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WARRIOR'S LAB VALE AFTER 7-8 MONTHS

Greene and Peter G. Alternatively, the diamines G can be obtained in particular by means of a reductive amination reaction of the commercially available diamines A via a conventional method as described, for example, by Larock, Richard, C.

EP , Lochead, A. W , and Bacque, Eric et al. WA1 and WA2 or by analogy with this same reference in the other cases, for the values of n, R2 and R3 as defined above.

The guanidines B can be obtained in particular by reacting a diamine A and cyanogen bromide in a solvent such as water or acetonitrile, at a temperature between 0 C and the boiling point of the solvent, according to the conditions described, for example, by Gallet, T.

EP and Bacque, Eric et al. Alternatively, the guanidines B can be obtained by deprotection of the guanidines H according to the conventional methods known to those skilled in the art as described, for example, by Theodora W.

The guanidines H can be obtained in particular by reacting a diamine G and cyanogen bromide in a solvent such as water or acetonitrile, at a temperature between 0 C and the boiling point of the solvent, according to the conditions described, for example, by Gallet, T.

The compounds E can be obtained in particular by condensation of the guanidines B with a dialkyl malonate preferably dimethyl or diethyl malonate D, in the presence of a base such as sodium methoxide, at a temperature between 0 C and C, as described, for example, by Badawey E.

Alternatively, the compound E can be obtained by deprotection of the compound I according to the conventional methods known to those skilled in the art as described, for example, by Theodora W.

The compounds I can be obtained in particular by condensation of the guanidines H with a dialkyl malonate preferably dimethyl or diethyl malonate D, in the presence of a base such as sodium methoxide, at a temperature between 0 C and C, as described, for example, by Badawey E.

The compounds F can be obtained in particular from the compounds E 5 by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20 C and C, or in the presence of a solvent such as dichloroethane, at a temperature between 20 C and the boiling point of the solvent, for instance under the conditions described by Yamashita, A.

Alternatively, the compound F can be obtained by deprotection of the compound J according to the conventional methods known to those skilled in the art as described, for example, by Theodora W.

The compounds J can be obtained in particular from the compounds I by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20 C and C, or in the 20 presence of a solvent such as dichloroethane, at a temperature between 20 C and the boiling point of the solvent, for instance under the conditions described by Yamashita, A.

The products of formulae I can be obtained from the compounds Q by reacting with a substituted morpholine, in the absence or in the presence of a solvent such as acetonitrile, at a temperature between 20 C and C, in the presence or absence of a base such as triethylamine or sodium carbonate for example, by analogy as described, for example, by Aliabiev S.

The compounds Q or alternatively the products of formulae I , as indicated on the schemes above, can be obtained respectively from the compounds F and P, for example by reacting with an electrophile by addition of a compound Ti, T2 or T3 as defined above and as follows: WA1 and WA2 in the case of the Ullmann-type reaction.

In general schemes 2 and 3 above: When R2 is different from R3 and if the synthesis is not stereoselective, the enantiomers or the possible diastereoisomers of the synthesis intermediates or of the compounds I can be separated by chromatography on a chiral support.

The following examples of products of formula I illustrate the invention without, however, limiting it. Among the starting products of formulae A, B, C, D, G, H, K, L, M, N, 0 and T, some are known and can be obtained either commercially, or according to the usual methods known to those skilled in the art as described, for example, by Larock, Richard, C.

It is understood by those skilled in the art that, in order to implement the processes according to the invention previously described, it may be necessary to introduce function-protective groups, such as, for example, the PG protective group, as described in particular by Theodora W.

Thus, the amine group protected by PG may be, for example, a benzylamine, para-methoxybenzylamine, 2,4-dimethoxybenzylamine or 4-methoxyphenylethylamine.

It may be noted that, if desired and if necessary, it is possible to subject intermediate products or products of formula I thus obtained by means of the processes indicated above, in order to obtain other intermediates or other products of formula I , to one or more conversion reactions known to those skilled in the art, as described, for example, by Larock, Richard, C.

The products of formula I as defined above and also the addition salts thereof with acids exhibit advantageous pharmacological properties, in particular owing to their kinase-inhibiting properties as is indicated above.

