at 150 ℃ for 30 minutes. After further addition of 4-chloro-2-picoline (24mg, 0.19mmol) and triethylamine (53. mu.L, 0.38mmol) the solution was stirred for a further 60 minutes at 150 ℃. It was diluted with ethyl acetate (15mL) and washed with 1M aqueous sodium carbonate (20mL), water (15mL) 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 passage chromatography (SiO)₂Purification of dichloromethane/methanol/triethylamine 95: 4.5: 0.5) gave the title compound as an off-white foam (34mg, 40%).

MS ISP(m/e)：452.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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 br，1H)，5.02(s br，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-pyrimidin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amin-e

a) [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -carbamic acid tert-butyl ester

Palladium (II) acetate (5.4mg, 0.024mmol) and 2- (dicyclohexylphosphino) biphenyl (17.4mg, 0.048mmol) in bis (N-ethyl-N-phenyl) at room temperature under nitrogen In an alkane (1.7mL) for 10 minutes. Sodium tert-butoxide (44mg, 0.33mmol), Boc-4-aminopiperidine (61.3mg, 0.3mmol) and 5-chloro-3-methyl- [1, 2, 4-mmol) were added]Thiadiazole (44.4 mg; 0.33mmol) and the reaction is heated to 150 ℃ in a microwave oven for 30 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from n-heptane/EtOAc 9: 1 to 1: 1(v/v) as eluent. The title compound was obtained as a yellow solid (39mg, 44%).

MS ISP(m/e)：299.2(43)[(M+H)⁺]243.2(100) [ (M-isobutene + H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-ylamine dihydrochloride

Stirring at room temperature to [1- (3-methyl- [1, 2, 4]]Thiadiazol-5-yl) -piperidin-4-yl]-tert-butyl carbamate (256mg, 0.86mmol) in CH₂Cl₂(8.6mL) was added a 2M HCl solution in diethyl ether (4.3mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was treated twice with diethyl ether to give the title compound as a yellow semi-solid (260mg, 100%)

MS ISP(m/e)：199.1(100)[(M+H)⁺]，182.1(52)。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [ (R) -1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -pyrrolidin-3-yl ] -amine

1- (3-methyl- [1, 2, 4)]Thiadiazol-5-yl) -piperidin-4-ylamine dihydrochloride (54.2mg, 0.2mmol), 4-benzyl-2-chloro-6-methyl-pyrimidine (48.1mg, 0.22mmol)) and N, N-diisopropylethylamine (120 □ L, 0.7mmol) in diisopropylethylamineThe solution in alkane (0.6mL) was heated in a microwave oven at 200 ℃ for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent. The title compound was obtained as a yellow viscous oil (22mg, 29%).

MS ISP(m/e)：381.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

1- (3-methyl- [1, 2, 4)]Thiadiazol-5-yl) -piperidin-4-ylamine dihydrochloride (54.2mg, 0.2mmol), 2- [ 2-chloro-6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl]-propan-2-ol (69.7mg, 0.22mmol) and N, N-diisopropylethylamine (120 □ L, 0.7mmol) in diisopropylethylamineThe solution in alkane (2mL) was heated in a microwave oven at 200 ℃ for 2 hours. The reaction was concentrated under reduced pressure and column chromatography was performed on silica gel using CH ₂Cl₂The residue was purified with MeOH 19: 1(v/v) as eluent. The title compound was obtained as a brown viscous oil (26mg, 27%).

MS ISP(m/e)：479.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol

In analogy to example 29, 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamine (59.5mg, 0.3mmol) was reacted with 2- [ 2-chloro-6- (4-chloro-phenyl) -pyrimidin-4-yl ] -propan-2-ol (85mg, 0.3mmol) to give the title compound as an off-white foam (55mg, 41%).

MS ISP(m/e)：445.2(98)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol

a)2- (2, 6-dichloro-pyrimidin-4-yl) -propan-2-ol

To a stirred solution of methyl 2, 6-dichloro-pyrimidine-4-carboxylate (1.03g, 5.0mmol) in tetrahydrofuran (40mL) was added a 3M solution of methyl magnesium chloride in tetrahydrofuran (3.66mL, 11.0mmol) at-75 deg.C over 10 minutes. The solution was stirred at-78 ℃ for 30min, then warmed to 0 ℃ over 10 min and stirring continued at 0 ℃ for 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (40mL) 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 heptane/0-20% ethyl acetate as eluent to yield the title compound as a pale yellow oil (0.76g, 73%).

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -propan-2-ol (1.04g, 5.0mmol) and N, O-bis (trimethyl-silyl) acetamide (1.49mL, 6.0mmol) was stirred at 100 ℃ for 4 h. The reaction mixture was cooled to 20 ℃ and purified by chromatography on silica gel using heptane/0-10% ethyl acetate as eluent to give the title compound as a colorless oil (1.16g, 83%).

¹H NMR(CDCl₃，300MHz)：□(ppm)＝7.60(s，1H)，1.57(s，6H)，0.21(s，9H)。

c) 2-chloro-4- (4-chloro-benzyl) -6- (1-methyl-1-trimethylsilyloxy-ethyl) -pyrimidine

To a solution of 2, 4-dichloro-6- (1-methyl-1-trimethylsilyloxy-ethyl) -pyrimidine (5.02g, 18.0mmol) in THF (60mL) was added Pd (TPP)₄(0.83g, 0.72 mmol). The solution was flushed with argon and subsequently a 0.5M solution of 4-chloro-benzylzinc chloride in tetrahydrofuran (36mL, 18.0mmol) was added over 1-3 minutes at 20 ℃. The reaction mixture was heated to 50 ℃ for 3h under argon atmosphere. After cooling the mixture to 20 ℃, saturated aqueous ammonium chloride (30mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (2x30mL) and the organic layer was washed with brine (2x30mL), dried over sodium sulfate and evaporated under reduced pressure. The residual oil was purified by chromatography on silica gel using heptane/0-30% ethyl acetate as eluent to give the title compound as a colorless oil (4.72g, 71%).

MS ISP(m/e)：369.0(54)[(M+H)⁺]。

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

A solution of 2-chloro-4- (4-chloro-benzyl) -6- (1-methyl-1-trimethylsilyloxy-ethyl) -pyrimidine (3.69g, 10.0mmol) and toluene-4-sulfonic acid monohydrate (0.19g, 1.0mmol) in 90% aqueous tetrahydrofuran (40mL) was stirred at 20 ℃ for 2 h. The solution was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual oil crystallized from cyclohexane to yield the title compound as a white solid (2.28g, 77%).

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol

In analogy to example 29, 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamine (65mg, 0.33mmol) was reacted with 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl ] -propan-2-ol (98mg, 0.33mmol) to give the title compound as a yellow foam (55mg, 36%).

MS ISP(m/e)：459.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-ylamino]-6-(4-trifluoromethyl-phenyl) -pyrimidin-4-yl]-propan-2-ol

a)1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-one O-benzyl-oxime 1- (5-methyl- [1, 3, 4 ]A solution of oxadiazol-2-yl) -piperidin-4-one (1.52g, 8.39mmol), O-benzylhydroxylamine hydrochloride (1.50g, 9.23mmol) and ammonium acetate (1.62g, 21.0mmol) in MeOH (34.5mL) was heated to reflux under nitrogen for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient from AcOEt to AcOEt/EtOH 9: 1(v/v) as eluent to give the title compound as a pale yellow viscous oil (2.32g, 96%).

MS ISP(m/e)：287.3(35)[(M+H)⁺]，309.4(10)[(M+Na)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-ylamine

To 1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-one O-benzyl-oxime (2.32g, 8.1mmol)) in 7M NH₃A solution in solution (in MeOH) (40.5mL) was hydrogenated under an atmosphere of hydrogen in the presence of palladium on charcoal (10%, 464mg)And (4) transforming. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (1.61g, 100%) as a yellow solid.

MS ISP(m/e)：183.1(100)[(M+H)⁺]，166.2(46)[(M-NH₃+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-ylamino]-6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl]-propan-2-ol

1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-ylamine (36.5mg, 0.2mmol), 2- [ 2-chloro-6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl]Propan-2-ol (69.1mg, 0.22mmol)) and N, N-diisopropylethylamine (52 □ L, 0.3mmol) in diisopropylethylamine The solution in alkane (2mL) was heated in a microwave oven at 160 ℃ for 5.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc/EtOH 9: 1(v/v) as eluent. The title compound was obtained as a white solid (29mg, 31%).

MS ISP(m/e)：463.2(100)[(M+H)⁺]，445.1(32)[(M-H₂O+H)⁺]，485.3(11)[(M+Na)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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)，1.658m，2H)，1.55(s，6H)。

EXAMPLE 41

(4-benzyl-6-methyl-pyrimidin-2-yl) - [1- (3-bromo- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amin-e

The reaction mixture was washed with (4-benzyl-6-methyl-pyrimidin-2-yl) -piperidin-4-yl-amine hydrochloride (125mg, 0.39mmol), 3-bromo-5-chloro- [1, 2, 4]A solution of thiadiazole (39mg, 0.19mmol) and N, N-diisopropylethylamine (66 □ L, 0.39mmol) in tetrahydrofuran (3mL) was heated to 95 ℃ for 4.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Use of the starting CH on silica gel by column chromatography₂Cl₂To CH₂Cl₂A gradient of/MeOH 19: 1(v/v) was used as eluent to purify the residue. The title compound (84mg, 96%) was obtained as a colorless oil.

MS ISP(m/e)：447.2/445.2(100/90)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-ylamino]-pyrimidin-4-yl } -propan-2-ol

1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-ylamine (50mg, 0.27mmol), 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl]Propan-2-ol (81.5mg, 0.27mmol)) and N, N-diisopropylethylamine (71 □ L, 0.41mmol) in diisopropylethylamineThe solution in alkane (2.8mL) was heated in a microwave oven for 6 hours at 160 ℃. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Use of the starting CH on silica gel by column chromatography₂Cl₂To CH₂Cl₂A gradient of/MeOH 19: 1(v/v) was used as eluent to purify the residue. The title compound (31mg, 26%) was obtained as a colorless foam.

MS ISP(m/e)：443.4/445.2(100/29)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (3-chloro- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amin-e

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

MS ISP(m/e)：401.3/403.4(100/45)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl) -piperidin-4-yl]-amines

a)4- (4-benzyl-6-methyl-pyrimidin-2-ylamino) -piperidine-1-carbonitrile

To (4-benzyl-6-methyl-pyrimidin-2-yl) -piperidin-4-yl-amine hydrochloride (255mg, 0.8mmol) in CH at 0 deg.C₂Cl₂(1.5mL) solution in Carbonic acidA suspension of sodium hydrogen (202mg, 2.49mmol) in water (0.5mL) was then added cyanogen bromide (106mg, 0.97mmol) in CH over 1 min₂Cl₂(1 mL). The reaction was stirred at 0 ℃ for 45 minutes and then at room temperature overnight. Will react with CH₂Cl₂Diluting with saturated NaHCO₃The aqueous solution and saturated aqueous NaCl solution were washed, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. From CH by column chromatography₂Cl₂To CH₂Cl₂A gradient of/MeOH 19: 1(v/v) was used as eluent to purify the residue. The title compound (135mg, 55%) was obtained as a colorless oil.

MS ISP(m/e)：308.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-2-yl) - [1- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl) -piperidin-4-yl]-amines

To a solution of 4- (4-benzyl-6-methyl-pyrimidin-2-ylamino) -piperidine-1-carbonitrile (135mg, 0.44mmol) and acetamide oxime (39mg, 0.53mmol) in EtOAc (1mL) and THF (1mL) was added a solution of zinc chloride (73mg, 0.53mmol) in EtOAc (1mL) over 10 minutes. After stirring at room temperature for 4 hours, the reaction was heated to reflux under nitrogen overnight. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Use of CH on silica gel by column chromatography ₂Cl₂The residue was purified with MeOH 19: 1(v/v) as eluent. The title compound was obtained as a colourless gum (98mg, 61%).

MS ISP(m/e)：365.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyrazin-2-amine

a)6- (4-fluoro-phenyl) -pyrazin-2-ylamine

Prepared in analogy to example 1d, starting from 2-amino-6-chloropyrazine and 4-fluorobenzeneboronic acid. The title compound was obtained as a pale brown solid (yield: 91%).

MS ISP(m/e)：190.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝8.27(s，1H)，8.04(dd，2H)，7.84(s，1H)，7.30(t，2H)，6.52(br s，2H)。

b) N- (6- (4-fluoro-phenyl) -pyrazin-2-yl) -N' -ethoxycarbonyl-thiourea

Prepared in analogy to example 1e, starting from 6- (4-fluoro-phenyl) -pyrazin-2-ylamine. The title compound precipitated from the reaction, which was filtered and washed with n-heptane, dried and obtained as white crystals (yield: 80%).

MS ISP(m/e)：321.2(100)[(M+H)⁺]，232.2(34)，275.2(25)。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝12.18(br s，1H)，11.92(brs，1H)，9.56(br 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 ] pyrazin-2-ylamine

Prepared in analogy to example 1f, starting from N- (6- (4-fluoro-phenyl) -pyrazin-2-yl) -N' -ethoxycarbonyl-thiourea. The reaction was diluted with water and the title compound was filtered and washed with MeOH/Et₂O4: 1 wash and then Et₂And O washing. Use of CH on silica gel by column chromatography₂Cl₂The product was purified with/MeOH (v/v ═ 19: 1) as eluent to give the title compound as white crystals (yield: 73%).

MS ISP(m/e)：230.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝8.83(s，1H)，8.19(s，1H)，8.12(dd，2H)，7.43(t，2H)，6.54(br s，2H)。

d)5- (4-fluorophenyl) -N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyrazin-2-amine

Prepared in analogy to example 1h, starting from 5- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyrazin-2-ylamine and 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one. The title compound was obtained as a white solid.

MS ISP(m/e)：411.3(67)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-difluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1h, starting from 8- (3, 4-difluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one. The title compound was obtained as a white solid.

MS ISP(m/e)：428.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1h, starting from 8- (3-chloro-4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one. The title compound was obtained as a white solid.

MS ISP(m/e)：444.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

a) 5-cyclopropyl-pyridin-2-ylamine

To a solution of 5-bromo-pyridin-2-ylamine (2g, 11.55mmol) and cyclopropylboronic acid (2.98g, 34.68mmol) in toluene (40mL) and water (2mL) under argon was added K₃PO₄(8.59g, 40.46 mmol). To this was added Pd (OAc)₂(259.52mg, 1.16mmol) and tricyclohexylphospha-cyclopentadiene (647.3mg, 2.3mmol) and stirred at 80 ℃ for 16 h. The reaction mixture was cooled to room temperature and water was added. 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/hexane as eluent. The title compound was obtained as an off-white solid (1.1g, 71%).

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝7.73(s，1H)，7.04-7.02(dd，J＝8.48 & 2.04Hz，1H)，6.34(d，J＝8.48 & 2.04Hz，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-pyridin-2-ylamine

To a solution of 5-cyclopropyl-pyridin-2-ylamine (1.1g, 8.19mmol) in anhydrous chloroform (100mL) at room temperature was added a solution of bromine (0.42mL, 8.2mmol) in chloroform (11mL) and stirred for 18 h. Aqueous sodium thiosulfate solution was added, 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 silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as a pale yellow oil (1.0g, 57%).

MS ESI(m/z)：213.0[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝7.77(d，J＝1.44Hz，1H)，7.39(d，J＝1.44Hz，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-pyridin-2-yl) -N' -ethoxycarbonyl-thiourea

To 3-bromo-5-cyclopropyl-pyridin-2-ylamine (1.0g, 4.69mmol) in dry 1, 4-bis under argonA solution in an alkane (20mL) was added ethoxycarbonyl isothiocyanate (0.55mL, 5.16mmol) and stirred at room temperature for 6 hours. The solvent was evaporated and the title compound was obtained as a pale yellow oil (1.5g, 98%).

MS ESI(m/z)：346.2[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝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＝7.12Hz，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-pyridin-2-yl) -N' -ethoxycarbonyl-thiourea (1.5g, 4.36mmol) in dry methanol (20mL) under argon was added hydroxylamine hydrochloride (1.41g, 21.8mmol) and diisopropylethylamine (12.14mL, 13.08mmol) and stirred at room temperature for 6 h. The methanol was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off-white solid (910mg, 82%).

MS ESI(m/z)：252.6[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝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 8-bromo-6-cyclopropyl- [1, 2, 4-]Triazolo [1, 5-a]Pyridin-2-ylamine (300mg, 1.29mmol) and 4-chlorophenylboronic acid (463mg, 2.96mmol) in bisNa was added to a solution in alkane (15mL) ₂CO₃Was added to the solution (2M, 2mL) and degassed with argon for 5 minutes. Adding PdCl₂(dppf)₂.CH₂Cl₂(30.34mg, 0.04mmol) and stirred at 80 ℃ for 90 min. The reaction mixture was cooled to room temperature and water (20mL) was added. 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/hexane as eluent. The title compound was obtained as an off-white solid (252mg, 75%).

MS ESI(m/z)：284.8[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝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 ] pyridine

To a solution of tert-butyl nitrite (0.18mL, 1.05mmol) in dry acetonitrile (7mL) under argon was added copper (II) bromide (234mg, 1.05mmol) and heated to 60 ℃ for 0.1 h. 8- (4-chloro-phenyl) -6-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (200mg, 0.7mmol) in acetonitrile (5mL) was added at 60 ℃. The reaction mixture was stirred at 75 ℃ for 3 hours and then cooled to room temperature. Water (10mL) was added. 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 ethyl acetate/hexane as eluent. The title compound was obtained as an off-white solid (150mg, 61%).

MS ESI(m/z)：348.2[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝8.81(s，1H)，8.14(d，J＝8.52Hz，2H)，7.72(s，1H)，7.62(d，J＝8.4Hz，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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Reacting 2-bromo-8- (4-chloro-phenyl) -6-cyclopropyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (50mg, 0.14mmol), 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine (see example 94a, 23mg, 0.12mmol) and sodium phenolate (21mg, 0.2mmol) in dry 1, 4-bisThe solution in alkane (3mL) was purged with argon in a sealed tube for 10 minutes. Pd is added₂(dba)₃.CHCl₃(8mg, 0.01mmol) and xanthhphos (2mg) were added to the solution and stirred at 160 ℃ for 15 h. The reaction mixture was cooled to room temperature and water (10mL) was added. 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 dichloromethane/methanol as eluent. Obtaining a light brown solid markTitle compound (5mg, 8%).

MS ESI(m/z)：460.0[(M+H)⁺]。

Example 49

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

A solution of 6-methyl-pyridin-2-ylamine (50g, 0.462mol) in acetic anhydride (200mL) was heated to 90 ℃ for 90 minutes. The reaction mixture was cooled to room temperature and evaporated. NaHCO is added ₃To the residue until pH 8. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent was evaporated. The title compound was obtained as a white solid (68g, 98%).

MS ESI(m/e)：151.2[(M+H)⁺]。

¹H NMR(DMSO-D6，400MHz)：(ppm)＝10.38(s，1H)，7。86(d，J＝8.2Hz，2H)，7.62(t，J＝7.8Hz，1H)，6.92(d，J＝7.4Hz，1H)，2.38(s，3H)，2.06(s，3H)。

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

A solution of N- (6-methyl-pyridin-2-yl) -acetamide (10g, 0.067mmol) in water (100mL) was heated to 75 ℃. Potassium permanganate (37g, 233mmol) was added portionwise at 75 ℃. After 4 hours at 75 ℃, the reaction mixture was cooled to room temperature and the solid was filtered. The aqueous layer was evaporated to half its original volume and acidified to pH 4-5 with HCl (12N). The precipitate was filtered and dried. The title compound was obtained as an off-white solid (4.5g, 37%).

MS ESI(m/z)：181.2[(M+H)⁺]。

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

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

A solution of 6-acetamido-pyridine-2-carboxylic acid (16g, 0.088mol) in methanol hydrochloride (4N, 50mL) was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and evaporated. Water was added to the residue and solid NaHCO was used₃Alkalizing. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and the solvent was evaporated. The title compound was obtained as a white solid (8g, 59%).

MS ESI(m/z)：153.0[(M+H)⁺]。

¹H NMR(DMSO-D6，400MHz)：(ppm)＝7.53(t，J＝7.52Hz，1H)，7。48(d，J＝7.28Hz，2H)，6.66(d，J＝8.04Hz，1H)，4.71(s，2H)，3.94(s，3H)。

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

To a solution of methyl 6-amino-pyridine-2-carboxylate (10g, 66.0mmol) in chloroform (450mL) at room temperature was added CHCl₃Bromine (3.4mL, 66.0mmol) in (100mL) and stirred for 40 h. Reaction mixture with CHCl₃Diluted and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as a yellow solid (3.3g, 22%).

MS ESI(m/e)：231.0[(M+H)⁺]。

¹H NMR(CDCl3，400MHz)：(ppm)＝7.76(d，J＝7.88Hz，1H)，7.34(d，J＝7.92Hz，1H)，5.23(s，2H)，3.94(s，3H)。

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

In step d), the isomeric methyl 6-amino-3-bromo-pyridine-2-carboxylate (3.0g, 19%) was isolated as a by-product.

MS ESI(m/e)：231.2[(M+H)⁺]。

¹H NMR(CDCl3，400MHz)：(ppm)＝7.60(d，J＝8.72Hz，1H)，6.47(d，J＝7.88Hz，1H)，4.71(s，2H)，3.94(s，3H)。

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

To 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (3.3g, 14.28mmol) in dry 1, 4-bis under argonA solution in an alkane (20mL) was added ethoxycarbonyl isothiocyanate (1.8mL, 15.7mmol) and stirred at room temperature for 16 h. The solvent was evaporated and the title compound (4.9g, 95%) was obtained as a yellow solid.

MS ESI(m/e)：362.0[(M+H)⁺]。

¹HNMR(DMSO-D6，400MHz)：(ppm)＝1.54(s，1H)，11.46(s，1H)，8.36(d，J＝8.16Hz，1H)，7.92(d，J＝8.16Hz，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 (2g, 5.52mmol) in dry methanol (10mL) under argon was added hydroxylamine hydrochloride (1.92g, 27.62mmol) and diisopropylethylamine (2.98mL, 16.57mmol) and stirred at room temperature for 4 hours. The solid was filtered and methanol (40mL) was added to the residue. The reaction mixture was heated to reflux for 12 hours. The solvent was evaporated and the title compound was obtained as an off white solid (800mg, 53%).

