Title of Invention	MALONAMIDE DERIVATIVES AS GAMMA-SECRETASE INHIBITORS AND THE PROCESS OF PREPARING THE SAME
Abstract	The invention relates to malonamide derivatives of formula (IA) or (IB) and to pharmaceutically suitable acid addition salts thereof. The compounds are ϝ-secretase inhibitors and the related compounds may be useful in the treatment of Alzheimer's disease.

Full Text

MALONAMIDE DERIVATIVES AS GAMMA-SECRETASE INHIBITORS The invention relates to malonamide derivatives of formula benzo[b]thiophenyl, tetrahydronaphthyl, indanyl, 2,2-dimethyI-[l,3]dioxolanyl or tetrahydrofuranyl; R1 and R1' are the same or different and are hydrogen, lower alkyl, halogen, benzyl, lower alkenyl; (R2) 1,2,3 is independently from each other hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R - is phenyl or benzyl, which are unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen or cyano, or is - lower alkyl, - two hydrogen atoms, -(CH2)1,2-S-lower alkyl, - (CH2)1,2-cydoaIkyl, - (CH2)1,2-OH, - CH2OCH2--phenyI, or the groups R4 is lower alkoxy, - mono-or dialkyl amino, -N(CH3)(CH2)1,2-OCH, or is a mono-, di or tricyclic group, unsubstituted or substituted by R5 to R10, and which groups may be linked by -N(CH3)(CH2)o,1,2, to the -C(O) -group in formula IB, X is-CH2,-S(0)2or-C(0)-; R11 is hydrogen or lower alkyl; R is hydrogen or halogen; R14 is hydrogen, lower alkyl, -(CH2)2OH or -(CH2)2CN; and to pharmaceutical^ suitable acid addition salts thereof. The mono-, di or tricyclic group, unsubstituted or substituted by R5 to R10, and which groups may be linked by -N(CH3) (CH2)o,1,2, to the -C(O) -group in formula IB, may be the followings: (R5)1,2 is independently from each other hydrogen, halogen, lower alkyl or -(CH2)1,2OH; R6 is hydrogen, halogen or lower alkoxy; R7 is hydrogen or -CH2OCH3; R8 is hydrogen or halogen; R9 is hydrogen, lower alkoxy, lower alkyl or amino; (R10)1,23 is independently from each other hydrogen, lower alkyl, lower alkoxy, lower cycloalkyl, halogen, hydroxy, =0, amino, nitro, -CH2CN, -OCH2C6H5, As used herein, the term "lower allcyl" denotes a saturated straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. The term "cycloalkyl" denotes a saturated carbocyclic group, containing 3-7 carbon atoms. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "lower alkoxy" denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom. The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. It has been found that the compounds of general formulas IA and IB are y-secretase inhibitors and the related compounds maybe useful in the treatment of Alzheimer's disease. Alzheimer's disease (AD) is the most common cause of dementia in later life. Pathologically AD is characterized by the deposition in the brain of amyloid in extracellular plaques and intracellular neurofibrillary tangles. The amyloid plaques are mainly composed of amyloid peptides (Abeta peptides) which originate from the {3-Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing. The Abeta peptides are derived from the same domain of the APP but differ at their N- and C-termini, the main species are of 40 and 42 amino-acid length. Abeta peptides are produced from APP through the sequential action of 2 proteolytic enzymes termed (3- and y-secretase. P-Secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP containing the TM- and cytoplasmatic domain (CTFp). CTFp is the substrate for y-secretase which cleaves at several adjacent positions within the TM to produce the Aβ peptides and the cytoplasmic fragment The majority of Abeta peptides is of 40 amino acids length (Aβ40), a minor species carries 2 additional amino acids at its C-terminus. Latter is supposed to be the more pathogenic amyloid peptide. The β-secretase is a typical aspartyl protease. The y-secretase is a proteolytic activity consisting of several proteins, its exact composition is incompletely understood. However, the presenilins are essential components of this activity and may represent a new group of atypical aspartyl proteases which cleave within the TM of their substates and which are themselves polytopic membrane proteins. Other essential components of y-secretase may be nicastrin and the products