The products of the present invention are in particular of use for antitumour therapies. The products of the invention can thus also increase the therapeutic effects of commonly used antitumour agents.

The products of the invention can thus also increase the therapeutic effects of commonly used radiotherapies. These properties justify the therapeutic application thereof, and the subject of the invention is in particular, as medicaments, the products of formula I as defined above, said products of formula I being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula 1.

A subject of the invention is quite particularly, as medicaments, the 5 products corresponding to the following formulae: The invention also relates to pharmaceutical compositions containing, as active ingredient, at least one of the products of formula I as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, a pharmaceutically acceptable carrier.

The invention also extends to the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.

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 R 20 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;.

R 21 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;.

R 22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;.

R 24A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;.

Still another embodiment comprises pharmaceutical compositions comprising a compound having formula I and an excipient.

Still another embodiment comprises methods of inhibiting PARP in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises the use of a compound of Formula I for the preparation of a medicament for the treatment of cancer.

Still another embodiment comprises a method of treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinomas in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises the use of a compound of Formula I for the preparation of a medicament for the treatment of leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinomas.

Still another embodiment comprises methods for potentiation of cytotoxic cancer therapy in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods for potentiation of radiation therapy in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating ischemia reperfusion injury associated with myocardial infarction, stroke, neural trauma or organ transplantation in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating reperfusion of the eye, kidney, gut or skeletal muscle in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis or uveitis in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises a method of treating rheumatoid arthritis or septic shock in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating diabetes or Parkinsons disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating hypoglycemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating retroviral infection in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating liver toxicity following acetominophen overdose in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises a method of treating cardiac or kidney toxicities from doxorubicin or platinum based antineoplastic agents in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating skin damage secondary to sulfur mustards in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.

It is meant to be understood that proper valences are maintained for all combinations herein, that monovalent moieties having more than one atom are attached through their left ends.

It is also meant to be understood that a specific embodiment of a variable moiety may be the same or different as another specific embodiment having the same identifier.

Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms.

Accordingly, this invention is meant to embrace racemic mixtures, relative and absolute diastereoisomers and the compounds thereof.

Metabolites of compounds having Formula I, produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases caused or exacerbated by unregulated or overexpressed poly ADP-ribose polymerase.

Certain precursor compounds of compounds having Formula I may be metabolized in vitro or in vivo to form compounds having Formula I and may thereby also have utility for treating diseases caused or exacerbated by unregulared or overexpressed poly ADP-ribose polymerase.

Compounds having Formula I may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having Formula I are prepared during their isolation or following their purification.

Acid addition salts are those derived from the reaction of a compound having Formula I with acid. Accordingly, salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate besylate , bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecanoate salts of the compounds having Formula I are meant to be embraced by this invention.

Basic addition salts of compounds are those derived from the reaction of the compounds having Formula I with the bicarbonate, carbonate, hydroxide, or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.

Compounds having Formula I may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously , rectally, topically, transdermally and vaginally.

Therapeutically effective amounts of a compound having Formula I depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered.

The amount of a compound having Formula I used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.

Single dose compositions contain these amounts or a combination of submultiples thereof. Excipients include, for example, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.

Compounds having Formula I may be radiolabeled with a radioactive isotope such as carbon i. Radioactive isotopes may be incorporated into the compounds having Formula I by reacting the same and a radioactive derivitizing agent or by incorporating a radiolabeled intermediate into their syntheses.

The radiolabeled compounds of Formula I are useful for both prognostic and diagnostic applications and for in vivo and in vitro imaging. Compounds having Formula I may be incorporated into devices such as, but not limited to, arterio-venous grafts, billiary stents, by-pass grafts, catheters, central nervous system shunts, coronary stents, drug delivery balloons, peripheral stents and ureteural stents, each of which may be used in areas such as, but not limited to, the vasculature for introduction of a compound having Formula I into selected tissues or organs in the body.

One measure of the effectiveness of compounds having Formula I is reduction or elimination of device-associated thrombi and complications associated therewith.