MS ESI(m/e)：270.8[(M+H)⁺]。

¹H NMR(DMSO-D6，400MHz)：(ppm)＝7.66(d，J＝8.04Hz，1H)，7。43(d，J＝8.12Hz，1H)，4.9(s，2H)，4.02(s，3H)。

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

To 2-amino-8-bromo- [1, 2, 4] at-40 deg.C]Triazolo [1, 5-a]A solution of pyridine-5-carboxylic acid methyl ester (900mg, 3.32mmol) in tetrahydrofuran was added methylmagnesium bromide (1.4M solution in toluene/tetrahydrofuran; 75/25) (9.49mL, 13.28mmol) and stirred at-30 ℃ for 1 h. The reaction mixture was warmed to room temperature and saturated NH was used₄Aqueous Cl solution was quenched. 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 silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound (400mg, 44%) was obtained as a yellow solid, doped with 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 2- (2-amino-8-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-5-yl) -propan-2-ol (doped with a ketone) (120mg, 0.443mmol) and 4-chlorophenylboronic acid (155mg, 0.987mmol) in diclofobonic acidNa was added to a solution in alkane (6mL)₂CO₃Was added to the solution (2M, 0.72mL) and degassed with argon for 5 minutes. To this solution PdCl was added ₂(dppf)₂.CH₂Cl₂(30.34mg, 0.04mmol) and stirred at 90 ℃ for 90 min. The reaction mixture was cooled to room temperature and addedWater (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 ethyl acetate/hexane as eluent. The title compound was obtained as an off-white solid (65mg, 48%) doped with 1- [ 2-amino-8- (4-chloro-phenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-5-yl]-ethanone.

MS 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-butyl nitrite (0.06mL, 0.47mmol) in dry acetonitrile (5mL) under argon was added copper (II) bromide (105mg, 0.47mmol) and heated to 60 ℃ for 0.1 h. 2- [ 2-amino-8- (4-chloro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-5-yl ] -propan-2-ol (a mixture of alcohol and ketone) (90mg, 0.32mmol) in acetonitrile (5mL) was added at 60 ℃ and stirred at 75 ℃ for 3 h. The reaction mixture was cooled to room temperature and water (10mL) was added. 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 ethyl acetate/hexane as eluent. The title compound was obtained as an off-white solid (20mg, 48%).

MS ESI(m/e)：368.0[(M+H)⁺]。

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

2- [ 2-bromo-8- (4-chloro-phenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-5-yl]-propan-2-ol (42mg, 0.11mmol), 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine (18mg, 0.1mmol) and sodium phenolate (17mg, 0.15mmol) in dry 1, 4-bisThe solution in alkane (6mL) was purged with argon in a sealed tube for 10 minutes. Pd is added₂(dba)₃.CHCl₃(8mg，0.012mmol) and xanthhphos (2mg) were added to the solution and degassing continued for a further 5 minutes, after which the reaction mixture was heated to 160 ℃ for 15 hours. The reaction mixture was cooled to room temperature and water (10mL) was added. 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 dichloromethane/methanol as eluent. The title compound was obtained as a white solid (7mg, 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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 48. The title compound was obtained as a brown solid.

MS ESI(m/z)：444.3[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝8.46(s，1H)，8.36(s，1H)，8.19-8.16(m，2H)，7.45(s，1H)，7.31(t，J＝8.88Hz，2H)，6.73-6.69(m，2H)，4.3(m，2H)，3.10(t，J＝11.64Hz，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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

To dibutyl tin chloride (10mg, 0.03mmol) and 8- (3-chloro-4-fluoro-phenyl) -6-cyclopropyl- [1, 2, 4 under argon]Triazolo [1, 5-a]A solution of pyridin-2-ylamine (prepared analogously to example 48a-e, 100mg, 0.33mmol) in anhydrous THF (1.5mL) was added 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-one (example 93b, 63mg, 0.33mmol) and phenylsilane (0.016mL, 0.4mmol) and heated in a microwave to 100 deg.C for 40 min. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was purified by preparative HPLC (acetonitrile/H)₂O) purifying the residue. The title compound was obtained as a white solid (20mg, 13%).

MS ESI(m/z)：477.8[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝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＝11.32Hz，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

1- (6-methylpyrimidin-4-yl) piperidin-4-amine dihydrochloride (133mg, 0.5mmol) was suspended in dichloromethane (15mL) and then extracted with aqueous sodium hydroxide (2M, 10 mL). The aqueous layer was extracted with dichloromethane (15mL) and the organic layers were combined, dried over sodium sulfate and carefully evaporated. After adding into anhydrous 1, 4-di2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] in an alkane (4mL)]Triazolo [1, 5-a]Pyridine (180mg, 0.55mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (23.1mg, 0.04mmol), tris (dibenzylideneacetone) dipalladium (o) chloroform adduct (21mg, 0.02mmol) and sodium phenolate (87mg, 0.75mmol), and then the reaction mixture was stirred in a microwave at 130 ℃ for 60 minutes under an argon atmosphere. Concentration and passage of the residue through chromatography (SiO)₂Purification of heptane: ethyl acetate 3: 1 to 0: 1) gave the title compound as a yellow foam (97mg, 44%).

MS ISP (m/e): 438.3 and 440.4[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 52, using 2-bromo-8- (3, 4-difluorophenyl) - [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. The title compound was obtained as a yellow foam.

MS ISP(m/e)：422.2[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 52, using 2-bromo-8- (3, 4-difluorophenyl) -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. The title compound was obtained as a yellow oil.

MS ISP(m/e)：436.3[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝8.51(s，1H)，8.15(d，1H)，7.90(ddd，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

Prepared in analogy to example 52, using 2-bromo-8- (3, 4-difluorophenyl) -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. The title compound was obtained as an orange viscous oil.

MS ISP(m/e)：440.4[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluorophenyl) -6-chloro-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 52, using 2-bromo-8- (3, 4-difluorophenyl) -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. The title compound was obtained as an orange viscous oil.

MS ISP(m/e)：440.4[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝8.51(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-methylpyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a)4- (8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester

Prepared in analogy to example 52, using tert-butyl 4-aminopiperidine-1-carboxylate instead of 1- (6-methylpyrimidin-4-yl) piperidin-4-amine. The title compound was obtained as a yellow foam.

MS ISP (m/e): 446.3 and 448.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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- (piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To 4- (8- (2-chloro-4-fluorophenyl) - [1, 2, 4]]Triazolo [1, 5-a]Solution of pyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester (810mg, 1.82mmol) in tetrahydrofuran (8mL) and methanol (6mL) was added hydrochloric acid solution (4.0M in bisIn alkane, 2.3mL, 9.1 mmol). The reaction mixture was stirred at 60 ℃ for 1.5 h and then concentrated in vacuo. The residue was taken up in ethyl acetate (40mL)) Diluted and washed with aqueous sodium carbonate (1M, 30mL), water (30mL) and brine (30 mL). The aqueous layer was further extracted with ethyl acetate (40 mL). The organic layers were combined, dried over magnesium sulfate and filtered. Concentration yielded the title compound as a yellow foam (639mg, 98%).

MS ISP (m/e): 346.2 and 348.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-methylpyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Reacting 8- (2-chloro-4-fluorophenyl) -N- (piperidin-4-yl) - [1, 2, 4-]Triazolo [1, 5-a]Pyridin-2-amine (69mg, 2mmol), 4-bromo-2-methylpyridine (34mg, 0.2mmol) and N, N-diisopropylethylamine (40mg, 0.3mmol) in 1, 4-bisThe mixture in alkane (0.8mL) was stirred at 150 ℃ for 30 minutes in a microwave. Purification of the reaction mixture by chromatography (SiO) ₂Heptane: ethyl acetate 1: 1 to ethyl acetate: methanol: ammonium hydroxide 80: 18: 2) gave the title compound as a yellow semi-solid (21mg, 24%).

MS ISP (m/e): 437.3 and 439.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 57c) using 4-bromo-2-chloropyridine instead of 4-bromo-2-methylpyridine. The title compound was obtained as a yellow solid.

MS ISP (m/e): 457.3, 459.3 and 461.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-methylpyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 57c) using 4-chloro-5-fluoro-2-methylpyridine instead of 4-bromo-2-methylpyridine. The title compound was obtained as a yellow solid.

MS ISP (m/e): 455.3 and 457.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared analogously to example 57c) by replacing 4-bromo-2-methylpyridine with 4-chloropyrimidine. The title compound was obtained as an orange semi-solid.

MS ISP (m/e): 424.2 and 426.1[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 61

Prepared analogously to example 57c) by replacing 4-bromo-2-methylpyridine with 4-chloro-2-methylpyrimidine. The title compound was obtained as a yellow semi-solid.

MS ISP (m/e): 438.3 and 440.3[ (M + H)⁺]。

Example 62

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

Prepared analogously to example 57c) by replacing 4-bromo-2-methylpyridine with 4-chloro-2, 6-dimethylpyrimidine. The title compound was obtained as a yellow semi-solid.

MS ISP (m/e): 452.2 and 454.3[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy 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. The title compound was obtained as a yellow foam.

MS ISP (m/e): 452.2 and 454.2[ (M + H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 1h, using 8- (2-chloro-4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to examples 1 a-f). The title compound was obtained as a yellow solid.

MS ISP(m/e)：444.2/446.1(100/30)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 1h, using 8- (2, 4-difluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to examples 1 a-f). The title compound was obtained as a white solid.

MS ISP(m/e)：428.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

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

3-Bromopyridin-2-amine (30g, 168mmol) and ethoxycarbonyl isothiocyanate (24.8g, 21.3mL, 185mmol) were dissolved in bisIn an alkane (300mL) and stirred at room temperature. After 4 hours, further ethoxycarbonyl isothiocyanate (1mL, 8.4mmol) was added. After 1 hour, the solvent was evaporated and the residue was dried in high vacuum for 12 hours. The title compound (51.2g, 100%) was obtained as a light yellow solid and used in the next step without purification.

MS ISP(m/e)：304.0/305.9(100/73)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 (58.5g, 842mmol) and N, N-diisopropylethylamine (65.3g, 86.3mL, 505mmol) were dissolved in methanol (200mL) and ethanol (200 mL). N- (3-bromo-pyridin-2-yl) -N' -ethoxycarbonyl-thiourea (51.2g, 168mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60 ℃ for 3 hours. The white precipitate was filtered and triturated with water for 25 minutes, filtered and triturated twice with diethyl ether. The solid was dried by co-evaporation with toluene and dried in vacuo. The title compound was obtained as a white solid (27.9g, 78%).

MS ISP(m/e)：213.0/215.1(86/95)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Reacting 8-bromo- [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-amine (500mg, 2.35mmol), 4-chlorophenylboronic acid (757mg, 4.69mmol), dichloro [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloromethane adduct (153mg, 0.188mmol) and Na₂CO₃Aqueous solution (2N, 2.35mL, 4.69mmol) in twoThe mixture in alkane (10mL) was stirred at 110 ℃ for 2 hours. The reaction mixture was diluted with 2N aqueous sodium carbonate solution and 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 pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572mg, 99%).

MS ISP(m/e)：245.3/247.2(100/38)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) - [1, 2, 4] triazolo [1, 5-a ] pyridine

A mixture of copper (II) bromide (150.6mg, 0.674mmol) and tert-butyl nitrite (89 □ L, 0.674mmol) in acetonitrile (5ml) was heated to 60 ℃ and 8- (4-chloro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (150mg, 0.613mmol) was added in small portions. After the addition was complete, the reaction mixture was heated to 75 ℃ for 1 hour. Copper (II) bromide (150.6mg, 0.674mmol) and tert-butyl nitrite (89 □ L, 0.674mmol) were further added and the mixture was heated to 75 ℃ for additional hours. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted three times 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 pentane/diethyl ether as eluent. The title compound was obtained as a white solid (165mg, 87%).

MS ISP(m/e)：308.0/310.0/312.1(85/100/31)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-4-amines

1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine dihydrochloride was neutralized with 2N NaOH solution (see example 36b, 2.3g, 8.48 mmol). CH for aqueous layer₂Cl₂Extracting three times with ethyl acetate, and mixing the organic phases over Na ₂SO₄Dry, filter and evaporate the solvent. Use of CH by flash chromatography₂Cl₂And MeOH in 50g Si-NH₂The crude product was purified on the column. The title compound was isolated as a pale yellow oil (1.2g, 71%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

To 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine (40mg, 202. mu. mol), 2-bromo-8- (4-chlorophenyl) - [1, 2, 4] with argon]Triazolo [1, 5-a]Pyridine (74.7mg, 242. mu. mol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (9.34mg, 16.1. mu. mol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (8.35mg, 8.07. mu. mol) and sodium phenolate (35.1mg, 303. mu. mol) in anhydrous dibenzanthraceneThe suspension in alkane (3mL) was bubbled for 5 minutes. The mixture was then irradiated at 150 ℃ for 60 minutes. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) was used to purify the crude material. An off-white foam was obtainedThe title compound (42mg, 49%).

MS ISP(m/e)：426.1/428.3(100/39)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：458.2/460.2(100/34)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a white foam.

MS ISP(m/e)：458.2/460.2(100/40)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as an off-white solid.

MS ISP(m/e)：442.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 1. The title compound was obtained as a white foam.

MS ISP(m/e)：432.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：440.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a light brown foam.

MS ISP(m/e)：478.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：432.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 1. The title compound was obtained as a white solid.

MS ISP(m/e)：482.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as an orange solid.

MS ISP(m/e)：488.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：478.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 66, starting in step a) from 3-bromo-5-fluoropyridin-2-amine instead of 3-bromopyridin-2-amine. The title compound was obtained as a white foam.

MS ISP(m/e)：446.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：460.2/462.2/464.1(100/70/14)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 79

MS ISP(m/e)：482.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a brown solid.

MS ISP(m/e)：446.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a)8- (3, 4-difluoro-phenyl) -6-fluoro-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Reacting 8- (3, 4-difluorophenyl) -6-fluoro- [1, 2, 4]Triazolo [1, 5-a]A solution of pyridin-2-amine (prepared in analogy to examples 66a-C starting from 3-bromo-5-fluoropyridin-2-amine, 237mg, 897. mu. mol) in ethanol (8mL) and HCl (25% in water, 144mg, 120. mu.L, 987. mu. mol) was hydrogenated at 80 ℃ and 80bar in the presence of Pd/C (237mg, 222. mu. mol) for 18 hours. The catalyst was filtered, washed thoroughly with MeOH and the solvent was evaporated. By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the crude material was purified. The title compound was obtained as a white foam (76mg, 32%).

MS ISP(m/e)：269.2(100)[(M+H)⁺]。

b) [8- (3, 4-difluoro-phenyl) -6-fluoro-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Dissolving 8- (3, 4-difluorophenyl) -6-fluoro-5, 6, 7, 8-tetrahydro- [1, 2, 4-tetrahydro ] in dichloroethane (6mL)]Triazolo [1, 5-a]A solution of pyridin-2-amine (74mg, 276. mu. mol), 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (82mg, 414. mu. mol), and titanium (IV) isopropoxide (240mg, 253. mu.L, 828. mu. mol) was heated to 85 ℃ for 12 hours. Further 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (54mg, 276. mu. mol) was added and stirred at 85 ℃ for two hours. Will be reversed The mixture was cooled to 50 deg.C, sodium borohydride (41.7mg, 1.1mmol) and ethanol (3mL) were added and stirred at 50 deg.C for one hour. The solvent was evaporated and the residue was taken up with 2N Na₂CO₃The solution was extracted with ethyl acetate. The organic layers were combined over Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) and the residue was then purified by preparative HPLC. The title compound was obtained as a pale green foam (37.1mg, 30%).

MS ISP(m/e)：450.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a) 3-bromo-6- (trifluoromethyl) pyridin-2-amine

A solution of 6- (trifluoromethyl) pyridin-2-amine (200mg, 1.23mmol) in dichloromethane (2.47mL) was cooled to 0 deg.C and bromine (197mg, 63.4. mu.L, 1.23mmol) was added slowly over 30 minutes. After 25 hours the reaction mixture was washed with saturated Na at 0 deg.C₂S₂O₃Solution, water and brine extraction under Na₂SO₄Dried and concentrated in vacuo. Use of CH on silica gel by flash chromatography₂Cl₂The crude material was purified with MeOH (10% ammonia) as eluent. The title compound (711mg, 24%) was obtained as a white solid.

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.80-7.77(m，1H)，6.91-6.89(m，1H)。

b) [8- (3, 4-difluoro-phenyl) -5-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 66, starting in step a) from 3-bromo-6- (trifluoromethyl) pyridin-2-amine instead of 3-bromopyridin-2-amine. The title compound was obtained as a pale yellow solid.

MS ISP(m/e)：496.3(53)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-5-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 66. The title compound was obtained as a pale yellow solid.

MS ISP(m/e)：408.3(100)[(M+H)⁺]

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：423.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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，2H)。

Example 85

[8- (2-chloro-4-fluoro-phenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared in analogy to examples 66a-d and f, using 1- (5-methyl- [1, 3, 4] in step f]Oxadiazol-2-yl) -piperidin-4-ylamine (see example 40b) instead of 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine. The title compound was obtained as a white solid.

MS ISP(m/e)：428.3/430.3(100/41)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 66, starting in step a) with 3-bromo-5-fluoropyridin-2-amine instead of 3-bromopyridin-2-amine. The title compound was obtained as an off-white solid.

MS ISP(m/e)：462.2/464.3(100/33)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-triazol-3-yl) -1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine

Prepared similarly to example 5. The title compound was obtained as a white foam.

MS ISP(m/e)：424.2/426.0(100/66)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as an off-white foam.

MS ISP(m/e)：411.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a brown oil.

MS ISP(m/e)：411.3(81)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

MS ISP(m/e)：470.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：446.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 1. The title compound was obtained as a yellow oil.

MS ISP(m/e)：450.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a)8- (6-methylpyrimidin-4-yl) -1, 4-dioxa-8-azaspiro [4.5] decane

1, 4-dioxa-8-azaspiro [4.5]]Decane (3.04g, 2.72mL, 21.2mmol), 4-chloro-6-methylpyrimidine (3.00g, 23.4mmol) and N, N-diisopropylethylamine (4.12g, 5.56mL, 31.8mmol) in dioxaneThe solution in alkane (50mL) was heated to 140 ℃ in a microwave for 40 minutes. The reaction mixture was concentrated and then directly subjected to flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane) ₄OH (9: 1)) purification. The title compound was obtained as an orange oil (4.64g, 93%).

MS ISP(m/e)：236.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-one

To 8- (6-methylpyrimidin-4-yl) -1, 4-dioxa-8-azaspiro [4.5 ]]A solution of decane (4.64g, 19.7mmol) in acetone (45mL) was added 2N HCl (180g, 150mL, 4.94mol) and stirred at 50 ℃ for 2 h. The reaction mixture was cooled to room temperature and then treated with NaHCO₃The solution was adjusted to pH 7. Using CH as the aqueous phase₂Cl₂Extracting for 4 times, combining organic layers, and purifying with Na₂SO₄Dried and the solvent evaporated. The title compound was obtained as a pale brown liquid (2.7g, 72%).

MS ISP(m/e)：192.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1h, using 1- (6-methylpyrimidin-4-yl) piperidin-4-one and 8- (2-fluoro-4-trifluoromethyl-phenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to example 1 d-g). The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：476.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a)1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine

With 2N NaOH solution and CH₂Cl₂To neutralize 1- (6-methylpyrimidin-4-yl) piperidin-4-amine dihydrochloride (see example 30b, 2g, 7.54mmol), the aqueous layer was washed with CH₂Cl₂Extracted three times, the combined organic layers were washed with Na₂SO₄Dry, filter and evaporate the solvent. The title compound was obtained as a brown oil (1.31g, 90%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-fluoro-pyridin-3-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared in analogy to examples 66a-d and f. In step f) 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine is used instead of 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine. The title compound was obtained as a light brown foam.

MS ISP(m/e)：405.5(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiophen-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 94. The title compound was obtained as a yellow oil.

MS ISP(m/e)：426.1/428.2(90/36)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 94. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：472.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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)，6.95-6.90(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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

MS ISP(m/e)：430.5(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 94. The title compound was obtained as a pale yellow solid.

MS ISP(m/e)：426.1/428.3(100/44)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 93. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：476.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -6-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (6-methyl-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared in analogy to examples 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-pyrimidin-4-yl) -piperidin-4-ylamine (see example 94a) instead of 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine in step f). The title compound was obtained as a brown foam.

MS ISP(m/e)：490.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 66, using 3-bromo-5- (trifluoromethyl) pyridin-2-amine instead of 3-bromopyridin-2-amine in step a). The title compound was obtained as a light brown foam.

MS ISP(m/e)：496.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 94. The title compound was obtained as a white foam.

MS ISP(m/e)：440.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 94. The title compound was obtained as a brown solid.

MS ISP(m/e)：405.3(15)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

MS ISP(m/e)：447.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：417.4(35)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 93. The title compound was obtained as a pale yellow oil.

MS ISP(m/e)：426.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared similarly to example 85. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：407.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared similarly to example 85. The title compound was obtained as a brown solid.

MS ISP(m/e)：395.2(51)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared similarly to example 85. The title compound was obtained as a light brown foam.

MS ISP(m/e)：462.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared in analogy to examples 66a-d and f, starting from 3-bromo-5-fluoropyridin-2-amine instead of 3-bromopyridin-2-amine in step a and using 1- (5-methyl- [1, 3, 4 ] in step f ]Oxadiazol-2-yl) -piperidin-4-ylamine (see example 40b) instead of 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine. The title compound was obtained as a light brown foam.