of the aph 1 and pen-2 genes. Proven substrates for y-secretase are the APP and the proteins of the Notch receptor family, however, y-secretase has a loose substrate specificity and may cleave further membrane proteins unrelated to APP and Notch. The y-secretase activity is absolutely required for the production of Abeta peptides. This has been shown both by genetic means, i.e., ablation of the presenilin genes and by low-molecular-weight inhibitory compounds. Since according to the amyloid hypothesis or AD the production and deposition of Abeta is the ultimate cause for the disease, it is thought that selective and potent inhibitors of y-secretase will be useful for the prevention and treatment of AD. Thus, the compounds of this invention will be useful treating AD by blocking the activity of y-secretase and reducing or preventing the formation of the various amyloidogenic Abeta peptides. Numerous documents describe the current knowledge on y-secretase inhibition, for example the following publications: Nature Reviews/Neuroscience, Vol. 3, April 2002/281, Biochemical Society Transactions (2002), Vol. 30. part 4, Current Topics in Medicinal Chemistry, 2002, 2,371-383, Current Medicinal Chemistry, 2002, Vol 9, No. 11,1087-1106, Drug Development Research, 56,211-227, 2002, Drug Discovery Today, Vol. 6, No. 9, May 2001,459-462, FEBS Letters, 483, (2000), 6-10, Science, Vol. 297,353-356, July 2002 and JouR11. of Medicinal Chemistry, Vol 44, No. 13, 2001, 2039-2060. Objects of the present invention are the compounds of formula IA or IB per se, the use of compounds of formulas IA or IB and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the y-secretase inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formulas IA or IB in the control or prevention of Alzheimer's disease. A further object of the invention are all forms of optically pure enantiomers, recemates or diastereomeric mixtures for compounds of formulas IA or IB. An embodiment of the invention are compounds of the general formula wherein R1and R1 are the same or different and are hydrogen, lower alkyl, halogen, benzyl, lower alkenyl or are together with the carbon atom to which they are attached lower cycloalkyl; (R2) 1,2,3 is independently from each other hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R3 is phenyl or benzyl, which are unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen or cyano, or is - lower alkyl, - two hydrogen atoms, -(CH2)1,2-S-lower alkyl, - (CH2)1,2-cycloakyl, - (CH2)1,2-OH, - CH2OCH2-phenyl, or the groups R4 is lower alkoxy, - mono-or dialkyl amino, - N(CH3)(CH2)1,2-C=OH, or is a mono-, di or tricyclic group, unsubstituted or substituted by R5 to R10 , and which groups maybe linked by-N(CH3)(CH2)0,1,2 to the-C(O) -group in formula IB, selected from the group consisting of wherein (R5)1,2 is independently from each other hydrogen, halogen, lower alkyl or -(CH2)1,2OH; R6 is hydrogen, halogen or lower alkoxy; R7 is hydrogen or -CH2OCH3; R8 is hydrogen or halogen; R9 is hydrogen, lower alkoxy, lower alkyl or amino; wherein X is-CH2-S(0)2or-C(0)-; R11 is hydrogen or lower alkyl; R is hydrogen or halogen; The most preferred compounds are those of formula IA, for example for (N-(3,5-difluoro-benzyl)-2-methyl-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-malonamide, Furthermore, compounds of formulas IA and IB are preferred, wherein at least one of (R ) 1,2,3 is fluoro. The present compounds of formulas IA and IB and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which processes comprise a) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are described above, or b) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are described above, or c) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are described above, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. The compounds of formulas IA and IB may be prepared in accordance with the following schemes 1, 2, and 3: In this scheme R and R5 are independently from each other lower alkyl and the other substituents are as described above. The detailed description can be found below and in Examples 1 - 150 and 159. To a solution of potassium or sodium hydroxide in a