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WARRIOR'S LAB VALE AFTER 7-8 MONTHS The title compound was prepared according to the procedure for EXAMPLEsubstituting 1- 2-chlorophenyl piperazine for furanylmethanamine. Difluoromethyl pyrazol live stream vfl osnabrück 0. The mixture was stirred at room temperature overnight, and was concentrated. The title compound was prepared according dafabet online casino the procedure for EXAMPLEsubstituting 2- 3-phenoxyphenyl acetic acid for 1-methylcyclopropanecarboxylic acid. More particularly, when NRxRy forms a winners casino online as defined above, such an aminated ring can be chosen in particular from piperidyl, morpholinyl, azetidine, oxaazaspiro[3. The residue was used the subsequent heute fussball without 7/8 purification. W methyl 3R,5R -3,5- 1. The reaction mixture was concentrated. In another embodiment of formula I, R 10 is R 10Awherein R 10A is phenyl which is unfused, wherein R 10 is substituted with F and further substituted with 7/8 11wherein R 11 is R 14wherein R 14 is heterocycloalkyl which is unsubstituted or substituted with one or two O. The mixture was stirred at ambient temperature for 16 hours, treated with 2M hydrochloric acid 1 mL and concentrated. After a lucky creek casino free bonus codes to ambient temperature, pokern um geld reaction medium is filtered and then the solvent is evaporated off. The reaction medium is heated at reflux for 5 h 45 min. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1-aminohomopiperidine for 4- 2-aminoethyl morpholine. The reaction medium is concentrated.

A subject of the present invention is also the use of the products of formula I as defined above, for preparing medicaments intended for cancer chemotherapy.

A subject of the present invention is therefore the products of formula I as defined above, for use thereof in cancer chemotherapy, alone or in combination.

The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.

Such therapeutic agents may be commonly used antitumour agents. A therapeutic benefit can in particular be expected when administering the products of the present application in combinations with varied targeted therapies.

These targeted therapies are in particular the following: Mol Cancer Ther , B; Hoang et al. A therapeutic effect can also be expected when combining the products of the present application with chemotherapy agents such as camptothecin, taxotere or 5-FU, for example; or else when combining them with radiotherapy J Li et al.

Eur J of Cancer , A. Such medicaments intended for the treatment of lysosomal diseases can be used alone or in combination, for example, with other therapeutic agents.

A subject of the present invention is also the use of a product of formula I as defined above, for preparing a medicament intended for the prevention or treatment of X-linked myotubular myopathies, Charcot-Marie-Tooth disease; where mutations of the proteins of the myotubularin family have been described I.

A subject of the present invention is thus the use as defined above, in which said products of formula I are alone or in combination.

Among the cancers, the treatment of solid or liquid tumours, and the treatment of cancers resistant to cytotoxic agents are of interest.

As kinase inhibitors, mention may be made of butyrolactone, flavopiridol, 2 2-hydroxyethylamino benzylaminomethylpurine known as olomucine, sorafenib, imatinib, erlotinib, gefitinib and lapatinib.

Thus, the present application relates in particular to the products of formula I as 5 defined above, for use thereof as a VPS34 inhibitor. Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of cancers.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of solid or liquid 10 tumours.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of cancers resistant to cytotoxic agents.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in cancer chemotherapy.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in cancer chemotherapy, alone 25 or in combination.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of X-linked myotubular myopathies and Charcot-Marie-Tooth disease.

A subject of the present invention is thus in particular, as novel industrial products, the starting products or synthesis intermediates as defined above and hereinafter: R4 -L R3 N.

The following examples which are products of formula I illustrate the invention without, however, limiting it.

The following examples which are products of formula I according to the present invention can be prepared according to the usual methods known to those skilled in the art, and in particular as indicated above or below, and in the schemes and Tables 1 to The mass spectra MS were obtained either by method A or by method B.

Acquity BEH C18 1. Waters ZQ apparatus; Ionization: The optical rotations ORs were measured on a model polarimeter from Perkin Elmer.

The intermediates of type F as defined in the schemes above, i. F1 to F9 defined in Table 1 below, resulting in Examples 1 to , can be prepared in the following way: Intermediate Fl S Chloro trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

Chiralpak AD; mobile phase: The laevorotatory enantiomer is concentrated so as to give 8. The dextrorotatory enantiomer is concentrated so as to obtain 8.

CINNCF I 60 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 34 g of 8R,8S hydroxy trifluoromethyl -6,7,8,9-tetrahyd ro-4 H-pyrim ido[1,2-a]pyrim id inone in ml of 1,2-dichloroethane.

The mixture obtained is then heated to 65 C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure.

The residue obtained is taken up in ml of cold water and ml of ethyl acetate. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give an orange residue.

This residue is purified by chromatography on silica eluent: The mixture obtained is brought to C for 75 minutes. The heterogeneous mixture thickens and becomes yellow, with a slight release of gas.

The residue obtained is triturated with ethyl ether. The solid formed is filtered off through a sintered glass funnel and then taken up with 20 ml of cold water.

The suspension obtained is filtered through a sintered glass funnel and the insoluble matter is rinsed with ethyl ether so as to give The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure.

The residue obtained is oven-dried, in the presence of P, so as to give 27 g of 4R,4S trifluoromethyl -1,4,5,6-tetrahydropyrimidinylamine hydrochloride, in the form of a grey solid, the characteristics of which are the following: The dextrorotatory enantiomer is concentrated so as to obtain 3.

After stirring for 4 hours at a temperature of 65 C and returning to a temperature of about 20 C, the reaction mixture is concentrated to dryness under reduced pressure.

The residue is diluted in ml of ethyl acetate and 10 ml of ice-cold water. At a temperature between 0 C and 10 C, a concentrated sodium hydroxide solution is added until a pH between 6 and 7 is obtained.

The solid form is filtered off so as to give 3. The filtrate is separated by settling out, and the organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure.

After purification of the residue on a silica column eluent: The two solids Si and S2 are combined so as to give 6.

After stirring the suspension for 3 hours at a temperature of C, the medium obtained is concentrated to dryness under reduced pressure.

The residue is taken up in diethyl ether and then dried with suction under vacuum. After 2 hours of stirring at a temperature of 0 C and then overnight at a temperature of about 20 C, the suspension is filtered and then the solid is dried with suction and dried under vacuum over P AS 20pm; mobile phase: The laevorotatory enantiomer is concentrated so as to give 2.

The dextrorotatory enantiomer is concentrated so as to obtain 2. The mixture obtained is then stirred at ambient temperature for one hour.

The reaction medium is cooled in an ice bath. The white solid formed is filtered off so as to give 7 g of the solid Si. After separation of the filtrate by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 0.

The solid Si is taken up with water and ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.

The two solids S2 and S3 are combined for purification by chromatography on silica eluent: Mass spectrum method A: The residue obtained is taken up in 30 ml of cold water and ml of ethyl acetate.

The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: Mass spectrum method B: The mixture obtained is then heated at reflux.

The residue obtained is taken up in 20 ml of cold water and ml of ethyl acetate. At the end of the addition, the mixture obtained is then heated at reflux for three hours in an oil bath preheated to C.

After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 11 ml of water, followed by 11 ml of 4N NaOH and then 22 ml of water are added dropwise.

The white precipitate formed is filtered off. The filtrate is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 9.

The reaction medium is cooled to 4 C in an ice bath, and then ml of water, followed by ml of ethyl acetate, are added dropwise.

The residue obtained is taken up with ml of methanol. The white solid formed is filtered off. The filtrate is concentrated under reduced pressure.

Alternatively, R chloro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up in 50 ml of cold water and ml of ethyl acetate. The reaction medium is stirred at ambient temperature for 18 hours.

