HK1190705B - Bridged piperidine derivatives - Google Patents

Description

Bridged 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 S or N;

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

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

R²is lower alkyl, lower alkyl substituted by halogen, lower alkoxy, cycloalkyl substituted by lower alkyl or lower alkyl substituted by halogen, or is lower alkyl substituted by hydroxy, furyl, O-benzyl, or- (CH)₂)_p-phenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkyl or by cyano;

R³is hydrogen or lower alkyl;

y is- (CH)₂)_n-、-CH₂OCH₂-、-CH₂O-、CH₂S-、-CH₂SCH₂-and to two of the ring carbon atoms, to ring carbon atoms a and b or to ring carbon atoms c and d;

p is 0 or 1;

m is 0, 1 or 2; if m is 2, R¹May be the same or different;

n is 2 or 3;

o is 0, 1 or 2, and if o is 2, 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 (cerebellar amyloid angiopathy), hereditary cerebral hemorrhage with amyloidosis (hereditary cerebral hemorrhage with amyloidosis), Dutch-type (HCHWA-D), multi-infarct dementia (multi-infatrementia), 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 aphl 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 replaced by halogenSubstituted, 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-membered heteroaryl group comprising 1 to 3 heteroatoms selected from S or N" is selected from the group consisting of;

preferred five membered heteroaryl is

The term "six-membered heteroaryl group containing 1 to 3 heteroatoms selected from S or N" is selected from the group consisting ofPreferred six membered heteroaryl groups are

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

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 medicaments 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 object of the present invention are the compounds of formula I

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

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

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

R²is lower alkyl, lower alkyl substituted by hydroxy or is- (CH) optionally substituted by halogen₂)_p-a phenyl group;

R³is hydrogen or lower alkyl;

y is- (CH)₂)_n-、-CH₂OCH₂-、-CH₂O-、CH₂S-、-CH₂SCH₂-and to two of the ring carbon atoms, to ring carbon atoms a and b or to ring carbon atoms c and d;

p is 0 or 1;

m is 0, 1 or 2; if m is 2, R¹May be the same or different;

n is 2 or 3;

o is 0, 1 or 2, R if o is 2²May be the same or different;

or a pharmaceutically active acid addition salt thereof.

An embodiment of the present invention are further compounds of formula I,

wherein

Heteroaryl I is pyridyl, 1,2, 4-thiadiazolyl, pyrazinyl or pyrimidinyl;

heteroaryl II is [1,2,4] triazolo [1,5-a ] pyridyl, [1,2,4] triazolo [1,5-a ] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridyl, [1,2,4] triazolo [1, 5-c ] pyrimidinyl, 4, 5, 6, 7-tetrahydro-benzothiazolyl or pyrimidinyl;

R¹is methyl, chlorine or CF₃：

R²Is methyl, n-propyl, fluorine, chlorine, trifluoromethyl, methoxy or is-C (CH)₃)₂OH is O-benzyl, cyclohexyl substituted by methyl or trifluoromethyl, furyl, or- (CH)₂)_p-phenyl, optionally substituted by one, twoOne or three halogen atoms selected from F or Cl, or substituted by cyano or methoxy;

R³is hydrogen or methyl;

y is- (CH)₂)_n-, or is-CH₂OCH₂-, or is-OCH₂-, or is-CH₂SCH₂-, or is-SCH₂And to two of the ring carbon atoms, to ring carbon atoms a and b or to ring carbon atoms c and d;

p is 0 or 1;

m is 0, 1 or 2;

n is 2, or 3;

o is 1 or 2, if o is 2, R²May be the same or different;

or a pharmaceutically active acid addition salt thereof.

An embodiment of the invention are further compounds of formula I, wherein Y is- (CH)₂)₂-, heteroaryl I isAnd heteroaryl II is a bicyclic ring system containing 1 to 4 heteroatoms, such as the following compounds:

[ (rac) -3-rac-8- (3-methyl- [1,2,4] thiadiazol-5-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-chloro-2-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3-cyano-4-fluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-chloro-6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [5, 6-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-benzyloxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-propyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (5-phenyl- [1,2,4] triazolo [1,5-a ] pyrazin-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 6-chloro-8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-methyl-5-propyl- [1,2,4] triazolo [1, 5-c ] pyrimidin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4, 4-dimethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (7-furan-2-yl- [1,2,4] triazolo [1,5-a ] pyrimidin-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-trifluoromethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-rac-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine or [ (rac) -8- (3, 4-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

A further embodiment of the invention are compounds of formula I, wherein Y is- (CH)₂)₂-, heteroaryl I isAnd heteroaryl II is a compound containing a substituent selected fromA six-membered heteroaryl group of 1 to 3 heteroatoms of S or N, for example the following compounds:

2- {6- (4-chloro-benzyl) -2- [ (rac) -3-endo-8- (3-methyl- [1,2,4] thiadiazol-5-yl) -8-aza-bicyclo [3.2.1] oct-3-ylamino ] -pyrimidin-4-yl } -propan-2-ol.

A further embodiment of the invention are compounds of formula I, wherein Y is- (CH)₂)_n-, heteroaryl I isAnd heteroaryl II is a bicyclic ring system containing 1 to 4 heteroatoms, such as the following compounds:

[ (rac) -3-rac-8- (2-chloropyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - [8- (3, 4-difluorophenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine or

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-trifluoromethyl-pyridin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

A further embodiment of the present invention are compounds of the formula I, wherein heteroaryl I isAnd heteroaryl II is a bicyclic ring system containing 1 to 4 heteroatoms, such as the following compounds:

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -6-oxa-3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-thia-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-oxa-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-exo-methyl-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-endo-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine or

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

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) make formula2Of (a) a compound

And formula3By reaction of a compound of

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) Make formula6Of (a) a compound

And formula7By reaction of a compound of

To produce a compound of formula I

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

c) Make formula8Of (a) a compound

And formula9By reaction of a compound of

To produce a compound of formula I

Wherein the radicals have the meanings indicated aboveAnd R is³Is hydrogen, and, in addition,

if desired, the compound obtained is converted 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.

The compounds of formula I and their pharmaceutically acceptable salts of the present invention can be prepared by reacting a compound of formula2Amine of the formula3By coupling of the halides of (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.

Alternatively, a halide3Can be reacted with a compound of the formula4Amine of the formula4In the presence of an amine ofThe piperidine nitrogen has a protecting group PG, such as Boc (see scheme 2). After deprotection using, for example, trifluoroacetic acid, piperidine6Can be combined with7To yield the compound of formula I.

R³Is hydrogen;

alternatively, general formula (II A) can be substituted9The aniline of (A) is used in the reaction with a compound of formula8Or10By reductive amination of ketones (see scheme 3) to obtain the desired product directly or after cleavage5Is followed by a halide with heteroaryl I as depicted in scheme 27After coupling to give compound I. 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).

General formula (VII)9With an aniline of the general formula8Or10The coupling of the ketones of (a) can alternatively be achieved according to the aza-Wittig/reduction scheme (see scheme 4). The general formula (la) can be prepared by first reacting a trialkylhalo-phosphine (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)9Conversion of anilines to their corresponding trialkylphosphazenes11. Then the general formula8Or10Containing phosphazenes prepared in situ11And heating the mixture. Then in the environment orTreatment of the resulting imine/enamine (enamine may be formed for compounds having a bridge Y between atoms a and b) 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 elevated temperature12Or13Thereby producing a compound of the formula5Or a compound of I (hydrogen for R3).

General formula (VII)5aThe triazolopyridines of (a) may alternatively be constructed by: general formula (II)14Conversion of the amine(s) to its corresponding isothiocyanate15(for example by reaction with thiophosgene or 1, 1' -thiocarbonyldiimidazole in dichloromethane in the presence of an organic or aqueous inorganic base) and with4(see scheme 5). The resulting thiourea16Can be activated by alkylation with methyl iodide and subsequently cyclized to the triazolopyridine by intense heating (> 130 ℃) in a polar solvent such as dimethylacetamide in the presence of a suitably functionalized hydroxylamine derivative such as O- (trimethylsilyl) -hydroxylamine5a。

D represents a carbocyclic ring, preferably

General formula (VII)5bThe triazolopyridines of (a) may be prepared by: first of all condensed cyclic hydrazides18And isothiocyanates19(prepared by methods known to those skilled in the art) to form thioureas20(see scheme 6). Thio groups by alkylation (e.g. methyl iodide, in DMF, at elevated temperatures)Temperature of) allowing its displacement by an azide (e.g. sodium azide, in DMF, at elevated temperature) to yield guanidinium azide22. Staudinger reduction with trimethylphosphine to give the intermediate phosphazene23Phosphazenes23Cyclization by heating to produce triazolopyridines5b。

The general formula which can be used as starting material for the preparation of the compounds of formula I can be prepared as described in the scheme below9Aniline of (2).

Scheme 7

A representsOrAnd X represents Cl or Br.

Anilines in which the heteroaryl group II is an annelated triazole moiety9a(see scheme 7) can be prepared from corresponding amino derivatives14Construction of amino derivatives14Are commercially available or may be prepared from the corresponding halides24Obtained by palladium-catalyzed Suzuki coupling with boronic acids or boronic esters (e.g. pinacol esters). Amines as pesticides14Can be reacted with ethoxycarbonyl isothiocyanates to give thiourea derivatives25Thiourea derivatives25Cyclization reaction by treatment with hydroxylamine in the presence of a base under carbon dioxide evolution to produce ring-extended triazoles9a(as described, for example, by M.Nettekoven et al, Synthesis 2003, 11, 1649-.

Scheme 8

A representsOrAnd X represents Cl or Br.

Alternatively, the order of the steps in scheme 7 may be changed (see scheme 8). Halide compound24Which are 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 a ring-extended triazole27. 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 JOC2010, 75, 1791-9a。

Scheme 9

A isOr

B isOr

Compounds can be hydrogenated using palladium on carbon as a catalyst9aThereby producing the corresponding partially saturated compounds9b(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, a metal such as magnesium may be used in an alcohol solution (e.g. ethanol) orReduction of compounds without activation by metals, e.g. by catalytic amounts of iodine9a。

Scheme 10

C represents a carbocyclic ring, preferably

Anilines in which the heteroaryl group II is an annelated thiazole9c(see scheme 10) can be prepared by α -bromoketone28Condensation with thiourea (e.g., by heating in a suitable solvent such as ethanol.) α -bromoketone is commercially available or can be readily prepared by methods known to those skilled in the art of organic synthesis, e.g., by reaction of a suitable ketone with bromine in chloroform.

The general formula which can be used as starting material for the preparation of the compounds of formula I can be prepared as described in the scheme below3A halide of (a).