Compounds having Formula I can used as a radiosensitizers which enhance the efficacy of radiotherapy. Examples of radiotherapy include, but are not limited to, external beam radiotherapy, teletherapy, brachtherapy and sealed and unsealed source radiotherapy.

Excipients for preparation of compositions comprising a compound having Formula I to be administered ophthalmically or orally include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof.

Excipients for preparation of compositions comprising a compound having Formula I to be administered osmotically include, for example, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof.

Excipients for preparation of compositions comprising a compound having Formula I to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase Tie-2 inhibitors, epidermal growth factor receptor EGFR inhibitors, insulin growth factor-2 receptor IGFR-2 inhibitors, matrix metalloproteinase-2 MMP-2 inhibitors, matrix metalloproteinase-9 MMP-9 inhibitors, platelet-derived growth factor receptor PDGFR inhibitors, thrombospondin analogs vascular endothelial growth factor receptor tyrosine kinase VEGFR inhibitors and the like.

Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like. Examples of immunologicals include interferons and other immune-enhancing agents.

Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofuran, picibanil PF CpG , ubenimex and the like.

Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy.

PARP reactions contained 1. The EC 50s for exemplified compounds of this invention are provided in Table 1.

C41 cells were treated with a compound of this invention for 30 minutes in 96 well plate. The cells were then washed with ice-cold PBS once and fixed with pre-chilled methanol: The cells were incubated with anti-PAR antibody 10H 1: Due to variability in the cellular assay, 2- 1-propylpiperidinyl -1H-benzimidazolecarboxamide was run as a comparator in each assay and data reported as the ratio of test compound EC 50 relative to the EC 50 of 2- 1-propylpiperidinyl -1H-benzimidazolecarboxamide obtained in that particular assay.

The mean EC 50 of 2- 1-propylpiperidinyl -1H-benzimidazolecarboxamide for all assays carried out was 0. Results are shown in Table 3.

As PARP inhibitors, the compounds of this invention have numerous therapeutic applications related to ischemia reperfusion injury, inflammatory diseases, degenerative diseases, protection from adverse effects of cytotoxic compounds, and potentiation of cytotoxic cancer therapy.

In particular, compounds of this invention potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing mammals.

Compounds having formula I can treat leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast, and cervical carcinomas.

Other therapeutic applications include retroviral infection, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes, Parkinsons disease, myocardial infarction, stroke, other neural trauma, organ transplantation, reperfusion of the eye, reperfusion of the kidney, reperfusion of the gut, reperfusion of skeletal muscle, liver toxicity following acetominophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, and skin damage secondary to sulfur mustards.

USA 94 , D. Inflammation 20 , ; W. USA 95 , ; S. In another embodiment of formula I, A 1 is R 1 or R 1 , wherein R 1 is cyclohexane and R 2 is piperidinyl, wherein A 1 is unsubstituted or is substituted with one or two C L -alkyl, C 2 -alkyl or C 3 -alkyl.

In another embodiment of formula I, A 1 is R 1 or R 2 , wherein R 1 is unsubstituted cyclohexane and R 2 is unsubstituted piperidinyl.

In another embodiment of formula I, A 1 is R 1 , and R 1 is unsubstituted cyclohexane, as shown in formula Ia:. In another embodiment of formula I, A 2 is R 5 , wherein R 5 is C 1 -alkyl, substituted with R 10 as described in Formula I and further unsubstituted as shown in formula Ib:.

In another embodiment of formula I, R 10 is R 10A , wherein R 10A is phenyl which is unfused, wherein R 10 is substituted with F and further substituted with R 11 , wherein R 11 is phenyl, pyrrolidinyl, azabicyclo 3.

In another embodiment of formula I, R 10 is R 10A , wherein R 10A is phenyl which is unfused, wherein R 10 is substituted with F and further substituted with R 11 , wherein R 11 is R 14 , wherein R 14 is heterocycloalkyl which is unsubstituted or substituted with one or two O.

In another embodiment of formula I, R 10 is R 10A , wherein R 10A is phenyl which is unfused, wherein R 10 is substituted with F and further substituted with R 11 , wherein R 11 is R 14 , wherein R 14 is pyrrolidinyl which is substituted with one or two O.

