Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• hetaryl is a five membered heteroaryl group, containing 1 to 3 heteroatoms, selected from
• R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by
• n 1 to 5;
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen
• the present compounds of formula I are modulators of ⁇ - secretase, they may be useful for the treatment or prevention of a disease associated with the deposition of ⁇ -amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• a disease associated with the deposition of ⁇ -amyloid in the brain in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• AD Alzheimer's disease
• AD Alzheimer's disease
• the amyloid plaques are mainly composed of amyloid peptides ( ⁇ peptides) which originate from the ⁇ -Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps.
• ⁇ peptides amyloid peptides
• APP ⁇ -Amyloid Precursor Protein
• Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing.
• the ⁇ peptides are derived from the same domain of the APP.
• ⁇ peptides are produced from APP through the sequential action of two proteolytic enzymes termed ⁇ - and ⁇ -secretase.
• ⁇ -Secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP (CTF 5) containing the TM- and cytoplasmatic domain.
• ⁇ is the substrate for ⁇ -secretase which cleaves at several adjacent positions within the TM to produce the ⁇ peptides and the cytoplasmic fragment.
• Various proteolytic cleavages mediated by ⁇ -secretase result in ⁇ peptides of different chain length, e.g. ⁇ 38, ⁇ 40 and ⁇ 42. The latter one is regarded to be the more pathogenic amyloid peptide because of its strong tendency to form neurotoxic aggregates.
• the ⁇ -secretase is a typical aspartyl protease.
• the ⁇ -secretase is a high molecular weight complex that consists of four essential subunits: Presenilin (PS,including PS1 and PS2), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2).
• Presenilin PS, including PS1 and PS2
• nicastrin nicastrin
• anterior pharynx defective 1 APH-1
• PEN-2 presenilin enhancer 2
• the presenilins are bearing the catalytic site and represent a group of atypical aspartyl proteases which cleave their substrates within the TM of and which are themselves polytopic membrane proteins.
• the other essential components of ⁇ -secretase , nicastrin and the products of the aphl and pen-2 genes are believed to be responsible for substrate recognition and recruitment.
• Proven substrates for ⁇ -secretase are APP and the proteins of the Notch receptor family, however, ⁇ -secretase has a loose substrate specificity and many further membrane proteins unrelated to APP and Notch have been reported to be cleaved by the ⁇ -secretase in vitro.
• ⁇ -secretase activity is absolutely required for the production of ⁇ peptides. This has been shown both by genetic means, i.e., ablation of the presenilin genes and by low-molecular- weight inhibitory compounds. According to the amyloid cascade hypothesis for AD the production and deposition of ⁇ is the ultimate cause for the disease. Therefore, it was believed that selective and potent inhibition of ⁇ -secretase might be useful for the prevention and treatment of AD.
• An alternative mode of treatment is the modulation of the ⁇ -secretase activity which results in a selective reduction of the ⁇ 42 production. This will lead in an increase of shorter ⁇ isoforms, such as ⁇ 38, ⁇ 37 or others, which have no or reduced capability for aggregation and plaque formation, and are not or less neurotoxic.
• Compounds which show this effect on modulating ⁇ -secretase activity include certain non-steroidal anti-inflammatory drugs (NSAIDs) and related analogues (Weggen et al. Nature, 414 (2001) 212-16).
• the compounds of this invention will be useful for the treatment or prevention of a disease associated with the deposition of ⁇ -amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• a disease associated with the deposition of ⁇ -amyloid in the brain in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• lower alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n- butyl, i-butyl, 2-butyl, t-butyl and the like.
• Preferred alkyl groups are groups with 1 - 4 carbon atoms.
• lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CF 3 CH 2 CF 2 CF 3 and the like.
• lower alkoxy denotes an alkyl group as defined above, which is bonded via an O-atom.
• halogen denotes chlorine, iodine, fluorine and bromine.
• lower alkoxy substituted by halogen denotes an alkyl group substituted by halogen as defined above, which is connected via an oxygen atom.
• S-lower alkyl substituted by halogen denotes an alkyl group substituted by halogen as defined above, which is connected via a sulfur atom.
• a five membered heteroaryl group, containing 1 to 3 heteroatoms, selected from O, S or N is selected from the roup consisting of
• pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like.
• Objects of the present invention are compounds of formula I, the use of such compounds for the preparation of medicaments for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi- infarct dementia, dementia pugilistica or Down syndrome, their manufacture and medicaments based on a compound of formula I in accordance with the invention.