Scheme 11

Halogenated triazoles3Can be prepared from aniline9(see scheme 11) is prepared 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 12

R^2’、R²"and R²"' is lower alkyl, hydroxy-substituted lower alkylOr is- (CH) optionally substituted by halogen₂)_p-phenyl radical

Wherein heteroaryl II is a halide of a pyrimidine3a(see scheme 12) can be prepared as described, for example, in k. baumann et al, WO2009103652 by: reduced trichloro-pyrimidines29Thereby producing dichloro-derivatives30For example by treatment with zinc (zink) in aqueous ammonia at 0 ℃. Subsequently, the process of the present invention,30the 4-chloro substituent of (a) may be substituted in a nucleophilic substitution reaction (e.g., with a Grignard reagent R)^2’MgX, for example benzylmagnesium chloride, is reacted in tetrahydrofuran at-80 to +20 ℃) or by displacement reaction assisted by a metal catalyst (for example using palladium acetate, 2- (dicyclohexylphosphino-biphenyl, tetrahydrofuran, microwave oven, 30min, 200 ℃). Alternatively to this, the first and second electrodes may be,29one of the reactive chlorine atoms of (A) is first substituted by a radical R^2’Substituted, followed by intermediates31With the second chlorine substituent being replaced by a group R^2”’Is substituted thereby to produce3a。

Scheme 13

R²Is- (CH) optionally substituted by halogen₂)_p-phenyl radical

Wherein heteroaryl II is a halide of a pyrimidine3b(see scheme 13) can be prepared from 2, 6-dichloro-pyrimidine-4-carboxylic acid methyl ester by reaction with, for example, methyl magnesium chloride in THF at-78 deg.C to 0 deg.C, 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 R²By 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 chloride3b. 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 chloride3b. To achieve these modifications, it may be necessary to protect the alcohol group of 2- (2, 6-dichloro-pyrimidin-4-yl) -propan-2-ol before 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 cleaved after modification in THF/water using, for example, p-TsOH.

General formula which can be used as starting material for the preparation of the compounds of the formula I8The ketones of (a) can be prepared as described in the following scheme.

Scheme 14

Ketones with formaldehyde and the appropriate amine PG-NH in scheme 14₂The Mannich reaction of (A) to give a ketone10a。10aThe protecting group(s) of (a) may be changed as desired (e.g. from benzyl to boc-protection). 2, 5-dimethoxy-tetrahydrofuran with diacid (biacid) in the appropriate amine PG-NH₂Condensation in the presence of (A) to provide a ketone10b。10bOr10aDeprotection and coupling with a suitable heteroaryl I halide under base, thermal or metal catalyzed conditions to generate ketones8。

General formula which can be used as starting material for the preparation of the compounds of the formula I2The amines of (a) can be prepared as described in the following scheme.

Scheme 15

Can be prepared from ketone8Via reductive amination with ammonia or hydroxylamine or other suitable amine precursorsReadily converted to amines2a(R³H) (see scheme 15). Amines as pesticides2b(R³Me) starting from methyl grignard reagents to ketones10aGrignard addition of (d). The resulting tertiary alcohol undergoes a Ritter reaction with acetonitrile under strongly acidic conditions. Saponification of the amide and conversion of the protecting group to heteroaryl I as previously described in scheme 14 yields amines2b。

Scheme 16

Wherein heteroaryl I is 3-methyl- [1,2,4]Amines of thiadiazoles2c(see scheme 15) can be prepared, for example, by: 5-chloro-3-methyl- [1,2, 4%]Palladium catalyzed coupling of thiadiazole to piperidin-4-yl-carbamic acid tert-butyl ester and subsequent cleavage of the Boc protecting group in the presence of acid. Alternatively, amines2cAminopiperidines which can be protected by Boc are prepared 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 after deprotection2c。

Scheme 17

R¹Is Cl R¹Is OMe or OEt

Measurement partition is treated with the appropriate sodium salt (NaOMe or NaOEt) in an appropriate alcoholic solvent such as methanol or ethanol, respectively, where R is¹Compounds of formula Ia which are halogens such as Cl can be converted to where R¹Compounds of the formula Ib which are alkoxy radicals (e.g. OMe, OEt) (see scheme 17).

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/oFCS). Subsequent 1: 1 dilutions 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 supernatant was transferred to a round bottom 96 well polypropylene plate for detection A β 42. 50 μ L of detection buffer (50mM Tris/Cl, pH7.4, 60mM NaCl, 0.5% BSA, 1% TWEEN20) was added to the wells followed by the addition of 100 μ L of detection antibody (ruthenium BAP150.0625 μ 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 (DynalM-280, 0.125mg/mL) were incubated for 1 hour at room temperature before addition to the assay plate. the assay plate was incubated for 3 hours at room temperature on a shaker and finally read in a Bioveris M8 Analyzer according to the manufacturer's instructions (Bioveris).

Briefly, after 50. mu.L of cell culture supernatant used to detect A β was removed, 20. mu.L of 1x MTS/PES solution was added to the cells and incubated at 37 ℃ with 5% CO₂Incubate 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 XLFit4.0 software (IDBS)₅₀The value is obtained.

The data for inhibition of a β 42 secretion (μ M) 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. 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 three minutes; tabletting on a suitable tabletting machine.

Capsule preparation

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

[ (rac) -3-rac-8- (2-chloropyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - [8- (3, 4-difluorophenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)3- (3, 4-difluorophenyl) -5-methylpyridin-2-amine

3-bromo-5-methylpyridin-2-amine (0.5g, 2.7mmol), 3, 4-difluorophenylboronic acid (0.5g, 3.2mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride-dichloromethane complex (0.1g, 0.1mmol) was dissolved under argonA mixture of an alkane (10mL) and 1M aqueous sodium carbonate (8mL) and the mixture was heated to 100 ℃ for 1 hour. The reaction was diluted with ethyl acetate, separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 1) as eluent. The title compound was obtained as a light brown crystalline solid (0.6g, quantitative).

MS ISP(m/e)：221.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：7.32-7.16(m，4H)，4.50(brs，2H)，2.38(s，3H)。

b)3- (3, 4-difluorophenyl) -2-isothiocyanato-5-methylpyridine

To a solution of 3- (3, 4-difluorophenyl) -5-methylpyridin-2-amine (0.6g, 2.7mmol) in dichloromethane (15mL) was added a solution of sodium bicarbonate (2.3g, 26.7mmol) in water (25mL), followed by a solution of thiophosgene (0.25mL, 3.2mmol) in dichloromethane (1mL) and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound as a crystalline yellow solid (0.7g, 100%).

MS ISP(m/e)：263.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：7.50(s，1H)，7.32-7.25(m，2H)，7.22-7.18(m，1H)，2.39(s，3H)。

c)1- ((rac) -3-exo-8-benzyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) -3- (3- (3, 4-difluorobenzene Yl) -5-methylpyridin-2-yl) thiourea

To a solution of 3- (3, 4-difluorophenyl) -2-isothiocyanato-5-methylpyridine (0.3g, 1.1mmol) in dimethylacetamide (0.2mL) was added (rac) -3-rac-8-benzyl-8-azabicyclo [3.2.1] oct-3-amine (0.3g, 1.1mmol) and the mixture was heated to 50 ℃ for 15 minutes. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and the solvent was partially evaporated under reduced pressure to crystallize the product. The title compound was obtained as an off-white crystalline solid (0.4g, 75%).

MS ISP(m/e)：479.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：12.24(d，1H)，8.21(s，1H)，7.89-7.82(m，3H)，7.47-7.44(m，3H)，7.35-7.30(m，2H)，7.21-7.16(m，1H)，7.13-7.09(m，1H)，4.97-4.86(m，1H)，4.10(d，2H)，3.80(s，2H)，2.93(t，2H)，2.35-2.17(m，8H)。

d)N' - ((rac) -3-rac-8-benzyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) -N- (3- (3, 4-difluorobenzene -5-methylpyridin-2-yl) aminoiminomethyl sulfide (methyl carbamimidothioate)

To a solution of 1- ((rac) -3-rac-8-benzyl-8-azabicyclo [3.2.1] oct-3-yl) -3- (3- (3, 4-difluorophenyl) -5-methylpyridin-2-yl) thiourea (0.3g, 0.6mmol) in dimethylacetamide (1.5mL) was added iodomethane (0.06mL, 1.0mmol) and the mixture was heated to 80 ℃ for 2 hours. The reaction was evaporated to dryness and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a pale yellow gum (0.3g, 94%).

MS ISP(m/e)：493.2[(M+H)⁺]。

e)((rac) -3-rac-8-benzyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) -8- (3, 4-difluorophenyl) -6- Methyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-amines

To a solution of methyl N' - ((rac) -3-rac-8-benzyl-8-azabicyclo [3.2.1] oct-3-yl) -N- (3- (3, 4-difluorophenyl) -5-methylpyridin-2-yl) aminoiminomethyl sulfide (0.05g, 0.1mmol) in DMF (0.5mL) was added O- (trimethylsilyl) -hydroxylamine (0.03mL, 0.2mmol) and the mixture was heated to 150 ℃ in a microwave for 1 hour, followed by 1 hour at 200 ℃. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 1 to 0: 1) as eluent. The title compound was obtained as a light brown gum (0.01g, 22%).

MS ISP(m/e)：460.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：7.94-7.90(m，1H)，7.40-7.16(m，1H)，4.93-4.82(m，7H)，4.39(s，1H)，4.30(d，1H)，4.07-3.95(m，1H)，3.60(s，2H)，3.27(s，2H)，2.38(s，3H)2.11-1.99(m，4H)，1.83-1.72(m，2H)，1.62(t，2H)。

f)((rac) -3-rac-8- (2-chloropyridin-4-yl) -8-azabicyclo [ 3.2.1)]Oct-3-yl) -8- (3, 4- Difluorophenyl) -6-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-2-amines

To a solution of ((rac) -3-exo-8-benzyl-8-azabicyclo [3.2.1] oct-3-yl) -8- (3, 4-difluorophenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-amine (0.02g, 0.03mmol) in methanol (1mL) was added a spoon of 10% palladium on charcoal followed by a drop of 25% aqueous hydrogen chloride and the mixture was stirred under an atmosphere of hydrogen (balloon) for 3 hours. The reaction was filtered through Hyflo and concentrated to dryness. The residue was redissolved in dimethylacetamide (1mL), the mixture was made basic by the addition of triethylamine, and 2-chloro-4-fluoropyridine (0.02g, 0.15mmol) was added. The mixture was heated to 120 ℃ for 3 hours, after which time it was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 7: 3 to 1: 7) as eluent. The title compound was obtained as an off-white solid (0.05g, 33%).

MS ISP(m/e)：481.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)=8.11(s，1H)，8.00(d，1H)，7.97-7.91(m，1H)，7.71-7.67(m，1H)，7.34(s，1H)，7.23-7.16(m，1H)，6.57(d，1H)，6.48(dd，1H)，4.37-4.26(m，3H)，2.18-2.11(m，4H)，2.05-2.00(m，2H)，1.61(t，2H)。

Example 2

[ (rac) -3-rac-8- (3-methyl- [1,2,4] thiadiazol-5-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

a)3- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-ylamino) - (rac) -3-rac-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

To a solution of 4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-ylamine (46mg, 0.2mmol) in dichloroethane (0.6mL) at room temperature was added BOC-nortropinone (64mg, 0.28mmol) and tetraisopropyl orthotitanate (178 μ L, 0.6mmol) with stirring. The reaction was stirred overnight at 90 ℃ under nitrogen in a sealed tube. At room temperature, ethanol (0.6mL) and sodium borohydride (15mg, 0.4mmol) were added and the reaction was stirred at 85 ℃ for 4 hours 30 minutes. Water was added, the reaction was 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 from CH₂Cl₂To CH₂Cl₂MeOH 19: purification of a gradient of 1(v/v) as eluent gave the title compound as a light brown solid (73mg, 83%).