MS ISP(m/e)：446.1/448.1(100/35)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to examples 66a-d and f, starting in step a from 3-bromo-5-fluoropyridin-2-amine instead of 3-bromopyridin-2-amine and in step f using 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine (see example 94a) instead of 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-amine. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：456.3/458.3(100/34)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared analogously to example 1h, using 1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-one (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 (prepared analogously to example 1 d-g). The title compound was obtained as a brown solid.

MS ISP(m/e)：466.3(71)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 94. The title compound was obtained as a pale yellow oil.

MS ISP(m/e)：401.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 & 115

a)8- (3, 4-difluoro-phenyl) -5-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Prepared in analogy to example 66 steps a-c, starting in step a from 3-bromo-6- (trifluoromethyl) pyridin-2-amine (see example 82 a). The title compound was obtained as an off-white solid.

MS ISP(m/e)：315.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Prepared in analogy to example 81a, using 8- (3, 4-difluoro-phenyl) -5-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine. The title compound was obtained as a white solid as a mixture of racemic diastereomers.

MS ISP(m/e)：319.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridine

Prepared in analogy to example 66d, using 8- (3, 4-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine. The title compound was obtained as a yellow oil as a mixture of racemic diastereomers.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 66f, using 2-bromo-8- (3, 4-difluoro-phenyl) -5-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridine. The two diastereomers were separated by preparative HPLC (configuration of diastereomer not specified).

Example 114: diastereomer a (racemic). Retention time 3.13 minutes (Gemini NX3u 50 × 4.6 mm). A white solid.

MS ISP(m/e)：499.9(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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: diastereomer B (racemic). Retention time 3.57 minutes (Gemini NX3u 50 × 4.6 mm). A white solid.

MS ISP(m/e)：500.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 & 117

a)8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Prepared in analogy to example 66a-c, starting from 3-bromo-5-trifluoromethyl-pyridin-2-ylamine. The title compound was obtained as a light gray solid.

MS ISP(m/e)：315.1(84)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -6-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

To 8- (3, 4-difluorophenyl) -6- (trifluoromethyl) - [1, 2, 4]Triazolo [1, 5-a]A solution of pyridin-2-amine (500mg, 1.59mmo1) and magnesium (309mg, 12.7mmol) in methanol (80mL) and THF (40mL) was added iodine (2mg, 7.88. mu. mol), stirred at room temperature for 10 min, and then sonicated for 30 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and Na₂SO₄Dried, then filtered, rinsed thoroughly with THF and the solvent evaporated. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the crude material was purified. The title compound was obtained as a white solid as a mixture of racemic diastereomers (324mg, 64%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -6-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 1h, using 8- (3, 4-difluoro-phenyl) -6-trifluoromethyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine. The cis and trans isomers were separated by preparative HPLC.

Example 116: (6R, 8R)/(6S, 8S) racemate. Retention time 3.2 minutes (Gemini NX3u 50 × 4.6 mm). White foam.

MS ISP(m/e)：500.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，600MHz)：(ppm)＝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) racemic body. Retention time 3.4 minutes (Gemini NX3u 50 × 4.6 mm). White foam.

MS ISP(m/e)：500.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，600MHz)：(ppm)＝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

Prepared similarly to example 85. The title compound was obtained as a white foam.

MS ISP(m/e)：430.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 94. The title compound was obtained as a light brown oil.

MS ISP(m/e)：454.3/456.3(100/78)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：440.3(75)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 94. The title compound was obtained as a yellow foam.

MS ISP(m/e)：405.4(59)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

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 example 66b, 500mg, 2.35mmol), phenol (442mg, 4.69mmol), copper (I) iodide (44.7mg, 235. mu. mol), picolinic acid (57.8mg, 469. mu. mol) and tripotassium phosphate (1.49g, 7.04mmol) in DMSO (10mL) was heated to 120 ℃. After 12 h, further phenol (442mg, 4.69mmol), copper (I) iodide (44.7mg, 235. mu. mol), picolinic acid (57.8mg, 469. mu. mol) and tripotassium phosphate (1.49g, 7.04mmol) were added and stirred at 120 ℃ for a further 18 h. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The crude material was purified by preparative HPLC. The title compound was obtained as an off-white solid (200mg, 38%).

MS ISP(m/e)：227.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

Reacting 8-phenoxy- [1, 2, 4]]Triazolo [1, 5-a]A solution of pyridin-2-amine (80mg, 354. mu. mol), 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93b, 101mg, 530. mu. mol) and titanium (IV) isopropoxide (302mg, 314. mu.L, 1.06mmol) in 1, 2 dichloroethane (5mL) was heated to 85 ℃ for 12 hours. Titanium (IV) isopropoxide (302mg, 314. mu.L, 1.06mmol) was further added and the mixture was stirred at 85 ℃ for a further 8 hours. The reaction mixture was cooled to 50 ℃ and NaBH was added₄(53.5mg, 1.41mmol) and ethanol (3mL) and the reaction mixture was stirred at 50 ℃ for one hour. The solvent was evaporated and the residue was taken up with 2N Na₂CO₃The solution was extracted with ethyl acetate. The organic layers were combined over Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was obtained as a white solid (27mg, 19%).

MS ISP(m/e)：402.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 94. The title compound was obtained as an orange foam.

MS ISP(m/e)：420.3/422.3(100/38)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 122, using 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one in step b) (see example 1 c). The title compound was obtained as a white solid.

MS ISP(m/e)：408.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-chloropyridin-4-yl) piperidin-4-yl) -8- (5-fluoropyridin-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 66, using 1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride in step e) (see example 169 b). The title compound was obtained as a pale yellow oil.

MS ISP(m/e)：424.2/426.3(100/27)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Similar to example 127. The title compound was obtained as an orange solid.

MS ISP(m/e)：541.3/543.3(100/39)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzonitrile

Similar to example 127. The title compound was obtained as a pale yellow solid.

MS ISP(m/e)：430.3/432.3(100/35)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 85. The title compound was obtained as a yellow foam.

MS ISP(m/e)：444.2/446.1(100/49)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：438.2/440.3(100/37)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Similar to example 127. The title compound was obtained as a yellow foam.

MS ISP(m/e)：435.3/437.3(100/31)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 122, using 1- (2-chloropyridin-4-yl) piperidin-4-one in step b) (see example 232 b). The title compound was obtained as a white foam.

MS ISP(m/e)：454.8(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 127. The title compound was obtained as an off-white solid.

MS ISP(m/e)：489.2/491.2(100/42)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 127. The title compound was obtained as a pale yellow solid.

MS ISP(m/e)：430.3/432.4(100/31)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared similarly to example 126. The title compound was obtained as a white solid.

MS ISP(m/e)：442.3/444.2(100/44)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzonitrile

MS ISP(m/e)：411.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a yellow solid.

MS ISP(m/e)：476.2(56)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：460.2/462.2/464.2(100/71/13)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a yellow oil.

MS ISP(m/e)：460.3/462.2(100/68)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：426.2/428.3(100/42)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared similarly to example 85. The title compound was obtained as a light brown oil.

MS ISP(m/e)：410.2/412.3(100/33)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] -c]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

a)8- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To 8- (3, 4-difluorophenyl) - [1, 2, 4 ]]Triazolo [1, 5-a]Solution of pyridin-2-amine (prepared analogously to examples 66a-c, 500mg, 2.03mmol) in methanol (60mL) and THF (30mL)Magnesium (395mg, 16.2mmol) and iodine (3mg) were added. After 1.5 h at room temperature, further magnesium (395mg, 16.2mmol) was added and the reaction mixture was stirred at 50 ℃ for 1 h. Magnesium (148mg, 6.09mmol) was again added and stirred at room temperature for 4 hours. The solvent was evaporated, the residue was dissolved in THF and Na₂SO₄And drying. The solvent was evaporated and chromatographed by flash chromatography (silica gel, 100g, 0% to 15% MeOH/NH)₃(9: 1) in dichloromethane for 45 minutes) the residue was purified. The title compound was obtained as a white solid (226mg, 45%).

MS ISP(m/e)：251.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4 ] -c]Triazolo [1, 5-a]Pyridin-2-yl]- [1- (5-methyl- [1, 3, 4 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

1- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) piperidin-4-one (79.6mg, 440. mu. mol) and 8- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4]Triazolo [1, 5-a]A solution of pyridin-2-amine (110mg, 440. mu. mol) in toluene (5mL) and acetic acid (280. mu.L) was heated to reflux on a Dean-Stark trap. The reaction mixture was cooled to room temperature and ethanol (3mL) was added, followed by sodium borohydride (66.5mg, 61.9. mu.L, 1.76 mmol). The reaction mixture was stirred at 50 ℃ for 3 hours. Sodium borohydride (66.5mg, 61.9 μ L, 1.76mmol) was further added and stirred at 50 ℃ for 3 hours. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with Na ₂SO₄Dried and the solvent evaporated. The product was purified by flash chromatography (silica gel, 100g,0% to 15% MeOH in dichloromethane, 40 min) was used. The title compound was obtained as a white solid (32.8mg, 18%).

MS ISP(m/e)：416.3(69)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a yellow foam.

MS ISP(m/e)：417.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 85. The title compound was obtained as a yellow solid.

MS ISP(m/e)：444.3/446.2(100/54)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 66. The title compound was obtained as a pale yellow oil.

MS ISP(m/e)：480.3(80)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：528.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：476.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：401.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-yl) -8- (3- (trifluoromethoxy) phenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-amines

MS ISP(m/e)：460.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：422.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a) 2-bromo-8- (3-chlorophenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine

Copper (II) bromide (365mg, 1.63mmol) and tert-butyl nitrite (168mg, 195. mu.L, 1.63mmol) were dissolved in acetonitrile (8.0mL) and heated to 60 ℃. 8- (3-chlorophenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (prepared analogously to example 122a, 387mg, 1.48mmol) was added in small portions, heated to 75 ℃ and stirred for 2 h.

Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with Na₂SO₄And drying. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 70g, 0% to 100% ethyl acetate in toluene, 35 min). The title compound (142mg, 30%) was obtained as a pale red solid.

MS ISP(m/e)：324.2/326.1(77/100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 66f, using 2-bromo-8- (3-chlorophenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine. The title compound was obtained as a white foam.

MS ISP(m/e)：442.3/444.3(100/40)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 143, using 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93 b). The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：444.3(64)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Prepared in analogy to example 66f, using 2-bromo-8- (3-chlorophenoxy) - [1, 2, 4]Triazolo [1, 5-a]Pyridine (see example 152a) and 1- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -piperidin-4-ylamine (see example 40 b). The title compound was obtained as a yellow oil.

MS ISP(m/e)：426.1(59)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

MS ISP(m/e)：512.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：444.3/446.2(100/27)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 1h, using 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93b) and 8- (3-dimethylamino-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to examples 66 a-c). The title compound was obtained as a white foam.

MS ISP(m/e)：429.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) -8- (6-methylpyridin-3-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

MS ISP(m/e)：407.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-yl) -4-phenylbenzo [ d ] thiazol-2-amine

a) 2-chloro-7-methoxy-4-phenylbenzo [ d ] thiazole

A solution of copper (II) chloride (78.7mg, 585. mu. mol) and tert-butyl nitrite (67.1mg, 77.6. mu.L, 585. mu. mol) dissolved in acetonitrile (5mL) was heated to 60 ℃. 7-methoxy-4-phenylbenzo [ d ] thiazol-2-amine (100mg, 390. mu. mol) was added in small portions. After the addition was complete, the reaction mixture was heated to 60 ℃ for three hours. The reaction mixture was cooled to room temperature, water was added and extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound as a light brown oil (100mg, 93%).

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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) piperidin-4-yl) -4-phenylbenzo [ d ] thiazol-2-amine

Reacting 2-chloro-7-methoxy-4-phenylbenzo [ d ]]Thiazole (100mg, 363. mu. mol), 1- (6-methylpyrimidin-4-yl) piperidin-4-amine dihydrochloride (115mg, 435. mu. mol) and Hunig's base (187mg, 253. mu.L, 1.45mmol) in bis The solution in alkane (2mL) was heated to 160 ℃ in a microwave oven for 30 minutes. N-methyl-2-pyrrolidone (0.5mL) was added and the reaction was heated to 200 ℃ in a microwave oven for 2 hours. Water was added and the reaction was extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The solvent was evaporated in vacuo and chromatographed on silica gelThe residue was purified using a gradient from dichloromethane to dichloromethane/methanol 9: 1(v/v) as eluent to yield the title compound as a light brown solid (40mg, 25%).

MS ISP(m/e)：432.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝8.51(s，1H)，7.77(d，2H)，7.43-7.29(m，4H)，6.72(d，1H)，6.39(s，1H)，5.53(br s，1H)，4.31(brd，2H)，3.98(s，3H)，3.79(m，1H)，3.10(m，2H)，2.36(s，3H)，2.20(brd，2H)，1.50(m，2H)。

Example 160

N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a)4- (2-nitropyridin-3-yl) morpholine

To a solution of 3-bromo-2-nitropyridine (207mg, 1mmol) in DMSO (2mL) was added morpholine (95.8mg, 95.8. mu.L, 1.1mmol), tetrabutylammonium iodide (18.5mg, 50.0. mu. mol) and potassium carbonate (152mg, 1.1mmol) at room temperature under stirring and nitrogen atmosphere. The reaction was stirred at 80 ℃ overnight. Water was added and the aqueous phase was extracted twice 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. The title compound was obtained after column chromatography (using a gradient from heptane/ethyl acetate 4: 1 to 1: 1(v/v) as eluent) as a yellow oil (57mg, 27%).

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝8.45(d，1H)，7.96(d，1H)，7.71(dd，1H)，3.67(t，4H)，3.00(t，4H)。

b) 3-morpholinopyridin-2-amines

To a solution of 4- (2-nitropyridin-3-yl) morpholine (155mg, 741. mu. mol) in ethyl acetate was added Pd/C10% (15.5mg, 146. mu. mol) and the reaction was hydrogenated under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered, washed with ethyl acetate and the solvent was evaporated under reduced pressure. The title compound was obtained as a purple solid (128mg, 96%).

MS ISP(m/e)：180.1(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-morpholin-4-yl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Prepared in analogy to example 1e-f), starting from 3-morpholinopyridin-2-amine. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent. The title compound was obtained as a pale brown solid (yield in 2 steps: 85%).

MS ISP(m/e)：220.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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) piperidin-4-yl) -8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1h, starting from 8-morpholin-4-yl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93 b). The title compound was obtained after column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) on silica gel as eluent) as a white solid (yield: 34%).

MS ISP(m/e)：395.2(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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

a) 8-bromo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine

Prepared in analogy to example 1e-f, starting from 2-amino-3-bromo-5-methylpyridine. The crude product was purified by crystallization from hot EtOAc. Most of the product is insoluble and precipitates during work-up. Filtering the material with water and CH₂Cl₂Washed, dried and combined with other substances. The title compound was obtained as a white solid (yield in two steps: 73%).

MS ISP(m/e)：227.1/229.2(100/84)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝8.43(s，1H)，7.63(s，1H)，6.13(br s，2H)，2.27(s，3H)。

b)4- (2-amino-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Reacting 8-bromo-6-methyl- [1, 2, 4]]A triazolo [1 ] group, a triazolo [1 ],5-a]pyridin-2-ylamine (1.14g, 5mmol), 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.39g, 7.5mmol), dichloro [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) methylene chloride adduct (204mg, 250. mu. mol) and Na₂CO₃In a solution of (2N, 12.5mL, 25mmol) in (B)The mixture in alkane (50mL) was stirred at 110 ℃ overnight. The reaction mixture was diluted with water and extracted twice with EtOAc. 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 EtOAc as eluent. The title compound was obtained as a pale yellow crystalline solid after stirring with diethyl ether, filtration and drying (1.54g, 93%).

MS ISP(m/e)：330.1(100)[(M+H)⁺]，274.1(87)，230.3(23)，201.3(20)。

c)4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Prepared in analogy to example 1H, starting from 4- (2-amino-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester and 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93 b). The title compound was obtained after column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) as eluent on silica gel) as a pale yellow solid (yield: 32%).

MS ISP(m/e)：505.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：□(ppm)＝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(brm，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) piperidin-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

Prepared in analogy to example 160b, from 8-bromo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester. The title compound was obtained after column chromatography (using ethyl acetate as eluent on silica gel) as a light brown solid (yield: 63%).

MS ISP(m/e)：229.3(100)[(M+H)⁺]。

b) 8-cyclohexenyl-6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1h, starting from 8-cyclohexenyl-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93 b). The title compound was obtained after column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) on silica gel as eluent) as a yellow viscous oil (yield: 17%).

MS ISP(m/e)：404.6(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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)，3.21(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

3- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamic acid tert-butyl ester

a) [3- (2-amino-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -benzyl ] -carbamic acid tert-butyl ester

Prepared in analogy to example 160b, starting from 8-bromo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and 3- ((tert-butoxycarbonylamino) methyl) phenylboronic acid. After precipitation from diethyl ether, the title compound was obtained as an off-white solid (yield: 99%).

MS ISP(m/e)：354.4(80)[(M+H)⁺]，298.4(100)，237.2(99)。

b)3- (2-bromo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamic acid tert-butyl ester

A solution of copper (II) bromide (213mg, 955. mu. mol) and tert-butyl nitrite (109mg, 127. mu.L, 955. mu. mol) dissolved in acetonitrile (3.2mL) was heated to 60 ℃. Tert-butyl 3- (2-amino-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamate (225mg, 637. mu. mol) was added in small portions. After the addition was complete, the reaction mixture was heated to 75 ℃ for two hours. The reaction mixture was cooled to room temperature, water was added and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound (114mg, 43%) as a pale yellow solid after column chromatography on silica gel using a gradient from heptane to a mixture of heptane/ethyl acetate 1: 1(v/v) as eluent.

MS ISP(m/e)：417.2/419.1(75/87)[(M+H)⁺]，361.1/363.0(94/100)。

c)3- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamic acid tert-butyl ester

1- (6-methylpyrimidin-4-yl) piperidin-4-amine (52.5mg, 273. mu. mol), 3- (2-bromo-6-methyl- [1, 2, 4-]Triazolo [1, 5-a]Pyridin-8-yl) benzylcarbamic acid tert-butyl ester (114mg, 273. mu. mol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (12.6mg, 21.9. mu. mol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (11.3mg, 10.9. mu. mol) and sodium phenolate (50.1mg, 410. mu. mol) in bisThe solution in alkane (3mL) was degassed three times and reacted in a microwave oven under nitrogen atmosphere at 140 ℃ for 1 hour. After column chromatography (gradient from dichloromethane to a mixture of dichloromethane/methanol 19: 1(v/v) on silica gel as eluent), the title compound was obtained as a pale yellow solid (46mg, 32%).

MS ISP(m/e)：529.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(br s，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)，1.70-1.46(m，2H)，1.46(s，9H)。

Example 164

3- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamic acid ethyl ester

a)8- (3- (aminomethyl) phenyl) -6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-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) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamate (46mg, 87.0 μmol) in dichloromethane (1mL) was added a 2M solution of HCl in ether (500 μ L). The suspension was stirred at room temperature overnight. The solvent was decanted and the residue was treated with diethyl ether (digerated) three times. The title compound was dried under reduced pressure and obtained as a yellow solid (39mg, 89%).

MS ISP(m/e)：429.3(100)[(M+H)⁺]，412.4(57)。

b)3- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) benzylcarbamic acid ethyl ester

To a suspension of 8- (3- (aminomethyl) phenyl) -6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine dihydrochloride (37mg, 73.8. mu. mol) in dichloromethane (0.75mL) was added N, N-diisopropylethylamine (38.1mg, 51.5. mu.L, 295. mu. mol). To the resulting yellow solution was added ethyl chloroformate (8.99mg, 7.89. mu.L, 81.2. mu. mol) and the reaction was stirred at room temperature overnight. The title compound was obtained after column chromatography (gradient from dichloromethane to a mixture of dichloromethane/methanol 19: 1(v/v) on silica gel as eluent) as a pale yellow solid (35mg, 95%).

MS ISP(m/e)：501.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝8.51(s，1H)，8.13(s，1H)，7.83(br s，2H)，7.44(t，1H)，7.36(s，1H)，7.33(d，1H)，6.41(s，1H)，5.08(br m，1H)，4.53(br d，1H)，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(br d，2H)，1.25(t，3H)。

Example 165

4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid ethyl ester

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

Prepared in analogy to example 164a, starting from 4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester. Since the product did not precipitate out of the reaction, it was diluted with water and extracted twice with dichloromethane. The aqueous layer was made basic using 1N aqueous sodium hydroxide and extracted 4 times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to give the title compound as a yellow solid (194mg, 77%).

MS ISP(m/e)：405.5(53)[(M+H)⁺]，376.4(100)。

b)4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid ethyl ester

Prepared in analogy to example 164b, starting from 6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (1, 2, 3, 6-tetrahydropyridin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and ethyl chloroformate. The title compound was obtained after column chromatography (gradient from dichloromethane to a mixture of dichloromethane/methanol 19: 1(v/v) on silica gel as eluent) as a pale yellow solid (yield: 36%).

MS ISP(m/e)：477.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝8.51(s，1H)，8.04(s，1H)，7.18(br 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

4- (6-methyl-2- (1- (6-methylpyrimidin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid isopropyl ester

Prepared in analogy to example 164b, from 6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (1, 2, 3, 6-tetrahydropyridin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and isopropyl chloroformate. After column chromatography (gradient from dichloromethane to a mixture of dichloromethane/methanol 19: 1(v/v) on silica gel as eluent), the title compound was obtained as a colorless solid (yield: 32%).