• One object of the invention is a compound of formula I-l
• hetaryl is a five membered heteroaryl group, containing 1 to 3 heteroatoms, selected from
• R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by
• R 1 is hydrogen, halogen, lower alkyl substituted by halogen or lower alkoxy
• R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, S-lower alkyl substituted by halogen;
• R 2 and R 3 form together with the carbon atoms, to which they are attached a ring, containing -0-CH 2 -0-;
• R 1 is hydrogen or halogen
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen; or a pharmaceutically active acid addition salts thereof, a racemic mixtures or its corresponding enantiomers or optical isomers or stereoisomers thereof.
• An embodiment of the invention are compounds of formula la,
• R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen or lower alkoxy substituted by halogen;
• R 1 is hydrogen, halogen, lower alkyl substituted by halogen or lower alkoxy substituted by halogen;
• R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, S-lower alkyl substituted by halogen;
• R 2 and R 3 form together with the carbon atoms, to which they are attached a ring, containing -O-CH 2 -O-;
• R 1 is hydrogen or halogen
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen
• (+)-N (8-endo)-3-(3-Methyl-l,2-thiazol-5-yl)-3-azabicyclo[3.2.1]octan-8-yl]-8-(2,3,4- trifluorophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridin-2-amine
• One further embodiment of the invention are compounds of formula lb,
• R 2 and R 3 form together with the carbon atoms, to which they are attached a ring, containing -O-CH 2 -O-;
• R 1 is hydrogen or halogen
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen
• One further embodiment of the invention are compounds of formula Ic,
• R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by
• R 1 is hydrogen, halogen, lower alkyl substituted by halogen or lower alkoxy
• R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, S-lower alkyl substituted by halogen;
• R 2 and R 3 form together with the carbon atoms, to which they are attached a ring, containing -O-CH 2 -O-;
• R 1 is hydrogen or halogen
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen
• One further embodiment of the invention are compounds of formula Id,
• R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen or lower alkoxy substituted by halogen;
• R 1 is hydrogen, halogen, lower alkyl substituted by halogen or lower alkoxy
• R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, S-lower alkyl substituted by halogen;
• R 2 and R 3 form together with the carbon atoms, to which they are attached a ring, containing -O-CH 2 -O-;
• R 1 is hydrogen or halogen
• R is hydrogen or lower alkyl substituted by halogen
• R is hydrogen or lower alkyl substituted by halogen
• the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
• Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
• the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
• Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in the examples, or by methods known in the art.
• the intermediate BB4 can be prepared from the kown 8-bromo- [l,2,4]triazolo[l,5-a]pyridin-2-amine by standard Suzuki coupling with the respective arylboronic acids or esters, for example palladium catalysed in the presence of a base and water in a solvent such as dioxane, to yield intermediate BB3 and subsequent Sandmeyer
• compounds of formula la can be obtained (Scheme 2) by Buchwald coupling of the corresponding 2-bromo-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridines of the general formula BBIO with amines such as BB2.
• amines such as BB2.
• Alkylation of phenylacetic acid esters by deprotonation with a base such as sodium hydride and reaction with 1,3-dihalopropane (halogen Br, CI or I) in a suitable solvent, for example dimethylformamide, leads to intermediate BB6.
• the ester BB6 is then hydrolysed to the acid, for example under basic conditions and the amide BB7 is prepared under standard conditions with tert-butyl hydrazinecarboxylate. Cleavage of the protecting group under acidic conditions yields the hydrazide BB8 which can be reacted to BB9 with cyanamide under acidic conditions. Subsequent Sandmeyer transformation of BB9 using tert-butylnitrite, copper(II)bromide in solvent such as acetonitrile leads to intermediate BBIO. The compounds of formula I are then obtained by Buchwald coupling with the corresponding amines.
• BB17 Alternatively the order of steps can be changed (Scheme 4).
• the heteroaryl groups are then introduced after deprotection of BB11 to yield the intermediate BB15, which is for example reacted with cyanic bromide to BB16 followed by ring closure to a 1 ,2,4-oxadiazole intermediate BB17 with hydroxyacetimidamide. Reduction of the annellated ring under conditions as descibed above yields compounds of formula lb.
• bromide BB 18 Scheme 5
• Scheme 5 Another order of steps to prepare compounds of formula lb starts from bromide BB 18 (Scheme 5) which can be obtained from the known 8-bromo-2-chloro-[l,2,4]triazolo[l,5-a]pyridine and (8-endo)-tert-butyl- 8-amino-3-azabicyclo[3.2.1]octane-3-carboxylate by substitution reaction in a solvent such as dimethylsulfoxide in the presence of cesium fluoride.