solvent, such as ethanol, a methyl-malonate of formula II is added and the mixture is refluxed for about 4 hours. After cooling the reaction mixture is concentrated and dried in conventinal manner and used without further purification in the next step. To a solution of the obtained methylmalonic acid monoethyl ester (III) in tetrahydrofuran, a compound of formula IV, for added. The mixture is stirred at room temperature for about 18 h. After concentration in vacuo HC1 is added and the mixture is extracted, dried and purified as usual. To the obtained solution of a compound of formula V water and lithium hydroxide are added and the mixture is refluxed for about 5 hours. After purification a compound of formula IA may be obtained as follows: To a solution of a compound of formula VI, for example stirred at room temperature for about 18 h. After concentrating, drying and purifying a compound of formula IA is obtained. A compound of formula IB maybe obtained under the same conditions as described above, using a compound of formula VIII. The compounds of formula IB-1 maybe prepared as described in scheme 1 for the last step (VI with VII or VIII-> IA or IB). The compounds of formula IB-1 are identical with those of formula IB, wherein R , R , R2 and R3 are described as above and wherein R4 is -NR R , R15 is hydrogen or lower alkyl and R16is lower alkyl, -(CH2)1,2-CsCH or-(CH2)0,1,2-mono-, di or tricyclic group, unsubstituted or substituted by R5 to R10 as described above. hydrochloride, 1-hydroxybenzotrizole and N,N-diisopropyl-ethylamine are added. The mixture is stirred at room temperature for about 12 h. After purification, a compound of formula X is obtained which is treated with an acid, for instance TFA, in a suitable solvent, for instance dichloromethane, to give a compound of formula XI. Using compounds of formula XI and IV, compounds of formula IA can be obtained following the amide coupling procedure described above. Some compounds of formula IA or IB maybe converted to a corresponding acid addition salt, for example compounds, containing an amine group. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyR11vic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or maybe brought out of solution with a less polar solvent. The acid addition salts of compounds of formula IA or IB maybe converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formulas IA and IB and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention may inhibit the y-secretase. The compounds were investigated in accoR5ance with the test given hereinafter. Description of y-secretase assay The activity of test compounds can be evaluated in assays which measure the proteolytic cleavage of suitable substrates by y-secretase activity. These can be cellular assays where e.g., a substrate of the y-secretase is fused in its cytoplasmic domain to a transcription factor. Cells are transfected with this fusion gene and a reporter gene, e.g., firefly luciferase, which expression is enhanced by the transcription factor. Cleavage of the fused substrate by y-secretase will lead to expression of the reporter gene which can be monitored in appropriate assays. The y-secretase activity can also be determined in cell-free in vitro asays where e.g., a cell lysate containing the y-secretase complex is incubated with a suitable APP-derived substrate which is cleaved to the Abeta peptides. The amount of produced peptides can be determined with specific ELISA assays. Cell lines of neuronal origin secrete Abeta peptides which can be measured with the specific ELISA assay. Treatment with compounds which inhibit y-secretase leads to a reduction of secreted Abeta thus providing a measure of inhibition. The in vitro assay of y-secretase activity uses a HEK293 membrane fraction as a source of y-secretase and a recombinant APP substrate. Latter consist of the C-terminal 100 amino acids of human APP fused to a 6xHistidin tail for purification which is expressed in E.coli in a regulatable expression vector, e.g. pEtl5. This recombinant protein corresponds to the tR11ncated APP fragment which results after β-secretase cleavage of the extracellular domain and which constitutes the y-secretase