MS ISP(m/e)：440.3(100)[(M+H)⁺]。

b)((rac) -3-exo-8-aza-bicyclo [ 3.2.1)]Oct-3-yl) - (4-phenyl-4, 5, 6, 7-tetrahydro-benzo Thiazol-2-yl) -amine hydrochloride

To a solution of tert-butyl 3- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-ylamino) - (rac) -3-rac-8-aza-bicyclo [3.2.1] octane-8-carboxylate (93mg, 0.21mmol) in dichloromethane (5mL) was added a 2M solution of hydrogen chloride in diethyl ether (1.1 mL). The reaction was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was treated with diethyl ether and evaporated. The title compound was obtained as a light brown solid (76mg, 96%).

MS ISP(m/e)：340.2(100)[(M+H)⁺]，231.2(34)。

c)[ (rac) -3-rac-8- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -8-aza-bicyclo [3.2.1]Octanoic acid 3-yl]- (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amines

Palladium (II) acetate (3.3mg, 0.015mmol) and 2- (dicyclohexylphosphino) biphenyl (11mg, 0.03mmol) were added under nitrogen at room temperature under nitrogenIn an alkane (1.7mL) for 10 minutes. Sodium tert-butoxide (27mg, 0.28mmol) and ((rac) -3-exo-8-aza-bicyclo [3.2.1] were added]Oct-3-yl) - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine hydrochloride (70mg, 0.19mmol), N-diisopropylethylamine (63. mu.L, 0.37mmol), and 5-chloro-3-methyl- [1,2, 4-methyl- ] -methyl ester]Thiadiazole (28 mg; 0.21mmol) 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 from CH₂Cl₂To CH₂Cl₂MeOH 19: purification with a gradient of 1(v/v) as eluent. The title compound was obtained as a pale yellow solid (48mg, 59%).

MS ISP(m/e)：438.2(100)[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)：7.18(t，2H)，7.11(t，1H)，4.70(m，0.5H)，4.51(m，0.5H)，4.21(m，1.5H)，4.00(m，1H)，3.60(m，0.5H)，2.72(m，2H)，2.47(s，1.5H)，2.42(s，1.5H)，2.32(m，1H)，2.15(m，3H)，2.18(m，5H)，1.65(m，3H)。

Example 3

2- {6- (4-chloro-benzyl) -2- [ (rac) -3-endo-8- (3-methyl- [1,2,4] thiadiazol-5-yl) -8-aza-bicyclo [3.2.1] oct-3-ylamino ] -pyrimidin-4-yl } -propan-2-ol

a)(rac) -3- [ (Z) -hydroxyimino group]-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

To a solution of Boc-nortropinone (1.13g, 5mmol) in ethanol (5mL) was added hydroxylamine hydrochloride (0.695g, 10mmol) in water (5mL) with stirring. Sodium bicarbonate (0.84g, 10mmol) was added in portions and the reaction was refluxed under nitrogen for 45 minutes and stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (1.28g, 100%).

b)(rac) -3-endo-3-amino-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

Reacting (rac) -3- [ (Z) -hydroxyimino group]-8-aza-bicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (635mg, 2.64mmol) in ethanol (4mL) and acetic acid (1mL) under an atmosphere of hydrogen at room temperature under PtO₂(42mg, 6.6 wt.%) was hydrogenated overnight. Adding another part of PtO₂(42mg) and the reaction was further hydrogenated overnight. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure and the residue was passed throughColumn chromatography on silica gel Using CH₂Cl₂/MeOH/NH₃19: 1: 0.1(v/v/v) as eluent to give the title compound as a yellow solid (622mg, 100%).

MS ISP(m/e)：227.3(100)[(M+H)⁺]。

c)(rac) - (3-endo) -3- [4- (4-chloro-benzyl) -6- (1-hydroxy-1-methyl-ethyl) -pyrimidin-2-ylamino Base of]-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

(rac) -3-endo-3-amino-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (189mg, 0.837mmol), 2- [ 2-chloro-6- (4-chloro-benzyl) -pyrimidin-4-yl]-propan-2-ol (342mg, 0.92mmol) and N, N-diisopropylethylamine (214 μ L, 1.26mmol) in bisThe solution in alkane (2mL) was heated in a microwave oven at 150 ℃ for 1 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 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel from CH₂Cl₂To CH₂Cl₂: MeOH 19: purification with a gradient of 1(v/v) as eluent. The title compound was obtained as a yellow oil (86mg, 21%).

MS ISP(m/e)：487.4(100)[(M+H)⁺]。

d)2- [2- [ (rac) - (3-endo) - (8-aza-bicyclo [3.2.1]]Oct-3-yl) amino]-6- (4-chloro-benzyl) Radical) -pyrimidin-4-yl]-propan-2-ol hydrochloride

To a solution of (rac) -3-endo-3- [4- (4-chloro-benzyl) -6- (1-hydroxy-1-methyl-ethyl) -pyrimidin-2-ylamino ] -8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (86mg, 0.177mmol) in dichloromethane (2mL) was added a 2M solution of hydrogen chloride in diethyl ether (0.9mL) with stirring at room temperature and stirred at room temperature overnight. The solvent was removed under reduced pressure and trifluoroacetic acid (2mL) was added. The solvent was removed under reduced pressure to give the title compound as a brown gum (95mg, 127%).

MS ISP(m/e)：387.4(100)[(M+H)⁺]。

e)2- { 644-chloro-benzyl) -2- [ (rac) -3-endo-8- (3-methyl- [1,2,4 [ ]]Thiadiazol-5-yl) -8-nitrogen Hetero-bicyclo [3.2.1]Oct-3-ylamino]-pyrimidin-4-yl } -propan-2-ol

Palladium (II) acetate (3.8mg, 0.017mmol) and 2- (dicyclohexylphosphino) biphenyl (12mg, 0.034mmol) were added under nitrogen at room temperature under nitrogenIn an alkane (1mL) for 10 minutes. Sodium tert-butoxide (32mg, 0.32mmol) and 2- [2- [ (rac) -3-endo- (8-aza-bicyclo [3.2.1] were added]Oct-3-yl) amino]-6- (4-chloro-benzyl) -pyrimidin-4-yl]-propane-2-ol hydrochloride (90mg, 0.213mmol), bisN, N-diisopropylethylamine (72.3. mu.l, 0.425mmol) and 5-chloro-3-methyl- [1,2,4] in an alkane (2mL)]Thiadiazole (32 mg; 0.234mmol) and the reaction was heated to 150 ℃ in a microwave oven for 1 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 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel from CH₂Cl₂To CH₂Cl₂: MeOH 19: purification with a gradient of 1(v/v) as eluent. The title compound was obtained as a light brown gum (55mg, 48%).

MS ISP(m/e)：485.4/487.4(100/33)[(M+H)⁺]，467.3/469.3(38/16)。

¹H NMR(CDCl₃，300MHz)：(ppm)＝7.28(d，2H)，7.19(d，2H)，6.43(s，1H)，4.94(brd，1H)，4.22(m，2H)，4.19(m，1H)，3.85(s，2H)，3.70(s，1H)，2.45(m，2H)，2.44(s，3H)，2.19(m，4H)，1.92(d，2H)，1.41(s，6H)。

Example 4

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-trifluoromethyl-pyridin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine

a)(rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1]Octanyl-8-amine

Reacting (racemic) -3-benzyl-3-azabicyclo [3.2.1]Oct-8-ketoxime (1.2g, 5.1mmol, WO2005/21536A2) was dissolved in methanol (20mL), a large scoop of Raney nickel was added and the mixture was stirred under an atmosphere of hydrogen for 1 hour, after which time it was passedFiltered and concentrated. The residue was purified by column chromatography on silica gel using CH₂Cl₂: a gradient of MeOH (v/v 9: 1-7: 3) was purified as eluent. The title compound was obtained as a waxy solid (0.3g, 26%), as well as the earlier eluting exo-isomer (0.4g, 36%).

MS ISP(m/e)：217.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.32-7.21(m，5H)，3.46(s，2H)，2.88(s，1H)，2.67(dd，2H)，2.11(d，2H)，1.97(brs，2H)，1.81-1.74(m，4H)。

b)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, additional 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)。

c) 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)。

d)8- (3, 4-difluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-ylamines

Reacting 8-bromo- [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (5.33g, 25)mmol), 3, 4-difluorophenylboronic acid (5.92g, 37.5mmol) and 2M aqueous sodium carbonate (62.5mL, 125mmol) in 1, 4-bisThe suspension in alkane (250mL) was treated with 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.02g, 1.25mmol) at room temperature and then stirred at 110 ℃ for 18 hours. The reaction was cooled to room temperature and separated between water (312mL) and ethyl acetate (500 mL). The aqueous layer was extracted with additional ethyl acetate (500 mL). The organic layers were washed with saturated aqueous sodium chloride (300mL), combined, dried over sodium sulfate, filtered off and evaporated. The brown solid was triturated with diethyl ether (130mL) and dichloromethane (25mL) to give the title compound as a light brown solid (6.33g, 97%).

MS ISP(m/e)：247.2(100)[(M+H)⁺]。

e)2-bromo-8- (3, 4-difluorophenyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound

A solution of copper (II) bromide (5.86g, 26.3mmol) and tert-butyl nitrite (3.01g, 3.48mL, 26.3mmol) in acetonitrile (93mL) was added portionwise at 60 deg.C 8- (3, 4-difluorophenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-amine (4.30g, 17.5 mmol). The reaction was stirred at 75 ℃ for 2 h, cooled to room temperature and quenched with 1M aqueous hydrogen chloride (186 mL). The mixture was extracted three times with dichloromethane (186 mL). The organic layers were combined, dried over sodium sulfate, filtered off and evaporated. Flash chromatography on silica gel (120g) with dichloromethane afforded the title compound as a pale yellow solid (4.30g, 79%).

MS ISP(m/e)：310.2/312.0(100/100)[(M+H)⁺]。

f)N- ((racemic) -8-endo-3-benzyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) -8- (3, 4-difluorophenyl) - [1，2，4]Triazolo [1,5-a]Pyridin-2-amines

Reacting 2-bromo-8- (3, 4-difluorophenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine (85mg, 0.27mmol),(rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1]Oct-8-amine (50mg, 0.23mmol) and sodium phenolate (40mg, 0.35mmol) in dry 1, 4-bisThe solution in the sealed tube in the alkane (1mL) was purged with argon for 10 minutes. Pd is added₂(dba)₃.CHCl₃(19mg, 0.02mmol) and xanthphos (21mg, 0.04mmol) were added to the solution and degassing continued for an additional 5 minutes, after which the reaction mixture was heated to 130 ℃ for 0.5 hours. The reaction was diluted with dichloromethane, washed with 1M aqueous sodium carbonate solution, the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 8: 2 to 1: 1) as eluent. The title compound was obtained as a pale yellow solid (88mg, 85%).