MS ISP(m/e)：491.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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) piperidin-4-yl) -7-phenyl-6, 7-dihydro-5H- [1, 2, 4]Triazolo [5, 1-b][1，3]Oxazin-2-amines

a) (3-bromo-3-phenylpropoxy) (tert-butyl) dimethylsilane

A suspension of tert-butyldimethyl (3-phenylpropoxy) silane (2.22g, 8.86mmol), N-bromosuccinimide (1.58g, 8.86mmol) and benzoyl peroxide (66.4mg, 266. mu. mol) in carbon tetrachloride (17.8mL) was heated to reflux for 3 hours. The reaction was filtered, the precipitate washed with carbon tetrachloride and the solvent evaporated. Water was added and the reaction was extracted twice 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. The title compound was obtained after column chromatography (heptane/ethyl acetate 19: 1(v/v) on silica gel as eluent) as a pale yellow oil (1.63g, 55%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.42-7.26(m，5H)，5.42(dd，1H)，3.76(m，1H)，3.68(m，1H)，2.48(m，1H)，2.28(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 (934mg, 2.84mmol) in acetonitrile (27mL) was stirred with sodium iodide (425mg, 2.84mmol) at room temperature under nitrogen for 15 minutes. Potassium carbonate (560mg, 4.05mmol) was added and the reaction heated to 60 ℃. At this temperature, 5-bromo-3-nitro-1H-1, 2, 4-triazole (532mg, 2.7mmol) dissolved in acetonitrile (5.3mL) was added over 30 minutes. The reaction was stirred at 85 ℃ for 2 hours. Water was added and the aqueous phase was extracted twice 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. The title compound was obtained after column chromatography (using a gradient from heptane to heptane/ethyl acetate 4: 1(v/v) as eluent on silica gel) as a colorless viscous oil (510mg, 42%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]Oxazines

To a solution of 5-bromo-1- (3- (tert-butyldimethylsilyloxy) -1-phenylpropyl) -3-nitro-1H-1, 2, 4-triazole (510mg, 1.16mmol) in tetrahydrofuran (11.6mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.47mL, 3.47mmol) at room temperature under a nitrogen atmosphere. The yellow solution was stirred at room temperature overnight. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained after column chromatography (using a gradient from heptane/ethyl acetate 4: 1 to 1: 1(v/v) as eluent on silica gel) as a pale yellow solid (174mg, 61%).

MS ISP(m/e)：247.2(100)[(M+H)⁺]，264.1(36)。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]Triazolo [5, 1-b][1，3]Oxazin-2-ylamine

To 2-nitro-7-phenyl-6, 7-dihydro-5H- [1, 2, 4]Triazolo [5, 1-b][1，3]A solution of oxazine (174mg, 707. mu. mol) in ethyl acetate (7mL) was added 10% palladium on charcoal (17.4mg, 164. mu. mol). The reaction was hydrogenated at room temperature under hydrogen atmosphere overnight. The catalyst was filtered and washed with ethyl acetate. The title compound was obtained as a white solid after stirring with diethyl ether (143.3mg, 94%).

MS ISP(m/e)：217.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝7.39-7.29(m，3H)，7.16(d，2H)，5.22(t，1H)，5.15(br s，2H)，4.35(m，1H)，4.21(m，1H)，2.50(m，1H)，2.15(m，1H)。

e) N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -7-phenyl-6, 7-dihydro-5H- [1, 2, 4]Triazolo [5, 1-b][1，3]Oxazin-2-amines

Prepared in analogy to example 1H from 7-phenyl-6, 7-dihydro-5H- [1, 2, 4]Triazolo [5, 1-b][1，3]Oxazin-2-amines and 1- (6-methylpyrimidine-4)-yl) piperidin-4-one (see example 93 b). The title compound was obtained after column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) as eluent on silica gel) as a pale yellow solid (yield: 17%).

MS ISP(m/e)：392.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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(br d，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-pyran-4-yl) -6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a)8- (3, 6-dihydro-2H-pyran-4-yl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 160b, from 8-bromo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan. The title compound was obtained after column chromatography (using ethyl acetate as eluent on silica gel) as a light brown solid (yield: 55%).

MS ISP(m/e)：231.2(50)[(M+H)⁺]，201.2(100)[(M-CH₂CO+H)⁺]。

b)8- (3, 6-dihydro-2H-pyran-4-yl) -6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1H, starting from 8- (3, 6-dihydro-2H-pyran-4-yl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93 b). After column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) on silica gel as eluent), the title compound was obtained as a yellow oil (yield: 5%).

MS ISP(m/e)：406.5(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝8.51(s，1H)，8.04(s，1H)，7.34(s，1H)，7.13(s，1H)，6.41(s，1H)，4.42(br s，2H)，4.34(br d，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

a)1- (2-Chloropyridin-4-yl) piperidin-4-ylcarbamic acid tert-butyl ester

To a mixture of 2-chloro-4-fluoropyridine (1.00g, 7.60mmol) and Boc-4-aminopiperidine (1.98g, 9.09mmol) in NMP (10mL) was added DIPEA (1.86mL, 10.6 mmol). Argon was bubbled through the turbid solution for 5 minutes, after which the reaction mixture was heated in a microwave for 2x30 minutes to 150 ℃. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50g, 0 to 50% ethyl acetate in heptane) yielded the title compound as a white solid (1.47g, 62%).

MS ISP(m/e)：312.1[(M+H)⁺]。

b)1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride

To a solution of tert-butyl 1- (2-chloropyridin-4-yl) piperidin-4-ylcarbamate (1.00g, 3.21mmol) in dichloromethane (16mL) was added HCl (2M in diethyl ether, 8.02mL, 16.0mmol) and the reaction mixture was stirred at room temperature overnight for 18 hours. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to give the title compound as a white solid (913mg, 99%).

MS ISP(m/e)：212.1/214.1[(M+H)⁺]。

c) N- (1- (2-chloropyridin-4-yl) piperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

A suspension of 1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride (142mg, 0.50mmol) in dichloromethane was washed with 2N NaOH, the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate and evaporated. The "free base" residue was dissolved in IITo an alkane (4mL) was added 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridine (prepared in analogy to example 66 a-d) (170mg, 0.55mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (23mg, 8 mol%), tris (dibenzylideneacetone) dipalladium chloroform complex (21mg, 4 mol%) and sodium phenolate (87mg, 0.75mmol), argon was bubbled through the reaction mixture for 5 minutes and then irradiated in the microwave at 130 ℃ for 1 hour. By flash chromatography (silica-NH) ₂20g, 0 to 100% ethyl acetate in heptane) was used to purify the crude material. The title compound was obtained as a yellow solid (103mg, 47%).

MS ISP(m/e)：232.1[(M+H)⁺]。

Example 170

Prepared in analogy to example 169c, using 1- (6-methoxypyrimidin-4-yl) piperidin-4-amine (122mg, 0.43mmol) instead of 1- (2-chloropyridin-4-yl) piperidin-4-amine.

The title compound was obtained as a pale yellow foam (90mg, 47%).

MS ISP(m/e)：438.3[(M+H)⁺]。

Example 171

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

Prepared in analogy to example 170, using 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (180mg, 0.55mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (71mg, 31%).

MS ISP(m/e)：454.2[(M+H)⁺]。

Example 172

Prepared in analogy to example 171, using 1- (6-ethoxypyrimidin-4-yl) piperidin-4-amine (100mg, 0.34mmol) instead of 1- (6-methoxypyrimidin-4-yl) piperidin-4-amine.

The title compound was obtained as a pale yellow foam (78mg, 49%).

MS ISP(m/e)：468.3/470.3[(M+H)⁺]。

Example 173

8- (3, 4-difluorophenyl) -N- (1- (6-ethoxypyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 172, using 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (116mg, 0.37mmol)) instead of 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (71mg, 46%).

MS ISP(m/e)：452.2[(M+H)⁺]。

Example 174

8- (3, 4-difluorophenyl) -N- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a)1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-ylcarbamic acid tert-butyl ester

To a mixture of 4-chloro-6- (trifluoromethyl) pyrimidine (0.82g, 4.49mmol) and Boc-4-aminopiperidine (1.17g, 5.84mmol) in NMP (5.7mL) was added DIPEA (1.10mL, 6.29mmol) and after 30 minutes the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70g, 0 to 50% ethyl acetate in heptane) yielded the title compound as a white solid (1.43g, 92%).

MS ISP(m/e)：347.2[(M+H)⁺]。

b)1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-amine dihydrochloride

To a solution of tert-butyl 1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-ylcarbamate (1.42g, 4.1mmol) in dichloromethane (20mL) was added HCl (2M in diethyl ether, 10.2mL, 20.5mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to give the title compound as a white solid (1.27g, 97%).

MS ISP(m/e)：247.2[(M+H)⁺]。

c)8- (3, 4-difluorophenyl) -N- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 173, using 1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-amine dihydrochloride (116mg, 0.37mmol)) instead of 1- (6-ethoxypyrimidin-4-yl) piperidin-4-amine.

The title compound was obtained as an off-white foam (93mg, 49%).

MS ISP(m/e)：476.2[(M+H)⁺]。

Example 175

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

Prepared in analogy to example 174c, using 2-bromo-8- (2-chloro-4-fluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (150mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (103mg, 51%).

MS ISP(m/e)：506.2/508.3[(M+H)⁺]。

Example 176

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

Prepared in analogy to example 174c, using 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (144mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (88mg, 45%).

MS ISP(m/e)：m/e＝492.2/494.2[(M+H)⁺]。

Example 177

8- (3, 4-difluorophenyl) -6-methyl-N- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 174c, using 2-bromo-8- (3, 4-difluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (143mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (89mg, 46%).

MS ISP(m/e)：m/e＝490.2[(M+H)⁺]。

Example 178

8- (3, 4-difluorophenyl) -6-fluoro-N- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 174c, using 2-bromo-8- (3, 4-difluorophenyl) -6-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine (144mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (50mg, 25%).

MS ISP(m/e)：m/e＝494.2[(M+H)⁺]。

Example 179

6-chloro-8- (3, 4-difluorophenyl) -N- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 174c, using 2-bromo-6-chloro-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (152mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (63mg, 31%).

MS ISP(m/e)：510.3/512.3[(M+H)⁺]。

Example 180

a)1- (6-Methylpyridazin-4-yl) piperidin-4-ylcarbamic acid tert-butyl ester

To a mixture of 5-chloro-3-methylpyridazine (1.3g, 10.1mmol) and Boc-4-aminopiperidine (2.63g, 13.1mmol) in NMP (13mL) was added DIPEA (2.47mL, 14.2 mmol). Argon was bubbled through the turbid solution for 5 minutes, after which the reaction mixture was heated in a microwave for 30 minutes to 150 ℃. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50g, 50 to 100% ethyl acetate in heptane) yielded the title compound as an off-white solid (2.18g, 74%).

MS ISP(m/e)：293.2[(M+H)⁺]。

b)1- (6-Methylpyridazin-4-yl) piperidin-4-amine dihydrochloride

To a solution of tert-butyl 1- (6-methylpyridazin-4-yl) piperidin-4-ylcarbamate (2.14g, 7.32mmol) in dichloromethane (36mL) was added HCl (2M in diethyl ether, 18.3mL, 36.6mmol) and the reaction mixture was stirred at room temperature for 24 h. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to yield the title compound as a white solid (2.35g, 82%).

MS ISP(m/e)：193.2[(M+H)⁺]。

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

Prepared in analogy to example 173, using 1- (6-methylpyridazin-4-yl) piperidin-4-amine dihydrochloride (14mg, 0.053mmol)) instead of 1- (6-ethoxypyrimidin-4-yl) piperidin-4-amine.

The title compound was obtained as a yellow foam (10mg, 45%).

MS ISP(m/e)：422.3[(M+H)⁺]。

Example 181

Prepared in analogy to example 173, using 1- (2-methoxypyridin-4-yl) piperidin-4-amine dihydrochloride (101mg, 0.36mmol) instead of 1- (6-ethoxypyrimidin-4-yl) piperidin-4-amine.

The title compound was obtained as an off-white foam (66mg, 42%).

MS ISP(m/e)：437.2[(M+H)⁺]。

Example 182

Prepared in analogy to example 181 using 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (129mg, 0.4mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (57mg, 35%).

MS ISP(m/e)：453.2/455.3[(M+H)⁺]。

Example 183

Prepared in analogy to example 169c, using 2-bromo-8- (3, 4-difluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (143mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (73mg, 40%).

MS ISP(m/e)：455.3[(M+H)⁺]。

Example 184

Prepared in analogy to example 169c, using 2-bromo-8- (3, 4-difluorophenyl) -6-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine (145mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white solid (36mg, 20%).

MS ISP(m/e)：459.2/461.2[(M+H)⁺]。

Example 185

Prepared in analogy to example 169c, using 2-bromo-8- (2-chloro-4-fluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (150mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (82mg, 43%).

MS ISP(m/e)：471.4/473.2[(M+H)⁺]。

Example 186

Prepared in analogy to example 169c, using 2-bromo-6-chloro-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (152mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (25mg, 13%).

MS ISP(m/e)：475.1/477.1[(M+H)⁺]。

Example 187

a)1- (pyrimidin-4-yl) piperidin-4-amines

To a solution of (1-pyrimidin-4-yl-piperidin-4-yl) -carbamic acid tert-butyl ester (1.00g, 3.59mmol) in dichloromethane (16mL) was added HCl (2M in diethyl ether, 8.98mL, 18.0mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was then diluted with NaOH (2N) at 0 ℃ and extracted with dichloromethane. The combined organic extracts were then dried over sodium sulfate and filtered to give the title compound as a pale yellow solid (511mg, 80%).

MS ISP(m/e)：179.2[(M+H)⁺]。

b)8- (3, 4-difluorophenyl) -N- (1- (pyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 169c, using 1- (pyrimidin-4-yl) piperidin-4-amine (71mg, 0.4mmol) instead of 1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride.

The title compound was obtained as a white foam (63mg, 39%).

MS ISP(m/e)：408.4[(M+H)⁺]。

Example 188

Prepared in analogy to example 187b, using 2-bromo-8- (3, 4-difluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (130mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a white foam (60mg, 36%).

MS ISP(m/e)：422.2[(M+H)⁺]。

Example 189

Prepared in analogy to example 187b using 2-bromo-8- (2-chloro-4-fluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (136mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a white foam (63mg, 36%).

MS ISP(m/e)：438.2[(M+H)⁺]。

Example 190

a)1- (2-Chloropyrimidin-4-yl) piperidin-4-amine dihydrochloride

To a solution of 1- (2-chloro-pyrimidin-4-yl) -piperidin-4-yl) -carbamic acid tert-butyl ester (1.00g, 3.20mmol) in dichloromethane (18mL) was added HCl (2M in diethyl ether, 8.0mL, 16.0mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to yield the title compound as a white solid (0.95g, 99%).

MS ISP(m/e)：213.1/215.4[(M+H)⁺]。

b)8- (2-chloro-4-fluorophenyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 171, using 1- (2-chloropyrimidin-4-yl) piperidin-4-amine dihydrochloride (286mg, 1.0mmol) instead of 1- (6-methoxypyrimidin-4-yl) piperidin-4-amine.

The title compound was obtained as a white foam (133mg, 29%).

MS ISP(m/e)：458.3/460.2[(M+H)⁺]。

Example 191

Prepared in analogy to example 169c, using 2-bromo-6, 8-bis (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (186mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (24mg, 11%).

MS ISP(m/e)：553.3[(M+H)⁺]。

Example 192

To a solution of 8- (2-chloro-4-fluorophenyl) -N- (1- (2-chloropyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 58) (46mg, 0.10mmol) in EtOH (1mL) was added sodium ethoxide solution (21% in ethanol, 56 □ L, 0.15mmol) and the reaction mixture was stirred under argon in a sealed tube at 60 ℃ for 16 h. After cooling to room temperature, the mixture was heated to 150 ℃ for 45 minutes in a microwave, then sodium ethoxide solution (21% in ethanol, 56uL, 0.15mmol) was added and the mixture was heated to 150 ℃ in a microwave again for 30. The mixture was then evaporated and diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 20g, 0 to 100% ethyl acetate in heptane) gave the title compound as a white foam (17mg, 35%).

MS ISP(m/e)：493.3/495.4[(M+H)⁺]。

Example 193

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

To a solution of 8- (2-chloro-4-fluorophenyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 190b) (71mg, 0.155mmol) in MeOH (1.5mL) was added sodium methoxide solution (30% in MeOH, 35 □ L, 0.186mmol) and the reaction mixture was stirred in a sealed tube under argon at 60 ℃ for 18 hours and then heated to 150 ℃ in a microwave for 30 minutes. The mixture was then evaporated.

Purification by chromatography (silica gel, 20g, 0 to 100% methanol in dichloromethane) gave the title compound as a pale yellow foam (33mg, 47%).

MS ISP(m/e)：454.3/456.2[(M+H)⁺]。

Example 194

8- (2-chloro-4-methoxyphenyl) -N- (1- (2-methoxypyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Purification by chromatography (silica gel, 20g, 0 to 100% methanol in dichloromethane) gave the title compound as a pale yellow foam (5mg, 7%).

MS ISP(m/e)：466.3/468.3[(M+H)⁺]。

Example 195

N- (1- (2-Chloropyrimidin-4-yl) piperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 190b, using 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (311mg, 1.0mmol) instead of 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white solid (149mg, 34%).

MS ISP(m/e)：442.2/444.3[(M+H)⁺]。

Example 196

To a solution of N- (1- (2-chloropyridin-4-yl) piperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 169c) (88mg, 0.20mmol) in EtOH (1mL) was added sodium ethoxide solution (21% in ethanol, 75 □ L, 0.2mmol) and the reaction mixture was heated to 150 ℃ in a microwave for 30 minutes. Sodium ethoxide solution (21% in ethanol, 75L, 0.2mmol) was added again and the resulting mixture was heated to 150 ℃ for 30 minutes again. The mixture was then evaporated. Purification by chromatography (silica gel, 20g, 0 to 100% methanol in dichloromethane) gave the title compound (3mg, 3%) as a colourless gum.

MS ISP(m/e)：451.3[(M+H)⁺]。

Example 197

8- (4-ethoxy-3-fluorophenyl) -N- (1- (pyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To a solution of N- (1- (2-chloropyridin-4-yl) piperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 169c) (88mg, 0.20mmol) in EtOH (1mL) was added sodium ethoxide solution (21% in ethanol, 75L, 0.2mmol) and the reaction mixture was heated to 150 ℃ in a microwave for 30 minutes, then sodium ethoxide solution (21% in ethanol, 75 □ L, 0.2mmol) was added and the resulting mixture was heated to 150 ℃ for another 30 minutes. The mixture was then evaporated.

Purification by chromatography (silica gel, 20g, 0 to 100% methanol in dichloromethane) gave the title compound as an off-white foam (7mg, 8%).

MS ISP(m/e)：433.5[(M+H)⁺]。

Example 198

8- (3, 4-difluorophenyl) -N- (1- (2-methoxypyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To a solution of N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 195) (88mg, 0.155mmol) in MeOH (2.0mL) was added sodium methoxide solution (30% in MeOH, 41 μ L, 0.22mmol) and the reaction mixture was heated in a microwave at 120 ℃ for 2 h. The mixture was then evaporated. Purification by chromatography (silica gel, 20g, 0 to 100% methanol in dichloromethane) gave the title compound as a white foam (71mg, 81%).

MS ISP(m/e)：438.3[(M+H)⁺]。

Example 199

Prepared similarly to example 49. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：498.0[(M+H)⁺]。

Example 200

a)1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-ylcarbamic acid tert-butyl ester

To a mixture of 4-iodo-2- (trifluoromethyl) pyridine (356mg, 1.3mmol) and Boc-4-aminopiperidine (340mg, 1.7mmol) in NMP (2.6mL) was added DIPEA (319 □ L, 1.83 mmol). Argon was bubbled through the turbid solution for 5 minutes, after which the reaction mixture was heated in a microwave for 3x 30 minutes to 150 ℃. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50g, 0 to 100% ethyl acetate in heptane) yielded the title compound as a white solid (343mg, 76%).

MS ISP(m/e)：346.2[(M+H)⁺]。

b)1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-amine

To a solution of tert-butyl 1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-ylcarbamate (314mg, 0.91mmol) in dichloromethane (4.5mL) was added HCl (2M in diethyl ether, 2.27mL, 4.55mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to give the title compound as an off-white solid (201mg, 90%).

MS ISP(m/e)：246.2[(M+H)⁺]。

c)8- (3, 4-difluorophenyl) -N- (1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 169c, using 1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-amine (70mg, 0.29mmo1) instead of 1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride.

The title compound was obtained as a white foam (72mg, 53%).

MS ISP(m/e)：475.2[(M+H)⁺]。

Example 201

Prepared in analogy to example 200c, using 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (93mg, 0.29mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (78mg, 56%).

MS ISP(m/e)：491.2[(M+H)⁺]。

Example 202

Prepared in analogy to example 180c, using 2-bromo-8- (3, 4-difluorophenyl) -6-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine (145mg, 0.44mmol)) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (87mg, 45%).

MS ISP(m/e)：440.3[(M+H)⁺]。

Example 203

Prepared in analogy to example 180c, using 2-bromo-8- (3, 4-difluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (143mg, 0.44mmol)) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (96mg, 50%).

MS ISP(m/e)：436.3[(M+H)⁺]。

Example 204

Prepared in analogy to example 180c, using 2-bromo-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (144mg, 0.44mmol)) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (73mg, 38%).

MS ISP(m/e)：438.1[(M+H)⁺]。

Example 205

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

Prepared in analogy to example 180c, using 2-bromo-6-chloro-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (152mg, 0.44mmol)) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (100mg, 50%).

MS ISP(m/e)：456.2[(M+H)⁺]。

Example 206

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

Prepared in analogy to example 180c, using 2-bromo-6-chloro-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (150mg, 0.44mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (96mg, 48%).

MS ISP(m/e)：452.1[(M+H)⁺]。

Example 207

a) 4-bromo-6-methylbenzo [ d ] thiazol-2-ylcarbamic acid tert-butyl ester

To 4-bromo-6-methylbenzo [ d ]]Suspension of thiazol-2-amine (1.0g, 4.32mmol) in dichloromethane (30mL) was added di-tert-butyl dicarbonate (1.0g, 4.75mmol), followed by4-dimethylaminopyridine (0.6g, 4.75mmol) was added and the mixture was stirred for 1 hour. The reaction is diluted with dichloromethane and addedIR120, the mixture was filtered through glass wool and concentrated to give the title compound as an orange powder (1.3g, 89%).