• BB25 is prepared starting from the known 3-bromo-6-(trifluoromethyl)pyridin-2-amine which is reacted with O- ethyl-carbonisothiocyanatidate to yield thiourea BB22 which undergoes a cyclization reaction upon treatment with hydroxylamine in the presence of a base under liberation of carbon dioxide to yield annelated triazole BB23 (as e.g. described by M. Nettekoven et al., Synthesis 2003, 11, 1649-1652). Introduction of the 8-aryl substituent by standard Suzuki resure leads to BB24 which is then transformed to bromide BB25 by Sandmeyer reaction.
• [l,2,4]triazolo[l,5-a]pyridin moiety can also be obtained (Scheme 7) by first hydrogenating BB24 to BB30 at a temperature of about 80°C and a pressure of 80 bar with palladium on carbon followed by Sandmeyer reaction to introduce the bromo substituent of BB31.
• Buchwald reaction with (8-endo)-tert-butyl-8-amino-3-azabicyclo[3.2.1]octane-3-carboxylate leads to BB32 which is then deprotected under acidic conditions to BB28.
• Introduction of the heteroarylgroup for example by reaction with 2-bromo-5-methyl-l,3,4-oxadiazole, leads to the compounds of formula Ic.
• Diastereoisomers and enantiomers can be separated by preparative HPLC.
• Human neuroglioma H4 cells overexpressing human APP695 with the Swedish double mutation (K595N/M596L) were plated at 30,000 cells/well/100 ⁇ in 96-well plates in IMDM media containing 10% FCS, 0.2 mg/1 Hygromycin B and incubated at 37°C, 5% C0 2 .
• compounds are a diluted in media and 50 ⁇ is added as 1.5-fold concentrate to achieve the final concentration.
• Compound incubation is performed for 24 hr.
• Final doses typically range from 4 ⁇ down to 0.0013 ⁇ in half-log steps resulting in a eight point dose response curve.
• the supernatant was subjected to quantification of secreted ⁇ 42 by the means of an AlphaLisa assay kit (Human Amyloid beta 1-42 Kit: Cat# AL203C, Perkin Elmer). 20 ⁇ of the cell culture supernatant was transferred to an assay plate. Then 10 ⁇ of a mixture of the AlphaLisa coupled capture antibody and the biotinylated detection antibody was added and incubated for 3 hours at room temperature while softly shaking the assay plate. After a further addition of 20 ⁇ of the Donor beads the assay plate was incubated for 30 min at room temperature and constant shaking without exposure to direct light. The assay plate was then read on a Paradigm AlphaLisa Reader using the build-in program with excitation at 680 nm and emission at 570 nm.
• the measured signals were then used to calculate IC 50 values for inhibition of ⁇ 42 secretion by nonlinear regression fit analysis using XLfit 5.3 software (IDBS).
• Example No. ECso ⁇ 42 Example No. ECso ⁇ 42
• the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
• the administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.
• the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
• Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises 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.
• pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the inhibition of ⁇ 42 secretion, such as of Alzheimer's disease.
• the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
• the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
• the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
• Tablet Formulation (Wet Granulation)
• tert-butyl ((8-endo)-3-(3-methylisothiazol-5-yl)-3- azabicyclo[3.2.1]octan-8-yl)carbamate (2.99 g, 9.24 mmol) was combined with dichloromethane (180 ml) to give a brown solution.
• Hydrochloric acid (25%, 10 ml) was added and the reaction mixture was stirred at room temperature for 2 hours.
• the reaction mixture was cooled in an icebath, water (50 ml) was added and the mixture was basified with aqueous sodium hydroxide (4N).
• tert-butyl nitrite (3.47 g, 4 ml, 33.6 mmol) and copper (II) bromide (7.52 g, 33.6 mmol) were combined with acetonitrile (120 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(4-(trifluoromethoxy)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (6.60 g, 22.4 mmol) was added. The temperature was raised to 80°C and stirring was continued for 2 hours. The mixture was cooled to room temperature and was concentrated in vacuo.
• tert-butyl 2-(5-chloro-2-(2-chloro-4- fluorophenyl)pentanoyl)hydrazinecarboxylate (660 mg, 1.74 mmol) was combined with ethyl acetate (5 ml) to give a light yellow solution.
• Hydrogen chloride (4N in ethyl acetate, 6.00 g, 5 ml, 20.0 mmol) was added and stirring was continued at room temperature overnight. The mixture was cooled in an ice bath and made alkaline with aqueous sodium hydroxide (4 N).
• tert-butyl nitrite (245 mg, 282 ⁇ , 2.37 mmol) and copper (II) bromide (530 mg, 2.37 mmol) were combined with acetonitrile (10 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(4-((trifluoromethyl)thio)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (491 mg, 1.58 mmol) was added.