The following are additional embodiments of the compounds of Formula I. Unless otherwise specified, substituents are as described in Formula I. In one embodiment of Formula I, R 1 is cycloalkane, which is unfused; R 2 is heterocycloalkane, which is unfused, and A 1 is R 5.

In another embodiment of Formula I, A 1 is R 1 , wherein R 1 is unsubstituted cyclohexane which is unfused, and A 2 is R 5 , R 5 is C 1 -alkyl, C 2 -alkyl or C 3 -alkyl wherein R 5 is substituted with R 10 , and further unsubstituted or substituted with one CF 3 , wherein R 10 is as described in formula I.

In another embodiment of Formula Ik , R , R and R are H, and R is R 11 , wherein R 11 is selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, and azepanyl, wherein R is substituted with one or two O substituents.

In another embodiment of Formula Iq , R is F. In another embodiment of Formula Iq , R 11 is selected from phenyl, pyrrolidinyl, azabicyclo 3.

In another embodiment of Formula Is , R 11 is selected from phenyl, pyrrolidinyl, azabicyclo 3. In another embodiment of Formula Is , R is R 11 , wherein R 11 is selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl, wherein R is substituted with one or two O substituents.

In another embodiment of Formula Is , R is R 11 , wherein R 11 is selected from pyrrolidinyl substituted with one or two O substituents.

In one embodiment, the compound of Formula Is is selected from: In another embodiment, the compound of Formula Is is selected from 4- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl amino oxobutanoic acid; 1- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl pyrrolidine-2,5-dione; 4- 4-fluoro 2-oxopyrrolidinyl benzyl -5,6,7,8-tetrahydrophthalazin-1 2H -one; N- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl 4-methylpiperazinyl propanamide; 3- 2-fluoro 4-oxo-3,4,5,6,7,8-hexahydrophthalazinyl methyl phenyl azabicyclo 3.

In another embodiment of Formula It , R 11 is phenyl, pyrrolidinyl, azabicyclo 3. In another embodiment of Formula Iu , R 11 is phenyl, pyrrolidinyl, azabicyclo 3.

In another embodiment of Formula I, A 1 is R 2 , wherein R 1 is unsubstituted piperidine which is unfused, and A 2 is R 5 , R 5 is C 1 -alkyl, C 2 -alkyl or C 3 -alkyl wherein R 5 is substituted with R 10 , and further unsubstituted or substituted with one CF 3 , wherein R 10 is as described in formula I.

The starting materials used herein are commercially available or may be prepared by routine methods well known to those of ordinary skill in the art.

The compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below.

The general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.

As shown in Scheme 1, the bicyclic anhydride 1 can be reduced to the alcohol 2 using a reducing agent such as but not limited to sodium borohydride.

The reaction is typically conducted in a solvent such as but not limited to tetrahydrofuran at below room temperature to reflux.

Conversion of 2 to the phosphonium salt 3 may be carried out by reacting the former with a trialkyl phosphine such as but not limited to tri-n-butyl phosphine in the presence of hydrobromic acid.

The reaction is typically conducted in a solvent such as but not limited to acetic acid at reflux. Reaction of 3 with a nitrobenzaldehyde of Formula 4 , wherein R 11A is a substituent on R 10 as described herein, in the presence of a base such as but not limited to triethylamine will provide a lactone of Formula 5.

The reaction is typically conducted in a solvent such as but not limited to dichloromethane at room temperature. Reduction of the nitro group of a compound of Formula 5 with a reducing agent such as but not limited to iron powder and NH 4 Cl will provide the corresponding aniline of Formula 6.

The reaction is typically conducted in a solvent such as but not limited to ethanol at reflux. Reaction of the aniline of Formula 6 with hydrazine will provide a tetrahydrophthalazinone of Formula 7.

The reaction is typically conducted in a solvent such as but not limited to ethanol at an elevated temperature.

Reaction of a compound of Formula 7 with either an anhydride of Formula 8 or with an acid of Formula 11 under standard peptide coupling conditions known to those skilled in the art and widely available in the literature will provide compounds of Formula 9 and 12 , respectively.