MS ISP(m/e)：343.2[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：□(ppm)＝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 4-bromo-6-methylbenzo [ d ]]A mixture of tert-butyl thiazol-2-ylcarbamate (0.6g, 1.75mmol), 3-chloro-4-fluorophenylboronic acid (0.5g, 2.62mmol), palladium (II) acetate (0.08g, 0.35mmol), triphenylphosphine (0.3g, 1.05mmol) was added degassed di-n-butyl carbamateAlkane (10mL) and degassed aqueous 1M sodium carbonate (5.24mL, 5.24 mmol). The mixture was heated to 100 ℃ under argon for 16 hours then diluted with ethyl acetate, washed with water, brine and concentrated. The residue was redissolved in trifluoroacetic acid (2mL) and stirred for 15 minutes. The solvent was evaporated, the residue redissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated. The product was purified by column chromatography on silica gel using n-heptane: ethyl acetate (v/v ═ 9: 1-4: 1) as eluent to give the title compound as a white solid (0.4g, 80%).

MS ISP(m/e)：293.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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 (II) bromide (0.18g, 0.8mmol) and tert-butyl nitrite (0.11mL, 0.9mmol) in acetonitrile (10mL) was added solid 4- (3-chloro-4-fluorophenyl) -6-methylbenzo [ d ] thiazol-2-amine (0.2g, 0.7 mmol). The ice bath was then removed and the reaction mixture was allowed to warm to room temperature over 0.5 hours. The reaction mixture was diluted with dichloromethane, washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated to give the title compound as a pale yellow solid (0.24g, 99%).

MS ISP(m/e)：356.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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- (1- (2-chloropyridin-4-yl) piperidin-4-yl) -6-methylbenzo [ d ] thiazol-2-amine

To a solution of 2-bromo-4- (3-chloro-4-fluorophenyl) -6-methylbenzo [ d ] thiazole (0.06g, 0.2mmol) in dimethylacetamide (1mL) was added 1- (2-chloropyridin-4-yl) piperidin-4-amine dihydrochloride (0.05g, 0.2mmol), followed by triethylamine (70 □ L, 0.5mmol) and the mixture heated to 175 ℃ in a microwave for 1 h. The reaction was then diluted with dichloromethane, washed with water, brine, dried over sodium sulfate and concentrated. The product was purified by preparative HPLC to give the title compound as a light yellow solid (0.02g, 24%).

MS ISP(m/e)：487.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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

Prepared in analogy to example 207d, starting from 2-bromo-4- (3-chloro-4-fluorophenyl) -6-methylbenzo [ d ] thiazole and 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-ylamine dihydrochloride. The title compound was obtained as a white solid.

MS ISP(m/e)：468.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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-difluorophenyl) -6-methyl-N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) benzo [ d ] thiazol-2-amine

Prepared in analogy to example 207b-c and following 208, starting from tert-butyl 4-bromo-6-methylbenzo [ d ] thiazol-2-ylcarbamate and 3, 4-difluorophenylboronic acid.

The title compound was obtained as a white solid.

MS ISP(m/e)：452.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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

Prepared in analogy to example 207b-d, starting from tert-butyl 4-bromo-6-methylbenzo [ d ] thiazol-2-ylcarbamate and 3, 4-difluorophenylboronic acid, to give the title compound as white solid.

MS ISP(m/e)：470.8[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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) piperidin-4-yl) benzo [ d ] thiazol-2-amine

Prepared in analogy to example 207b-c and then 208, starting from tert-butyl 4-bromo-6-methylbenzo [ d ] thiazol-2-ylcarbamate and 2-chloro-4-fluorophenylboronic acid. The title compound was obtained as a white solid.

MS ISP(m/e)：468.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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

Prepared in analogy to the preparation of examples 207b-d, starting from tert-butyl 4-bromo-6-methylbenzo [ d ] thiazol-2-ylcarbamate and 2-chloro-4-fluorophenylboronic acid. The title compound was obtained as a white solid.

MS ISP(m/e)：487.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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

a) 2-Nitropyridin-3-yl trifluoromethanesulfonate

To an ice-cold solution of 2-nitropyridin-3-ol (10.0g, 71mmol) and triethylamine (14.9mL, 107mmol) in dichloromethane (150mL) was added dropwise trifluoromethanesulfonic anhydride (14.5mL, 86mmol) and the mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 2: 8 to 3: 7) as eluent. The title compound was obtained as a pale brown liquid (18.4g, 95%).

MS ISP(m/e)：273.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.65(dd，1H)，8.00(dd，1H)，7.80(dd，1H)。

b)3- (4-Fluoropiperidin-1-yl) -2-nitropyridines

To a solution of 4-fluoropiperidine hydrochloride (1.54g, 11mmol) and triethylamine (4.5mL, 33mmol) in dimethylacetamide (30mL) was added 2-nitropyridin-3-yl trifluoro-methanesulfonate (3.00g, 11mmol) and the mixture was heated to 110 ℃ for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the product was used without further purification. The title compound was obtained as a yellow oil (2.22g, 89%).

MS ISP(m/e)：226.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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-Fluoropiperidin-1-yl) pyridin-2-Amines

To a solution of 3- (4-fluoropiperidin-1-yl) -2-nitropyridine (2.0g, 8.9mmol) in methanol (25mL) was added a large spoon of rainey nickel and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction was then filtered on Hyflo and the solvent was evaporated in vacuo to yield the product, which was used without further purification. The title compound was obtained as a dark brown solid (1.7g, 100%).

MS ISP(m/e)：196.2[(M+H)⁺]。

d) N- (3- (4-fluoropiperidin-1-yl) -pyridin-2-yl) -N' -ethoxycarbonyl-thiourea

Prepared in analogy to example 1e, starting from 3- (4-fluoropiperidin-1-yl) pyridin-2-amine. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 1 to 3: 7) as eluent to give the title compound as a yellow solid (yield: 73%).

MS ISP(m/e)：327.1[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝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

Prepared in analogy to example 1f, starting from N- (3- (4-fluoropiperidin-1-yl) -pyridin-2-yl) -N' -ethoxycarbonyl-thiourea to yield the title compound as light yellow solid without further purification (yield: 100%).

MS ISP(m/e)：236.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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)，2.21-2.02(m，4H)。

f) N- (1- (2-chloropyridin-4-yl) piperidin-4-yl) -8- (4-fluoropiperidin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1h, starting from 5- (4-fluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine and 1- (2-chloropyridin-4-yl) piperidin-4-one to yield the title compound as colorless gum (yield: 7%).

MS ISP(m/e)：430.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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) piperidin-4-yl) -8- (4- (trifluoromethyl) piperidin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 213 from 2-nitropyridin-3-yl trifluoro-methanesulfonate (example 213b) and 4-trifluoromethylpiperidine hydrochloride. The residue was purified by preparative HPLC to give the title compound as a colorless gum (yield: 37%).

MS ISP(m/e)：430.2[(M+H)⁺]。

Example 215

(S) -6- (2- (1- (2-chloropyridin-4-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -6-azaspiro [2.5] octan-4-ol

Prepared in analogy to example 213, starting from 2-nitropyridin-3-yl trifluoro-methanesulfonate (example 213b) and (S) -6-azaspiro [2.5] octane-4-ol hydrochloride (US2009/23713a 1). The residue was purified by preparative HPLC to give the title compound as a colorless gum (yield: 30%).

MS ISP(m/e)：454.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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

Prepared in analogy to example 213 from 2-nitropyridin-3-yl trifluoro-methanesulfonate (example 213b) and 4, 4-difluoropiperidine hydrochloride. The residue was purified by preparative HPLC to give the title compound as a colorless gum (yield: 37%).

MS ISP(m/e)：488.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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

a)2- (2-chloro-4-fluorophenyl) pent-4-enoic acid methyl ester

To a cold (-78 ℃ C.) solution of lithium hexamethyldisilazide (27.1mL, 1M in THF, 27.1mmol) in THF (30mL) was added methyl 2- (2-chloro-4-fluorophenyl) acetate (5g, 24.7mmol) in THF (10 mL). After stirring for 0.5 h, allyl bromide (2.4mL, 27.1mmol) was added in one portion, the cold bath was removed and the reaction was warmed to room temperature (0.5 h). The reaction was diluted with ethyl acetate, washed with water, brine, and the organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 0 to 9: 1) as eluent. The title compound (6.0g, 100%) was obtained as a colorless liquid.

MS ISP(m/e)：264.3[(M+Na)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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)2- (2-chloro-4-fluorophenyl) -3- (oxiran-2-yl) propionic acid methyl ester

To an ice-cold solution of methyl 2- (2-chloro-4-fluorophenyl) pent-4-enoate (6.0g, 24.7mmol) in dichloromethane (50mL) was added m-chloroperoxybenzoic acid (6.7g, 70% purity, 27.2 mmol). The cold bath was removed and the reaction was stirred for 16 hours. The reaction was filtered, the filtrate was washed repeatedly with 1N sodium hydroxide, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 9 to 2: 8) as eluent. The title compound (5.1g, 80%) was obtained as a colorless liquid.

MS ISP(m/e)：259.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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，0.5H)，2.86-2.80(m，0.5H)，2.76(t，0.5H)，2.70(t，0.5H)，2.51(dd，0.5H)，2.41(dd，0.5H)，2.37(dt，0.5H)，2.25(dt，0.5H)，2.06(dt，0.5H)，1.85(dt，0.5H)。

c) (3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-ylcarbamic acid tert-butyl ester

To a solution of methyl 2- (2-chloro-4-fluorophenyl) -3- (oxiran-2-yl) propionate (4.56g, 17.6mmol) in 2-propanol (20mL) was added tert-butyl carbazate (2.3g, 17.6mmol) and the reaction was heated to reflux for 16 h. The reaction was then concentrated to dryness, redissolved in toluene (20mL) and 1, 5, 7-azidobicyclo (4.4.0) dec-5-ene (0.6g, 4.4mmol) was added and the mixture was heated to reflux for 3 hours. The reaction was then diluted with ethyl acetate, washed with 1N HCl, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was recrystallized from hot ethyl acetate to obtain the title compound (1.7g, 26%) as a colorless solid. The mother liquor contains the trans isomer.

MS ISP(m/e)：359.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.23(dd，1H)，7.12(dd，1H)，6.98(td，1H)，6.90(br，1H)，4.39-4.35(m，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-one

To tert-butyl (3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-ylcarbamate (1.67g, 4.7mmol) was added HCl (10mL, 4N in bis)In an alkane) and the reaction was stirred for 1 hour. The reaction was then concentrated to dryness, redissolved in dichloromethane, washed with sodium bicarbonate, dried over sodium sulfate and the solvent evaporated in vacuo to afford the title compound as a pale yellow crystalline solid (1.11g, 92%).

MS ISP(m/e)：259.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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)4- (3- ((3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-yl) thioureido) piperidine-1-carboxylic acid tert-butyl ester

To a solution of (3SR, 5SR) -1-amino-3- (2-chloro-4-fluorophenyl) -5-hydroxypiperidin-2-one (0.8g, 2.9mmol) in dimethylacetamide (1mL) was added tert-butyl 4-isothiocyanatopiperidine-1-carboxylate (0.8g, 3.2mmol, US2006/14958a1) and the reaction was stirred at 80 ℃ for 2 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The product alkane was triturated from dichloromethane by the addition of heptane to give the title compound as a colourless powder (1.2g, 83%).

MS ISP(m/e)：501.2[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝7.45-40(m，2H)，7.20(td，1H)，4.30-4.15(m，4H)，3.92-3.79(m，3H)，2.93-2.82(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)4- (((3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-ylimino) (methylsulfanyl) methylamino) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3- ((3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-yl) thioureido) piperidine-1-carboxylate (1.2g, 2.4mmol) in DMF (5mL) was added iodomethane (0.2mL, 3.6mmol) and the reaction was heated to 90 ℃ for 15 min. The reaction was evaporated to dryness, redissolved in ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate and the solvent evaporated in vacuo. The title compound (mixture of geometric isomers) was used in the next step without purification (1.2g, 99%).

MS ISP(m/e)：515.2[(M+H)⁺]。

g)4- (8- (2-chloro-4-fluorophenyl) -6-hydroxy-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (((3SR, 5SR) -3- (2-chloro-4-fluorophenyl) -5-hydroxy-2-oxopiperidin-1-ylimino) (methylsulfanyl) methylamino) piperidine-1-carboxylate (1.1g, 2.1mmol) in DMF (5.5mL) was added sodium azide (0.2g, 3.2mmol) and the reaction was heated to 100 ℃ for 48 hours. The reaction was then concentrated to dryness, redissolved in ethyl acetate, washed with water, brine, dried over sodium sulfate and the solvent evaporated. The residue was redissolved in THF, trimethylphosphine (2.1mL, 1M in toluene, 2.1mmol) was added and the reaction was heated to 160 ℃ in a microwave for 12 hours. The reaction was then concentrated in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate/MeOH (v/v 1: 0 to 9: 1) as eluent. The title compound was obtained as a pale yellow foam (0.2g, 20%) (an inseparable 1: 1 mixture of diastereomers).

MS ISP(m/e)：466.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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-fluorophenyl) -2- (1- (2-chloropyridin-4-yl) piperidin-4-ylamino) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-ol

To 4- (8- (2-chloro-4-fluorophenyl) -6-hydroxy-5, 6, 7, 8-tetrahydro- [1, 2, 4-methyl phenyl)]Triazolo [1, 5-a]Pyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester (0.05g, 0.1mmol) was added HCl (3mL, 4N in bisIn an alkane) and the reaction was stirred for 0.5 hours. The reaction was then concentrated to dryness, the residue redissolved in dimethylacetamide (0.5mL), triethylamine added until the mixture was basic, followed by the addition of 2-chloro-4-fluoropyridine (0.04g, 0.3mmol) and heating of the mixture to 80 ℃ for 1 hour. The reaction was evaporated to dryness, redissolved in ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate and the solvent evaporated in vacuo. Column chromatography on silica gel with ethyl acetate/MeOH (v/v 1: 0)To 95: 5) as eluent. The title compound was obtained as a pale yellow gum (0.04g, 76%) (an inseparable 1: 1 mixture of diastereomers).

MS ISP(m/e)：477.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1 step h) starting from 1- (2-chloropyridin-4-yl) piperidin-4-one (see example 232b) and 8- (3-tert-butylphenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine. The latter compound can be prepared in analogy to example 1 steps d-f) starting from 2-amino-6-bromo-pyridine and 3-tert-butylphenyl-boronic acid (EP2243785a 1). The title compound was obtained as a colorless foam.

MS ISP(m/e)：461.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：□(ppm)＝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

a) (Z) -phenyl N' -cyano-N- (3, 4-difluorophenyl) iminoformate (carbamidate)

To a solution of 3, 4-difluoroaniline (646mg, 5mmol) in isopropanol (10mL) was added diphenylcyanoimidate (1.19g, 5mmol) and the suspension was stirred at room temperature overnight. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to give the title compound as a white solid (1.18g, 86%).

MS ISP(m/e)：274.1(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝10.92(s，1H)，7.65(m，1H)，7.43(m，3H)，7.29(m，4H)。

b) (Z) -phenyl N' -cyano-N- (3, 4-difluorophenyl) -N- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) iminoformate

To a solution of (Z) -phenyl N' -cyano-N- (3, 4-difluorophenyl) iminoformate (286mg, 1.05mmol) and 2- (3-bromopropoxy) tetrahydro-2H-pyran (369mg, 277 μ L, 1.57mmol) in DMF (10.5mL) under a nitrogen atmosphere at room temperature was added potassium carbonate (289mg, 2.09 mmol). The suspension was heated to 85 ℃ overnight. Additional 2- (3-bromopropoxy) tetrahydro-2H-pyran (140. mu.L, 0.8mmol) and potassium carbonate (145mg, 1.05mmol) were added and the reaction was heated to 85 ℃ for 5H. Water was added and the reaction was extracted twice 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. The title compound was obtained after column chromatography (using a gradient of heptane/ethyl acetate 4: 1 to 1: 1(v/v) as eluent) as a pale yellow viscous oil (202mg, 46%).

MS ISP(m/e)：332.1(100)[(M-THP+H)⁺]，416.3(5)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-difluorophenyl) -N3- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) -4H-1, 2, 4-triazole-3, 5-diamine

To a solution of (Z) -phenyl N' -cyano-N- (3, 4-difluorophenyl) -N- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) iminoformate (73mg, 176. mu. mol) in methanol (0.5mL) was added hydrazine hydrate 25% (35.2mg, 34.8. mu.L, 176. mu. mol) in water. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol 19: 1(v/v) as eluent. The title compound was obtained as a pale yellow viscous oil (46mg, 74%).

MS ISP(m/e)：354.2(25)[(M+H)⁺]，270.3(100)[(M-THP+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-triazol-3-yl) (3, 4-difluorophenyl) amino) propan-1-ol

To a solution of N3- (3, 4-difluorophenyl) -N3- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) -4H-1, 2, 4-triazole-3, 5-diamine (43mg, 122 μmol) in methanol (1mL) was added 2N aqueous hydrochloric acid. The solution was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was taken up in saturated aqueous sodium bicarbonate solution. It was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound (34mg, quantitative) as a white solid without further purification.

MS ISP(m/e)：270.3(100)[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-difluoro-phenyl) -4, 5, 6, 7-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrimidin-2-ylamine

To a solution of 3- ((5-amino-4H-1, 2, 4-triazol-3-yl) (3, 4-difluorophenyl) amino) propan-1-ol (31mg, 115. mu. mol) in tetrahydrofuran (1.15mL) was added triphenylphosphine (45.3mg, 173. mu. mol) at 0 ℃ under a nitrogen atmosphere. The reaction was stirred for 15 min and then DEAD (31.0mg, 28.2. mu.L, 173. mu. mol) was added. The reaction was stirred at 0 ℃ for 30 minutes and then at room temperature overnight. The same procedure was repeated with additional triphenylphosphine (45.3mg, 173. mu. mol) and DEAD (31.0mg, 28.2. mu.L, 173. mu. mol). Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained after column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) as eluent on silica gel) as a colorless solid (14mg, 48%).

MS ISP(m/e)：252.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.82(m，1H)，7.41-7.33(m，2H)，4.00(t，2H)，3.93(b s，2H)，3.72(t，2H)，2.30(pent，2H)。

f)4- (3, 4-difluorophenyl) -N- (1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -4, 5, 6, 7-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrimidin-2-amine

To a solution of 4- (3, 4-difluorophenyl) -4, 5, 6, 7-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrimidin-2-amine (41mg, 163. mu. mol) in tetrahydrofuran (1mL) was added hexachloroethane (61.0mg, 245. mu. mol), triethylamine (49.5mg, 68.2. mu.L, 490. mu. mol) and a 1M solution of trimethylphosphine in toluene (245. mu.L, 245. mu. mol) under a nitrogen atmosphere. The suspension was stirred at room temperature for 30 minutes. 1- (6-methylpyrimidin-4-yl) piperidin-4-one dissolved in tetrahydrofuran (0.5mL) was added (see example 93b, 46.8mg, 245. mu. mol) and the yellow suspension was heated to 150 ℃ for 30 minutes. A1M solution of borane tetrahydrofuran complex in dichloromethane (490. mu.L, 490. mu. mol) was added and the reaction was heated to 100 ℃ for one hour. The reaction was diluted with water and extracted twice 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. After column chromatography (using a gradient from dichloromethane to dichloromethane/methanol 19: 1(v/v) as eluent on silica gel) and subsequent purification with preparative HPCL, the title compound was obtained as a colorless solid (14mg, 20%).

MS ISP(m/e)：427.3(100)[(M+H)⁺]，176.3(81)。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a)8- (2-methoxypyridin-4-yl) -1, 4-dioxa-8-azaspiro [4.5] decane

Palladium (II) acetate (62.5mg, 279. mu. mol) and 2- (dicyclohexylphosphino) biphenyl (201mg, 557. mu. mol) were added in bisA solution in an alkane (1.5mL) was stirred at room temperature for 10 minutes under argon, then added to 4-chloro-2-methoxypyridine (500mg, 3.48mmol), 1, 4-dioxa-8-azaspiro [4.5]]Decane (499mg, 446. mu.L, 3.48mmol) and sodium tert-butoxide (502mg, 5.22mmol) in bisA solution in alkane (1.5mL) was degassed and bubbled through the reaction with argon for 5 minutes. The reaction mixture was heated to 130 ℃ in a microwave for 30 minutes.

The reaction mixture was filtered through a plug of celite, water was added to the filtrate and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 70g, 80% to 100% ethyl acetate in heptane). The title compound was obtained as a brown oil (700mg, 80%).

MS ISP(m/e)：251.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-methoxypyridin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to the preparation of example 93b-c, using 8- (2-methoxypyridin-4-yl) -1, 4-dioxa-8-azaspiro [4.5] decane. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：459.4(83)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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)。

Example 221

MS ISP(m/e)：426.1/428.2(100/47)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 1h, using 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (see example 1c) and 8- (3-dimethylamino-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to examples 66 a-c). The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：435.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：411.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-pyrimidin-4-yl) -piperidin-4-yl ] -amine

MS ISP(m/e)：526.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：436.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a) (8-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Under argon to 8-bromo- [1, 2, 4]]Triazolo [1, 5-a]A suspension of pyridin-2-amine (see example 66b, 80mg, 376. mu. mol) and hexachloroethane (133mg, 563. mu. mol) in dry THF (3mL) was added triethylamine (114mg, 157. mu.L, 1.13mmol), followed by trimethylphosphine (1M in THF, 563. mu.L, 563. mu. mol). The reaction mixture was stirred at room temperature for 0.5 h, then 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (88.9mg, 451. mu. mol) was added and the mixture was heated in a microwave to 150 ℃ for 30 min. 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (40mg, 188. mu. mol) was further added and heated to 150 ℃ for another 30 minutes. Adding NaBH to the reaction mixture ₄(56.8mg, 1.5mmol) and EtOH (2.0mL) and heated to 65 ℃ for 1 hour. Further adding NaBH₄(56.8mg, 1.5mmol) and stirred at 65 ℃ for a further hour. Further adding NaBH₄(56.8mg, 1.5mmol) and the reaction was carried out at 65 deg.CStirred for 1 hour. Reacting the mixture with CH₂Cl₂And water extraction, combining the organic layers, under Na₂SO₄Dry, filter and evaporate the solvent.

By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was obtained as a white foam (140mg, 95%).