MS ISP(m/e)：446.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.35(d，1H)，7.90(dd，1H)，7.70-7.65(m，1H)，7.46(d，1H)，7.33-7.24(m，6H)，6.86(t，1H)，4.48(d，1H)，3.68(d，1H)，3.53(s，2H)，2.74(dd，2H)，2.33-2.30(m，4H)，1.86-1.62(m4H)。

g)[8- (3, 4-difluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- [ (rac) -8-endo-3- (2-trifluoromethyl-pyridin-4-yl) -3-aza-bicyclo [3.2.1]Oct-8-yl]-amines

N- ((rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] in methanol (5mL)]Oct-8-yl) -8- (3, 4-difluorophenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (0.09g, 0.2mmol) was added to a large spoon of palladium on 10% charcoal, followed by a few drops of 25% aqueous hydrochloric acid and the mixture was stirred under an atmosphere of hydrogen for two days. Then the reactants are reacted inFiltered and concentrated to dryness. The residue was dissolved in dimethylacetamide (1mL), triethylamine was added until the pH was basic, then 4-iodo-2- (trifluoromethyl) pyridine (0.05g, 0.2mmol) was added and the mixture was heated to 135 ℃ for 16 hours. The reaction was then diluted with ethyl acetate, washed repeatedly with water, then brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1: 1) as eluent. The title compound was obtained as a pale yellow solid (8.4mg, 9%).

MS ISP(m/e)：501.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.35(d，1H)，8.40(d，1H)，7.90(dd，1H)，7.71-7.68(m，1H)，7.46(d，1H)，7.31-7.24(m，1H)，7.00(d，1H)，6.92(t，1H)，6.73(dd，1H)，4.57(d，1H)，3.98(d，1H)，3.72(dd，2H)，3.23(d，2H)，2.65(s，2H)，2.04-1.98(m，2H)，1.68-1.62(m2H)。

Example 5

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-8- (2, 3, 4-trifluorophenyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound

The title compound was prepared in analogy to example 4 steps d to e from 8-bromo- [1,2,4] triazolo [1,5-a ] pyridin-2-amine and 2, 3, 4-trifluorophenylboronic acid.

b)N- ((racemic) -8-endo-3-benzyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) -8- (2, 3, 4-trifluorobenzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-amines

The title compound was prepared in analogy to example 4f from (rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] oct-8-amine and 2-bromo-8- (2, 3, 4-trifluorophenyl) - [1,2,4] triazolo [1,5-a ] pyridine.

MS ISP(m/e)：464.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)=8.35(d，1H)，7.69-7.64(m，1H)，7.58-7.52(m，1H)，7.44(dt，1H)，7.33-7.24(m，5H)，6.86(t，1H)，4.48(d，1H)，3.66(d，1H)，3.52(s，2H)，2.74(dd，2H)，2.33-2.30(m，4H)，1.83-1.74(m4H)。

c)[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1]Oct-8-yl]-[8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from N- ((rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] oct-8-yl) -8- (2, 3, 4-trifluorophenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-amine and 4-chloro-6-methylpyrimidine in analogy to example 4g, as a light brown foam.

MS ISP(m/e)：466.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)=8.51(s，1H)，8.37(d，1H)，7.55-7.49(m，2H)，7.11-7.05(m，1H)，7.31-7.24(m，1H)，6.92(t，1H)，6.36(s，1H)，4.70(d，1H)，3.96(d，1H)，3.38(t，1H)，3.15(d，2H)，2.85(s，2H)，2.55(brs，2H)，2.40-2.35(m，4H)，1.88-1.85(m2H)。

Example 6

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a) [ (rac) -8-endo-benzyl-3-aza-bicyclo [3.2.1]]Oct-8-yl]-carbamic acid tert-butyl ester

To a solution of (rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] oct-8-amine (3.9g, 17.9mmol) in dichloromethane (40mL) was added Boc-anhydride (6.19mL, 26.9mmol) and the reaction mixture was stirred at 25 ℃ for 2 h. The solvent was removed under reduced pressure, after which the resulting crude material was purified by column chromatography on common silica gel (0-10% EtOAc/hexanes) to give the title compound as a white solid (4.5g, 79%).

¹H NMR(DMSO-d₆，400MHz)：(ppm)=7.33-7.27(m，4H)，7.23-7.21(m，1H)，6.60(brs，1H，NH)，3.44(s，2H)，3.25(m，1H)，2.58(dm，2H)，2.07(br d，2H)，2.03(br s，1H)，1.70(br m，2H)，1.55(br m，2H)，1.37(s，9H)。

b) [ (rac) -8-endo-3-aza-bicyclo [3.2.1]]Oct-8-yl]-carbamic acid tert-butyl ester

To a solution of [ (rac) -8-endo-benzyl-3-aza-bicyclo [3.2.1] oct-8-yl ] -carbamic acid tert-butyl ester (4.5g, 14.2mmol) in methanol (60mL) was added Pd/C (10%; 750mg) and the reaction mixture was stirred under a hydrogen balloon atmosphere at 25 ℃ for 3 hours. The reaction mixture was filtered through a celite bed, and the filtrate was evaporated in vacuo to give the title compound as a white solid (3.1g, 96%).

MS ISP(m/e)：227.2(95)[(M+H)⁺]，171.2(100)。

¹H NMR(DMSO-d₆，400MHz)：(ppm)=6.52(br s，1H，NH)，2.55(m，4H)，1.91(br s，2H)，1.68(m，2H)，1.42(m，2H)，1.37(s，9H)。

c) [ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]-carbamic acid tert-butyl ester

To a solution of [ (rac) -8-endo-3-aza-bicyclo [3.2.1] oct-8-yl ] -carbamic acid tert-butyl ester (3.5g, 15.4mmol) in ethanol (40mL) in a sealed tube was added 5-chloro-3-methyl- [1,2,4] thiadiazole (1.73mL, 18.5mmol) and triethylamine (3.26mL, 23.2 mmol). The reaction mixture was stirred at 100 ℃ for 12 hours. The solvent was removed in vacuo. The resulting crude material was purified by column chromatography on common silica gel (0-15% EtOAc/hexanes) to give the title compound as a white solid (3.9g, 91%).

MS ISP(m/e)：325.2(95)[(M+H)⁺]，269.0(100)。

d) (rac) -8-endo-3- (3-methyl- [1,2, 4)]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octa-8- Amines as pesticides

To a solution of [ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -carbamic acid tert-butyl ester (700mg, 2.16mmol) in dichloromethane (15mL) was added trifluoroacetic acid (2.5mL) and the reaction mixture was stirred at 25 ℃ for 2 hours. The volatiles were removed in vacuo. The resulting residue was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated in vacuo to give the title compound as a white solid (480mg, 96%).

MS ISP(m/e)：225.0(100)[(M+H)⁺]。

e) [ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-fluoro-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 8-2-chloro-4-fluoro-phenyl) -6-methyl- [1,2，4]Triazolo [1,5-a]Pyridin-2-yl]-amines

To 2-bromo-8- (2-chloro-4-fluorophenyl) -6-methyl- [1,2,4]Triazolo [1,5-a]Pyridine (CAS 1329673-52-0; US20110201605) (30mg, 0.088mmol) in dry 1, 4-bisA solution in alkane (2mL) was added (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octyl-8-amine (29.6mg, 0.13mmol) and sodium phenolate (15.3mg, 0.132 mmol). The mixture was purged with argon for 10 minutes. Then adding Pd to the mixture₂(dba)₃.CHCl₃(7.3mg, 0.007mmol) and xantphos (8.16mg, 0.014 mmol). The reaction mixture was again purged with argon for 10 minutes. The reaction mixture was heated to 130 ℃ in a microwave for 0.5 hours. It was diluted with EtOAc (10mL) and washed with water (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off in vacuo. The resulting crude material was purified by preparative HPLC to give the title compound as an off-white solid (8.8mg, 21%).

MS ISP(m/e)：484.2/486.2(100/35)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)=8.57(br s，1H，NH)，7.59(m，2H)，7.33(m，2H)，6.70(d，1H)，4.02(q，1H)，3.75(m，1H)，3.55(brm，1H)，3.36(d，2H)，2.33(s，3H)，2.27(s，3H)，1.91(m，2H)，1.39(br d，2H)。

Example 7

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4]Triazolo [1,5-a]Pyridine compound

To a solution of copper (II) bromide (60mg, 0.268mmol) and tert-butyl nitrite (27.8mg, 0.268mmol) in acetonitrile (2mL) at 60 ℃ was added 8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1319068-45-5; WO2011092272) (50mg, 0.179mmol) in one portion and the reaction was stirred at 75 ℃ for 2 hours. The reaction mixture was cooled to 25 ℃ and quenched with aqueous HCl (1M, 5 mL). The reaction mixture was diluted with water (5mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (55mg, crude) as a brown solid, which was used in the next step without any further purification.

MS ISP(m/e)：344.2/346.2(98/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2，4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (48.8mg, 0.021mmol) and 2-bromo-8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4] triazolo [1,5-a ] pyridine (CAS 1319068-45-5; WO2011092272) (50mg, 0.14mmol) as a white solid (11.3mg, 16%).

MS ISP(m/e)：488.0/489.1(100/35)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)=9.11(q，1H)，7.66-7.60(m，3H)，7.37(t，1H)，6.87(d，1H)，3.75(d，1H)，3.58(br m，2H)，3.35(d，2H)，2.45(br s，2H)，2.27(s，3H)，1.91(m，2H)，1.39(br d，2H)。

Example 8

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-chloro-2-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-8- (4-fluoro-2-methoxyphenyl) - [1,2，4]Triazolo [1,5-a]Pyridine compound

The title compound was prepared in analogy to example 4 steps d to e from 8-bromo- [1,2,4] triazolo [1,5-a ] pyridin-2-amine and 4-fluoro-2-methoxyphenylboronic acid.

MS ISP(m/e)：322.2/324.2(100/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2 ]，4]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 8-4-chloro-2-methoxy-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (52.1mg, 0.23mmol) and 2-bromo-8- (4-fluoro-2-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (50mg, 0.14mmol) as an off-white solid (13.8mg, 19%).

MS ISP(m/e)：466.0(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)=8.61(br s，1H，NH)，7.57(t，1H)，7.43(d，1H)，7.04(dd，1H)，6.92(t，1H)，6.88(dt，1H)，6.73(d，1H)，3.76(s，3H)，3.77(m，1H)，3.58(brm，2H)，3.37(d，2H)，2.27(s，3H)，1.92(m，2H)，1.40(br d，2H)。

Example 9

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3-cyano-4-fluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)5- (2-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-8-yl) -2-fluorobenzonitriles

The title compound was prepared in analogy to example 4 steps d to e from 8-bromo- [1,2,4] triazolo [1,5-a ] pyridin-2-amine and 4-fluoro-3-cyanophenylboronic acid.