The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with 10 ml of ice-cold water. The mixture is concentrated to dryness under reduced pressure.

The residue obtained is purified by chromatography on silica eluent: R hydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

At the end of the addition, the mixture obtained is then heated at reflux for two hours in an oil bath preheated to C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give 11 g of a brown foam.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give a residue of 11 g of a thick oil.

This residue is purified on a silica column, eluent: At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 72 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 9. The filtrate is dried over MgSO4 and then concentrated under reduced pressure, so as to give HN F HN and R Chlorofluoro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

FJL I CI -N N ml of trifluoroacetic acid are added, at ambient temperature and under an argon atmosphere, to a solution of 4 g of R chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one in 30 ml of 1,2-dichloromethane.

The reaction medium turns a dark violet colour. The residue obtained is taken up with ml of dichloromethane and 50 ml of ice-cold water.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue obtained is taken up with ethyl ether and the white solid formed is filtered off, so as to give 2.

The filtrate is concentrated to dryness under reduced pressure and the residue obtained is purified by chromatography on silica eluent: The two solids Si and S2 are combined so as to give 2.

R Chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

R Fluorohydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up with ml of cold water. The solid formed is filtered off and then washed three times with ethyl ether.

The solid is oven-dried under vacuum in the presence of P, so as to give 15 g of R fluorohydroxy S 4-methoxyphenyl ethyl trifl uoromethyl -3,4-d ihyd ro-1H-pyri m ido[1,2-a]pyrim id in-6 2H -one, which is used as it is in the next step.

The reaction medium is heated at 65 C for 7 h 15 min. It is then evaporated to dryness under reduced pressure 2. The aqueous phase is extracted with 20 ml of ethyl acetate.

The organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated to dryness under reduced pressure 2.

The crude obtained is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, mg of 2-chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrim id inone are obtained, in the form of a white solid mixture of enantiomers.

Prochrom Chiral stationary phase: UV nm After evaporation of the fractions under reduced pressure, 93 mg of 8R chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are obtained, in the form of a white solid.

Gilson Chiral stationary phase: UV nm After evaporation of the fractions, mg of 8S chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are also obtained, in the form of a white solid.

Retention time by chiral phase HPLC: UV nm 2-Hydroxymethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

The reaction medium is heated at reflux for 5 h 45 min. After cooling, the reaction medium is evaporated to dryness under reduced pressure.

The residue obtained is taken up in 0. The reaction medium is stirred in the cold bath for approximately 15 minutes and then, after having added approximately 3 ml of ethyl ether to the reaction medium, the latter is filtered through a sintered glass funnel.

After drying under vacuum, 92 mg of 2-hydroxymethyl trifl uoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrimidinone are obtained, in the form of a beige solid.

After evaporation to dryness under reduced pressure, mg of 4-methyl trifluoromethyl tetrahydropyrimidin-2 1H -imine hydrobromide are obtained in the form of a yellow solid.

The reaction medium is then filtered through celite and the filtrate is then evaporated to dryness. Toluene is added to the residue obtained and then the resulting product is evaporated to dryness, so as to give 1.

The aqueous phase is extracted with ethyl ether, then the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated in a rotary evaporator under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

N1-benzy,4,4-trifluoromethylbutane-1,3-diamine can be prepared in the following way. The reaction medium is stirred at ambient temperature for 72 hand is then diluted with 80 ml of ethyl ether and 15 ml of THF and cooled to approximately 0 C, and 2.

The filtrate is dried over magnesium sulfate and then, after filtration through a sintered glass funnel, the filtrate obtained is evaporated to dryness under reduced pressure 2.

The crude is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, 1.

The reaction medium is stirred at ambient temperature for 62 h and then 3. The reaction medium is stirred at ambient temperature for 27 h and then evaporated to dryness under reduced pressure 2.

After evaporation of the fractions under reduced pressure, 2. HCI A mixture of 4. The reaction medium is heated at 90 C for 4 h. A mixture of acetonitrile and toluene is added and then the mixture is evaporated to dryness under reduced pressure.

Ethyl 3-amino-4,4,4-trifluoromethylbutanoate and methyl 3-amino-4,4,4-trifluoromethylbutanoate can be prepared in the following way.

Jj 0 , F and F A solution of 1. The reaction medium is diluted with 20 ml of methylene chloride and then evaporated to dryness under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

A mixture of mg 4. Intermediate F6 2-Chloro-8,8-dimethy,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

The medium is concentrated to dryness. The residue is taken up in 50 ml of ethyl acetate and 10 ml of water and then cooled in an ice bath.

The aqueous phase is extracted with ethyl acetate and then the organic phase is dried over magnesium sulfate. After the solvent has been evaporated off, 0.

After 4 h of heating, the reaction medium is concentrated to dryness. The oil obtained is taken up in ethyl ether.

The precipitate formed is filtered off, washed with ethyl ether and oven-dried under vacuum. The mixture is stirred at ambient temperature for 2 h.

The mixture is filtered and then evaporated to dryness. The reaction crude is solubilised in 20 ml of water, cooled with an ice bath.

After a return to ambient temperature, the product is precipitated with ethyl ether and filtration is carried out. The powder obtained is oven-dried at 70 C.

After a return to ambient temperature, the reaction medium is filtered and then the solvent is evaporated off. Et20 are added and the mixture is heated for 1 h 30 min at 70 C.

The organic phase is separated by settling out, washed with a saturated NaCI solution and then dried over magnesium sulfate.

After a return to ambient temperature, the reaction medium is filtered and then taken up with a saturated aqueous NH4CI solution. The aqueous phase is extracted with ethyl acetate, washed with an NaCI solution, then dried over magnesium sulfate and evaporated to dryness.

The solid obtained is placed in suspension in ml of water and stirred. The precipitated product is filtered off, rinsed with ether and then oven-dried under vacuum at 65 C.

The residue is taken up in ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. Concentrated NaOH is added to pH After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure.

The residue obtained is triturated from ethyl ether and the solid is filtered and then dried, so as to give 2. HO N N H A suspension of 5 g of 4,4-dimethy,4,5,6-tetrahydropyrimidinamine, 29 g of dimethyl fluoromalonate and 3.

The residue obtained is taken up with ethyl ether. The solid formed is filtered off and then dried. The suspension is filtered and then the solid is washed with 5 ml of water and then dried under vacuum over P, so as to give 3.

S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one can be prepared in the following way.

Y F CI N N F 11 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 5.

The resulting mixture is then heated to 70 C. The residue obtained is taken up in 5 ml of cold water and ml of ethyl acetate. The organic phase is then separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 6 g of S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one, the characteristics of which are the following: The resulting mixture is refluxed for 18 hours.

After cooling, the mixture obtained is concentrated to dryness under reduced pressure. The resulting suspension is stirred in an ice bath for two hours and then filtered through a sintered glass funnel.

The insoluble matter obtained is rinsed with water twice 4 ml and then dried so as to give 5. At the end of the addition, the reaction mixture is stirred at 5 C for 30 minutes.

The ice bath is then withdrawn and the mixture obtained is stirred at ambient temperature for 3 hours. The resulting mixture is then concentrated under reduced pressure.

The residue obtained is taken up twice with ml of ethanol and then twice with ml of toluene, and evaporated to dryness each time. The solid obtained is triturated with ethyl ether and then filtered off, so as to give 4.

The aqueous phase is subsequently separated by settling out and then extracted with 4 times ml of ethyl ether. The mixture obtained is then filtered and the filtrate is evaporated to dryness.