MS ISP(m/e)：394.1/395.9(100/98)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 66c, using (8-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine and 2-chloro-5- (trifluoromethyl) -phenylboronic acid. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：494.3/496.2(100/41)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] - (6-phenyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) -amine

Prepared in analogy to example 66, starting from 5-bromopyridin-2-amine in step a). The title compound was obtained as an orange solid.

MS ISP(m/e)：392.2(40)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 220. The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：541.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

MS ISP(m/e)：532.0(57)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：□(ppm)＝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

Prepared in analogy to example 1h, using 1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-one (see example 1c) and 8- (4-dimethylamino-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamine (prepared in analogy to examples 66 a-c). The title compound was obtained as a white foam.

MS ISP(m/e)：435.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝8.23-8.21(m，1H)，7.91-7.88(m，2H)，7.48-7.45(m，1H)，6.88-6.81(m，3H)，4.52-4.49(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-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -1- (6-methylpyrimidin-4-yl) piperidine-4-carbonitrile

To a solution of 1- (6-methylpyrimidin-4-yl) piperidin-4-one (see example 93b, 100mg, 0.523mmol) and 8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (129mg, 0.523mmol) in AcOH was added trimethylsilyl cyanide (196. mu.L, 1.57mmol) dropwise and the resulting mixture was stirred at room temperature for 88 hours. The mixture was then poured onto NaOH (6M, 6mL) and stirred for 10 minutes. The precipitate was then filtered and dried. Purification by chromatography (silica gel, 20g, 30 to 100% ethyl acetate in heptane) yielded the title compound as a yellow solid (20mg, 9%).

MS ISP(m/e)：447.4[(M+H)⁺]。

Example 232

a)8- (2-Chloropyridin-4-yl) -1, 4-dioxa-8-azaspiro [4.5] decane

To 1, 4-dioxa-8-azaspiro [4.5]]Decane (895. mu.L, 6.98mmol) and 2-chloro-4-fluoropyridine (1.01g, 7.68mmol) in bisTo a solution in an alkane (15mL) was added N, N-diisopropylethylamine (1.83mL, 10.5 mmol). Argon was bubbled through the reaction mixture for 5 minutes, after which it was heated to 120 ℃ in a microwave for 3 hours. After evaporation, purification by chromatography (silica gel, 20g, 30 to 10% ethyl acetate in heptane) yielded the title compound as a yellow solid (1.3g, 73%).

MS ISP(m/e)：255.3[(M+H)⁺]。

b)1- (2-chloropyridin-4-yl) piperidin-4-one

To a solution of 8- (2-chloropyridin-4-yl) -1, 4-dioxa-8-azaspiro [4.5] decane (1.26g, 4.95mmol) in acetone (11mL) was added HCl (2N, 39.6mL, 79.1mmol) and the resulting mixture was stirred at 50 ℃ for 2 hours then cooled to room temperature. The pH was set to-8 by addition of solid sodium bicarbonate, followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid (1.03g, 99%).

MS ISP(m/e)：211.1[(M+H)⁺]。

c)1- (2-Chloropyridin-4-yl) -4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-4-carbonitrile

Prepared in analogy to example 231, using 1- (2-chloropyridin-4-yl) piperidin-4-one (150mg, 0.44mmol) instead of 1- (6-methylpyrimidin-4-yl) piperidin-4-one.

The title compound was obtained as a pale yellow solid (31mg, 14%).

MS ISP(m/e)：466.3[(M+H)⁺]。

Example 233

8- (3, 4-difluorophenyl) -N- ((3S, 4R) -3-methoxy-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a) (3S, 4R) -tert-butyl 4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -3-methoxypiperidine-1-carboxylate

Prepared in analogy to example 169c, using (3S, 4R) -4-amino-1-Boc-3-methoxy-pyridine (100mg, 0.43mmol) instead of 1- (2-chloropyridin-4-yl) piperidin-4-amine.

The title compound was obtained as a yellow gum (40mg, 20%).

MS ISP(m/e)：460.3[(M+H)⁺]。

b)8- (3, 4-difluorophenyl) -N- ((3S, 4R) -3-methoxypiperidin-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-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -3-methoxypiperidine-1-carboxylate (37mg, 80.5 □ mol) in dichloromethane (1mL) was added HCl (2M in diethyl ether, 201 □ L, 403 □ mol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethyl ether and dried to give the title compound as an off-white solid (32mg, 92%).

MS ISP(m/e)：360.2[(M+H)⁺]。

c)8- (3, 4-difluorophenyl) -N- ((3S, 4R) -3-methoxy-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Reacting 8- (3, 4-difluorophenyl) -N- ((3S, 4R) -3-methoxypiperidin-4-yl) - [1, 2, 4-]Triazolo [1, 5-a]Pyridine-2-amine dihydrochloride (28mg, 64.8. mu. mol) was extracted with dichloromethane/2M NaOH. The organic layer was washed with brine, dried over sodium sulfate and evaporated. Dissolving the residue in II Alkane (0.5mL) and 4-chloro-6-methylpyrimidine (9.2mg, 71.2. mu. mol) and DIPEA (17.0. mu.L, 97.2. mu. mol) were added to this solution. Argon was bubbled through the solution for 5 minutes, then heated in a microwave at 130 ℃ for 2x 30 minutes. After evaporation, purification by chromatography (silica gel, 10g, 0 to 10% methanol in dichloromethane) gave the title compound as an off-white foam (18mg, 62%).

MS ISP(m/e)：452.3[(M+H)⁺]。

Example 234

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

To a solution of 4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -1- (6-methylpyrimidin-4-yl) piperidine-4-carbonitrile (example 231) (50mg, 112 μmol) in THF (2mL) was added methylmagnesium bromide (1.4M in toluene: THF, 240 μ L, 336 μmol) dropwise at 0 deg.C, and the resulting mixture was warmed to room temperature and stirred for 3 hours. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 10g, 0 to 10% methanol in dichloromethane) gave the title compound (9mg, 19%) as a pale yellow solid.

MS ISP(m/e)：436.3[(M+H)⁺]。

Example 235

8- (3, 4-difluorophenyl) -N- (4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a) 4-carbamoyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester

To a solution of 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (2.85g, 11.7mmol) in DMF (57mL) was added CDI (2.28g, 14.1 mmol). The mixture was stirred at 60 ℃ for 30 minutes and then cooled to room temperature. Ammonium hydroxide (18.2mL, 117mmol) was added carefully and stirring was continued for 1 hour. The mixture was then evaporated to yield a colorless oil. It was extracted with ethyl acetate and the organic layer was washed with HCl (1M), water, sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. The residue was taken up in toluene, then hexane was added and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with hexanes and dried to give the title compound as a white solid (2.55g, 90%).

MS ISP(m/e)：243.3[(M+H)⁺]。

b) 4-amino-4-methylpiperidine-1-carboxylic acid tert-butyl ester

To a suspension of tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (2.52g, 10.4mmol) in acetonitrile (7.6mL) and water (23.4mL) at 0 deg.C was added KOH (2.63g, 46.8 mmol). Then 1, 3-dibromo-5, 5-dimethylhydantoin (1.64g, 5.72mmol) was added at 0 ℃ in one portion and And after stirring at 0 ℃ for 30 minutes, the solution was allowed to warm to room temperature and stirred for 1 hour. Sodium sulfite (131mg, 1.04mmol) was added and the mixture was stirred at room temperature for 15 min, then ethyl acetate was added and the reaction was cooled to 10 ℃. Adding K₃PO₄(2.34g, 11.0mmol) and the mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound as a colorless oil (2.1g, 94%).

MS ISP(m/e)：215.3[(M+H)⁺]。

c) 4-methylpiperidine-4-amine bis (4-methylbenzenesulfonate)

A solution of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (1.96g, 9.15mmol) in MeOH (15.2mmol) was added dropwise over 30 minutes at 60 ℃ to a solution of p-toluenesulfonic acid monohydrate (4.00g, 21.0mmol) in 2-propanol (7.9 mL). The reaction mixture was then heated to 60 ℃ for 16 h. After cooling to 0 ℃, the precipitate was filtered off and washed with 2-propanol and dried to yield the title compound as a white solid (3.91g, 93%).

MS ISP(m/e)：115.1[(M+H)⁺]。

d) 4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-amine

To a mixture of 4-methylpiperidine-4-aminebis (4-methylbenzenesulfonate) (3.91g, 8.53mmol) and 4-chloro-6-methylpyrimidine (1.10g, 8.53mmol) in NMP (35mL) was added K ₃PO₄(3.12g, 17.9mmol) and the reaction mixture was stirred at 80 ℃ for 18 h.

After cooling to room temperature, 0.5M K was added₃PO₄The aqueous solution was extracted twice with dichloromethane. The combined organic layers were extracted twice with HCl (1N). The combined aqueous layers were made basic with NaOH (6N), extracted twice with dichloromethane and the organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. By chromatography (silica gel, 70g, 0 to 100% ethyl acetate in heptane; then 0 to 50% methanol in ethyl acetate, containing10% triethylamine) yielded the title compound as a light yellow semi-solid (1.09g, 62%).

MS ISP(m/e)：207.2[(M+H)⁺]。

e)4- (4-isothiocyanato-4-methylpiperidin-1-yl) -6-methylpyrimidine

To a solution of 4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-amine (1.09g, 5.28mmol) in dichloromethane (17.2mL) was added 1, 1' -thiocarbonyldipidin-2 (1H) -one (1.84g, 7.92mmol) and the reaction mixture was stirred at room temperature for 16H. After cooling to room temperature, the mixture was evaporated. Purification by chromatography (silica gel, 3 × 70g, 50 to 100% ethyl acetate in heptane) yielded the title compound as a light yellow solid (1.2g, 91%).

MS ISP(m/e)：249.1[(M+H)⁺]。

f)1- (4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) thiourea

A solution of 4- (4-isothiocyanato-4-methylpiperidin-1-yl) -6-methylpyrimidine (1.18g, 0.53mmol) in ammonia (7M in MeOH, 13.6mL, 95.0mmol) was stirred in a sealed tube at room temperature for 3h and then heated at 50 ℃ for 18 h. After cooling to room temperature, the mixture was evaporated. Purification by chromatography (silica gel, 50g, 0 to 20% methanol in dichloromethane) gave the title compound as a white foam (1.2g, 100%).

MS ISP(m/e)：266.2[(M+H)⁺]。

gi) methyl 4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-yliminothiocarbamate hydroiodide

To a solution of 1- (4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) thiourea (1.28g, 4.82mmol) in EtOH (11.7mL) was added MeI (332 □ L, 5.31mmol) and the reaction mixture was stirred under argon at 75 ℃ for 3 h. The reaction mixture was then evaporated and the residue (white foam) was stirred with diethyl ether (15mL) at room temperature for 1 hour. The solid was then washed with diethyl ether and dried to give the title compound as a white solid (1.89g, 96%).

MS ISP(m/e)：190.3[(M+H)⁺]。

gii) 5-chloro-2- (3, 4-difluorophenyl) pentanoic acid

To a solution of 3.4-difluorophenylacetic acid (5.00g, 29.0mmol) in THF (58mL) at 0 deg.C was added NaHM S (1M in THF, 58.1mL, 58.1mmol) dropwise. The reaction mixture was then stirred at 0 ℃ for 20min, then 1-chloro-3-iodopropane (3.12mL, 29.0mmol) was added dropwise at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h. The mixture was then quenched with water (3mL) under ice bath cooling and evaporated. NaOH (1N, 150mL) was added to the residue and the resulting solution was extracted with diethyl ether (2 × 100 mL). The aqueous layer was acidified with HCl (1N, 200mL) and extracted with diethyl ether (2X100 mL). The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 2 × 50g, 0 to 50% ethyl acetate in heptane) yielded the title compound as a pale yellow oil (2.02g, 28%).

MS ISP(m/e)：247.0/249.1[(M-H)^-]。

h)8- (3, 4-difluorophenyl) -N- (4-methyl-1- (6-methylpyrimidin-4-yl) piperidin-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) piperidin-4-ylimidethiocarboxylate hydroiodide (1.85, 4.54mmol) comprising 5-chloro-2- (3, 4-difluorophenyl) pentanoic acid (1.24, 5.00mmol), EDC (0.87, 4.54mmol) and 1-hydroxybenzotriazole hydrate (1.39g, 9.08mmol) in DMF (22.3mL) was added DIPEA (1.98mL, 11.4mmol) and the reaction mixture was stirred at room temperature for 18 h. Then hydrazine monohydrate (0.57mL, 18.2mmol) was added and the reaction mixture was stirred at 70 ℃ for 5 h. The reaction mixture was then poured into water, extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 2 × 50g, 0 to 20% methanol in dichloromethane) gave the title compound as a light red foam (14mg, 1%).

MS ISP(m/e)：440.3[(M+H)⁺]。

Example 236

N- (1- (2-Chloropyridin-4-yl) -4-methylpiperidin-4-yl) -8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 234, using 1- (2-chloropyridin-4-yl) -4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-4-carbonitrile (18mg, 36 □ mol) instead of 4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -1- (6-methylpyrimidin-4-yl) piperidine-4-carbonitrile.

The title compound was obtained as an off-white solid (2.5mg, 14%).

MS ISP(m/e)：455.2[(M+H)⁺]。

Example 237

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

Prepared in analogy to example 57c) using 4-chloro-6-methylpyrimidine instead of 4-bromo-2-methylpyridine and 8- (3, 4-difluorophenyl) -N- (2-methylpiperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine instead of 8- (2-chloro-4-fluorophenyl) -N- (piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine.

The title compound was obtained as a light brown foam.

MS ISP(m/e)：436.3[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a) 4-Trimethylsilyloxy-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-oxopiperidine-1-carboxylate (10g, 48.7mmol) was dissolved in anhydrous DMF (12.0 mL). Trimethylsilyl chloride (6.35g, 7.39mL, 58.4mmol) and triethylamine (11.8g, 16.2mL, 117mmol) were added under argon and the reaction mixture was stirred at 80 ℃ for 16 h. The reaction mixture was cooled to room temperature and saturated NaHCO was added ₃The solution was extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated. By flash chromatography (1 drop Et was added during pretreatment of the column)₃N) (silica gel, 100g in Et₂0% to 100% pentane in O, 45 minutes) the residue was purified. The title compound (13.2g, 99%) was obtained as a colorless liquid.

MS ISP(m/e)：272.2/216.3(41/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-trimethylsilyloxy-3, 6-dihydro-2H-pyridine-1-carboxylate (13.2g, 48.6mmol) was dissolved in acetonitrile (250 mL). Adding 1-chloromethyl-4-fluoro-1, 4-diazobicyclo [2.2.2]Octane bis (tetrafluoroborate) (19.0g, 53.5mmol) and the reaction mixture was stirred at room temperature for 2 hours. Brine was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 100g, 0% to 100% EtOAc in heptane). The title compound was obtained as a white solid (5.66g, 53%).

MS ISP(m/e)：161.2(100)[(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-fluoropiperidine-1-carboxylate

A mixture of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (1.255g, 5.78mmol), sodium triacetoxyborohydride (1.89g, 8.67mmol) and benzylamine (681mg, 695. mu.L, 6.35mmol) in 1, 2-dichloroethane (15mL) was maintained at room temperature for 3 hours. Aqueous sodium carbonate (2M) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with Na ₂SO₄Dried and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 100g, 0% to 100% EtOAc in heptane). By removing the trans isomer(yellow oil, 200mg, 11%) the title compound was obtained as a yellow oil (982mg, 55%).

MS ISP(m/e)：309.3/253.2(50/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.35-7.27(m，5H)，4.85-4.67(br，1H)，4.33br，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-fluoropiperidine-1-carboxylate, Pd/C (102mg, 95.5. mu. mol) in MeOH (20mL) was hydrogenated at room temperature for 6 hours. The catalyst was filtered, washed thoroughly with MeOH and the solvent was evaporated. The title compound was obtained as a pale yellow foam (690mg, 99%).

MS ISP(m/e)：219.2/163.3(3/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) piperidine-1-carboxylate

Argon was bubbled through cis-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (350mg, 1.6mmol), 2-bromo-8- (2, 3, 4-trifluorophenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridine (prepared analogously to examples 66a-d, 579mg, 1.76mmol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (66.4mg, 64.1. mu. mol), sodium phenate (279mg, 2.41mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (74.2mg, 128. mu. mol) in anhydrous diutane Suspension in alkane (12mL) for 5 min, then heated to 150 ℃ for 60 min. The crude material was purified by flash chromatography (silica gel, 100g, 0% to 100% EtOAc in heptane). The title compound was obtained as a pale yellow oil (231mg, 31%).

MS ISP(m/e)：466.3/410.3(58/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-fluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To (cis) -tert-butyl 3-fluoro-4- (8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] at 0 deg.C]Triazolo [1, 5-a]Pyridin-2-ylamino) piperidine-1-carboxylic acid ester (462mg, 993. mu. mol) in CH₂Cl₂(10mL) TFA (792mg, 535. mu.L, 6.95mmol) was added and stirred at room temperature for 18 h. The reaction mixture was saturated NaHCO₃The solution was extracted with ethyl acetate and the organic layers were combined and washed with Na₂SO₄Dry, filter and evaporate the solvent. The product was co-evaporated with toluene twice. The title compound was obtained as a pale yellow foam (363mg, 100%). The crude product was used for the next step without further purification.

MS ISP(m/e)：366.2/346.1(58/100)[(M+H)⁺/(M-HF)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

2- (dicyclohexylphosphino) biphenyl (9.21mg, 26.3. mu. mol) and palladium (II) acetate (2.95mg, 13.1. mu. mol) in two The degassed solution in alkane (2mL) was stirred at room temperature for 10 min, then (cis) -N- (3-fluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridin-2-amine (60mg, 164. mu. mol), 5-chloro-3-methyl-1, 2, 4-thiadiazole (24.3mg, 181. mu. mol) and sodium tert-butoxide (23.7mg, 246. mu. mol) in bisSolution in alkane (2 mL). Argon was bubbled through the solution for 5 minutes and then heated to 140 ℃ in a microwave for 30 minutes. 2- (dicyclohexylphosphino) biphenyl (9.21mg, 26.3. mu. mol) and palladium (II) acetate (2.95mg, 13.1. mu. mol) were added again in bisA degassed solution in alkane (2mL) followed by the addition of 5-chloro-3-methyl-1, 2, 4-thiadiazole (24.3mg, 181 μmol) and heating to 140 ℃ for a further 30 minutes and then to 150 ℃ for a further 30 minutes. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) directly purified the reaction mixture. The title compound was obtained as a pale yellow foam (19.7mg, 26%).

MS ISP(m/e)：464.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Separation of racemic (cis) -N- (3-fluoro-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 238, 52mg) by chiral hplc (chiralpak ad) using isopropanol/N-heptane 2: 3 as eluent provided two enantiomers (absolute configuration of enantiomer not specified).

Example 239: enantiomer 1(-), retention time 15.76 min (19mg)

Example 240: enantiomer 2(+), Retention time 26.72 min (16mg)

Example 241

Prepared similarly to example 238. The title compound was obtained as a pale yellow oil.

MS ISP(m/e)：428.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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，2H)，3.54-3.31(m，2H)，2.42(s，3H)，2.11-2.02(m，2H)。

Example 242

Reacting 8- (3, 4-difluorophenyl) -N- (cis-3-fluoropiperidin-4-yl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridin-2-amine (prepared analogously to examples 238a-f, 60.0mg, 173. mu. mol), 4-chloro-6-methylpyrimidine (24.4mg, 190. mu. mol) and N, N-diisopropylamine (33.5mg, 44.1. mu.L, 259. mu. mol) in diisopropylamine The solution in alkane (4mL) was heated to 150 ℃ in a microwave for 2 hours. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) directly purified the reaction mixture. The title compound was obtained as an orange foam (52mg, 69%).

MS ISP(m/e)：440.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 238. The title compound was obtained as a white foam.

MS ISP(m/e)：446.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

To 8- (3, 4-difluorophenyl) -N- (cis-3-fluoropiperidin-4-yl) - [1, 2, 4]Triazolo [1, 5-a]A mixture of pyridin-2-amine (prepared analogously to examples 238a-f, 60mg, 173. mu. mol) and 2-chloro-4-fluoropyridine (22.7mg, 173. mu. mol) in NMP (3mL) was added DIPEA (31.3mg, 42.2. mu.L, 242. mu. mol). Argon was bubbled through the turbid solution for 5 minutes before it was heated to 150 ℃ in a microwave oven for 60 minutes. 2-chloro-4-fluoropyridine (22.7mg, 173. mu. mol) and DIPEA (31.3mg, 42.2. mu.L, 242. mu. mol) were further added and heated to 150 ℃ for another 30 minutes. The reaction mixture is poured into H ₂In O, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, over Na₂SO₄Dried and the solvent evaporated. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was obtained as a white foam (26mg, 33%).

MS ISP(m/e)：459.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared similarly to example 242. The title compound was obtained as an orange foam.

MS ISP(m/e)：458.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

2- (dicyclohexylphosphino) biphenyl (9.21mg, 26.3. mu. mol) and palladium (II) acetate (2.95mg, 13.1. mu. mol) in twoThe degassed solution in alkane (2mL) was stirred at room temperature for 10 min, then added to (cis, rac) -N- (3-fluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridin-2-amine (60mg, 164. mu. mol), 4-chloro-2-methoxypyridine (see example 238f, 25.9mg, 181. mu. mol) and sodium tert-butoxide (23.7mg, 246. mu. mol) in dioxane Solution in alkane (2 mL). Argon was bubbled through the solution for 5 minutes and then heated to 140 ℃ in a microwave for 30 minutes. 2- (dicyclohexylphosphino) biphenyl (9.21mg, 26.3. mu. mol) and palladium (II) acetate (2.95mg, 13.1. mu. mol) were added again in bisA degassed solution in alkane (2mL) was followed by addition of 4-chloro-2-methoxypyridine (25.9mg, 181 μmol) and heating to 140 ℃ in a microwave for another 30 minutes. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) and subsequent preparative HPLC directly. The title compound was obtained as an off-white foam (25mg, 32%).