substrate. The assay principle is described in Li YM et al, PNAS 97(11), 6138-6143 (2000). Hek293 cells are mechanically disR11pted and the microsomal fraction is isolated by differential centrifugation The membranes are solubilized in detergent (0.25 % CHAPSO) and incubated with the APP substrate. The Abeta peptides which are produced by y-secretase cleavage of the substrate are detected by specific ELISA assays as described (Brockhaus M et al, Neuroreport 9(7), 1481-1486 (1998). The preferred compounds show a IC5o The compounds of formula IA or IB and the pharmaceutically acceptable salts of the compounds of formula IA or IB can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions. The compounds of formula IA or IB can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, coR11 starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or haR5ened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula IA and IB or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula IA and IB and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. In accoR5ance with the invention compounds of formula IA and IB as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the inhibition of the y-secretase, such as of Alzheimer's disease. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. Tablet Formulation (Wet Granulation) Item Ingredients mg/tablet 5 mg 25 mg 100 mg 500 mg 1. Compound of formula IA or IB 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1111 Total 167 167 167 831 Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through suitable milling equiµMent. 4. Add item 5 and mix for three minutes; compress on a suitable press. Capsule Formulation Item Ingredients mg/capsule 5mg 25 mg 100 mg 500 mg 1. Compound of formula IA or IB 5 25 100 500 2. Hydrous Lactose 159 123 148 3. CoR11 Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 12 2 5 Total 200 200 300 600 Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule. Example 1 To a solution of 6.44 g (115 mmol) potassium hydroxide in 200 ml of ethanol 20.0 g diethyl methyl-malonate (115 mmol) was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture was concentrated on a rotary evaporator, 50 ml of water was added and the mixture was extracted with ether (two times 50 ml). The aqueous solution was acidified with 4M hydrochloric acid and extracted with ethyl acetate (three times 50 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and used without further purification. MS m/e (%): 101.1 (M-EtO, 100), 147.1 (M+H+, 8). b) N-(3,5-Difluoro-benzvl)-2-methyl-malonamic acid ethyl ester To a solution of 2.92 g (20 mmol) methyl-malonic acid monoethyl ester in 100 ml of tetrahydrofuran 2.86 g (20 mmol) of 3,5-difluorobenzylamine, 3.83 g (20 mmol) of N-β-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 2.70 g (20 mmol) of 1-hydroxybenzotrizole hydrate and 2.58 g (20 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HC1 (50 ml) was added and the mixture was extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate = 3:1) to yield 4.29 g (79 %) of the title compound as white crystalline solid. MS m/e (%): 272.2 (M+H+, 100). c) N-(3,5-Difluoro-benzvl)-2-methyl-malonamic acid To a solution of 4.0 g (14.75 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid ethyl ester in 300 ml of ethanol, 15 ml of water and 1.41 g (59 mmol) of lithium hydroxide were added and the mixture was refluxed for 5 hours. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (four times 30 ml). The combined organic layers from the second extraction were dried (MgSO4) and evaporated in vacuo to yield an orange oil. The mixture was dissolved in a small amount of ethyl acetate and hexane and left oveR11ight. The resulting white crystals were collected by filtration to give 11.4 g (74.8 %) of the title compound. MS m/e (%): 142.1 (C6H3F2-CH=NH2+ > 100), 243.1 (M+H+, 16). d) (RS)-N-(3,5-Difluoro-benzyl)-2-methyl-N'-(l-methyl-2-oxo-5-phenyl-23-dihydro-1 H-benzo [e ][ 1,4] diazepin-3-yl) -malonamide To a solution of 0.073 g (0.3 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid in 5 ml of tetrahydrofuran 0.080 g (0.3 mmol) of (3RS)~3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one, 0.058 g (0.3 