MS ISP(m/e)：317.0/319.0(98/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [8- (3-cyano-4-fluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (39.2mg, 0.17mmol) and 5- (2-bromo- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2-fluoro-benzonitrile (37mg, 0.11mmol) as an off-white solid (14.6mg, 27%).

MS ISP(m/e)：461.4(100)[(M+H)⁺]。

Example 10

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4]Triazolo [1,5-a]Pyridine compound

The title compound was prepared from 8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS1319068-34-2, WO2011092272) (50mg, 0.159mmol) in analogy to example 7a, brown solid, (57mg, crude).

MS ISP(m/e)：378.0/380.1(100/98)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (44.4mg, 0.19mmol) and 2-bromo-8- (3, 4-difluoro-phenyl) 6-trifluoro [1,2,4] triazolo [1,5-a ] pyridine (CAS1319068-34-2, WO2011092272) (50mg, 0.13mmol) as an off-white solid (22.0mg, 14%).

MS ISP(m/e)：522.2(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)＝9.35(br s，1H，NH)，8.38(dd，1H)，8.12(m，1H)，8.08(s，1H)，7.59(q，1H)，7.27(d，1H)，3.84(d，1H)，3.59(br m，2H)，3.39(d，2H)，2.54(br s，2H)，2.28(s，3H)，1.98(m，2H)，1.44(br d，2H)。

Example 11

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (51.5mg, 0.23mmol) and 2-bromo-8-methoxy-1- [1,2,4] triazolo [1,5-a ] pyridine (CAS 1319067-40-7; WO2011092272) (35mg, 0.15mmol) as a white solid (15.3mg, 27%).

MS ISP(m/e)：372.2(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)＝8.21(br d，1H)，6.92(d，1H)，6.79(t，1H)，6.56(d，1H)，3.91(s，3H)，3.81(d，1H)，3.57(br m，2H)，3.38(d，2H)，3.23(m，1H)，2.27(s，3H)，1.94(m，2H)，1.41(br d，2H)。

Example 12

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-chloro-6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-8-chloro-6-trifluoromethyl [1,2,4]]Triazolo [ 1]，5-a]Pyridine compound

The title compound was prepared from 8-chloro-6-trifluoro-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1206640-61-0; WO2011092272) (50mg, 0.212mmol) in analogy to example 7a, as a brown solid, (60mg, crude).

MS ISP(m/e)：300.2/302.0(80/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 8-chloro-6-trifluoromethyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (56.0mg, 0.25mmol) and 2-bromo-8-chloro-6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridine (CAS 1206640-61-0; WO2011092272) (50mg, 0.167mmol) as an off-white solid (8.7mg, 12%).

MS ISP(m/e)：444.2/445.2(100/36)[(M+H)⁺]。

Example 13

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [5, 6-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-5, 6-dimethyl- [1,2,4]]Triazolo- [1,5-a]Pyridine compound

The title compound was prepared from 5, 6-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1319067-94-1; WO2011092272) (40mg, 0.24mmol) in analogy to example 7a, as a brown solid, (50mg, crude).

MS ISP(m/e)：226.2/228.0(90/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [5, 6-dimethyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (74.3mg, 0.33mmol) and 2-bromo-5, 6-dimethyl- [1,2,4] triazolo [1,5, -a ] pyridine (CAS 1319067-94-1; WO2011092272) (50mg, 0.22mmol) as a white solid (11.9mg, 15%).

MS ISP(m/e)：369.8(100)[(M+H)⁺]。

Example 14

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-benzyloxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)8-benzyloxy-2-bromo- [1,2, 4%]Triazolo [1,5-a]Pyridine compound

The title compound was prepared from 8-benzyloxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1319067-83-8; WO2011092272) (40mg, 0.167mmol) in analogy to example 7a, as a brown solid, (50mg, crude).

MS ISP(m/e)：304.1/306.0(98/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 8-benzyloxy- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (55.2mg, 0.24mmol) and 8-benzyloxy-2-bromo- [1,2,4] triazolo [1,5-a ] pyridine (CAS 1319067-83-8; WO2011092272) (50mg, 0.16mmol) as a white solid (15.9mg, 22%).

MS ISP(m/e)：448.0(100)[(M+H)⁺]。

Example 15

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-propyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-5-propyl- [1,2,4]]Triazolo- [1,5-a]Pyridine compound

The title compound was prepared from 5-propyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1319067-63-4; WO2011092272) (40mg, 0.22mmol) in analogy to example 7a as a white solid, (53mg, crude).

MS ISP(m/e)：240.0/242.0(96/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 5-propyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (70mg, 0.31mmol) and 2-bromo-5-propyl- [1,2,4] triazolo [1,5-a ] pyridine (CAS 9067-63-4; WO2011092272) (50mg, 0.20mmol) as an off-white solid (11.2mg, 14%).

MS ISP(m/e)：384.0(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)＝7.40(t，1H)，7.29(d，1H)，6.76(d，1H)，6.67(d，1H)，3.85(d，1H)，3.57(br m，2H)，3.40(d，2H)，2.96(t，2H)，2.28(s，3H)，1.96(m，2H)，1.79(q，2H)，1.43(br d，2H)，0.95(t，3H)。

Example 16

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (5-phenyl- [1,2,4] triazolo [1,5-a ] pyrazin-2-yl) -amine

a)2-amino-5-phenyl- [1,2, 4%]Triazolo [1,5-a]Pyrazine esters

Dissolving in the solvent ofA solution of 6- (4-fluorophenyl) pyrazin-2-amine (1.484g, 7.84mmol) in an alkane (60mL) was added ethoxycarbonyl isothiocyanate (1.02mL, 8.63mmol) to give a yellow suspension. The reaction mixture was stirred at room temperature for two days, whereby the color turned from yellow to red and became a light brown suspension. The reaction mixture was evaporated to dryness under reduced pressure. The crude product was used directly in the next step (2.92g, crude). MS ISP (m/e): 321.1(100) [ (M + H)⁺]。

The crude product was added to a suspension of hydroxylamine hydrochloride (2.72g, 39.2mmol) and N, N-diisopropylethylamine (4.03mL, 23.5mmol) suspended in methanol (20mL) and ethanol (20 mL). After stirring at room temperature for 1 hour, the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 100g, 0% to 15% MeOH in dichloromethane/NH 4OH) twice to give the title compound as an off-white solid (985mg, 55%).

MS ISP(m/e)：230.3[(M+H)⁺]。

b)2-bromo-5-phenyl- (1, 2, 4) triazolo (1, 5-a) pyrazines

The title compound was prepared from 2-amino-5-phenyl- [1,2,4] triazolo [1,5-a ] pyrazine (145.9mg, 0.69mmol)) in analogy to example 7a as light yellow crystalline solid (210mg, quantitative).

MS ISP(m/e)：277.1/275.1(100/99)[(M+H)⁺]。

c)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- (5-phenyl- [1,2, 4)]Triazolo [1,5-a]Pyrazin-2-yl) -amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (42.6mg, 0.19mmol) and 2-bromo-5-phenyl- (1, 2, 4) triazolo (1, 5-a) pyrazine (35mg, 0.08mmol) as a white solid (10.9mg, 20%).

MS ISP(m/e)：419.4(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(br s，1H，NH)，8.24(s，1H)，8.09(brd，2H)，7.61-7.54(m，3H)，6.23(d，1H)，3.90(d，1H)，3.59(br m，2H)，3.39(d，2H)，2.95(bs，1H)，2.32(s，3H)，1.96(m，2H)，1.43(br d，2H)。

Example 17

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-5-trifluoromethyl [1,2,4]]Triazolo- [1,5-a]Pyridine compound

The title compound was prepared from 5-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1319067-64-5; WO2011092272) (50mg, 0.248mmol) in analogy to example 7a as a brown solid, (60mg, crude).

MS ISP(m/e)：266.0[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 5-trifluoromethyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (63mg, 0.28mmol) and 2-bromo- (5-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) amine (CAS 1319067-64-5; WO2011092272) (50mg, 0.188mmol) as an off-white solid (13.2mg, 17%).

MS ISP(m/e)：410.2(100)[(M+H)⁺]。

¹H NMR(DMSO-d₆，400MHz)：(ppm)＝7.80(d，1H)，7.61(t，1H)，7.48(m，1H)，7.13(d，1H)，3.88(d，1H)，3.57(br m，2H)，3.39(d，2H)，2.28(s，3H)，1.95(m，2H)，1.44(br d，2H)。

Example 18

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 6-chloro-8- (3, 4-fluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (48.8mg, 0.218mmol) and 2-bromo-6-chloro-8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (CAS 1329673-51-9; US20110201605) (50mg, 0.145mmol) as an off-white solid (10.2mg, 14%).

MS ISP(m/e)：488.2/490.2(100/37)[(M+H)⁺]。

Example 19

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-methyl-5-propyl- [1,2,4] triazolo [1, 5-c ] pyrimidin-2-yl ] -amine

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (65.8mg, 0.29mmol) and 2-bromo-7-methyl-5-propyl- [1,2,4] triazolo [1, 5-c ] pyrimidine (CAS 1792-18-3; Miller, G.W.; Rose, F.L. journal of Chemical Society1965, 3357-68) (50mg, 0.196mmol) as an off-white solid (8.8mg, 11%).

MS ISP(m/e)：399.2(100)[(M+H)⁺]。

Example 20

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4, 4-dimethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)N- (3- (1-hydroxy-4, 4-dimethylcyclohexyl) pyridin-2-yl) trimethylacetamide

To a solution of N- (pyridin-2-yl) trimethylacetamide (1.1g, 6mmol) in tetrahydrofuran (30mL) at-78 deg.C under nitrogen and with stirring was added a 1.6M solution of N-butyllithium in hexane (7.88mL, 12.6 mmol). The reaction was exothermic and it turned pale yellow. The reaction was stirred at-78 ℃ for 15 minutes and then at 0 ℃ for 2 hours. The reaction was cooled to-78 ℃ and 4, 4-dimethylcyclohexanone (937mg, 7.2mmol) dissolved in tetrahydrofuran (5mL) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride 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 under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give the title compound as a white powder (1.034g, 57%).

MS ISP(m/e)：305.3(15)[(M+H)⁺]，287.3(93)，327.3(100)。

b)3- (4, 4-dimethyl-cyclohex-1-enyl) -pyridin-2-ylamine

To a solution of N- (3- (1-hydroxy-4, 4-dimethylcyclohexyl) pyridin-2-yl) trimethylacetamide (1.034g, 3.34mmol) in ethanol (51mL) was added 2M aqueous sodium hydroxide (16.98mmol, 8.5 mL). The reaction was heated at 100 ℃ overnight. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give the title compound as a white solid (706mg, quantitative).