• the reaction mixture was heated at 80°C for 1 hour.
• tert-butyl nitrite 330 mg, 380 ⁇ , 3.2 mmol
• copper (II) bromide 714 mg, 3.2 mmol
• the reaction mixture was heated to 60°C and 8-(4-(perfluoroethyl)phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (700 mg, 2.13 mmol) in acetonitrile (2ml) was added slowly.
• the reaction mixture was heated at 80°C for 2 hours.
• tert-butyl nitrite (556 mg, 640 ⁇ , 5.39 mmol) and copper (II) bromide (1.2 g, 5.39 mmol) were combined with acetonitrile (25 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(2-(trifluoromethyl)phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (CAS 1262198-08-2, 1.00 g, 3.59 mmol) was added. The mixture was heated at 80°C for 2 hours.
• N-((8-endo)-3-(3-methylisothiazol-5-yl)-3- azabicyclo[3.2.1]octan-8-yl)-8-(2-(trifluoromethyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-amine 330 mg, 681 ⁇
• magnesium 132 mg, 5.45 mmol
• iodine 1.73 mg, 6.81 ⁇
• the reaction mixture was heated at 80°C for 4 hours.
• tert-butyl nitrite 500 mg, 576 ⁇ , 4.85 mmol
• copper (II) bromide (1.08 g, 4.85 mmol)
• acetonitrile 15 ml
• the reaction mixture was heated to 60°C, then 8-(3-(trifluoromethyl)phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (CAS 1202616-57-6, 900 mg, 3.23 mmol) was added.
• the reaction was heated at 80°C for lhour.
• N-((8-endo)-3-(3-methylisothiazol-5-yl)-3- azabicyclo[3.2.1]octan-8-yl)-8-(3-(trifluoromethyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-amine 145 mg, 299 ⁇
• magnesium 58.2 mg, 2.39 mmol
• iodine 760 ⁇ g, 2.99 ⁇
• tert-butyl nitrite 526 mg, 606 ⁇ , 5.1 mmol
• copper (II) bromide 1.14 g, 5.1 mmol
• acetonitrile 30 ml
• the reaction mixture was heated to 60°C, then 8-(2-(trifluoromethoxy)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1.00 g, 3.4 mmol) was added.
• the reaction was heated at 80°C for 2 hours.
• the mixture was cooled to room temperature and concentrated in vacuo.
• N-((8-endo)-3-(3-methylisothiazol-5-yl)-3- azabicyclo[3.2.1]octan-8-yl)-8-(2-(trifluoromethoxy)phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2- amine 85 mg, 170 ⁇
• magnesium 33 mg, 1.36 mmol
• iodine 431 ⁇ g, 1.7 ⁇
• tert-butyl nitrite 526 mg, 606 ⁇ , 5.1 mmol
• copper (II) bromide (1.14 g, 5.1 mmol)
• acetonitrile (16.7 ml)
• the reaction mixture was heated to 60°C, then 8-(3-(trifluoromethoxy)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1 g, 3.4 mmol) was added.
• the mixture was heated at 80°C for 1 hour.
• the mixture was then cooled to room temperature, hydrochloric acid (IN, 30 ml) was added and the reaction mixture was extracted with ethyl acetate (3 x 100 ml).
• tert-butyl nitrite (632 mg, 728 ⁇ , 6.13 mmol) and copper (II) bromide (1.37 g, 6.13 mmol) were combined with acetonitrile (34 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(3,4,5-trifluorophenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (1.20 g, 4.09 mmol) was added.
• the mixture was heated at 80°C for 2 hours and then cooled to room temperature.
• the reaction mixture was concentrated in vacuo.
• tert-butyl nitrite (647 mg, 746 ⁇ , 6.28 mmol) and copper (II) bromide (1.4 g, 6.28 mmol) were combined with acetonitrile (30 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(4-fluoro-3-(trifluoromethyl)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1.24 g, 4.19 mmol) was added.
• the reaction was heated at 80°C for 2 hours.
• the reaction mixture was cooled to room temperature and concentrated in vacuo.
• tert-butyl nitrite (882 mg, 1.02 ml, 8.56 mmol) and copper (II) bromide (1.91 g, 8.56 mmol) were combined with acetonitrile (60 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(3-fluoro-5-(trifluoromethyl)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1.69 g, 5.71 mmol) was added.
• the reaction was heated at 80°C for 2 hours.
• the reaction mixture was cooled to room temperature and concentrated in vacuo.