mmol) of N-(3-dimethylaminopropyl)-NJ-ethylcarbodiimide hydrochloride, 0.040 g (0.3 mmol) of 1-hydroxybenzotrizole hydrate and 0.039 g (0.3 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HC1 (5 ml) was added and the mixture was extracted with dichloromethane (three times 5 ml). The combined organic layers were extracted with 0.5 N aqueous NaHC03 solution, dried (MgsO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate = 3:1) to yield 0.099 g (67 %) of the diastereomeric mixture of title compound as white solid. MS m/e (%):491.2 (M+H+, 100). Example 2 N-(3,5-Difluoro-benzyl)-2-fluoro-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro- 1 H-benzo [e] [ 1,4] diazepin-3-yl)-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using 2-fluoro-2-methyl-malonic acid diethyl ester instead of diethyl methyl-malonate in step a). MS m/e (%): 509.3 (M+H+, 100). Example 3 (3RS)-N-(3,5-Difluoro-benzy)-2,2-dimethyl-N'(1-methyl-2-oxo-5-phenyl-2,3- dihydro-lH-benzo[e][l,4]diazepin-3-yl)-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using 2,2-dimethyl-malonic acid diethyl ester instead of diethyl methyl-malonate in step a). MS m/e (%): 505.2 (M+H+, 100). Example 4 (3RS)-N-(3,5-Difluoro-benzyl)-N!-(l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using diethyl malonate instead of diethyl methyl-malonate in step a). MS m/e (%): 477.2 (M+H+ 100). Example 5 N-(3,5-Difluoro-benzyl)-2-fluoro-2-methyl-N'-(4-oxo-l-phenyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-hi]indol-3-yl)-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using 2-fluoro-2-methyl-malonic acid diethyl ester instead of diethyl methyl-malonate in step a) and (3RS)-3-amino-l-phenyl-6,7-dihydro-3H-[l,4]diazepino[6,7)l-hi]indol-4-one instead of (3RS)-3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one in step d). MS m/e (%): 521.1 (M+H+, 100). Example 6 N-(3,5-Difluoro-benzyl)-2-methyl-N'-{(S)-phenyl-[(4-phenyl-morpholin-2-yImethyl)- carbamoyl] -methyl}-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using (2S)-2-amino-2-phenyl-N-((2RS)-4-phenyl-morpholin-2- ylmethyl)-acetamide instead of (3RS)-3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one in step d). MS m/e (%): 551.2 (M+H+, 100). Example 7 (2S)-2-[2-(RS)-(3,5-Difluoro-benzylcarbamoyl)-propionylamino]-phenyl-aceticacid tert-butyl ester The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using (S)-phenylglycine tertbutyl ester instead of (3RS)-3- amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one in step d). MS m/e (%): 377.3 (M+H+, 100). Example 8 diethyl methyl-malonate in step a) and (RS)-3~amino-3,4-dihydro-lH-quinolin-2-one instead of (3RS)-3-amino-lJ3-dihydro-l-methyl-5-phenyl-2H-l,4-ben2odiazepin-2-one in step d). MS m/e (%): 406.4 (M+H+, 100). Example 12 N-(5-Benzyl-l-methy]-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-N'-(3,5-difluoro-benzyl)-2-methyl-malonamide a) (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[1][l,4]diazepin-3-yl)-carbamicacid tert-butyl ester To a solution of 0.94 g (3.38 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester dissolved in 20 ml of tetrahydrofurane at -78 °C , 3.4 ml of lithium bis(trimethylsilyl)amide (IN solution in tetrahydrofurane) were added. The reaction mixture was stirred for 30 minutes at - 78 °C and was allowed to reach room temperature. Iodomethane was slowly added and stirring was continued for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHSO4 solution and separated. The aqueous phase was extracted twice with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (2 x 100 ml), with brine (1 x 100 ml), dried over MgSO4, filtered and evaporated. The residue was purified by chromatography (heptane/ethyl acetate = 7:3) to yield 0.855 g (87 %) of the product as a light yellow solid. MS m/e (%): 292.2 (M+H-, 100) b) (5-Benzyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzofb][l,4]diazepin-3-yl)- carbamic acid tert-butyl To a solution of 0.087 g (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dimethylformamide 0.138 g of potassium carbonate and 0.062 g of benzyl bromide were added. The reaction mixture was shaken for 16 hours at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over