MS ISP(m/e)：473.6(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

a)3- (benzotriazol-1-ylmethyl-benzyl-amino) -propionic acid ethyl ester

To a solution of 1H-benzo [ d ] [1, 2, 3] triazole (5.46g, 45.8mmol) in MeOH (32mL) at 0 deg.C were added ethyl 3- (benzylamino) propionate (10g, 45.8mmol) and aqueous formaldehyde (36%, 4.56mL, 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 on 330g flash pack using a gradient of EtOAc/heptane 5-50% over 40 min. The title compound was obtained as a colorless oil (12.62g, 81%).

b)3- (benzyl (3-ethoxy-3-oxopropyl) amino) -2, 2-difluoropropionic acid ethyl ester

TMS-Cl (3.60g, 4.24mL, 33.2mmol) was added to a suspension of activated zinc dust (4.13g, 63.2mmol) in dry THF (100mL) under argon. After 10 min, ethyl bromodifluoroacetate (7.05g, 4.49mL, 34.7mmol) was added slowly, thereby keeping the temperature below 30 ℃ (cooling with water bath). A solution of 3- (benzotriazol-1-ylmethyl-benzyl-amino) -propionic acid ethyl ester (10.69g, 31.6mmol) in dry THF (100mL) was then added. The exothermic reaction was maintained between 20 and 25 ℃ using a water bath. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 5% NaHCO₃The aqueous solution was filtered over a pad of celite. The filtrate was extracted three times with ethyl acetate. The organic layer was washed with water and 1N HCl, then over Na₂SO₄Dry, filter and evaporate the solvent. The residue was purified by flash chromatography (silica gel, 100g, 0% to 50% EtOAc in heptane) to yield the title compound as a colorless liquid (10.78g, 99%).

MS ISP(m/e)：344.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) 1-benzyl-5, 5-difluoro-4-oxopiperidine-3-carboxylic acid ethyl ester

To a solution of ethyl 3- (benzyl (3-ethoxy-3-oxopropyl) amino) -2, 2-difluoropropionate (10.78g, 31.4mmol) in NMP (100mL) at 0 deg.C was added potassium tert-butoxide (5.64g, 50.2mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was cooled to 0 ℃ and NH was added ₄Aqueous Cl solution. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Drying and dissolvingAnd (4) evaporating. The residue was purified by flash chromatography using a gradient of EtOAc/heptane 0-70% (over 40 min) to yield the title compound as a white solid (5.56g, 60%).

MS ISP(m/e)：298.4/316.2(19/100)[(M+H)⁺/(M+H₂O)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoropiperidine-4, 4-diol

A solution of ethyl 1-benzyl-5, 5-difluoro-4-oxopiperidine-3-carboxylate (4.272g, 14.4mmol) dissolved in 3N HCl (175mL) was heated at reflux for 14 hours. The reaction mixture was cooled to room temperature and then solid NaHCO was added₃Until pH 8 and extracted three times with ethyl acetate, the combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated. The title compound was obtained as a white solid (3.5g, 100%).

MS ISP(m/e)：244.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.33-7.30(m，5H)，3.62(s，2H)，2.85-2.77(m，4H)，2.62-2.58(m，2H)，1.99-1.96(m，2H)。

e)3, 3-difluoro-4, 4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester

A suspension of 1-benzyl-3, 3-difluoropiperidine-4, 4-diol (3.5g, 14.4mmol), di-tert-butyl dicarbonate (3.45g, 3.64mL, 15.8mmol) and palladium on charcoal (10%) (459mg, 432. mu. mol) in ethanol (75mL) was hydrogenated at room temperature overnight. The catalyst was filtered, washed thoroughly with MeOH and the solvent was evaporated to give the title compound as a pale yellow oil (4.3g, 100%; purity: 85%).

MS ISN(m/e)：294.3/312.2(46/100)[(M-H₂O+AcO)^-/(M+AcO)^-]。

f) 4-benzylamino-3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3, 3-difluoro-4, 4-dihydroxypiperidine-1-carboxylate (1g, 3.36mmol) and benzylamine (539mg, 550. mu.L, 5.03mmol) in dry toluene (70mL) was heated to reflux using a dean stark apparatus for 12 hours. Further benzylamine (20 μ L, 185 μmol) was added and heated to reflux using a dean stark apparatus for another 12 hours. About 50mL of toluene was distilled off, the residue was cooled to 55 ℃ and ethanol (35mL) and NaBH were added₄(508mg, 13.4mmol) and the reaction mixture was stirred at 55 ℃ for 2 h. Further adding NaBH₄(508mg, 13.4mmol) and stirred for an additional hour. Further adding NaBH₄(508mg, 13.4 mmol). After 2 hours, the reaction mixture was concentrated and then 2N Na was added₂CO₃The solution was extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated. The residue was purified by flash chromatography (70g, 0% to 100% EtOAc in hexanes). The title compound was obtained as a colorless oil (875mg, 80%).

MS ISP(m/e)：327.3/271.3(18/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-piperidine-1-carboxylic acid tert-butyl ester

A suspension of 4-benzylamino-3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (830mg, 2.54mmol), Pd/C (81.2mg, 76.3. mu. mol) in MeOH (30mL) was hydrogenated at room temperature for 14 h. The catalyst was filtered, washed thoroughly with MeOH and the solvent was evaporated. The title compound (601mg, 100%) was obtained as a colorless oil.

MS ISP(m/e)：181.1(61)[(M-tBu)⁺]。

h)3, 3-difluoro-4- [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino ] -piperidine-1-carboxylic acid tert-butyl ester

Argon was bubbled through 4-amino-3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (90mg, 381. mu. mol), 2-bromo-8- (2, 3, 4-trifluorophenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridine (prepared analogously to examples 66a-d, 162mg, 495. mu. mol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (15.8mg, 15.2. mu. mol), sodium phenate (65.2mg, 533. mu. mol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (17.6mg, 30.5. mu. mol) in anhydrous dibenzSuspension in an alkane (5.0mL) for 5 minutes, then heated to 160 ℃ in a microwave for 60 minutes. Filtering the catalyst with CH₂Cl₂Washed and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 70g, 0% to 100% EtOAc in heptane). The title compound was obtained as an orange solid (27mg, 15%).

MS ISP(m/e)：484.2/428.2(45/100)[(M+H)⁺/(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-Difluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To 3, 3-difluoro-4- [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] at 0 deg.C]Triazolo [1, 5-a]Pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110mg, 228. mu. mol) in CH ₂Cl₂(4mL) solution TFA (182mg, 123. mu.l, 1.59mmol) was added) And stirred at room temperature for 18 hours. TFA (182mg, 123. mu.l, 1.59mmol) was further added and stirred at 50 ℃ for 6 hours. The reaction mixture was saturated with NaHCO₃The solution was extracted with ethyl acetate and the organic layers were combined and washed with Na₂SO₄Dry, filter and evaporate the solvent. The product was co-evaporated with toluene four times. The title compound was obtained as a pale yellow foam (87mg, 100%).

MS ISP(m/e)：384.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

2- (dicyclohexylphosphino) biphenyl (12.7mg, 36.3. mu. mol) and palladium (II) acetate (4.08mg, 18.2. mu. mol) in twoThe degassed solution in alkane (2mL) was stirred at room temperature for 10 min, then N- (3, 3-difluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] was added]Triazolo [1, 5-a]Pyridin-2-amine (87mg, 227. mu. mol), 5-chloro-3-methyl-1, 2, 4-thiadiazole (30.5mg, 227. mu. mol) and sodium tert-butoxide (32.7mg, 340. mu. mol) in bisSolution in alkane (2 mL). Argon was bubbled through the solution for 5 minutes and then heated to 150 ℃ in a microwave for 60 minutes. 2- (dicyclohexylphosphino) biphenyl (12.7mg, 36.3. mu. mol) and palladium (II) acetate (4.08mg, 18.2. mu. mol) were added again in bis A degassed solution in alkane (2mL) was followed by the addition of 5-chloro-3-methyl-1, 2, 4-thiadiazole (30.5mg, 227 μmol) and heating to 150 ℃ for another 60 minutes in a microwave. 2- (dicyclohexylphosphino) biphenyl (12.7mg, 36.3. mu. mol) and palladium (II) acetate (4.08mg, 18.2. mu. mol) were added again in bisA degassed solution in alkane (2mL) was followed by the addition of 5-chloro-3-methyl-1, 2, 4-thiadiazole (30.5mg, 227 μmol) and heating to 150 ℃ in a microwave for a further 60 minutes. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) and then the crude material was purified by preparative HPLC. The title compound was obtained as a white foam (42mg, 38%).

MS ISP(m/e)：482.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

Prepared in analogy to example 236, using phenylmagnesium bromide (1M in THF, 0.625mL, 0.625mmol) instead of methylmagnesium bromide.

The title compound was obtained as an off-white solid after purification by HPLC (21mg, 20%).

MS ISP(m/e)：517.2[(M+H)⁺]。

Example 249

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

Prepared in analogy to example 234, using phenylmagnesium bromide (1M in THF, 0.625mL, 0.625mmol) instead of methylmagnesium bromide.

After purification by HPLC, the title compound was obtained as a white solid (27mg, 27%).

MS ISP(m/e)：498.3[(M+H)⁺]。

Example 250

Prepared similarly to example 49. The title compound was obtained as an off-white solid.

MS ESI(m/z)：462.0[(M+H)⁺]。

¹H NMR(DMSO，400MHz)：(ppm)＝8.36(s，1H)，8.15-8.11(m，2H)，7.75(d，J＝7.84Hz，1H)，7.32(t，J＝8.88Hz，2H)，7.13(d，J＝7.84Hz，1H)，6.87(d，J＝7.36Hz，1H)，6.74(s，1H)，5.81(s，1H)，4.28(d，J＝12.52Hz，2H)，3.16(t，J＝11.28Hz，2H)，2.25(s，3H)，2.01(d，J＝2.49Hz，2H)，1.72(s，6H)，1.54-1.46(m，2H)。

Example 251

MS ESI(m/z)：480.0[(M+H)⁺]。

Example 252

Prepared in analogy to example 200c, using 2-bromo-8- (2-chloro-4-fluorophenyl) -6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (102mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a pale yellow foam (88mg, 58%).

MS ISP(m/e)：505.3/507.2[(M+H)⁺]。

Example 253

Prepared in analogy to example 200c, using 2-bromo-8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (98mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (72mg, 49%).

MS ISP(m/e)：499.3[(M+H)⁺]。

Example 254

Prepared in analogy to example 200c, using 2-bromo-8- (2, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (93mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (81mg, 57%).

MS ISP(m/e)：475.3[(M+H)⁺]。

Example 255

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

Prepared in analogy to example 200c, using 2-bromo-6-chloro-8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (108mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (50mg, 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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 200c, using 8- (3, 5-bis (trifluoromethyl) phenyl) -2-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridine (123mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as a yellow foam (94mg, 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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 200c, using 2-bromo-8- (2-chloro-4-fluorophenyl) -6-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine (103mg, 0.3mmol) instead of 2-bromo-8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine.

The title compound was obtained as an off-white foam (61mg, 40%).

MS ISP(m/e)：509.2/511.2[(M+H)⁺]。

Example 258

Prepared similarly to example 226. The title compound was obtained as a white foam.

MS ISP(m/e)：451.2/453.2(100/35)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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)，3.40-3.31(m，2H)，2.41(s，3H)，2.27-2.22(m，2H)，1.72-1.59(m，2H)。

Example 259

(3, 4-difluorophenyl) -N- ((3RS, 4SR) -3-fluoro-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

(cis, rac) -8- (3, 4-difluorophenyl) -N- (3-fluoropiperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (prepared analogously to examples 238 a-f) was reacted with 4-iodo-2- (trifluoromethyl) pyridine prepared analogously to example 242 to give the title compound as a pale brown foam (yield: 35%).

MS ISP(m/e)：493.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] - (6-phenoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) -amine

To (6-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-2-yl) - [1- (3-methyl- [1, 2, 4]]Thiadiazoles-5-yl) -piperidin-4-yl]Amine (prepared analogously to example 226a, using 6-bromo- [1, 2, 4] prepared analogously to examples 66a-b]Triazolo [1, 5-a]Pyridin-2-ylamine) (78mg, 198. mu. mol), phenol (37.2mg, 34.8. mu.L, 396. mu. mol), copper (I) iodide (1.77mg, 19.8. mu. mol), picolinic acid (4.87mg, 39.6. mu. mol) and tripotassium phosphate (126mg, 593. mu. mol) were mixed with DMSO (1mL) and heated to 120 ℃ for 12 hours. Phenol (37.2mg, 34.8. mu.l, 396. mu. mol), picolinic acid (4.87mg, 39.6. mu. mol), copper (I) iodide (1.77mg, 19.8. mu. mol) and tripotassium phosphate (126mg, 593. mu. mol) in DMSO (1mL) were further added and stirred at 120 ℃ for another 16 hours. Water was added to the reaction mixture and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases are in Na ₂SO₄Dried and the solvent evaporated. By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH)₄OH (9: 1), in dichloromethane, 45 min) and then preparative HPLC. The title compound was obtained as an off-white foam (15mg, 18%).

MS ISP(m/e)：408.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Under argon, to 7-bromo- [1, 2, 4]]Triazolo [1, 5-a]Pyridine-2-amine (prepared analogously to examples 66a-b, starting from 4-bromo-pyridin-2-ylamine) (250mg, 1.17mmol) and a suspension of hexachloroethane (333mg, 1.41mmol) in anhydrous THF (12.5mL) were added triethylamine (356mg, 491. mu.L, 3.52mmol) and the mixture was heated to 50 ℃ for 10 min. Trimethylphosphine (1M in THF, 1.41mL, 1.41mmol) was added. The reaction mixture was stirred at room temperature for 0.5h, then 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (278mg, 1.41mmol) was added and the mixture was heated in a microwave to 150 ℃ for 30 min. To the reaction mixture was added decaborane (143mg, 153. mu.L, 1.17mmol) in dry methanol (3mL) and stirred at room temperature for 3 hours. Decaborane (34.4mg, 36.6. mu.L, 282. mu. mol) in dry methanol (1.00mL) was further added. The reaction mixture was heated to 60 ℃ for 12 hours. Decaborane (17mg) dissolved in methanol (1mL) was further added and heated to 70 ℃ for 3 hours. Adding NaHCO ₃Aqueous solution and aqueous phase with CH₂Cl₂Extracting, mixing the organic layers, and adding Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was obtained as an off-white solid (300mg, 65%).

MS ISP(m/e)：394.0/396.0(96/100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) -7-phenyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 66c, starting from (7-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine and phenylboronic acid. The title compound was obtained as an off-white foam.

MS ISP(m/e)：392.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

a) N- {3- [ (4-fluoro-phenyl) -hydroxy-methyl ] -pyridin-2-yl } pivaloamide

To a solution of N- (pyridin-2-yl) pivaloamide (1.84g, 10mmol) in tetrahydrofuran (100mL) at-78 deg.C under nitrogen was added 1.6M butyllithium in hexane (13.1mL, 21 mmol). The reaction was slightly exothermic and yellow in color appeared. The reaction was warmed to 0 ℃ over 15 minutes and stirred at 0 ℃ for 2 hours. A white suspension formed. The reaction was cooled to-78 deg.C and 4-fluorobenzaldehyde (1.52g, 1.29mL, 12.0mmol) was added to tetrahydrofuran (6.55 mL). The reaction was allowed to warm to room temperature overnight to yield an orange suspension. Saturated aqueous ammonium chloride was added and the reaction was extracted twice with ethyl acetate and once with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solution was washed with brine The agent was evaporated under reduced pressure. By column chromatography (using a secondary CH on silica gel)₂Cl₂To CH₂Cl₂gradient/MeOH 19: 1(v/v) as eluent) to yield the title compound as a yellow viscous oil (1.058g, 35%).

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 } pivaloamide (890mg, 2.94mmol) in ethanol (44mL) was added 2N aqueous sodium hydroxide solution (7.36mL, 14.7 mmol). The reaction was heated to 100 ℃ for 5 hours. Water was added and the reaction was extracted twice 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 to give the title compound (548mg, 85%) as a pale yellow solid 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

Prepared in analogy to example 1e-f), starting from (2-amino-pyridin-3-yl) - (4-fluoro-phenyl) -methanol. After the reaction was poured onto water, washed and dried, the title compound was obtained as a white solid (yield of two steps: 63%).

MS ISP(m/e)：259.1(19)[(M+H)⁺]，241.2(100)。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Prepared in analogy to example 219f) from (2-amino- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) (4-fluorophenyl) methanol and 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one. Decaborane in methanol was used as a reducing agent at 50 ℃ overnight. Use of the starting CH on silica gel by column chromatography₂Cl₂To CH₂Cl₂The crude product was purified with a gradient of/MeOH 19: 1(v/v) as eluent to give {8- [ (4-fluoro-phenyl) -methoxy-methyl) -as a colorless oil which eluted first]-[1，2，4]Triazolo [1, 5-a]Pyridin-2-yl } - [1- (3-methyl- [1, 2, 4] methyl ester]Thiadiazol-5-yl) -piperidin-4-yl]Amine (yield: 4%).

MS ISP(m/e)：454.3(100)[(M+H)⁺]，422.2(98)，241.2(98)。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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)。

The next eluted (4-fluorophenyl) (2- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol was further purified by preparative HPLC. The title compound was obtained as a white solid (yield: 42%).

MS ISP(m/e)：440.2(100)[(M+H)⁺]，422.1(69)。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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(br s，1H)，6.07(br s，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-thiadiazol-5-yl) piperidin-4-yl) -8-phenyl-6, 8-dihydro-5H- [1, 2, 4]Triazolo [5, 1-c][1，4]Oxazin-2-amines

a) (2-oxo-ethoxy) -phenyl-acetic acid methyl ester

Allyloxy-phenyl-acetic acid methyl ester (described in EJOC 2000, 3145-3163; 3g, 14.5mmol) was dissolved in dichloromethane (300mL) and cooled to-75 ℃. Mixing O with ₃Bubble through the solution for 6 hours until the solution turns blue. Argon was bubbled through the solution for 1 hour, then dimethylsulfide (9.04g, 10.8mL, 145mmol) was added to the reaction mixture and held at room temperature for 12 hours. The reaction mixture was evaporated and chromatographed by flash chromatography (on 50g SiO₂The residue was purified on flash pack using a gradient of 10-100% EtOAc in heptane, 60 min) to yield the title compound as a pale yellow oil (2.72g, 90%).

¹H NMR(CDCl₃，300MHz)：(ppm)＝9.75(s，1H)，7.47-7.36(m，5H)，5.03(s，1H)，4.13(s，2H)，3.74(s，3H)。

b)2- (2- (2-methoxy-2-oxo-1-phenylethoxy) ethylene) hydrazinecarboxylic acid tert-butyl ester

(2-oxo-ethoxy) -phenyl-acetic acid methyl ester (2.7g, 13.0mmol) and tert-butyl carbazate (1.75g, 13.0mmol) were dissolved in toluene (290mL) and heated to 65 ℃ overnight.

The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 100g, 0% to 100% EtOAc in heptane, 60 min) to yield the title compound as a yellow viscous oil (2.81g, 67%).

MS ISP(m/e)：323.3(42)[(M+H)⁺]，267.1(100))[(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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)2- (2- (2-methoxy-2-oxo-1-phenylethoxy) ethyl) hydrazinecarboxylic acid tert-butyl ester

Tert-butyl 2- (2- (2-methoxy-2-oxo-1-phenylethoxy) ethylene) hydrazinecarboxylate (4.7g, 14.6mmol) in MeOH (175mL) was hydrogenated in a Parr bottle in the presence of Raney nickel (4.69g, 37.2mmol) at 3.5bar and 30 deg.C for 20 h. The reaction mixture was filtered and washed with MeOH. The solvent was evaporated to give the title compound as a brown oil (4.5g, 95%), which was used in the next step without purification.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-phenylmorpholin-3-ones

Tert-butyl 2- (2- (2-methoxy-2-oxo-1-phenylethoxy) ethyl) hydrazinecarboxylate (390mg, 1.2mmol) in water (85mL) was heated to 95 ℃ for 12 h. The reaction mixture was extracted with dichloromethane, the organic layers were combined and washed with Na₂SO₄The solvent was evaporated to give the title compound (183mg, 79%) as a pale yellow oil.

MS ISP(m/e)：193.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]Oxazin-2-amines

4-amino-2-phenylmorpholin-3-one (175mg, 910. mu. mol) and cyanamide (230mg, 179. mu.L, 5.46mmol) were dissolved in ethanol (4 mL). P-toluenesulfonic acid monohydrate (260mg, 209. mu.L, 1.37mmol) was added and the mixture was heated at reflux for 24 h at 80 ℃.

After cooling to room temperature, triethylamine (461mg, 634. mu.L, 4.55mmol) was added and the mixture was heated at 80 ℃ for 3 days under reflux.

The reaction mixture was extracted with saturated sodium bicarbonate solution and EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and the solvent evaporated. By chromatography (at 10g NH)₂On a flash pack, using 0-15% MeOH/NH in dichloromethane₃Gradient (9: 1) the residue was purified to give the title compound as an off-white solid (41mg, 21%).

MS ISP(m/e)：217.3(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-4-yl) -8-phenyl-6, 8-dihydro-5H- [1, 2, 4]Triazolo [5, 1-c][1，4]Oxazin-2-amines

Prepared analogously to example 261a by using 8-phenyl-6, 8-dihydro-5H- [1, 2, 4]Triazolo [5, 1-c][1，4]Oxazin-2-amine and 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one (see example 1 d). The title compound was obtained as a white foam.

MS ISP(m/e)：398.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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) piperidin-4-yl) -8-phenyl-6, 8-dihydro-5H- [1, 2, 4]Triazolo [5, 1-c][1，4]Oxazin-2-amines

Prepared in analogy to example 264, using 1- (6-methyl-pyrimidin-4-yl) -piperidin-4-one in step f) (see example 93 b). The title compound was obtained as a pale yellow foam.