The oil obtained is taken up with a 3N hydrochloric acid solution 50 ml. The mixture obtained is extracted with diethyl ether 3 x 50 ml.

The aqueous phase is then evaporated to dryness, taken up with methanol, and then again evaporated to dryness. The yellowish solid obtained is dried under vacuum, so as to give 5.

Substantial evolution of gas and a temperature rise to 8 C are observed. At the end of the addition, the temperature is left to come back up to ambient temperature, and then the reaction mixture is left stirring for 18 h.

The mixture obtained is cooled to 4 C, followed by very slow dropwise addition of 2 ml of water. Substantial evolution of gas and a temperature rise to 12 C are observed.

The white precipitate formed is filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 2.

The cold bath is then withdrawn to allow the mixture to warm up to ambient temperature. The organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The mixture obtained is then heated at reflux for 18 hours, during which time 0. After cooling, the reaction mixture is concentrated under reduced pressure.

The residue obtained is purified by filtration on silica eluent: S - 6-Fluorochloromethyl trifluoromethyl -2,3-dihydroimidazo[1,2-a]pyrimidin-5 1H -one can be obtained in the following way.

The organic phase is then separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue obtained is purified by silica column chromatography eluent: The resulting mixture is refluxed for 3 hours. The reaction mixture is evaporated to dryness under reduced pressure.

The filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica eluent: Starting intermediates of type F Intermediate:: The mixture was stirred at ambient temperature for 16 hours, treated with 2M hydrochloric acid 1 mL and concentrated.

This example was prepared as the trifluoroacetate salt as described in EXAMPLE 42 by substituting 1- tert-butoxycarbonyl azetidine carboxylic acid for 3- 1-piperidinyl propionic acid.

The mixture was acidified with 2N hydrochloric acid and partitioned between ethyl acetate and brine. The organic layer was washed with water and concentrated, and the concentrate was purified by flash chromatography on silica gel with ethyl acetate.

To a solution of EXAMPLE 49C 75 mg in N,N-dimethylformamide 3 mL was added N-isopropylethylenediamine 27 mg , 1- 3-dimethylaminopropyl ethylcarbodiimide hydrochloride 50 mg , 1-hydroxybenzotriazole hydrate 35 mg and triethylamine 0.

The mixture was stirred at ambient temperature for 16 hours and was partitioned between brine and water. The organics were washed with brine and concentrated.

This example was prepared as the trifluoroacetate salt as described in EXAMPLE 41 by substituting morpholinyl-acetic acid for 3- 1-piperidinyl propionic acid.

The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1- 2-aminoethyl pyrrolidine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2-methylpyrrolidine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1-aminohomopiperidine for 4- 2-aminoethyl morpholine.

The title compound was prepared according to procedure for EXAMPLE 51 substituting tert-butyl 1-piperazine carboxylate for 4- 2-aminoethyl morpholine.

The solution was stirred at room temperature for 1 hour, and was concentrated. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 3-aminoN-Boc-azetidine for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting N,N-dimethyl-1,4-phenylenediamine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2- 4-methyl-piperazinyl -ethylamine for 4- 2-aminoethyl morpholine.

A solution of isoxazolecarboxylic acid 32 mg, 0. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 4-phenylpiperidine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting tert-butyl 2- aminomethyl piperidinecarboxylate for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 4-aminomethyl-piperidinecarboxylic acid tert-butyl ester for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2- piperidinyl ethanamine for 4- 2-aminoethyl morpholine.

The mixture was stirred at room temperature for 2 hours before sodium cyanoborohydride 13 mg, 0. The residue was dissolved in 1: The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-bromo-pyridinecarbaldehyde for 2-fluoroformylbenzonitrile.

After cooling, the solid material was filtered off, and the filtrate was concentrated. The residual solid was washed with methanol, and dried to provide the title compound.

The residue was washed with methanol, and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-methylthiopyrimidine-carboxyaldehyde for 2-fluoroformylbenzonitrile.

The reaction mixture was stirred at room temperature for 4 hours, and concentrated. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 6-bromo-pyridinecarbaldehyde for 2-fluoroformylbenzonitrile.

The solution was stirred at room temperature for 16 hours, and was concentrated. To a solution of 3- piperidinyl propanoic acid 31 mg in anhydrous dichloromethane 2 mL was added oxalyl chloride The solution was stirred for 1 hour, and was concentrated.

The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated.

The organic phase was washed with brine, and concentrated to provide the title compound. After cooling, the reaction mixture was concentrated.

A microwave tube was charged with tris dibenzylideneacetone dipalladium 0 5. After concentration, the residue was partitioned between ethyl acetate and brine.

The organic phase was concentrated. The residual solid was dissolved in dichloromethane 4 mL and treated with trifluoroacetic acid 2 mL at room temperature for 1 hour.

The title compound was prepared according to procedure for EXAMPLE 98, substituting 1- tert-butoxycarbonyl azetidinecarboxylic acid for 3- piperidinyl propanoic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 1- tert-butoxycarbonyl azetidinecarboxylic acid for 1- tert-butoxycarbonyl azetidinecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting methanesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting propanesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting benzenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting pyridinesulfonyl chloride hydrochloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting furansulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting 1-methyl-1H-imidazolesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting thiophenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting 4-cyanobenzenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting naphthalenesulfonyl chloride for dimethylsulfamoyl chloride.

After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 5-bromothiophenecarbaldehyde for 2-fluoroformylbenzonitrile.

To a solution of 2- 2- -t-Boc-aminoethoxy ethoxy ethyl bromide Toronto, mg, 0. The organic phase was washed with brine, and concentrated.

The solution remained at room temperature for 1 hour, and was concentrated. The trifluoroacetic acid salt was dissolved in a mixture of methylene chloride and methanol, and was treated with 1M solution of HCl in ether.

Removal of the volatiles afforded the title compound as a HCl salt. The residue was dissolved in a 1: The title compound was prepared according to the procedure for EXAMPLE , substituting 2-methylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-ethoxypropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S oxopyrrolidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting R oxopyrrolidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-carbamoylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-phenylpropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 2,5-dimethoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-phenylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- m-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- o-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- p-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting R methoxyphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S methoxyphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4- thiophenyl butanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-acetylpiperidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 3,5-difluorophenyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting S acetamidomethylpentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting S dipropylamino propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-oxophenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2-benzamidoacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 3-methoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 4-methoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 3,4-dimethylphenoxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting R hydroxyphenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-phenoxybutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-oxo thiophenyl butanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 4-methylpyrimidinylthio acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 2-chlorophenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 4-chlorophenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3-methylphenylpentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 4-chloromethylphenoxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 5-oxo phenylamino pentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4- 4-methoxyphenyl oxobutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2,2-diphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- phenylsulfonyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-phenoxyphenyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-ethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-fluoromethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,3-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,4-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-ethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- diethylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-butoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting furancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethylfurancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting isoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-dimethylisoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting nicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting isonicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-hydroxypicolinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylpyrazinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1H-indolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylphenyl-1H-pyrazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-chloro-2H-chromenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

N 3 ,N 3 -dimethyl-N 1 - 3- 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl -beta-alaninamide. The title compound was prepared according to the procedure for EXAMPLE , substituting 3- dimethylamino propanoic acid for 1-methylcyclopropanecarboxylic acid.

To a solution of 2- 3-bromophenyl acetic acid 4. The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine.

The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed with water and concentrated.