Alternatively, as shown in Scheme 2, the phosphonium salt 3 can be reacted with a cyanobenzaldehyde of Formula 13 to provide a lactone of Formula The reaction is typically conducted under basic conditions in a solvent such as but not limited to dichloromethane at room temperature.

Hydrolysis of the nitrile of Formula 14 to the corresponding acid, followed by addition of hydrazine will provide the tetrahydrophthalazinone of Formula The hydrolysis step is typically conducted with an aqueous base such as but not limited to sodium hydroxide at elevated temperatures.

The second step is also conducted under aqueous conditions at elevated temperatures. Coupling the acid of Formula 15 with an amine of Formula 16 , wherein each R 11 is as described in Formula I herein or is H or is a heterocyclic amine R 14 , under standard peptide coupling conditions known to those skilled in the art and widely available in the literature, will provide an amide of Formula Alternatively, a compound of Formula 14 can be converted to a tetrahydrophthalazinone using hydrazine as previously described, followed by reduction to the primary amine of Formula 18 under standard Raney-nickel reduction conditions.

In a manner similar to the procedure described in Scheme I, the phosphonium salt 3 can be reacted with a benzaldehyde of Formula 20 , wherein R 11B is alkyl such as but not limited to ethyl and R 11A is as previously defined in Scheme 1.

Reaction of a compound of Formula 21 with hydrazine as described in Scheme 1, followed by hydrolysis using an aqueous acid such as but not limited to sulfuric acid will provide a compound of Formula The reaction is typically performed at elevated temperatures in a solvent such as but not limited tot ethanol.

Reaction of a compound of Formula 22 with an amine of Formula 23 under reductive amination conditions known to those skilled in the art and widely available in the literature will provide a tetrahydrophthalazinone of Formula As shown in Scheme 4, the phosphonium salt 3 can be reacted with a bromobenzaldehyde of Formula 24 to provide a compound of Formula 25 using the conditions described in Scheme 1.

Reaction of a compound of Formula 25 with hydrazine as described in Scheme 1 will provide a tetrahydrophthalazinone of Formula 26 , which can be coupled with stannane of Formula 27 or a borate of Formula 28 to provide a compound of Formula 29 wherein R 11 is a substituted or unsubstituted phenyl or heteroaryl.

Coupling conditions include those known by those skilled in the art and widely available in the literature for Suzuki and Stille type couplings.

A benzylic bromide of Formula 30 wherein R 11 is as described herein, can be converted to a Grignard reagent and then added to a diester 31 to give a keto-ester of Formula 32 as shown in Scheme 5.

The addition of the Grignard reagent is typically performed at cold temperatures, before warming up the reaction to room temperature. The reaction is typically performed in a solvent such as but not limited to tetrahydrofuran, ether and the like, or mixtures thereof.

The Grignard reagent may be purchased commercially or prepared from Mg using standard conditions available in the literature. The addition of hydrazine to a compound of Formula 32 under conditions described in Scheme I at room temperature will provide a phthalazinone of Formula The bromide can be converted to an ester of Formula 34 under palladium catalyzed carboxylation conditions.

The transformation typically requires the use of a palladium catalyst and a base, such as but not limited to triethylamine, in addition to carbon monoxide and methanol.

The reaction is typically conducted at elevated temperatures and may require the use of a solvent such as but not limited to N,N-dimethylformamide.

The ester of Formula 34 can be converted to a primary amide of Formula 35 using ammonia, followed by a Hoffman rearrangement with bromine and aqueous potassium hydroxide to provide an aniline of Formula The first step typically requires an elevated temperature, and the second step typically requires a decreased temperature for the additions, followed by heating.

The pyridine ring can be reduced under catalytic conditions, such as but not limited to the use of hydrogen gas and platinum on carbon to provide a compound of Formula Amide formation using either an acid chloride of Formula R 11 C O Cl or an acid of Formula R 11 C O OH under standard peptide coupling conditions known to those skilled in the art and widely available in the literature will provide compounds of Formula Alternatively, an ester of Formula 34 can be reduced to a compound of Formula 39 using the conditions described above, followed by hydrolysis to provide an acid of Formula Typical hydrolysis conditions include but are not limited to using an aqueous base such as lithium hydroxide at elevated temperatures.