MS ISP(m/e)：392.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 & 267

N- ((3R, 4S, 5S) -3, 5-dimethyl-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and

n- ((3S, 5S) -3, 5-dimethyl-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [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-one (prepared according to A.A. Calabrese et al, US20050176772, methods 12-14) (2.08g, 9.57mmol), di-tert-butyl dicarbonate (2.3g, 2.42mL, 10.5mmol) and palladium on charcoal (10%) (306mg, 287. mu. mol) in ethanol (47.5mL) was hydrogenated at room temperature for 12 hours. The catalyst was filtered, washed thoroughly with MeOH and the solvent was evaporated to give the title compound as a white solid (2.38 g).

MS ISP(m/e)：172.2(100)[(M-tBu)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino ] -piperidine-1-carboxylic acid tert-butyl ester

To 8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] in argon atmosphere]Triazolo [1, 5-a]A solution of pyridin-2-amine (prepared analogously to examples 66 a-c) (300mg, 1.14mmol) and hexachloroethane (296mg, 1.25mmol) in dry THF (8mL) was added triethylamine (287mg, 396. mu.L, 2.84mmol) followed by trimethylphosphine (1M in THF, 1.25mL, 1.25 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then (3R, 5S) -tert-butyl 3 was added5-dimethyl-4-oxopiperidine-1-carboxylate (315mg, 1.25mmol) and the mixture is heated in a microwave to 150 ℃ for 3 hours. Decaborane (139mg, 148. mu.L, 1.14mmol) in MeOH (3mL) was added to the reaction mixture and stirred at 50 ℃ for 2 h. Decaborane (139mg, 148. mu.l, 1.14mmol) in MeOH (3mL) was further added and stirred at 50 ℃ for an additional 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layers were combined over Na₂SO₄Dried and evaporated. By flash chromatography (at 70g SiO)₂The residue was purified on flash pack using a gradient of 0-100% EtOAc in heptane, 35 min) to yield the title compound as an off-white foam (208mg, 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-piperidin-4-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl ] -amine

To 3, 5-dimethyl-4- (8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] at 0 deg.C]Triazolo [1, 5-a]Pyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester (200mg, 421. mu. mol) in CH₂Cl₂(5mL) trifluoroacetic acid (336mg, 227. mu.L, 2.94mmol) was added to the solution and the mixture was stirred at room temperature for 18 hours. Trifluoroacetic acid (336mg, 227. mu.L, 2.94mmol) was further added at 0 ℃ and stirred at room temperature for a further 2 hours. Saturated NaHCO₃The solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc. The organic layers were combined over Na₂SO₄Dry, filter and evaporate the solvent. The product was co-evaporated with toluene. The title compound was isolated as a white solid (106mg, 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-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and

2- (dicyclohexylphosphino) biphenyl (14.9mg, 42.6. mu. mol) and palladium (II) acetate (4.78mg, 21.3. mu. mol) in twoThe degassed solution in alkane (2mL) was stirred at room temperature for 10 min, then N- (3, 5-dimethylpiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-2-amine (100mg, 266. mu. mol), 5-chloro-3-methyl-1, 2, 4-thiadiazole (39.4mg, 293. mu. mol) and sodium tert-butoxide (38.4mg, 400. mu. mol) in bisSolution in alkane (2 mL). Argon was bubbled through the solution for 5 minutes and then heated to 150 ℃ in a microwave for 30 minutes. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) and the crude material was again purified by flash chromatography (silica gel, 20g, 0-100% EtOAc in heptane) to yield:

example 266: n- ((3R, 4S, 5S) -3, 5-dimethyl-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine as an off-white solid (45mg, 36%).

MS ISP(m/e)：474.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃300 MHz): (ppm) ═ 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) in the following order And

example 267: n- ((3S, 5S) -3, 5-dimethyl-1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine as an off-white foam (23mg, 18%).

MS ISP(m/e)：474.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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

N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -7-phenoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 260, using (7-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine (see example 261a) instead of (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-yl) - [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine. The title compound was obtained as an off-white foam.

MS ISP(m/e)：408.4(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 & 270 & 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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

a)4- [8- (3, 5-bis-trifluoromethyl-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino ] -3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

To 8- (3, 5-bis (trifluoromethyl) phenyl) - [1, 2, 4] under argon ]Triazolo [1, 5-a]A suspension of pyridin-2-amine (prepared analogously to examples 66 a-c) (80mg, 231. mu. mol) and hexachloroethane (65.6mg, 277. mu. mol) in dry THF (4mL) was added triethylamine (70.1mg, 96.6. mu.L, 693. mu. mol), followed by trimethylphosphine (1M in THF, 277. mu.L, 277. mu. mol). The reaction mixture was stirred at room temperature for 0.5 h, then 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (example 238b, 60.2mg, 277. mu. mol) was added and the mixture was heated in a microwave to 150 ℃ for 30 min. A solution of decaborane (28.2mg, 30.0. mu.L, 231. mu. mol) in dry methanol (1mL) was added to the reaction mixture and stirred at room temperature for 3 hours. NaHCO is added₃The aqueous solution is added to the reaction mixture and the aqueous phase is extracted with CH₂Cl₂Combining the organic layers in Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was obtained as an off-white foam (107mg, 85%) which was cisA mixture of the formula (la) and the trans isomer.

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-piperidin-4-yl) -amine

To 4- [8- (3, 5-bis-trifluoromethyl-phenyl) - [1, 2, 4] at 0 deg.C ]Triazolo [1, 5-a]Pyridin-2-ylamino]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (180mg, 329. mu. mol) in CH₂Cl₂(3mL) trifluoroacetic acid (262mg, 177. mu.L, 2.3mmol) was added to the solution and then stirred at room temperature for 18 hours. Trifluoroacetic acid (262mg, 177. mu.L, 2.3mmol) was further added and stirred at 40 ℃ for 6 hours. Saturated NaHCO₃Aqueous solution was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate, the organic layers were combined and washed with Na₂SO₄Dry, filter and evaporate the solvent. The product was co-evaporated twice with toluene. The title compound was obtained as a pale yellow foam (142mg, 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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Palladium (II) acetate (2.73mg, 12.2. mu. mol) and 2- (dicyclohexylphosphino) biphenyl (8.52mg, 24.3. mu. mol) in twoThe degassed solution in alkane (1mL) was stirred at room temperature for 10 minutes, then added to 8- (3, 5-bis (trifluoromethyl) phenyl) -N- (3-fluoropiperidin-4-yl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-2-amine (68mg, 152. mu. mol), 5-chloro-3-methyl-1, 2, 4-thiadiazole (24.5mg, 182. mu. mol) and sodium tert-butoxide (21.9mg, 228. mu. mol) in bis Solution in alkane (2 mL). Argon was bubbled through the solution for 5 minutes and then heated to 150 ℃ in a microwave for 45 minutes. Palladium (II) acetate (3.1mg, 13.8. mu. mol) and 2- (dicyclohexylphosphino) biphenyl (9.69mg, 27.6. mu. mol) were added again in twoA degassed solution in alkane (1mL) was followed by the addition of 5-chloro-3-methyl-1, 2, 4-thiadiazole (24.5mg, 182 μmol) and an additional 45 minutes to 150 ℃. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the crude material was purified. The title compound was obtained as a colorless oil (30mg, 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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Ethanol and CO were used on a Chiralpak AD-H column by Supercritical Fluid Chromatography (SFC)₂The mixture of cis and trans isomers was separated as eluent to yield the trans isomer (racemate) (example 269) and the two cis enantiomers (examples 270 and 271) (absolute configuration of enantiomers was not specified).

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] thiadiazol-5-yl) -piperidin-4-yl ] -amine

Retention time: 4.00/4.33 min.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-yl ] -amine or enantiomer

Retention time: 5.06 minutes.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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] thiadiazol-5-yl) -piperidin-4-yl ] -amine or enantiomer

Retention time: 6.33 minutes.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 & 273 & 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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Will dissolve in anhydrous II8- (3, 5-bis (trifluoromethyl) phenyl) -N- (3-fluoropiperidin-4-yl) - [1, 2, 4] in an alkane (2mL) ]Triazolo [1, 5-a]Pyridin-2-amine (example 269b, 68mg, 152. mu. mol), 2-bromo-5-methyl-1, 3, 4-A solution of oxadiazole (32.2mg, 198. mu. mol) and diisopropylethylamine (39.3mg, 53.1. mu.L, 304. mu. mol) was stirred at 70 ℃ for 12 h and then at 110 ℃ for 1 h. Diisopropylethylamine (39.3mg, 53.1. mu.L, 304. mu. mol) and 2-bromo-5-methyl-1, 3, 4-Oxadiazole (32.2mg, 198. mu. mol) and heated to 110 ℃ for a further hour. The solvent was evaporated and chromatographed by flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was directly purified. The title compound was obtained as a colorless oil (46mg, 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 ]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Ethanol and CO were used on a Chiralpak AD-H column by Supercritical Fluid Chromatography (SFC)₂The mixture of cis and trans isomers was separated as eluent to yield the trans isomer (racemate) (example 272) and the two cis enantiomers (examples 273 and 274) (absolute configuration of enantiomers not specified).

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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Retention time: 4.11/4.37 min.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Retention time: 5.72 minutes.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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]]Oxadiazol-2-yl) -piperidin-4-yl]-amines

Retention time: 8.18 minutes.

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

a)3, 3-difluoro-4- [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino ] -piperidine-1-carboxylic acid tert-butyl ester

To 8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] under argon]Triazolo [1, 5-a]Pyridin-2-amine (prepared analogously to examples 66a-c, 200mg, 757. mu. mol) and hexachloroethane (215mg, 908. mu. mol) in the absence of water A suspension in THF (10mL) was added triethylamine (230mg, 317. mu.L, 2.27mmol), followed by trimethylphosphine (1M in THF, 908. mu.L, 908. mu. mol). The reaction mixture was stirred at room temperature for 0.5 h, then 3, 3-difluoro-4, 4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (see example 247e, 230mg, 908. mu. mol) was added and the mixture was heated in a microwave to 150 ℃ for 30 min. Decaborane (92.5mg, 98.4. mu.L, 757. mu. mol) in MeOH (1mL) was added to the reaction mixture, which was then stirred at room temperature for 12 hours. A solution of decaborane (92.5mg, 98.4. mu.L, 757. mu. mol) in MeOH (5mL) was added again and heated to 70 ℃ for 18 hours. NaHCO is added₃The aqueous solution is added to the reaction mixture and the aqueous phase is treated with CH₂Cl₂Extracting, mixing the organic layers, and adding Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified, whereby 85mg of the intermediate imine, 3, 3-difluoro-4- [ (E) -8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4 ]]Triazolo [1, 5-a]Pyridin-2-ylimino]Tert-butyl-piperidine-1-carboxylate was isolated and redissolved in anhydrous MeOH (3 mL). Decaborane (21.6mg, 23.0. mu.L, 177. mu. mol) was added and heated to 70 ℃ for 30 minutes. NaHCO is added ₃The aqueous solution is added to the reaction mixture and the aqueous phase is treated with CH₂Cl₂Extracting, mixing the organic layers, and adding Na₂SO₄Dry, filter and evaporate the solvent. By flash chromatography (silica gel, 50g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified (along with the impurity product fractions from the first chromatography) to yield the title compound as a white foam (300mg, 82%).

MS ISP(m/e)：484.3/428.1/384.2(13/100/41)[(M+H)⁺/(M-tBu)⁺/(M-Boc)⁺]。

b) N- (3, 3-Difluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

To 3, 3-difluoro-4- [8- (2, 3, 4-trifluoro-phenyl) - [1, 2, 4] at 0 deg.C]Triazolo [1, 5-a]Pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (110mg, 228. mu. mol) in CH₂Cl₂(4mL) TFA (182mg, 123. mu.l, 1.59mmol) was added and stirred at room temperature for 18 h. TFA (182mg, 123. mu.l, 1.59mmol) was further added and stirred at 50 ℃ for 6 hours. The reaction mixture was washed with saturated NaHCO₃The solution was extracted with ethyl acetate and the organic layers were combined and washed with Na₂SO₄Dry, filter and evaporate the solvent. The product was co-evaporated with toluene four times. The title compound was obtained as a pale yellow foam (87mg, 100%).

MS ISP(m/e)：384.2(100)[(M+H)⁺]。

c) N- (3, 3-difluoro-1- (6-methylpyrimidin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Mixing N- (3, 3-difluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4 ]]Triazolo [1, 5-a]Pyridin-2-amine (75mg, 196. mu. mol), 4-chloro-6-methylpyrimidine (27.7mg, 215. mu. mol) and N, N-diisopropylethylamine (37.9mg, 49.9. mu.L, 293. mu. mol) in dioxaneThe solution in alkane (4mL) was heated to 150 ℃ in a microwave for 1 hour. 4-chloro-6-methylpyrimidine (27.7mg, 215. mu. mol) and N, N-diisopropylethylamine (37.9mg, 49.9. mu.L, 293. mu. mol) were further added and heated to 150 ℃ for a further hour in a microwave. 4-chloro-6-methylpyrimidine (27.7mg, 215. mu. mol) and N, N-diisopropylethylamine (37.9mg, 49.9. mu.L, 293. mu. mol) were further added and heated to 110 ℃ for 12 hours. By flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) directly on the crude materialAnd (5) purifying. The title compound was obtained as a pale yellow foam (25mg, 22%).

MS ISP(m/e)：476.1(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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-difluoro-1- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridin-2-amines

Mixing N- (3, 3-difluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4 ]]Triazolo [1, 5-a]Pyridin-2-amine (see example 275b, 75mg, 196. mu. mol), 2-bromo-5-methyl-1, 3, 4- Oxadiazole (41.5mg, 254. mu. mol) and diisopropylethylamine (50.6mg, 68.3. mu.L, 391. mu. mol) were dissolved in anhydrous dioxaneThe solution in alkane (4mL) was stirred at 110 ℃ for 3 hours. Diisopropylethylamine (50.6mg, 68.3. mu.L, 391. mu. mol) and 2-bromo-5-methyl-1, 3, 4-Oxadiazole (41.5mg, 254. mu. mol) and heated to 110 ℃ for 12 h. The solvent was evaporated and chromatographed by flash chromatography (silica gel, 70g, 0% to 15% MeOH/NH in dichloromethane)₄OH (9: 1)) the residue was purified. The title compound was a white foam (36mg, 40%).

MS ISP(m/e)：466.0(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：(ppm)＝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 ] pyridin-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 (50mg, 0.19mmol) and hexachloroethane (54mg, 0.226mmol) in THF (1.5mL) was added triethylamine (79 μ L, 0.57mmol), followed by trimethylphosphine (1M in THF, 0.226mL, 0.23mmol) and the resulting mixture was stirred under argon for 30 min. The ketone 1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-one (46mg, 0.19mmol) was then added and the resulting mixture was heated in a microwave for 30 minutes at 120 ℃. Trimethylsilyl cyanide (48 μ L, 0.38mmol) was then added followed by MeOH (1.5mL), followed by acetic acid (44 μ L, 0.75mmol) and the resulting mixture was heated to 70 ℃ for 24 hours. After cooling to room temperature, the mixture was evaporated and the residue was extracted with dichloromethane and washed with a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50g, 0 to 20% ethyl acetate in heptane) gave the title compound as a white foam (20mg, 21%).

MS ISP(m/e)：516.2[(M+H)⁺]。

Example 278

N- ((3RS, 4SR) -3-fluoro-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

(cis, rac) -N- (3-fluoropiperidin-4-yl) -8- (2, 3, 4-trifluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (example 238f) was reacted with 4-iodo-2- (trifluoromethyl) pyridine prepared in analogy to example 242 to give the title compound as an off-white foam (yield: 33%).

MS ISP(m/e)：511.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝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) piperidin-4-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 234, using 4- (8- (2-chloro-4-fluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -1- (2- (trifluoromethyl) pyridin-4-yl) piperidine-4-carbonitrile (100mg, 0.19mmol) instead of 4- (8- (3, 4-difluorophenyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-ylamino) -1- (6-methylpyrimidin-4-yl) piperidine-4-carbonitrile.

The title compound was obtained as a white foam (25mg, 26%).

MS ISP(m/e)：505.2[(M+H)⁺]。

Example 280

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

Prepared in analogy to example 279, using phenylmagnesium bromide (1M in THF, 0.582mL, 0.582mmol) instead of methylmagnesium bromide.

The title compound was obtained as a white foam (19mg, 17%).

MS ISP(m/e)：567.2[(M+H)⁺]。

Example 281

N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-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

Prepared in analogy to example 262 steps a-b) starting from N- (pyridin-2-yl) pivaloamide and 4- (trifluoromethyl) cyclohexanone. In column chromatography (on silica gel, using a column from CH)₂Cl₂To CH₂Cl₂Gradient of/MeOH 19: 1(v/v) as eluent) to give 3- (4-trifluoromethyl-cyclohex-1-enyl) -pyridin-2-ylamine as a white solid (yield in two steps: 26%).

MS ISP(m/e)：243.3(100)[(M+H)⁺]，226.3(14)。

1- (2-Aminopyridin-3-yl) -4- (trifluoromethyl) cyclohexanol as a white solid eluted next (yield in two steps: 15%).

MS ISP(m/e)：261.1(100)[(M+H)⁺]，243.3(52)。

b)8- (4- (trifluoromethyl) cyclohex-1-enyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 1e-f) starting from 3- (4-trifluoromethyl-cyclohex-1-enyl) -pyridin-2-ylamine. The title compound was obtained after column chromatography (on silica gel, using ethyl acetate as eluent) as a white solid (yield in two steps: 84%).

MS ISP(m/e)：283.1(100)[(M+H)⁺]。

c) N- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-yl) -8- (4- (trifluoromethyl) cyclohex-1-enyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine

Prepared in analogy to example 219f) from 8- (4- (trifluoromethyl) cyclohex-1-enyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine and 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one. Sodium borohydride in ethanol at 4 equivalents was used as the reducing agent overnight at 70 ℃. 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-D₆，300MHz)：(ppm)＝8.51(d，1H)，7.38(d，2H)，7.29(br 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-thiadiazol-5-yl) piperidin-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

Prepared in analogy to example 1e-f) starting from 1- (2-aminopyridin-3-yl) -4- (trifluoromethyl) cyclohexanol. The title compound was obtained after column chromatography (on silica gel, using ethyl acetate as eluent) as a white solid (yield of two steps: 81%).

MS ISP(m/e)：301.2(40)[(M+H)⁺]，283.1(100)。

b)1- (2- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -4- (trifluoromethyl) cyclohexanol

Prepared in analogy to example 219f) from 1- (2-amino- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) -4- (trifluoromethyl) cyclohexanol and 1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-one. Sodium borohydride in ethanol at 4 equivalents was used as the reducing agent overnight at 70 ℃. The title compound was obtained after column chromatography (on silica gel, using ethyl acetate as eluent) as a white solid (yield: 46%).

MS ISP(m/e)：482.3(100)[(M+H)⁺]，464.2(29)，243.2(37)。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝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-thiadiazol-5-yl) piperidin-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-thiadiazol-5-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (72mg, 164. mu. mol) in dichloromethane (0.82mL) was added diethylaminosulfur trifluoride (DAST) (58.7mg, 48.1. mu.L, 328. mu. mol) under a nitrogen atmosphere. The reaction turned yellow and was stirred at room temperature for 3 hours. Water was added and the reaction was extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The title compound was obtained as a white solid after purification by column chromatography (on silica gel, using ethyl acetate as eluent) (20.1mg, 27%).

MS ISP(m/e)：442.4(44)[(M+H)⁺]，422.1(100)。

¹H NMR(DMSO-D₆，300MHz)：(ppm)＝8.29(d，1H)，7.49-7.43(m，3H)，7.06(t，2H)，6.90(d，J＝44.7Hz，1H)，6.85(t，1H)，4.49(d，1H)，3.89(m，3H)，3.35(br t，2H)，2.42(s，3H)，2.22(br d，2H)，1.65(m，2H)。

Claims

1. A compound of formula I

Wherein

Heteroaryl group I is

Heteroaryl II is a five or six membered heteroaryl selected from the group consisting of:

or a bicyclic ring system selected from the group consisting of:

R¹is C_1-7Alkyl radical, C_1-7Alkoxy, halogen substituted C_1-7Alkyl or halogen;

R²is benzo [1, 3 ]]Dioxolyl, or

Is- (CHR)_p-phenyl, optionally substituted with: halogen, C_1-7Alkyl radical, C_1-7Alkoxy, S (O)₂-C_1-7Alkyl, cyano, nitro, halogen-substituted C_1-7Alkoxy, dimethylamino or halogen substituted C_1-7Alkyl, and R is hydrogen, halogen, hydroxy or C_1-7Alkoxy radical, or

Is C_3-6Cycloalkenyl or C_3-6Cycloalkyl optionally substituted by hydroxy or by halogen C_1-7Alkyl is substituted, or

Is thatOptionally substituted by halogen, C_1-7Alkyl radical, C_1-7Alkoxy or dimethylamino substituted, or

Is O-phenyl optionally substituted with halogen;

R³is hydrogen;

R⁴is C_1-7Alkoxy radical, C_1-7Alkyl 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, R if o is 2 or 3²May be the same or different;

Or a pharmaceutically active acid addition salt thereof.

2. A compound of formula I according to claim 1, wherein

Heteroaryl II is a bicyclic ring system selected from the group consisting of:

3. a compound which is

(4-fluorophenyl) (2- (1- (3-methyl-1, 2, 4-thiadiazol-5-yl) piperidin-4-ylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol, or

4. A compound of formula I according to claim 1, wherein

5. a compound which is

2- {6- (4-chloro-phenyl) -2- [1- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -piperidin-4-ylamino ] -pyrimidin-4-yl } -propan-2-ol, or

6. A process for preparing a compound according to any one of claims 1 to 5, comprising the steps of:

a) reacting a compound of formula 2

With a compound of formula 3

To produce a compound of formula I

Wherein X is halogen and the other groups have the meanings as indicated in claim 1, and, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt;

or

b) Reacting a compound of formula 6

With a compound of formula 7

To produce a compound of formula I

Wherein X is halogen and the other radicals have the meanings as indicated in claim 1, or

c) Reacting a compound of formula 8

With a compound of formula 9

To produce a compound of formula I

7. A medicament comprising one or more compounds as claimed in any one of claims 1 to 5 and pharmaceutically acceptable excipients.

8. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.