The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2,2,2-trifluorophenylethanone for 2-fluoroformylbenzonitrile.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetamidobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-hydroxynaphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro methylthio benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,4-diethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a trifluoroacetic acid salt according to the procedure for EXAMPLE , substituting 2- phenylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-phenethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-bromochlorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methylbenzoyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-iodobenzoic acid for 1-methylcyclopropaneccarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a free base according to the procedure for EXAMPLE 39, substituting 3-acetamidophenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- methylsulfonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-carbamoylphenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- dimethylcarbamoyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 1,1,1-trifluorophenylpropanone for 2-fluoroformylbenzonitrile.

The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The title compound was prepared according to the procedure for EXAMPLE A, substituting 4- benzyloxycarbonyl tert-butoxycarbonyl piperazinecarboxylic acid for 2- 3-bromophenyl acetic acid.

The catalyst was removed by filtration, and the filtrate was concentrated. The solid material was filtered off, and the filtrate was concentrated to give the title compound.

The mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in absolute ethanol 5 mL , and was treated with sodium ethoxide 0.

A solution of 2-phenoxyacetic acid 28 mg, 0. The residue was re-dissolved in anhydrous dichloromethane 5 ml.

The reaction mixture was stirred at room temperature overnight, and was concentrated. After cooling, the reaction mixture was diluted with methanol 20 ml , and filtered.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- morpholinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE substituting 2- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- cyclopropylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2- dimethylamino ethylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl -phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-carbamoylphenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylsulfonamido phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-acetamidophenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-chloronitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methoxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-hydroxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methylnitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

A solution of 3-bromoethyl benzene 2 g, 11 mmol. After cooling, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine.

The organic layer was washed with brine, and was concentrated. After cooling to room temperature, the solid material was collected by filtration, washed with toluene, and dried to provide the title compound.

A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione 0. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours.

After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. To a solution of 4- 4-methoxyphenyl oxobutanoic acid 29 mg, 0.

The reaction mixture was stirred at room temperature for 16 hours, and was concentrated. The reaction mixture was cooled and concentrated on a rotary evaporator.

The title compound was prepared according to the procedure for EXAMPLE A, substituting 2- 3-bromofluorophenyl acetic acid for 2- 3-bromophenyl acetic acid.

A mixture of 4-oxophenylbutanoic acid 50 mg, 0. The reaction mixture was stirred at room temperature for another 1 hour, and was diluted with 5 mL of methanol.

The solid material was collected by filtration, washed with methanol, and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE , substituting hexahydroisobenzofuran-1,3-dione for oxabicyclo 3.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,3-dimethyldihydrofuran-2,5-dione for oxabicyclo 3.

A mL round bottom flask was charged with 3-bromofluorobenzaldehyde 1. The mixture was purged with nitrogen, and anhydrous dioxane 15 mL , and 5-methylpyrrolidinone 0.

After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine.

The organic phase was dried over MgSO 4 , filtered and concentrated. The residue was dissolved in ethanol 5 mL and treated with hydrazine monohydrate 0.

The mixture was allowed to cool and the precipitated solid was filtered and dried to provide the title compound.

The reaction mixture was concentrated, and the residual solid was dissolved in dioxane 3 mL. The residue was stirred with a mixture of ethyl acetate and water.

The precipitated solid was filtered, washed with water, and dried to provide the title compound. The combined organics were concentrated and dried under vacuum to provide the title compound.

After cooling to room temperature, the precipitated solid was filtered, and dried to provide the title compound. The reaction mixture was concentrated and dried to provide the title compound.

The reaction mixture was concentrated. The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyridinylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinyl propanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- piperidinyl propanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-morpholinopropanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzyloxycarbonylamino acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-oxo 4-phenoxyphenyl butanoic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- benzyloxycarbonyl piperidinecarboxylic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- p-tolyloxy acetic acid for 4-oxophenylbutanoic acid. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methoxyphenoxy acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-tert-butylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-fluoromethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3-chloromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-chloromethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3-bromomethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-bromomethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxy trifluoromethyl aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-aminomethylphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-aminomethylphenol for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-methoxymethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methoxymethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminomethoxyphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-tert-butylmethoxyaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting N- 3-aminomethoxyphenyl acetamide for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,3-dihydrobenzo b 1,4 dioxinamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-chloro-2,4-dimethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylthio aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- methylthio aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- piperidinyl aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-morpholinoaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N 1 - 4-methoxyphenyl benzene-1,2-diamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminonaphthalenol for furanylmethanamine.

To a solution of dimethylpyridine-2,3-dicarboxylate 1. The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water.

After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The reaction mixture was concentrated to about 5 mL.

The solid was collected by filtration, washed with ethanol and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE A, substituting 2-chlorofluorobenzyl magnesium chloride for 4-fluorobenzyl magnesium chloride.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-o-tolylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-p-tolylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-fluorophenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-bromophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-bromophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- biphenylyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-phenoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethylphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-ethoxymethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-ethoxymethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,5-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzo d 1,3 dioxolyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dichlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dichlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,6-dichlorophenyl ethanamine for furanylmethanamine. A solution of 1- 3-bromofluorophenyl ethanone After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes and at reflux overnight.

After cooling, 1N HCl 10 mL was slowly added and the reaction mixture was concentrated. The organic phase was washed with water, and concentrated.

After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water ml and ethyl acetate ml.

The residue was purified by flash chromatography 2. The mixture was filtered, and the filtrate was concentrated. A mixture of magnesium turnings mg, 37 mmol and 2-bromo bromomethyl fluorobenzene 1.

The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour.

The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate 1.

The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzylamino ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N-methyl pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl -N-methylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting piperidinecarboxamide for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting piperazinecarbaldehyde for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- piperazinyl ethanone for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- pyridinyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl pyrimidine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2- piperazinyl ethoxy ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 4-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-chlorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl piperazinyl azepane for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLEs 2, 3 and 4, substituting 3-nitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

To a solution of 4-fluoronitrobenzoic acid 5 g, The reaction mixture was concentrated and partitioned between ethyl acetate mL and brine mL. The catalyst was filtered off, and the filtrate was concentrated.

The residue was used the subsequent step without further purification. The residue was partitioned between ethyl acetate mL and brine 75 mL.

The organic layer was washed with brine, and concentrated. The reaction was quenched with water, and the mixture was partitioned between ethyl acetate and diluted HCl solution.

The organic layer was washed with brine, and concentrated on a rotary evaporator. To a solution of 2-bromofluoroiodobenzene The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes.

Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol 15 mL.

The residue was dissolved in methylene chloride 40 mL , and was treated with triethylamine 5. Water was added, and the mixture was washed with sodium bicarbonate, brine and water.

The organic phase was dried over magnesium sulfate, filtered and concentrated. After cooling to room temperature, the solids were collected by filtration, washed with ethanol and dried to provide the title compound.

The solution was stirred at room temperature for 30 minutes, and benzyl chloromethylether 1. The reaction mixture was stirred at room temperature overnight.

After quenching with water, the reaction mixture was partitioned between water and ethyl acetate. Anhydrous dioxane 3 mL was added.

The suspension was purged with nitrogen, and was capped with a microwave septum. After cooling, the reaction mixture was partitioned between ethyl acetate and brine.

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Such pharmaceutical compositions of the present invention can also, where appropriate, contain active ingredients of other anti-mitotic medicaments, such as, in particular, those based on taxol, cisplatin, DNA-intercalating agents, and the like.

These pharmaceutical compositions can be administered orally, parenterally or locally by topical application to the skin and the mucous membranes or by intravenous or intramuscular injection.

These compositions may be solid or liquid and be in any of the pharmaceutical forms commonly used in human medicine, for instance simple or sugar-coated tablets, pills, lozenges, gel capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.

The active ingredient may be incorporated therein with excipients normally used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, or preservatives.