• N-((8-endo)-3-(3-methylisothiazol-5-yl)-3- azabicyclo[3.2.1]octan-8-yl)-8-(4-(2,2,2-trifluoroethoxy)phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (30 mg, 58.3 ⁇ mol), magnesium (11.3 mg, 466 ⁇ ) and iodine (148 ⁇ g, 0.583 ⁇ ) were combined with methanol (5 ml) and tetrahydrofurane (2.5 ml) to give a dark red suspension.
• the reaction mixture was heated at 80°C for 2 hours. Iodine (148 ⁇ g, 0.583 ⁇ ) was added again and stirring was continued for 1 hour. Magnesium (11.3 mg, 466 ⁇ ) and iodine (148 ⁇ g, 0.583 ⁇ ) were added again and stirring was continued at 80°C overnight. The reaction mixture was cooled to room temperature, methanol (10 ml) was added and and the mixture was filtered through sintered glass.
• tert-butyl nitrite (313 mg, 361 ⁇ , 3.04 mmol) and copper (II) bromide (679 mg, 3.04 mmol) were combined with acetonitrile (30 ml) to give a black solution.
• the reaction mixture was heated to 60°C, then 8-(5-fluoro-2-(trifluoromethyl)phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (600 mg, 2.03 mmol) was added.
• the reaction was heated at 80°C for 2 hours.
• the reaction mixture was cooled to room temperature and concentrated in vacuo.
• tert-butyl nitrite 549 mg, 633 ⁇ , 5.33 mmol
• copper (II) bromide 1.19 g, 5.33 mmol
• acetonitrile 25 ml
• the reaction mixture was heated to 60°C, then 8-(4-fluoro-2-methylphenyl)- [l ,2,4]triazolo[l ,5-a]pyridin-2-amine (CAS 1262197-62-5, 860 mg, 3.55 mmol) was added.
• the reaction was heated at 80°C for 2 hours.
• the mixture was cooled to room temperature and stirred overnight.
• N-((8-endo)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2,3,4- trifluorophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridin-2-amine 915 mg, 2.42 mmol
• sodium bicarbonate 224 mg, 2.67 mmol
• ethanol 35 ml
• reaction mixture was stirred at room temperature for 2 hours and then hydrochloric acid (606 ⁇ , 7.28 mmol) was added. The mixture was heated at 60°C for 5 hours. The reaction mixture was concentrated in vacuo, poured into 50 ml saturated aqueous sodiumbicarbonate.
• Trifluoroacetic acid (1.03 g, 695 ⁇ , 9.02 mmol) was added and stirring was continued at room temperature for 3 hours.
• the reaction mixture was poured into 15 ml water, basified with aqueous sodium hydroxide (2N) and extracted with dichloromethane (5 x 25 ml). The organic layers were dried over sodium sulfate, concentrated and dried in vacuo to yield the title compound as light brown solid (365 mg, quant.).
• MS: m/z 406.2 [M+H] + .
• N-((8-endo)-3-azabicyclo[3.2.1]octan-8-yl)-8-(4-fluoro-3- (trifluoromethyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-amine 360 mg, 888 ⁇
• sodium bicarbonate 82.1 mg, 977 ⁇
• N-((8-endo)-3-azabicyclo[3.2.1]octan-8-yl)-8-bromo- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1.17 g, 3.63 mmol) and sodium bicarbonate (336 mg, 3.99 mmol) were combined with ethanol (27 ml) to give a white suspension.
• Cyanic bromide (423 mg, 3.99 mmol) was added and stirring was continued at roomm temperature overnight.
• N-((8-endo)-3-azabicyclo[3.2.1]octan-8-yl)-8-(4-(trifluoromethoxy)phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-amine (362 mg, 897 ⁇ ) was dissolved in ethanol (4ml).
• Sodium bicarbonate (82.9 mg, 987 ⁇ ) and cyanic bromide (108 mg, 987 ⁇ ) were added.
• the reaction mixture was stirred under argon at room temperature overnight, ion ). Cyanic bromide (29.5 mg) and sodium bicarbonate (22.6 mg) were added and stirring was continued at room temperature for 2 hours.
• tert-butyl nitrite (291 mg, 335 ⁇ , 2.82 mmol) and copper (II) bromide (629 mg, 2.82 mmol) were combined with acetonitrile (50 ml) to give a black solution.
• the reaction mixture was heated to 60°C and 5-(trifluoromethyl)-8-(2,3,4-trifluorophenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-amine (624 mg, 1.88 mmol) was added.
• the reaction mixture was heated at 80°C for 2 hours.

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• 2016
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