MS ISP(m/e)：203.3(100)[(M+H)⁺]。

c)N- [3- (4, 4-dimethyl-cyclohex-1-enyl) -pyridin-2-yl]-N′-ethoxycarbonyl-thiourea

To a solution of 3- (4, 4-dimethyl-cyclohex-1-enyl) -pyridin-2-ylamine (704mg, 3.48mmol) in bisA solution in an alkane (21mL) was added ethoxycarbonyl isothiocyanate (433mL, 3.48mmol) at room temperature. The reaction was stirred at rt overnight and the solvent was removed to give the crude product as a yellow oil (1.42g, quantitative).

d)8- (4, 4-dimethyl-cyclohex-1-enyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-ylamines

To a solution of N- [3- (4, 4-dimethyl-cyclohex-1-enyl) -pyridin-2-yl ] -N' -ethoxycarbonyl (carboethoxy) -thiourea (1.42g, 3.48mmol) in ethanol (4.3mL) was added hydroxylamine hydrochloride (1.50g, 21.4mmol) and methanol (4.3mL) at room temperature. The yellow suspension was heated to 70 ℃ overnight. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel first with ethyl acetate as eluent and then again with a heptane/ethyl acetate (1: 1v/v) mixture as eluent to give the title compound as a yellow solid (526mg, 51%).

MS ISP(m/e)：243.3(100)[(M+H)⁺]。

e)8- (4, 4-dimethyl-cyclohexyl) - [1,2,4 [ ]]Triazolo [1,5-a]Pyridin-2-ylamines

To a solution of 8- (4, 4-dimethyl-cyclohex-1-enyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (30mg, 0.124mmol) in methanol (4mL) was added 10% Pd/C (30mg), and the reaction mixture was stirred under a hydrogen balloon atmosphere at 25 ℃ for 2 hours. The reaction mixture was filtered through celite bed and the filtrate was evaporated in vacuo to give the title compound (30mg, 99%) as a white solid which was used in the next step without further purification.

MS ISP(m/e)：245.0(100)[(M+H)⁺]。

f)2-bromo-8- (4, 4-dimethyl-cyclohexyl) - [1,2,4]Triazolo [ 1]，5-c]Pyridine compound

The title compound was prepared from 8- (4, 4-dimethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamine (36mg, 0.14mmol) in analogy to example 7a as a white solid, (43mg, crude).

MS ISP(m/e)：308.2/310.2(98/100)[(M+H)⁺]。

g)[(Rac) -8-endo-3- (3-methyl- [1,2,4]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [8- (4, 4-dimethyl-cyclohexyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (46.9mg, 0.209mmol) and 2-bromo-8- (4, 4-dimethyl-cyclohexyl) - (1, 2, 4) triazolo (1, 5-a) pyridine (43mg, 0.14mmol) as a white solid (12.3mg, 19%).

MS ISP(m/e)：452.2(100)[(M+H)⁺]。

Example 21

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (7-furan-2-yl- [1,2,4] triazolo [1,5-a ] pyrimidin-2-yl) -amine

a)2-bromo-7-furan-2-yl- [1,2,4]Triazolo [1,5-a]Pyrimidines

The title compound was prepared in analogy to example 7a from 7-furan-2-yl- [1,2,4] triazolo [1,5-a ] pyrimidin-2-yl-amine (CAS 338793-16-1; WO2004005323) (30mg, 0.14mmol) as a brown solid (50mg, crude).

MS ISP(m/e)：265.0[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- (7-furan-2-yl- [1,2, 4)]Triazolo [1,5-a]Pyrimidin-2-yl) -amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (46.9mg, 0.209mmol) and 2-bromo-7-furan-2-yl- [1,2,4] triazolo [1,5-a ] pyrimidine as a white solid (15.6mg, 27%).

MS ISP(m/e)：409.0(100)[(M+H)⁺]。

Example 22

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)2-bromo-7-trifluoromethyl [1,2,4]]Triazolo [1,5-a]Pyridine compound

The title compound was prepared from 7-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (CAS 1260811-97-9; WO2011092272) (30mg, 0.14mmol) in analogy to example 7a, as a brown solid, (39mg, crude).

MS ISP(m/e)：266.0/268.0(85/100)[(M+H)⁺]。

b)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [ 7-trifluoromethyl- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (49.2mg, 0.22mmol) and 2-bromo-7-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridine (educt amine) CAS 0811261-97-9; WO2011092272) (39mg, 0.147mmol) as an off-white solid (25.1mg, 42%).

MS ISP(m/e)：410.2(100)[(M+H)⁺]。

Example 23

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-trifluoromethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

b)8- (4-trifluoromethyl-cyclohexyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl-amines

To a solution of 8- (4-trifluoromethyl-cyclohexenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamine (CAS1329673-42-8, US20110201605) (30mg, 0.106mmol) in methanol (5mL) was added 10% Pd/C (30mg), and the reaction mixture was stirred at 25 ℃ for 2 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered through a celite bed and the filtrate was evaporated in vacuo to yield the title compound as a white solid (30mg, 99%) which was used in the next step without further purification.

MS ISP(m/e)：285.2(100)[(M+H)⁺]。

b)2-bromo-8- (4-trifluoromethyl-cyclohexyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound

The title compound was prepared from 8- (4-trifluoromethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine (30mg, 0.10mmol) in analogy to example 7a as a white solid, (37mg, crude).

MS ISP(m/e)：348.0/350.0(100/85)[(M+H)⁺]。

c)[ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octanoic acid 8-radical]- [8- (4-trifluoromethyl-cyclohexyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 6e from (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-amine (34.2mg, 0.15mmol) and 2-bromo-8- (4-trifluoromethyl-cyclohexyl) - [1,2,4] triazolo (1, 5-a) pyridine (37mg, 0.10mmol) as a light brown solid (4mg, 8%).

MS ISP(m/e)：499.2(100)[(M+H)⁺]。

Example 24

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -6-oxa-3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)(rac) -3-benzyl-6-oxa-3-aza-bicyclo [3.2.1]Octan-8-ones

A solution of benzylamine (1.26mL, 11.6mmol) in methanol (2mL) was added dropwise under nitrogen over a period of 3 hours to a refluxing solution of dihydro-furan-3-one (1g, 11.6mmol), paraformaldehyde (1.04g, 34.84mmol) and glacial acetic acid (0.67mL, 11.61mmol) in methanol (8 mL). Reflux was continued for 1 hour, after which the brown reaction mixture was stirred at 23 ℃ for 16 hours. The reaction mixture was concentrated in vacuo. The resulting oil was diluted with water and basified with 6N aqueous NaOH. The aqueous solution was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel with 25-30% ethyl acetate in hexane as eluent. The title compound was obtained as a colorless viscous liquid (500mg, 20%).

b)(rac) -3-benzyl-6-oxa-3-aza-bicyclo [3.2.1]Octan-8-ketoxime

A mixture of (rac) -3-benzyl-6-oxa-3-aza-bicyclo [3.2.1] oct-8-one (500mg, 2.30mmol), hydroxylamine hydrochloride (224mg, 3.22mmol) and pyridine (0.32mL) in ethanol (5mL) was heated to 100 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5N aqueous sodium hydroxide (10mL) was added to the residue. The resulting solution was extracted with ethyl acetate (50mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with a 5-10% ethyl acetate/hexane mixture as eluent to give the title compound as a brown viscous liquid (220mg, 43%).

c)(rac) -8-endo-3-benzyl-6-oxa-3-aza-bicyclo [3.2.1]Octan-8-ylamine

To a deoxygenated solution of (rac) -3-benzyl-6-oxa-3-aza-bicyclo [3.2.1] octa-8-one oxime (6.6g, 28.4mmol) in methanol (140mL) was added Raney nickel (1.36g) under an argon atmosphere. It was hydrogenated using a hydrogen balloon at 23 ℃ for 1 hour. The reaction was filtered through a celite bed and the filtrate was concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (0.5 to 1.5% methanol in dichloromethane as eluent). A mixture of exo-and endo-isomers was obtained. Column chromatography was repeated twice to obtain the endo-isomer as a colorless oil (260mg, 42%).

d)((rac) -8-endo-3-benzyl-6-oxa-3-aza-bicyclo [ 3.2.1)]Oct-8-yl) - [8- (2, 3, 4- Trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

Microwave vial with 2-bromo-8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine (100mg, 0.30mmol), (rac) -8-endo-3-benzyl-6-oxa-3-aza-bicyclo [ 3.2.1%]Oct-8-ylamine (66mg, 0.305mmol) and sodium phenolate (45mg, 0.39mmol) in dry 1, 4-bisThe solution in alkane (4mL) was purged with argon for 10 minutes. Pd is added₂(dba)₃.CHCl₃(11mg, 0.011mmol) and xanthhphos (13mg, 0.022mmol) were added to the solution and degassing was continued for another 5 minutes, after which the reaction mixture was heated in a microwave at 130 ℃ for 30 minutes. The reaction was diluted with dichloromethane (20mL) and washed with 1M aqueous sodium carbonate (1 × 30 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using MeOH/dichloromethane (3%) as eluent to give the title compound as a light brown solid (85mg, 59%).

e)(rac) -8-endo-6-oxa-3-aza-bicyclo [3.2.1]Oct-8-yl- [8- (2, 3, 4-trifluoro-benzene) Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

To a deoxygenated solution of ((rac) -8-endo-3-benzyl-6-oxa-3-aza-bicyclo [3.2.1] oct-8-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (85mg, 0.18mmol) in methanol (15mL) was added 10% palladium on charcoal (19mg) and several drops of 25% aqueous hydrochloric acid. The reaction mass was stirred under a hydrogen balloon at atmospheric pressure and at 23 ℃ for 2 days. The reaction mass was filtered through celite bed and the filtrate evaporated to dryness under reduced pressure to give the title compound as a brown viscous solid (68mg, 99%).

f)[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -6-oxa-3-aza-bicyclo [3.2.1]Octa-8- Base of]- [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

To a solution of (rac) -8-endo-6-oxa-3-aza-bicyclo [3.2.1] oct-8-yl- [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (68mg, 0.181mmol) in NMP (1mL) was added triethylamine until the pH of the resulting solution was basic. To the reaction was added 4-chloro-6-methyl-pyrimidine (70mg, 0.544mmol) and the mixture was heated to 135 ℃ for 2 hours. The reaction mass was cooled and partitioned between ethyl acetate (50mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting crude residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffered water as solvents and an Xbridge column to give the title compound as a light brown solid (24.0mg, 28%).