The usual dosage, which is variable according to the product used, the individual treated and the condition in question, can be, for example, from 0.

A subject of the present invention is also the use of products of formula I as defined above, for preparing a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of the activity of a protein or lipid kinase.

Such a medicament can in particular be intended for the treatment or prevention of a disease in a mammal. A subject of the present invention is in particular the use of a product of formula I as defined above, for preparing a medicament intended for the prevention or treatment of diseases associated with an uncontrolled proliferation.

A subject of the present invention is thus quite particularly the use of a product of formula I as defined above, for preparing a medicament intended for the treatment or prevention of diseases in oncology, and in particular intended for the treatment of cancers.

A subject of the present invention is the products of formula I as defined above, for use thereof in the treatment of solid or liquid tumours.

A subject of the present invention is also the use of the products of formula I as defined above, for preparing medicaments intended for cancer chemotherapy.

A subject of the present invention is therefore the products of formula I as defined above, for use thereof in cancer chemotherapy, alone or in combination.

The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.

Such therapeutic agents may be commonly used antitumour agents. A therapeutic benefit can in particular be expected when administering the products of the present application in combinations with varied targeted therapies.

These targeted therapies are in particular the following: Mol Cancer Ther , B; Hoang et al. A therapeutic effect can also be expected when combining the products of the present application with chemotherapy agents such as camptothecin, taxotere or 5-FU, for example; or else when combining them with radiotherapy J Li et al.

Eur J of Cancer , A. Such medicaments intended for the treatment of lysosomal diseases can be used alone or in combination, for example, with other therapeutic agents.

A subject of the present invention is also the use of a product of formula I as defined above, for preparing a medicament intended for the prevention or treatment of X-linked myotubular myopathies, Charcot-Marie-Tooth disease; where mutations of the proteins of the myotubularin family have been described I.

A subject of the present invention is thus the use as defined above, in which said products of formula I are alone or in combination.

Among the cancers, the treatment of solid or liquid tumours, and the treatment of cancers resistant to cytotoxic agents are of interest.

As kinase inhibitors, mention may be made of butyrolactone, flavopiridol, 2 2-hydroxyethylamino benzylaminomethylpurine known as olomucine, sorafenib, imatinib, erlotinib, gefitinib and lapatinib.

Thus, the present application relates in particular to the products of formula I as 5 defined above, for use thereof as a VPS34 inhibitor.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of cancers. Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of solid or liquid 10 tumours.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of cancers resistant to cytotoxic agents.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in cancer chemotherapy.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in cancer chemotherapy, alone 25 or in combination.

Thus, the present application relates in particular to the products of formula I as defined above, for use thereof in the treatment of X-linked myotubular myopathies and Charcot-Marie-Tooth disease.

A subject of the present invention is thus in particular, as novel industrial products, the starting products or synthesis intermediates as defined above and hereinafter: R4 -L R3 N.

The following examples which are products of formula I illustrate the invention without, however, limiting it.

The following examples which are products of formula I according to the present invention can be prepared according to the usual methods known to those skilled in the art, and in particular as indicated above or below, and in the schemes and Tables 1 to The mass spectra MS were obtained either by method A or by method B.

Acquity BEH C18 1. Waters ZQ apparatus; Ionization: The optical rotations ORs were measured on a model polarimeter from Perkin Elmer.

The intermediates of type F as defined in the schemes above, i. F1 to F9 defined in Table 1 below, resulting in Examples 1 to , can be prepared in the following way: Intermediate Fl S Chloro trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

Chiralpak AD; mobile phase: The laevorotatory enantiomer is concentrated so as to give 8. The dextrorotatory enantiomer is concentrated so as to obtain 8.

CINNCF I 60 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 34 g of 8R,8S hydroxy trifluoromethyl -6,7,8,9-tetrahyd ro-4 H-pyrim ido[1,2-a]pyrim id inone in ml of 1,2-dichloroethane.

The mixture obtained is then heated to 65 C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure.

The residue obtained is taken up in ml of cold water and ml of ethyl acetate. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give an orange residue.

This residue is purified by chromatography on silica eluent: The mixture obtained is brought to C for 75 minutes. The heterogeneous mixture thickens and becomes yellow, with a slight release of gas.

The residue obtained is triturated with ethyl ether. The solid formed is filtered off through a sintered glass funnel and then taken up with 20 ml of cold water.

The suspension obtained is filtered through a sintered glass funnel and the insoluble matter is rinsed with ethyl ether so as to give The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure.

The residue obtained is oven-dried, in the presence of P, so as to give 27 g of 4R,4S trifluoromethyl -1,4,5,6-tetrahydropyrimidinylamine hydrochloride, in the form of a grey solid, the characteristics of which are the following: The dextrorotatory enantiomer is concentrated so as to obtain 3.

After stirring for 4 hours at a temperature of 65 C and returning to a temperature of about 20 C, the reaction mixture is concentrated to dryness under reduced pressure.

The residue is diluted in ml of ethyl acetate and 10 ml of ice-cold water. At a temperature between 0 C and 10 C, a concentrated sodium hydroxide solution is added until a pH between 6 and 7 is obtained.

The solid form is filtered off so as to give 3. The filtrate is separated by settling out, and the organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure.

After purification of the residue on a silica column eluent: The two solids Si and S2 are combined so as to give 6. After stirring the suspension for 3 hours at a temperature of C, the medium obtained is concentrated to dryness under reduced pressure.

The residue is taken up in diethyl ether and then dried with suction under vacuum. After 2 hours of stirring at a temperature of 0 C and then overnight at a temperature of about 20 C, the suspension is filtered and then the solid is dried with suction and dried under vacuum over P AS 20pm; mobile phase: The laevorotatory enantiomer is concentrated so as to give 2.

The dextrorotatory enantiomer is concentrated so as to obtain 2. The mixture obtained is then stirred at ambient temperature for one hour. The reaction medium is cooled in an ice bath.

The white solid formed is filtered off so as to give 7 g of the solid Si. After separation of the filtrate by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 0.

The solid Si is taken up with water and ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.

The two solids S2 and S3 are combined for purification by chromatography on silica eluent: Mass spectrum method A: The residue obtained is taken up in 30 ml of cold water and ml of ethyl acetate.

The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: Mass spectrum method B: The mixture obtained is then heated at reflux.

The residue obtained is taken up in 20 ml of cold water and ml of ethyl acetate. At the end of the addition, the mixture obtained is then heated at reflux for three hours in an oil bath preheated to C.

After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 11 ml of water, followed by 11 ml of 4N NaOH and then 22 ml of water are added dropwise.

The white precipitate formed is filtered off. The filtrate is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 9.

The reaction medium is cooled to 4 C in an ice bath, and then ml of water, followed by ml of ethyl acetate, are added dropwise.

The residue obtained is taken up with ml of methanol. The white solid formed is filtered off. The filtrate is concentrated under reduced pressure.

Alternatively, R chloro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up in 50 ml of cold water and ml of ethyl acetate. The reaction medium is stirred at ambient temperature for 18 hours.

The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with 10 ml of ice-cold water.

The mixture is concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on silica eluent: R hydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

At the end of the addition, the mixture obtained is then heated at reflux for two hours in an oil bath preheated to C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give 11 g of a brown foam.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give a residue of 11 g of a thick oil.

This residue is purified on a silica column, eluent: At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 72 hours.

The reaction medium is cooled to 4 C in an ice bath, and then 9. The filtrate is dried over MgSO4 and then concentrated under reduced pressure, so as to give HN F HN and R Chlorofluoro trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

FJL I CI -N N ml of trifluoroacetic acid are added, at ambient temperature and under an argon atmosphere, to a solution of 4 g of R chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one in 30 ml of 1,2-dichloromethane.