MgsO4, filtered and evaporated. The residue was purified by chromatography (heptane/ethyl acetate = 2:1) to yield 0.10 g (87 %) of the product as a light yellow foam. MS m/e (%): 382.3 (M+H+, 100). c) N-(5-Benzenesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin- 3-yl)-N'-(3,5-difluoro-benzyl)-2-methyl-malonamide To a solution of 0.086 g (5-benzyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dichloromethane, 1 ml of trifluoracetic acid was added. The reaction mixture was allowed to stir at room temperature for 2-3 h while monitoring the reaction progress by LC-MS. Upon completion of the reaction, the solvent and excess of trifluoracetic acid were evaporated and the residue was dried under high vacuo for 1 hour. To the foam obtained dissolved in 1 ml of tetrahydrofurane, 0.060 g N-(35-difluoro-benzyl)-2-methyl-malonamic acid 0.043 g of N-(3-dimethylaminopropyl)-N'-ethyIcarbodiimide hydrochloride, 0.030 g of 1-hydroxybenzotrizole hydrate and 0.087 g of N,N-diisopropyl-ethylamine were added. After stirring the mixture at room temperature for 18 h, 0.5 N HC1 (1 ml) was added and the mixture was extracted with dichloromethane (2 ml) The organic layer was extracted with 0.5 N aqueous NaHCCb solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was crystallized with heptane/EtOAc=4:l to yield 0.057 g (50 %) of the epimeric mixture of title compound as white solid. MS m/e (%): 507.3 (M+H+, 100). Example 13 N- (5-Benzenesulfonyl- l-methyl-2-oxo-2,3,4,5-tetrahydro-1 H-benzo [b] [ 1,4] diazepin-3-yl)-N'-(3,5-difluoro-benzyl)-2-methyl-malonamide a) (5-Benzenesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzofb][l,4ldiazepin-3- yP-carbamic acid tert-butyl ester To a solution of 0.087 g (l-methyl-2-oxo-2J3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dichloromethane, 0.064 g of benzene sulfonyl chloride and 0.052 g of pyridine were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by addition of 1 M HC1 (1 ml) and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, dried (MgsO4) and evaporated on the rotary evaporator to yield 0.113 g (95 %) of the product as a light yellow foam. MS m/e (%): 432.3 (M+H+, 100). b) N-(5-Benzenesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzofb][1,4]diazepin- 3-yl)-N'-(35-difluoro-benzyl)-2-methyl-malonamide The title compound was obtained in comparable yields accoR5ing to the procedure described for example 12c) using (5-benzenesulfonyH-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester instead of (5-benzyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert- butyl ester. MS m/e (%): 557.2 (M+H+, 100). Example 14 N-(5-Benzoyl-l-methyI-2-oxo-2,3,4,5-te1xahydro-lH-b enzo[b] [ l,4]diazepin-3-yl)-N'-(3,5-difluoro-benzyl)-2-methyl-malonamide a) (5-Benzoyl-l-methyl-2-oxo-23,4,5-tetrahydro-lH-benzofb1fL4ldiazepin-3-yl)- carbamic acid tert-butyl ester To a solution of 0.087 g (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dichloromethane, 0.051 g of benzoyl chloride and 0.061 g of triethylamine were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by addition of 1 M HC1 (1 ml) and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, dried (MgsO4) and evaporated on the rotary evaporator to yield 0.125 g (97 %) of the product as a light yellow foam. MS m/e (%): 396.3 (M+H+ 100). b) N-(5-Benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)- N'-(3,5-difluoro-benzyl1-2-methyI-malonamide The title compound was obtained in comparable yields accoR5ing to the procedure described for example 12c) using (5-benzenesulfonyl-l-methyl-2-oxo-2J3>4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester instead of (5-benzyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester. MS m/e (%): 521.3 (M+H+, 100). Example 15 N-(7-CMoro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-N'-(3,5-difluoro-benzyl)-2-methyl-malonamide The title compound was obtained in comparable yields accoR5ing to the procedures described for example 1 using (3RS)-3-amino-l,3-dihydro-7-chloro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one instead of (3RS)-3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one in step d). MS m/e (%): 525.3 (M+H+, 100). Example 16 