MS ISP(m/e)：468.4[(M+H)⁺]。

Example 25

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-thia-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)(rac) -7-benzyl-3-thia-7-aza-bicyclo [3.3.1]Nonan-9-ones

The title compound was prepared from tetrahydro-thiopyran-4-one (10g, 86.0mmol) in analogy to example 24a as a light yellow solid (4g, 17%).

b)(rac) -7-benzyl-3-thia-7-aza-bicyclo [3.3.1]Nonan-9-ketoxime

The title compound was prepared as a solid (2.4g, 90%) from (rac) -7-benzyl-3-thia-7-aza-bicyclo [3.3.1] nonan-9-one in analogy to example 24 b.

c)(rac) -9-rac-7-benzyl-3-thia-7-aza-bicyclo [3.3.1]Non-9-ylamine

The title compound was prepared as a solid (150mg, 10%) from (rac) -7-benzyl-3-oxa-7-aza-bicyclo [3.3.1] nonan-9-one oxime (1.5g, 5.7mmol) in analogy to example 24 c.

d)((rac) -9-rac-7-benzyl-3-thia-7-aza-bicyclo [ 3.3.1)]Non-9-yl) - [8- (2, 3, 4- Trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 24d from 2-bromo-8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (150mg, 0.457mmol) and (rac) -9-rac-7-benzyl-3-thia-7-aza-bicyclo [3.3.1] non-9-ylamine (124.7mg, 0.503mmol) as a light brown solid (90.0mg, 39%).

e)((rac) -9-rac-3-thia-7-aza-bicyclo [ 3.3.1)]Non-9-yl) - [8- (2, 3, 4-trifluoro-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from ((rac) -9-rac-7-benzyl-3-thia-7-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (90mg, 0.182mmol) in analogy to example 24e as light yellow solid (70.0mg, 95%).

f)[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-thia-7-aza-bicyclo [3.3.1]Nonane-9- Base of]- [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from ((rac) -9-rac-3-thia-7-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (70mg, 0.173mmol) in analogy to example 24f as a light brown solid (8.7mg, 10%).

MS ISP(m/e)：498.4[(M+H)⁺]。

Example 26

[ (rac) -9-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)(rac) -3-benzyl-3-aza-bicyclo [3.3.1]Nonan-9-ketoxime

The title compound was prepared from 3-benzyl-3-aza-bicyclo [3.3.1] non-9-one (commercially available) (1.5g, 6.54mmol) in analogy to example 24b as an oily liquid (1.4g, 87%).

b)(rac) -9-endo/exo-3-benzyl-3-aza-bicyclo [3.3.1]Non-9-ylamine

The title compound was prepared in analogy to example 24c from (rac) -3-benzyl-3-aza-bicyclo [3.3.1] non-9-one oxime (1.4g, 5.72mmol) as a light yellow solid (1.2g, 91%).

c)((rac) -9-endo/exo-3-benzyl-3-aza-bicyclo [ 3.3.1)]Non-9-yl) - [8- (2, 3, 4-trifluoro- Phenyl) - [ 1] (iii) is (iii),2，4]triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 24d from 2-bromo-8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (200mg, 0.61mmol) and (rac) -9-endo/exo-3-benzyl-3-aza-bicyclo [3.3.1] non-9-ylamine (140mg, 0.457mmol) as a light brown viscous solid (80mg, 27%).

d)((rac) -9-endo/exo-3-aza-bicyclo [ 3.3.1)]Non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1，2，4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from ((rac) -9-endo/exo-3-benzyl-3-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (65mg, 0.165mmol) in analogy to example 24e as a brown viscous solid (64mg, 99%).

e)[ (rac) -9-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.3.1]Non-9-yl]-[8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from ((rac) -9-endo/exo-3-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (80mg, 0.166mmol) in analogy to example 24f as a light brown solid (6.0mg, 7.6%).

MS ISP(m/e)：480.4[(M+H)⁺]。

Example 27

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-oxa-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)(rac) -3-benzyl-3-aza-bicyclo [3.3.1]Nonan-9-ones

The title compound was prepared from tetrahydro-pyran-4-one (10g, 99mmol) in analogy to example 24a as a light yellow oil (4g, 17%).

b)(rac) -7-benzyl-3-oxa-7-aza-bicyclo [3.3.1]Nonan-9-ketoxime

The title compound was prepared from (rac) -3-benzyl-3-aza-bicyclo [3.3.1] nonan-9-one (4g, 17.3mmol) in analogy to example 24b as an oily liquid (4g, 94%).

c)(rac) -9-endo/exo-7-benzyl-3-oxa-7-aza-bicyclo [3.3.1]Non-9-ylamine

The title compound was prepared as a solid (4g, 85%) from (rac) -7-benzyl-3-oxa-7-aza-bicyclo [3.3.1] nonan-9-one oxime (5g, 20.3mmol) in analogy to example 24 c.

d)(rac) -9-endo/exo-7-benzyl-3-oxa-7-aza-bicyclo [3.3.1]Non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 24d from 2-bromo-8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (150mg, 0.45mmol) and (rac) -9-endo/exo-7-benzyl-3-oxa-7-aza-bicyclo [3.3.1] non-9-ylamine (116.7mg, 0.50mmol) as a light brown solid (150mg, 68%).

e)(rac) -9-endo/exo-3-oxa-7-aza-bicyclo [3.3.1]Non-9-yl) - [8- (2, 3, 4-trifluoro- Phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from (rac) -9-endo/exo-7-benzyl-3-oxa-7-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (150mg, 0.313mmol) in analogy to example 24e as light yellow solid (120mg, 98%).

f)[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-oxa-7-aza-bicyclo [3.3.1]Nonane-9- Base of]- [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared analogously to example 24f from (rac) -9-endo/exo-3-oxa-7-aza-bicyclo [3.3.1] non-9-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (121mg, 0.311mmol) as a light brown solid (20.9mg, 14%).

MS ISP(m/e)：482.4[(M+H)⁺]。

Example 28

[ (rac) -8-exo-methyl-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-endo-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

a)(rac) -8-endo/exo-3-benzyl-8-endo/exo-methyl-3-aza-bicyclo [3.2.1]Octanol-8-ol

To a solution of (rac) -3-benzyl-3-aza-bicyclo [3.2.1] oct-8-one (7g, 32.5mmol) in dry tetrahydrofuran (100mL) was added a solution of methylmagnesium bromide in THF (1.4M, 104mL, 146.5mmol) at-20 ℃ with a syringe under a nitrogen atmosphere. The reaction mixture was stirred at-20 ℃ for 30 minutes and then at 23 ℃ for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 75mL), washed with water and brine, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (15-20% ethyl acetate in hexanes as eluent) to give the title compound (5g, 66%) as a pale yellow oil.

b)N- ((rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [ 3.2.1)]Oct-8-endo-yl) -acetamide

To a solution of (rac) -8-endo/exo-3-benzyl-8-endo/exo-methyl-3-aza-bicyclo [3.2.1] octan-8-ol (5.4g, 23.3mmol) in acetonitrile (27mL) was added concentrated sulfuric acid (22mL) over a period of 10 minutes at 23 ℃. The reaction mixture was stirred at 23 ℃ for 16 hours. The reaction mixture was poured into ice and the resulting solution was adjusted to pH10 with aqueous potassium hydroxide. It was extracted with ethyl acetate (3 × 50mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (25-30% ethyl acetate in hexanes as eluent) to give the title compound as a light yellow solid (1g, 16%).

c)(rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [3.2.1]Octa-8-endo-amine

To a solution of 3-N- ((rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [3.2.1] oct-8-endo-yl) -acetamide (1g, 3.67mmol) in 6N aqueous HCl (40mL) was refluxed for 36 hours. The reaction mixture was made basic with 20% aqueous NaOH (pH 11) and extracted with ethyl acetate (3 × 50mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (2 to 3.5% methanol in dichloromethane as eluent) to give the title compound as a light brown semisolid (225mg, 27%).

d)(rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [3.2.1]Oct-8-endo-yl) - [8- (2, 3, 4- Trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared in analogy to example 24d from 2-bromo-8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (100mg, 0.305mmol) and (rac) -3-benzyl-8-rac-methyl-3-aza-bicyclo [3.2.1] oct-8-ylamine (77.1mg, 0.335mmol) as a light brown solid (60mg, 41%).

e)(rac) -8-exo-methyl-3-aza-bicyclo [3.2.1]Oct-8-endo-yl) - [8- (2, 3, 4-trifluoro-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from (rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [3.2.1] oct-8-endo-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (44mg, 0.092mmol) in analogy to example 24e as a light yellow solid (35mg, 98%).

f)[ (rac) -8-rac-methyl-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1]Octa-8-endo- Base of]- [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-amines

The title compound was prepared from (rac) -3-benzyl-8-exo-methyl-3-aza-bicyclo [3.2.1] oct-8-endo-yl) - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine (35mg, 0.09mmol) in analogy to example 24f as a light brown solid (1.8mg, 4.2%).

MS ISP(m/e)：480.4[(M+H)⁺]。

Example 29

[ (rac) -8- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-rac-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine

a)N- ((racemic) -8-exo-3-benzyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) - (rac) -8- (4-fluoro Phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4]Triazolo [1,5-a]Pyridin-2-amines

To a solution of (rac) -8- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-amine (CAS 1262197-53-4; US20110201605) (128mg, 551 μmol) and (rac) -3-benzyl-3-azabicyclo [3.2.1] oct-8-one (178mg, 827 μmol) in 1, 2-dichloroethane (5mL) was added titanium isopropoxide (470mg, 489 μ L, 1.65mmol) under stirring and nitrogen atmosphere and stirred at 85 ℃ overnight. After cooling to room temperature, ethanol (5mL) was added and then sodium borohydride (83.4mg, 2.2mmol) was added carefully. The reaction was stirred at 85 ℃ overnight. After cooling, water was added and the reaction was stirred for 30 minutes. The precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure and water was added. The reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane to dichloromethane/methanol (v/v 19: 1) as eluent. The title compound was obtained as crude (84mg) as a yellow viscous oil and used in the next step without further purification.

MS ISP(m/e)：432.4(100)[(M+H)⁺]，218.3(87)，275.2(24)。

b)N- ((rac) -8-exo-3-azabicyclo [ 3.2.1)]Oct-8-yl) - (rac) -8- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro- [1,2, 4-]Triazolo [1,5-a]Pyridine-2-amine hydrogen chloride

To a solution of N- ((rac) -8-rac-3-benzyl-3-azabicyclo [3.2.1] oct-8-yl) -8- (rac) -8- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-amine (84mg, 195 μmol) in methanol (1.95mL) was added one drop of 25% aqueous hydrogen chloride and Pd/C10% (20.7mg, 195 μmol). The reaction was hydrogenated under hydrogen atmosphere overnight. The catalyst was filtered off and washed with methanol. The filtrate was evaporated under reduced pressure to give the title compound as a light brown solid (80 mg). The crude material was used directly in the next step without further purification.

c)[ (rac) -8- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4]triazolo [1,5-a]Pyridine-2- Base of]- [ (rac) -8-rac-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Oct-8-yl]- Amines as pesticides

To a solution of N- ((rac) -8-rac-3-azabicyclo [3.2.1] oct-8-yl) - (rac) -8- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-amine hydrochloride (79mg, 209 μmol) in ethanol (1mL) was added triethylamine (63.5mg, 87.4 μ L, 627 μmol) and 5-chloro-3-methyl-1, 2, 4-thiadiazole (38.5mg, 272 μmol) dissolved in ethanol (0.5 mL). The reaction was stirred at 100 ℃ overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using a gradient from dichloromethane to a mixture of dichloromethane/methanol (v/v 19: 1) as eluent. The compound was purified a second time on silica gel using a gradient from ethyl acetate to a mixture of ethyl acetate/methanol (v/v 9: 1) as eluent to give the title compound as a pale yellow solid (33mg, 36%).