The reaction medium turns a dark violet colour. The residue obtained is taken up with ml of dichloromethane and 50 ml of ice-cold water.

After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue obtained is taken up with ethyl ether and the white solid formed is filtered off, so as to give 2. The filtrate is concentrated to dryness under reduced pressure and the residue obtained is purified by chromatography on silica eluent: The two solids Si and S2 are combined so as to give 2.

R Chlorofluoro S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

R Fluorohydroxy S 4-methoxyphenyl ethyl trifluoromethyl -3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6 2H -one can be prepared in the following way.

The residue obtained is taken up with ml of cold water. The solid formed is filtered off and then washed three times with ethyl ether.

The solid is oven-dried under vacuum in the presence of P, so as to give 15 g of R fluorohydroxy S 4-methoxyphenyl ethyl trifl uoromethyl -3,4-d ihyd ro-1H-pyri m ido[1,2-a]pyrim id in-6 2H -one, which is used as it is in the next step.

The reaction medium is heated at 65 C for 7 h 15 min. It is then evaporated to dryness under reduced pressure 2. The aqueous phase is extracted with 20 ml of ethyl acetate.

The organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated to dryness under reduced pressure 2.

The crude obtained is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, mg of 2-chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrim id inone are obtained, in the form of a white solid mixture of enantiomers.

Prochrom Chiral stationary phase: UV nm After evaporation of the fractions under reduced pressure, 93 mg of 8R chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are obtained, in the form of a white solid.

Gilson Chiral stationary phase: UV nm After evaporation of the fractions, mg of 8S chloromethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone are also obtained, in the form of a white solid.

Retention time by chiral phase HPLC: UV nm 2-Hydroxymethyl trifluoromethyl -6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

The reaction medium is heated at reflux for 5 h 45 min. After cooling, the reaction medium is evaporated to dryness under reduced pressure.

The residue obtained is taken up in 0. The reaction medium is stirred in the cold bath for approximately 15 minutes and then, after having added approximately 3 ml of ethyl ether to the reaction medium, the latter is filtered through a sintered glass funnel.

After drying under vacuum, 92 mg of 2-hydroxymethyl trifl uoromethyl -6,7,8,9-tetrahydro-4 H-pyrim ido[1,2-a]pyrimidinone are obtained, in the form of a beige solid.

After evaporation to dryness under reduced pressure, mg of 4-methyl trifluoromethyl tetrahydropyrimidin-2 1H -imine hydrobromide are obtained in the form of a yellow solid.

The reaction medium is then filtered through celite and the filtrate is then evaporated to dryness. Toluene is added to the residue obtained and then the resulting product is evaporated to dryness, so as to give 1.

The aqueous phase is extracted with ethyl ether, then the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated in a rotary evaporator under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

N1-benzy,4,4-trifluoromethylbutane-1,3-diamine can be prepared in the following way. The reaction medium is stirred at ambient temperature for 72 hand is then diluted with 80 ml of ethyl ether and 15 ml of THF and cooled to approximately 0 C, and 2.

The filtrate is dried over magnesium sulfate and then, after filtration through a sintered glass funnel, the filtrate obtained is evaporated to dryness under reduced pressure 2.

The crude is purified by flash chromatography on silica [eluent: After evaporation of the fractions under reduced pressure, 1. The reaction medium is stirred at ambient temperature for 62 h and then 3.

The reaction medium is stirred at ambient temperature for 27 h and then evaporated to dryness under reduced pressure 2. After evaporation of the fractions under reduced pressure, 2.

HCI A mixture of 4. The reaction medium is heated at 90 C for 4 h. A mixture of acetonitrile and toluene is added and then the mixture is evaporated to dryness under reduced pressure.

Ethyl 3-amino-4,4,4-trifluoromethylbutanoate and methyl 3-amino-4,4,4-trifluoromethylbutanoate can be prepared in the following way.

Jj 0 , F and F A solution of 1. The reaction medium is diluted with 20 ml of methylene chloride and then evaporated to dryness under reduced pressure the bath temperature is maintained below 25 C and the pump vacuum is maintained above mbar.

A mixture of mg 4. Intermediate F6 2-Chloro-8,8-dimethy,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidinone can be prepared in the following way.

The medium is concentrated to dryness. The residue is taken up in 50 ml of ethyl acetate and 10 ml of water and then cooled in an ice bath.

The aqueous phase is extracted with ethyl acetate and then the organic phase is dried over magnesium sulfate.

After the solvent has been evaporated off, 0. After 4 h of heating, the reaction medium is concentrated to dryness. The oil obtained is taken up in ethyl ether.

The precipitate formed is filtered off, washed with ethyl ether and oven-dried under vacuum. The mixture is stirred at ambient temperature for 2 h.

The mixture is filtered and then evaporated to dryness. The reaction crude is solubilised in 20 ml of water, cooled with an ice bath.

After a return to ambient temperature, the product is precipitated with ethyl ether and filtration is carried out. The powder obtained is oven-dried at 70 C.

After a return to ambient temperature, the reaction medium is filtered and then the solvent is evaporated off. Et20 are added and the mixture is heated for 1 h 30 min at 70 C.

The organic phase is separated by settling out, washed with a saturated NaCI solution and then dried over magnesium sulfate. After a return to ambient temperature, the reaction medium is filtered and then taken up with a saturated aqueous NH4CI solution.

The aqueous phase is extracted with ethyl acetate, washed with an NaCI solution, then dried over magnesium sulfate and evaporated to dryness.

The solid obtained is placed in suspension in ml of water and stirred. The precipitated product is filtered off, rinsed with ether and then oven-dried under vacuum at 65 C.

The residue is taken up in ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. Concentrated NaOH is added to pH After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure.

The residue obtained is triturated from ethyl ether and the solid is filtered and then dried, so as to give 2. HO N N H A suspension of 5 g of 4,4-dimethy,4,5,6-tetrahydropyrimidinamine, 29 g of dimethyl fluoromalonate and 3.

The residue obtained is taken up with ethyl ether. The solid formed is filtered off and then dried. The suspension is filtered and then the solid is washed with 5 ml of water and then dried under vacuum over P, so as to give 3.

S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one can be prepared in the following way. Y F CI N N F 11 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 5.

The resulting mixture is then heated to 70 C. The residue obtained is taken up in 5 ml of cold water and ml of ethyl acetate. The organic phase is then separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 6 g of S chloromethyl trifluoromethyl -2,3-dihydroimidazo [1,2-a]pyrimidin-5 1H -one, the characteristics of which are the following: The resulting mixture is refluxed for 18 hours.

After cooling, the mixture obtained is concentrated to dryness under reduced pressure. The resulting suspension is stirred in an ice bath for two hours and then filtered through a sintered glass funnel.

The insoluble matter obtained is rinsed with water twice 4 ml and then dried so as to give 5. At the end of the addition, the reaction mixture is stirred at 5 C for 30 minutes.

The ice bath is then withdrawn and the mixture obtained is stirred at ambient temperature for 3 hours. The resulting mixture is then concentrated under reduced pressure.

The residue obtained is taken up twice with ml of ethanol and then twice with ml of toluene, and evaporated to dryness each time.

The solid obtained is triturated with ethyl ether and then filtered off, so as to give 4. The aqueous phase is subsequently separated by settling out and then extracted with 4 times ml of ethyl ether.

The mixture obtained is then filtered and the filtrate is evaporated to dryness. The oil obtained is taken up with a 3N hydrochloric acid solution 50 ml.