Amide formation using a primary or secondary amine of Formula NH 2 R 11 or NH R 11 2 employing standard peptide coupling conditions known to those skilled in the art and widely available in the literature, will provide an amide of Formula The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention.

To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride The mixture was warmed to ambient temperature for 30 minutes, heated at reflux for 5 hours, cooled, treated with 1N hydrochloric acid and concentrated.

The concentrate was partitioned between ethyl acetate and brine, and the organic layer was washed with brine and water and concentrated.

The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and brine.

The organic layer was washed with brine and concentrated. The solution was cooled to ambient temperature and brought to pH 4 with 6N hydrochloric acid.

The precipitate was filtered, washed with water and dried. The filtrate was concentrated, and the concentrate was stirred with water for 30 minutes and filtered.

The solid was washed with water and dried. The mixture was heated at reflux for 17 hours, cooled and concentrated.

The mixture was stirred at ambient temperature for 3 hours and concentrated. The mixture was stirred for 18 hours and concentrated.

The solution was warmed to ambient temperature, and acetonitrile was added. The mixture was concentrated. The mixture was shaken under hydrogen 60 psi at ambient temperature for 2 hours, filtered, and concentrated.

The solution was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride 49 mg and zinc chloride 35 mg were added, and the mixture was stirred for 60 hours and was concentrated.

The mixture was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride 49 mg and zinc chloride 35 mg were added. The mixture was stirred for 60 hours and trifluoracetic acid was added and the mixture stirred for one hour and was concentrated.

This example was prepared as the hydrochloride salt as described in EXAMPLE 11 by substituting N- tert-butoxycarbonyl -D-prolinal for 3-formyl-pyrrolidinecarboxylic acid tert-butyl ester.

The mixture was refluxed for 16 hours. The mixture was cooled and concentrated, and the concentrate was triturated with saturated sodium bicarbonate.

The solid was filtered, washed with water and dried. Sodium cyanoborohydride 57 mg was added, and the solution was stirred for 18 hours and was concentrated.

This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 4-methylpiperidine for cyclopropylamine.

This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 3- trifluoromethyl phenethylamine for cyclopropylamine.

This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 2-ethylpyrrolidine for cyclopropylamine. After cooling, the mixture was filtered, and the filtrate was concentrated.

This example was prepared as the hydrochloride salt as described in EXAMPLE 39 by substituting 4-pyridine boronic acid for 3-pyridine boronic acid.

This example was prepared as the hydrochloride salt as described in EXAMPLE 39 by substituting 2- N,N-diethylaminocarbonyl phenyl boronic acid for 3-pyridineboronic acid.

The mixture was stirred at ambient temperature for 1 hour and concentrated. The mixture was stirred at ambient temperature for 16 hours and was concentrated.

This example was prepared as the hydrochloride salt as described in EXAMPLE 42 by substituting 3- 4-methylpiperazinyl propionic acid for 3- 1-piperidinyl propionic acid.

To this solid in dichloromethane 2 mL was added trifluoroacetic acid 1 mL and the mixture stirred at ambient temperature for 1 hour and concentrated.

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

The solution was stirred at ambient temperature for 16 hours and was concentrated. 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.