MS ISP(m/e)：440.5(100)[(M+H)⁺]。

Example 30

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine

a)N- ((racemic) -8-endo-3-benzyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) -8- (3, 4-difluorophenyl) - [1，2，4]Triazolo [1,5-a]Pyridin-2-amines

To the reaction solution of 2-bromo-8- (3, 4-difluorophenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine (CAS 1329672-92-5; US20110201605) (372mg, 1.2mmol) and (rac) -8-endo-3-benzyl-3-azabicyclo [ 3.2.1%]Octanyl-8-amine (216mg, 1mmol) in bisA solution in an alkane (7mL) was added under nitrogen and with stirring sodium phenolate (183mg, 1.5mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (94.5mg, 160. mu. mol) and tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (85.4mg, 80.0. mu. mol). The reaction was degassed three times and heated to 130 ℃ in a microwave oven for 30 minutes. It was diluted with dichloromethane, washed with 1M aqueous sodium carbonate and with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of heptane/ethyl acetate (v/v 4: 1 to 1: 1) as eluent. The title compound was obtained as a brown viscous oil (188mg, 42%).

MS ISP(m/e)：446.5(50)[(M+H)⁺]，337.4(100)

b)[8- (3, 4-difluoro-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- [ (rac) -8-endo-3- (2-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1]Oct-8-yl]-amines

To a solution of N- ((rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] oct-8-yl) -8- (3, 4-difluorophenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-amine (70mg, 157 μmol) in methanol (1.6mL) under nitrogen and with stirring was added one drop of 25% aqueous hydrogen chloride. The reaction was hydrogenated at 1 bar overnight. The catalyst was filtered off and washed with ethanol. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (1.6 mL). Triethylamine (47.7mg, 65.7. mu.L, 471. mu. mol) and 4-chloro-2-methylpyrimidine (25.0mg, 189. mu. mol) were added and the reaction was heated to 150 ℃ in a microwave oven for 30 minutes. After cooling to room temperature the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient from ethyl acetate to ethyl acetate/methanol (v/v 9: 1) as eluent. The title compound was obtained as a pale yellow solid (36mg, 51%).

MS ISP(m/e)：448.5(100)[(M+H)⁺]，225.0(80)。

Example 31

[ (rac) -8- (3, 4-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine

a)N- ((racemic) -8-endo-3-azabicyclo [ 3.2.1)]Oct-8-yl) - (rac) - (3, 4-difluorophenyl) - 5, 6, 7, 8-tetrahydro- [1,2, 4-]Triazolo [1,5-a]Pyridine-2-amine hydrochloride

A suspension of N- ((rac) -8-endo-3-benzyl-3-azabicyclo [3.2.1] oct-8-yl) - (rac) 8- (3, 4-difluorophenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-amine (107mg, 240. mu. mol), Pd/C10% (107mg, 1.01mmol) and concentrated aqueous hydrochloric acid (90.0mg, 75.0. mu.L, 617. mu. mol) in ethanol (6.27mL) was hydrogenated at 50 ℃ under a hydrogen atmosphere of 50 bar for 24 h. The catalyst was filtered off and washed with ethanol, and the solvent was removed under reduced pressure to give the title compound as a white semi-solid (85mg, 89%).

MS ISP(m/e)：360.6(100)[(M+H)⁺]。

b)[ (rac) -8- (3, 4-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4 [ ] -]Triazolo [1,5-a]Pyridine- 2-radical]- [ (rac) -8-endo-3- (3-methyl- [1,2,4]]Thiadiazol-5-yl) -3-aza-bicyclo [3.2.1]Octa-8- Base of]-amines

To a solution of N- ((rac) -8-endo-3-azabicyclo [3.2.1] oct-8-yl) - (rac) - (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-amine hydrochloride (83mg, 210 μmol) in ethanol (2.1mL) was added triethylamine (63.6mg, 87.7 μ L, 629 μmol) and 5-chloro-3-methyl-1, 2, 4-thiadiazole (35.6mg, 252 μmol) dissolved in ethanol (0.5 mL). The reaction was heated to 100 ℃ overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient from ethyl acetate to a mixture of ethyl acetate/methanol (v/v 9: 1) as eluent. The title compound was obtained as a white solid (55mg, 57%).

MS ISP(m/e)：458.6(100)[(M+H)⁺]，230.0(50)。

Claims (15)

1. A compound of formula I

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

heteroaryl II is a bicyclic ring system containing 1 to 4 heteroatoms selected from S or N, wherein at least one ring is aromatic in nature, selected from the group consisting of:

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

R²is lower alkyl, lower alkyl substituted by halogen, lower alkoxy, cycloalkyl substituted by lower alkyl or lower alkyl substituted by halogen, or is lower alkyl substituted by hydroxy, furyl, O-benzyl, or- (CH)₂)_p-phenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkyl or by cyano;

R³is hydrogen or lower alkyl;

y is- (CH)₂)_n-、-CH₂OCH₂-、-CH₂O-、CH₂S-、-CH₂SCH₂-and to two of the ring carbon atoms, to ring carbon atoms a and b or to ring carbon atoms c and d;

p is 0 or 1;

m is 0, 1 or 2; if m is 2, R¹May be the same or different;

n is 2 or 3;

o is 0, 1 or 2, and if o is 2, R²May be the same or different;

wherein "lower alkyl" refers to a saturated straight or branched chain group containing 1 to 7 carbon atoms,

"lower alkoxy" means an alkyl group, as described above, bonded through an O atom,

or a pharmaceutically active acid addition salt thereof.

2. A compound of formula I according to claim 1,

wherein

Heteroaryl I is pyridyl, 1,2, 4-thiadiazolyl, pyrazinyl or pyrimidinyl;

heteroaryl II is [1,2,4] triazolo [1,5-a ] pyridyl, [1,2,4] triazolo [1,5-a ] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridyl, [1,2,4] triazolo [1, 5-c ] pyrimidinyl or 4, 5, 6, 7-tetrahydro-benzothiazolyl;

R¹is methyl, chlorine or CF₃：

R²Is methyl, n-propyl, fluorine, chlorine, trifluoromethyl, methoxy or is-C (CH)₃)₂OH is O-benzyl, cyclohexyl substituted by methyl or trifluoromethyl, furyl, or- (CH)₂)_p-phenyl, optionally substituted by one, two or three halogen atoms selected from F or Cl or by cyano or methoxy;

R³is hydrogen or methyl;

y is- (CH)₂)_n-, or is-CH₂OCH₂-, or is-OCH₂-, or is-CH₂SCH₂-，

Or is-SCH₂And to two of the ring carbon atoms, to ring carbon atoms a and b or to ring carbon atoms c and d;

p is 0 or 1;

m is 0, 1 or 2;

n is 2, or 3;

o is 1 or 2, if o is 2, R²May be the same or different;

or a pharmaceutically active acid addition salt thereof.

3. A compound of formula I according to any one of claims 1 or 2, wherein Y is- (CH)₂)₂-, heteroaryl I isAnd heteroaryl II is [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1,5-a]Pyrazinyl, 5, 6, 7, 8-tetrahydro- [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1, 5-c]Pyrimidinyl or 4, 5, 6, 7-tetrahydro-benzenesAnd a thiazolyl group.

4. A compound of formula I according to any one of claims 1 or 2, wherein the compound is

[ (rac) -3-rac-8- (3-methyl- [1,2,4] thiadiazol-5-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - (4-phenyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2-chloro-4-fluoro-phenyl) -6-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-chloro-2-methoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3-cyano-4-fluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (3, 4-difluoro-phenyl) -6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-chloro-6-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [5, 6-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 8-benzyloxy- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-propyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (5-phenyl- [1,2,4] triazolo [1,5-a ] pyrazin-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 5-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 6-chloro-8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-methyl-5-propyl- [1,2,4] triazolo [1, 5-c ] pyrimidin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4, 4-dimethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - (7-furan-2-yl- [1,2,4] triazolo [1,5-a ] pyrimidin-2-yl) -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [ 7-trifluoromethyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (4-trifluoromethyl-cyclohexyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8- (4-fluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-rac-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine or [ (rac) -8- (3, 4-difluoro-phenyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

5. A compound of formula I according to any one of claims 1 or 2, wherein Y is- (CH)₂)_n-, heteroaryl I isAnd heteroaryl II is [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1,5-a]Pyrazinyl, 5, 6, 7, 8-tetrahydro- [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1, 5-c]Pyrimidinyl or 4, 5, 6, 7-tetrahydro-benzothiazolyl.

6. A compound of formula I according to any one of claims 1 or 2, wherein the compound is

[ (rac) -3-rac-8- (2-chloropyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-3-yl ] - [8- (3, 4-difluorophenyl) -6-methyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine or

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-trifluoromethyl-pyridin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

7. A compound of formula I according to any one of claims 1 or 2, wherein heteroaryl I isAnd heteroaryl II is [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1,5-a]Pyrazinyl, 5, 6, 7, 8-tetrahydro- [1,2,4]]Triazolo [1,5-a]Pyridyl, [1,2,4] or a salt thereof]Triazolo [1, 5-c]Pyrimidinyl or 4, 5, 6, 7-tetrahydro-benzothiazolyl, and the other definitions are as described in claim 1.

8. A compound of formula I according to any one of claims 1 or 2 or wherein the compound is

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-endo-3- (6-methyl-pyrimidin-4-yl) -6-oxa-3-aza-bicyclo [3.2.1] oct-8-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-thia-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-endo-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -9-rac-7- (6-methyl-pyrimidin-4-yl) -3-oxa-7-aza-bicyclo [3.3.1] non-9-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine

[ (rac) -8-exo-methyl-3- (6-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-endo-yl ] - [8- (2, 3, 4-trifluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -amine or

[8- (3, 4-difluoro-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - [ (rac) -8-endo-3- (2-methyl-pyrimidin-4-yl) -3-aza-bicyclo [3.2.1] oct-8-yl ] -amine.

9. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 8, comprising the steps of:

a) make formula2Of (a) a compound

And formula3By reaction of a compound of

To produce a compound of formula I

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

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

or

b) Make formula6Of (a) a compound

And formula7By reaction of a compound of

To produce a compound of formula I

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

c) Make formula8Of (a) a compound

And formula9By reaction of a compound of

To produce a compound of formula I

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

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

10. A medicament comprising one or more compounds as defined in any one of claims 1 to 8 and pharmaceutically acceptable excipients.

11. A medicament according to claim 10 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.

12. Use of a compound as claimed in any one of claims 1 to 8 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.

13. A compound according to any one of claims 1-2 for use as therapeutically active substance.

14. Use of a compound as claimed in any one of claims 1 to 8 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.

15. A compound according to any one of claims 1-2 for use in 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.