The mixture obtained is extracted with diethyl ether 3 x 50 ml. The aqueous phase is then evaporated to dryness, taken up with methanol, and then again evaporated to dryness.

The yellowish solid obtained is dried under vacuum, so as to give 5. Substantial evolution of gas and a temperature rise to 8 C are observed.

At the end of the addition, the temperature is left to come back up to ambient temperature, and then the reaction mixture is left stirring for 18 h.

The mixture obtained is cooled to 4 C, followed by very slow dropwise addition of 2 ml of water. Substantial evolution of gas and a temperature rise to 12 C are observed.

The white precipitate formed is filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 2.

The cold bath is then withdrawn to allow the mixture to warm up to ambient temperature. The organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2-methylpyrrolidine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1-aminohomopiperidine for 4- 2-aminoethyl morpholine.

The title compound was prepared according to procedure for EXAMPLE 51 substituting tert-butyl 1-piperazine carboxylate for 4- 2-aminoethyl morpholine.

The solution was stirred at room temperature for 1 hour, and was concentrated. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 3-aminoN-Boc-azetidine for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting N,N-dimethyl-1,4-phenylenediamine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2- 4-methyl-piperazinyl -ethylamine for 4- 2-aminoethyl morpholine.

A solution of isoxazolecarboxylic acid 32 mg, 0. The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 4-phenylpiperidine for 4- 2-aminoethyl morpholine.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting tert-butyl 2- aminomethyl piperidinecarboxylate for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 4-aminomethyl-piperidinecarboxylic acid tert-butyl ester for tert-butyl 1-piperazine carboxylate.

The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2- piperidinyl ethanamine for 4- 2-aminoethyl morpholine.

The mixture was stirred at room temperature for 2 hours before sodium cyanoborohydride 13 mg, 0. The residue was dissolved in 1: The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-bromo-pyridinecarbaldehyde for 2-fluoroformylbenzonitrile.

After cooling, the solid material was filtered off, and the filtrate was concentrated. The residual solid was washed with methanol, and dried to provide the title compound.

The residue was washed with methanol, and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-methylthiopyrimidine-carboxyaldehyde for 2-fluoroformylbenzonitrile.

The reaction mixture was stirred at room temperature for 4 hours, and concentrated. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 6-bromo-pyridinecarbaldehyde for 2-fluoroformylbenzonitrile.

The solution was stirred at room temperature for 16 hours, and was concentrated. To a solution of 3- piperidinyl propanoic acid 31 mg in anhydrous dichloromethane 2 mL was added oxalyl chloride The solution was stirred for 1 hour, and was concentrated.

The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The organic phase was washed with brine, and concentrated to provide the title compound.

After cooling, the reaction mixture was concentrated. A microwave tube was charged with tris dibenzylideneacetone dipalladium 0 5.

After concentration, the residue was partitioned between ethyl acetate and brine. The organic phase was concentrated. The residual solid was dissolved in dichloromethane 4 mL and treated with trifluoroacetic acid 2 mL at room temperature for 1 hour.

The title compound was prepared according to procedure for EXAMPLE 98, substituting 1- tert-butoxycarbonyl azetidinecarboxylic acid for 3- piperidinyl propanoic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 1- tert-butoxycarbonyl azetidinecarboxylic acid for 1- tert-butoxycarbonyl azetidinecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting methanesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting propanesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting benzenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting pyridinesulfonyl chloride hydrochloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting furansulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting 1-methyl-1H-imidazolesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting thiophenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting 4-cyanobenzenesulfonyl chloride for dimethylsulfamoyl chloride.

The title compound was prepared according to the procedure for EXAMPLE 97, substituting naphthalenesulfonyl chloride for dimethylsulfamoyl chloride.

After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 5-bromothiophenecarbaldehyde for 2-fluoroformylbenzonitrile.

To a solution of 2- 2- -t-Boc-aminoethoxy ethoxy ethyl bromide Toronto, mg, 0. The organic phase was washed with brine, and concentrated.

The solution remained at room temperature for 1 hour, and was concentrated. The trifluoroacetic acid salt was dissolved in a mixture of methylene chloride and methanol, and was treated with 1M solution of HCl in ether.

Removal of the volatiles afforded the title compound as a HCl salt. The residue was dissolved in a 1: The title compound was prepared according to the procedure for EXAMPLE , substituting 2-methylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-ethoxypropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S oxopyrrolidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting R oxopyrrolidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-carbamoylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-phenylpropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 2,5-dimethoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-phenylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- m-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- o-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- p-tolyloxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting R methoxyphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting S methoxyphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4- thiophenyl butanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-acetylpiperidinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 3,5-difluorophenyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting S acetamidomethylpentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting S dipropylamino propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-oxophenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2-benzamidoacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 3-methoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 4-methoxyphenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 3,4-dimethylphenoxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting R hydroxyphenylbutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4-phenoxybutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-oxo thiophenyl butanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 4-methylpyrimidinylthio acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 2-chlorophenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- 4-chlorophenyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3-methylphenylpentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2- 4-chloromethylphenoxy acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 5-oxo phenylamino pentanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 4- 4-methoxyphenyl oxobutanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 2,2-diphenylacetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to procedure for EXAMPLE , substituting 3- phenylsulfonyl propanoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-phenoxyphenyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-ethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-fluoromethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,3-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,4-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-ethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-isopropoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- diethylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-butoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro trifluoromethyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting furancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethylfurancarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylthiophenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,5-dimethyl-1H-pyrrolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting thiazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting isoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,5-dimethylisoxazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting nicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting isonicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-hydroxypicolinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl acetic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylpyrazinecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1H-indolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methylphenyl-1H-pyrazolecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 6-chloro-2H-chromenecarboxylic acid for 1-methylcyclopropanecarboxylic acid.

N 3 ,N 3 -dimethyl-N 1 - 3- 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl -beta-alaninamide. The title compound was prepared according to the procedure for EXAMPLE , substituting 3- dimethylamino propanoic acid for 1-methylcyclopropanecarboxylic acid.

To a solution of 2- 3-bromophenyl acetic acid 4. The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine.

The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed with water and concentrated. The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2,2,2-trifluorophenylethanone for 2-fluoroformylbenzonitrile.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-hydroxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxymethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-naphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-acetamidobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-propoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-hydroxynaphthoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-chloro methylthio benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,4-diethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a trifluoroacetic acid salt according to the procedure for EXAMPLE , substituting 2- phenylamino benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as according to the procedure for EXAMPLE , substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-phenethylbenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-bromochlorobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methylbenzoyl benzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-iodobenzoic acid for 1-methylcyclopropaneccarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid.

The title compound was prepared as a free base according to the procedure for EXAMPLE 39, substituting 3-acetamidophenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- methylsulfonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- pyrrolidinecarbonyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-carbamoylphenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4- dimethylcarbamoyl phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step.

The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 1,1,1-trifluorophenylpropanone for 2-fluoroformylbenzonitrile.

The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The title compound was prepared according to the procedure for EXAMPLE A, substituting 4- benzyloxycarbonyl tert-butoxycarbonyl piperazinecarboxylic acid for 2- 3-bromophenyl acetic acid.

The catalyst was removed by filtration, and the filtrate was concentrated. The solid material was filtered off, and the filtrate was concentrated to give the title compound.

The mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in absolute ethanol 5 mL , and was treated with sodium ethoxide 0.

A solution of 2-phenoxyacetic acid 28 mg, 0. The residue was re-dissolved in anhydrous dichloromethane 5 ml.