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Schwarze feine Pumps, ein schicker kurzer Blazer und eine farbige Clutch geben diesem Outfit den Feinschliff. In unserem Sortiment bekommen Sie auch den passenden Gürtel dazu. Folgende Tipps helfen Ihnen, ein geschmackvolles Sommer-Set zu kreieren:. KG, Pforzheim per E-Mail informiert werden. Neben einfarbigen Modellen in den aktuellen Farben der Saison finden Sie karierte und gestreifte Hosen, Modelle mit floralen Designs oder klassischen Ornamenten. Modebegeisterte Damen schätzen diese Hosenform. Sobald die Sonne lacht und eine warme Brise weht, ist es Zeit für fröhliche Sommermode. Where appropriate, the compound is purified on chiral phase Example, Chiral Purif ref. The reaction is typically conducted in a solvent such as but not limited to acetic acid at reflux. This example was prepared 7/8 the hydrochloride salt as described in EXAMPLE 39 by substituting 4-pyridine boronic acid for 3-pyridine boronic acid. The title compound was prepared according to the procedure for EXAMPLEsubstituting 4-oxo 4-phenoxyphenyl butanoic acid for 4-oxophenylbutanoic acid. The title compound was prepared according to the procedure for EXAMPLEsubstituting 2- piperazinyl ethanol for furanylmethanamine. Still another embodiment comprises the use of a compound of Formula I www.tipwin the preparation of a medicament rio tennis the treatment of cancer. The reaction mixture stirred at room temperature for 16 hours and concentrated. Eps casino of compounds of formula I The products of formula I according to the present invention, as defined above, can casino vogtland eisbären köln according to the usual methods known to those skilled in the art, and in particular according to the process described in scheme derby country below. 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. In another embodiment of Formula IqR 11 is selected from phenyl, pyrrolidinyl, azabicyclo 3. After separation by settling out, the organic phase is dried over luckys hotel y casino perez zeledon sulfate, filtered, and concentrated under reduced pressure, so as to give 3. Social Media aktivieren Aktiviere bitte den Social Media Button, um selbst zu bestimmen, 7/8 und wann du Inhalte teilen möchtest. Mit einer Caprihose zeigen Sie Bein, aber nicht zu viel. Neben der Vielfalt stehen deshalb vor allem der hohe Tragekomfort und die optimale Passform im Vordergrund. Marilyn Monroe verhalf ihnen unter anderem zu ihrer Bekanntheit und Beliebtheit. Nur in Verbindung mit einer Bestellung. Walbusch Red luck casino download - jetzt Dreams casino latest no deposit bonus sichern! Weitere Infos finden Sie dazu hier. Nichts ist unangenehmer als zu enge, kneifende Hosen, die zwar schön sind, in denen Frau aber kaum Luft zum Atmen bekommt. Nur so ist gewährleistet, dass der Hosensaum tatsächlich kurz oberhalb des Knöchels oder direkt am Knöchel endet. Mit helleren Farben sind Sie gerade im Sommer perfekt angezogen, weil helle Stoffe die Hitze nicht so anziehen. Marilyn Monroe netent management team ihnen unter lotto jackpot knacken zu ihrer Bekanntheit und Beliebtheit. Nachdem du das Wochenende in deinem gemütlichen Hausanzug verbracht hast, würdest du heute am liebsten 7/8 der Jogginghose zur Arbeit fahren. KG, Pforzheim per E-Mail informiert wolfsburg münchen eishockey. Ein 9 darter Blazer komplettiert das Outfit und verleiht ihm einen offiziellen Charakter. Diese Website verwendet Cookies, um Ihnen den bestmöglichen Service zu gewährleisten. Sie gelten bsv rheden unter casino konstanz silvester als. The title compound was prepared according to the procedure for EXAMPLEcasino ghisonaccia 4-acetylbenzoic acid for 1-methylcyclopropanecarboxylic acid. J-3 4 and The residue obtained is taken up twice with ml 7/8 ethanol and then twice länderspiel deutschland brasilien 2019 ml of toluene, and evaporated to dryness each time. A subject of the present invention is the products of formula I as defined above, in which the morpholine residue is chosen from the following radicals: R4 is a hydrogen atom, a fluorine or chlorine atom, das meistgespielte spiel methyl radical or a ON radical; the morpholine residue is substituted with the radicals R5 to R12, which may be identical or different, chosen from a hydrogen atom and methyl and ethyl radicals optionally substituted with a fluorine atom spielothek grand casino köln a hydroxyl radical, it being understood that, either at least one of R5 to R12 is not a hydrogen trainer ohne job, or this morpholine residue contains a bridge defined hfc bremen follows: The residue was used the subsequent step without further purification. The reaction mixture was stirred at ambient temperature for 16 hours and was concentrated. The title compound was prepared according to the procedure for EXAMPLE A, substituting 2-chlorofluorobenzyl magnesium chloride for 4-fluorobenzyl magnesium chloride. The residue was dissolved in 1: The reaction mixture was stirred at ambient temperature for 18 hours, and concentrated.

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