N-(3,5-Difluoro-benzyl)-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-yl methyl)-2-oxo-ethyl]-2-methyl-malonamide Example 17 The title compound, MS: m/e = 506.3 (M+H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-phenylalanine. Example 18 The title compound, MS: m/e = 536.4 (M+H+), was prepared in analogy to example 16 from N-(tert-butoxycarbonyl)-0-benzyl-L-serine. Example 19 The title compound, MS: m/e = 492.3 (M+H+), was prepared in analogy to example 16 from N-alpha-(rerr-butoxycarbonyl)-L-phenylglycine. Example 20 The tide compound, MS; m/e = 492.3 (M+H+), was prepared in analogy to example 16 from N-alpha-(tert-butoxycarbonyl)-D-phenylglycine. Example 21 The tide compound, MS: m/e = 446.3 (M-f H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-serine. Example 22 The title compound, MS: m/e = 540.4 (M+), was prepared in analogy to example 16 from N-alpha-(tert-butyloxycarbonyl)-p-chloro-L-phenylalanine. Example 23 The title compound, MS: m/e = 562.4 (M+H+), was prepared in analogy to example 16 fromN-alpha-(tert-butyloxycarbonyl)-L-benzothienylalanine. Example 24 The title compound, MS: m/e = 574.3 (M+), was prepared in analogy to example 16 from N-alpha-(tert-butyloxycarbonyl)-m,p-dichloro-L-phenylalanine. Example 25 The title compound, MS: m/e = 511.6 (M+H+), was prepared in analogy to example 16 from N-alpha-(tert-butyloxycarbonyl)- L-cyclohexylalanine. Example 26 The title compound, MS: m/e = 490.4 (M+H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-methionine. Example 27 The title compound, MS: m/e = 472.3 (M+H+), was prepared in analogy to example 16 from N-alpha-tert-butyloxycarbonyl-L-2-aminocaproic acid. Example 28 The title compound, MS: m/e = 486.4 (M+H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-neopentylglycine. Example 29 The title compound, MS: m/e = 444.4 (M+H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-2-aminobutanoic acid. Example 30 The title compound, MS: m/e = 531.4 (M+H+), was prepared in analogy to example 16 fromN-alpha-(tert-butyloxycarbonyI)-o-cyano-L-phenylalanine. Example 31 The title compound, MS: m/e = 472.4 (M+H+), was prepared in analogy to example 16 from tert-butyloxycarbonyl-L-isoleucine. Example 32 N-(3,5-Difluoro-benzyl)-2-methyl-malonamic acid (3.00 g, 12.3 mmol), L-tryptophan-tert-butylester hydrochloride (3.66 g, 12.3 mmol), TBTU (O-(benzotriazol-l-yl)-N, N, N\ N'-tetramethyluronium-tetrafluoroborate, 3.96 g, 12.3 mmol) and triethylamin (3.74 g, 3.70 mmol) were dissolved in DMF (15 ml) and stirred for 5 h at r.L. The reaction mixture was poured into water and the product mixture was extracted with ethyl acetate. The organic layers were dried (Na2S04). After evaporation of the solvent, the title compound, MS: m/e = 486.4 (M+H+), (6.45 g, quant.) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2CI2). trifluoroacetic acid (15 ml) was added at 0 °C. The mixture was stirred overnight at r.t. until all starting material was consumed (analytical HPLC). The volatiles were evaporated, the residue was taken up in ethyl acetate and washed with water. The organic layers were dried (Na2S04). After evaporation of the solvent, the title compound, MS: m/e = 429.4 (M+H+), (3.5 g, 66 %) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2CI2). DMF (1ml). TPTU (0-[2-oxo-l(2H)-pyridyl]-N, N, 1ST, N?-tetramethyluronium-tetrafluoroborate, 49 mg, 0.165 mmol) and 6-methoxy-l,2,3,4-tetrahydro-isoquinoline (24 mg, 0.15 mmol) were added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e = 575.3 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50 x 20 mm, solvent gradient 5-95 % CH3CN in 0.1 % TFA(aq) over 6.0 min, λ = 230 nm, flow rate 40 ml/min). isoquinoline. Example 37 The title compound, MS: m/e = 605.3 (M+H+), was prepared in analogy to example 32 from 7,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline. Example 38 The title compound, MS: m/e = 584.4 (M+H ), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and (RS)-l-pyrazin-2-yl-1,2,3,4-tetrahydro-isoquinoline. Example 39 The title compound, MS: m/e = 520.