The reaction mixture was stirred at room temperature overnight, and was concentrated. After cooling, the reaction mixture was diluted with methanol 20 ml , and filtered.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- morpholinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE substituting 2- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinecarbonyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- cyclopropylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2- dimethylamino ethylcarbamoyl phenylboronic acid for 3- morpholinecarbonyl -phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-carbamoylphenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylsulfonamido phenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-acetamidophenylboronic acid for 3- morpholinecarbonyl phenylboronic acid.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-chloronitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methoxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-hydroxynitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methylnitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

A solution of 3-bromoethyl benzene 2 g, 11 mmol. After cooling, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine.

The organic layer was washed with brine, and was concentrated. After cooling to room temperature, the solid material was collected by filtration, washed with toluene, and dried to provide the title compound.

A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione 0. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours.

After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. To a solution of 4- 4-methoxyphenyl oxobutanoic acid 29 mg, 0.

The reaction mixture was stirred at room temperature for 16 hours, and was concentrated. The reaction mixture was cooled and concentrated on a rotary evaporator.

The title compound was prepared according to the procedure for EXAMPLE A, substituting 2- 3-bromofluorophenyl acetic acid for 2- 3-bromophenyl acetic acid.

A mixture of 4-oxophenylbutanoic acid 50 mg, 0. The reaction mixture was stirred at room temperature for another 1 hour, and was diluted with 5 mL of methanol.

The solid material was collected by filtration, washed with methanol, and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE , substituting hexahydroisobenzofuran-1,3-dione for oxabicyclo 3.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3,3-dimethyldihydrofuran-2,5-dione for oxabicyclo 3.

A mL round bottom flask was charged with 3-bromofluorobenzaldehyde 1. The mixture was purged with nitrogen, and anhydrous dioxane 15 mL , and 5-methylpyrrolidinone 0.

After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO 4 , filtered and concentrated.

The residue was dissolved in ethanol 5 mL and treated with hydrazine monohydrate 0. The mixture was allowed to cool and the precipitated solid was filtered and dried to provide the title compound.

The reaction mixture was concentrated, and the residual solid was dissolved in dioxane 3 mL. The residue was stirred with a mixture of ethyl acetate and water.

The precipitated solid was filtered, washed with water, and dried to provide the title compound. The combined organics were concentrated and dried under vacuum to provide the title compound.

After cooling to room temperature, the precipitated solid was filtered, and dried to provide the title compound. The reaction mixture was concentrated and dried to provide the title compound.

The reaction mixture was concentrated. The title compound was prepared according to the procedure for EXAMPLE , substituting thiophenylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting pyridinylmethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyrrolidinyl propanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3- piperidinyl propanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-morpholinopropanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzyloxycarbonylamino acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-oxo 4-phenoxyphenyl butanoic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- benzyloxycarbonyl piperidinecarboxylic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- p-tolyloxy acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-methoxyphenoxy acetic acid for 4-oxophenylbutanoic acid.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-tert-butylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 4-tert-butylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-fluoromethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 3-chloromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-chloromethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-bromomethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-bromomethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-fluoromethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-methoxy trifluoromethyl aniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-aminomethylphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3-aminomethylphenol for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-methoxymethylaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-methoxymethylaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminomethoxyphenol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-tert-butylmethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N- 3-aminomethoxyphenyl acetamide for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2,3-dihydrobenzo b 1,4 dioxinamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 5-chloro-2,4-dimethoxyaniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- methylthio aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- methylthio aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- piperidinyl aniline for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4-morpholinoaniline for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting N 1 - 4-methoxyphenyl benzene-1,2-diamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 5-aminonaphthalenol for furanylmethanamine.

To a solution of dimethylpyridine-2,3-dicarboxylate 1. The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water.

After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The reaction mixture was concentrated to about 5 mL.

The solid was collected by filtration, washed with ethanol and dried to provide the title compound. The title compound was prepared according to the procedure for EXAMPLE A, substituting 2-chlorofluorobenzyl magnesium chloride for 4-fluorobenzyl magnesium chloride.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2-o-tolylethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2-p-tolylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 4- pyridinyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 3- 2-methoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 4- 2-methoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-fluorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2-chlorophenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-chlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-bromophenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-bromophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- biphenylyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4- trifluoromethyl phenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-phenoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethylphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3-ethoxymethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 4-ethoxymethoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,4-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,5-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,5-dimethoxyphenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzo d 1,3 dioxolyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,3-dichlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dichlorophenyl ethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2,6-dichlorophenyl ethanamine for furanylmethanamine. A solution of 1- 3-bromofluorophenyl ethanone After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes and at reflux overnight.

After cooling, 1N HCl 10 mL was slowly added and the reaction mixture was concentrated. The organic phase was washed with water, and concentrated.

After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water ml and ethyl acetate ml.

The residue was purified by flash chromatography 2. The mixture was filtered, and the filtrate was concentrated. A mixture of magnesium turnings mg, 37 mmol and 2-bromo bromomethyl fluorobenzene 1.

The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour.

The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate 1. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- benzylamino ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting N-methyl pyridinyl ethanamine for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 3,4-dimethoxyphenyl -N-methylethanamine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting piperidinecarboxamide for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting piperazinecarbaldehyde for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- piperazinyl ethanone for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl ethanol for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLE , substituting 1- pyridinyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- piperazinyl pyrimidine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 2- 2- piperazinyl ethoxy ethanol for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 4-fluorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1- 2-chlorophenyl piperazine for furanylmethanamine.

The title compound was prepared according to the procedure for EXAMPLE , substituting 1-methyl piperazinyl azepane for furanylmethanamine. The title compound was prepared according to the procedure for EXAMPLEs 2, 3 and 4, substituting 3-nitrobenzaldehyde for 4-fluoronitrobenzaldehyde.

To a solution of 4-fluoronitrobenzoic acid 5 g, The reaction mixture was concentrated and partitioned between ethyl acetate mL and brine mL. The catalyst was filtered off, and the filtrate was concentrated.

The residue was used the subsequent step without further purification. The residue was partitioned between ethyl acetate mL and brine 75 mL.

The organic layer was washed with brine, and concentrated. The reaction was quenched with water, and the mixture was partitioned between ethyl acetate and diluted HCl solution.

The organic layer was washed with brine, and concentrated on a rotary evaporator. To a solution of 2-bromofluoroiodobenzene The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes.

Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated.

To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol 15 mL. The residue was dissolved in methylene chloride 40 mL , and was treated with triethylamine 5.

Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated.

After cooling to room temperature, the solids were collected by filtration, washed with ethanol and dried to provide the title compound. The solution was stirred at room temperature for 30 minutes, and benzyl chloromethylether 1.

The reaction mixture was stirred at room temperature overnight. After quenching with water, the reaction mixture was partitioned between water and ethyl acetate.

Anhydrous dioxane 3 mL was added. The suspension was purged with nitrogen, and was capped with a microwave septum.

After cooling, the reaction mixture was partitioned between ethyl acetate and brine. The residue was recrystallized from methanol 4 mL to provide the title compound.

The solid was collected by filtration, washed with methanol and dried to provide the title compound. A mixture of 1.

After cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to about 10 mL.

The solid was collected by filtration, washed with methanol, and dried to provide the title compound. A solution of EXAMPLE 1 g, 3 mmol in anhydrous dimethylformamide ml was treated with potassium t-butoxide 1N solution in tetrahydrofuran, 3 mL, 3 mmol at room temperature for 30 minutes.

Piperazinyl pyrimidine dihydrochloride 78 mg, 0. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes, and under reflux for 5 hours.

After cooling to room temperature, 1N HCl was added, and the reaction mixture concentrated.

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