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-fert-butylester hydrochloride and 4-methyl-1,2,3,4-tetrahydro-isoquinoline. Example 40 The tide compound, MS: m/e = 531.3 (M+H+), was prepared in analogy to example 32 from isoindoline. Example 41 The title compound, MS: m/e = 589.5 (M+H+),was prepared in analogy to example 32 from6,7,8,9-tetrahydro-[13]dioxolo[4,-h]isoquinoline. Example 42 The title compound, MS: m/e = 583.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and l,2,3,4-tetrahydro-l-(2-pyridyl)isoquinoline. Example 43 The title compound, MS: m/e = 559.4 (M+H+), was prepared in analogy to example 32 from4-methyl-l,2,3,4-tetrahydro-isoquinoline. Example 44 The title compound, MS: m/e = 532.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanme-tert-butylester hydrochloride and 9-aza-tricyclo[6.2.2.0 2,7]dodeca-2,4,6-triene. Example 45 The title compound, MS: m/e = 635.4 (M+H+), was prepared in analogy to example 32 from 6,7,8-trimethoxy-l,2,3,4-tetrahydro-isoquinoline. Example 46 The title compound, MS: m/e = 668.5 (M+H+), was prepared in analogy to example 32 Example 47 The title compound, MS: m/e = 545.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 1,2,3,4-tetrahydro-beta-carboline. Example 48 The title compound, MS: m/e = 540.4 (M+), was prepared in analogy to example 32 from Example 49 The title compound, MS: m/e = 533.4 (M+H+), was prepared in analogy to example 32 from 4,4-difluoropiperidine. Example 50 The title compound, MS: m/e = 550.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 5,6,7,8-tetrahydro-l,3-dioxolo(4,5-G)isoquinoline. Example 51 tetrahydro-isoquinoline. Example 52 N-(3,5-Difluoro-benzyl-N'-[1-(1H-indol-3-ylmethyl)-2-(3-methyl-piperidin-1-yl)-2-oxo-ethyl] -2-methyl-malonamide The title compound, MS: m/e = 511.4 (M+H+), was prepared in analogy to example 32 from 3-methylpiperidine. Example 53 tetrahydro-isoquinoline. Example 54 The title compound, MS: m/e = 512.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and trans-decahydroisoquinoline. Example 55 The title compound, MS: m/e = 492.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and Isoindoline. Example 56 The title compound, MS: m/e = 494.6 (M+H+), was prepared in analogy to example 32 from 1,2,3,6-tetrahydropyridine. Example 57 The title compound, MS; m/e = 550.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 6,7,8,9-tetrahydro-[ 1,3 ] dioxolo [4,5-h] isoquinoline. Example 58 The title compound, MS: m/e = 596.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline. Example 59 The title compound, MS: m/e = 458.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and piperidine. Example 60 The title compound, MS: m/e = 515.4 (M+H+), was prepared in analogy to example 32 from 4-fluoropiperidine. Example 61 The title compound, MS: m/e = 605.3 (M+H+), was prepared in analogy to example 32 from 6>7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline. Example 62 The title compound, MS: m/e = 481.4(M+H+) was prepared in analogy to example 32 from 1 -isopropyl-1,2,3,4-tetrahydro-isoquinoline. Example 63 The title compound, MS: m/e = 548.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and isopropyl- 1,2,3,4-tetrahydro-isoquinoline. Example 64 The title compound, MS: m/e = 456.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 8-chloro-l,2?3,4-tetrahydro-isoquinoline. Example 65 The title compound, MS: m/e = 540.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 8-chloro-l,2,3,4-tetrahydro-isoquinoline. Example 66 The title compound, MS: m/e = 605.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and l-cyanomethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline. Example 67 The title compound, MS: m/e = 586.3 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 7-bromo-l,2,3,4-tetrahydro-isoquinoline. Example 68 The title compound, MS: m/e = 633.4 (M+H+), was prepared in analogy to example 32 from 6,7-diethoxy-l,2,3,4-tetrahydro-isoquinoline. Example 69 The title compound, MS: m/e = 546.4 (M+H+), was prepared in analogy to example 32 from2,3-dihydro-lH-isoindol-4-ylamine. Example 70 The title compound, MS: m/e = 579.3 (M+), was prepared in analogy to example 32 from 8-chloro-l,2,3,4-tetrahydro-isoquinoline. Example 71 The title compound, MS: m/e = 483.3 (M+H+), was prepared in analogy to example 32 from pyrrolidine. Example 72 The title compound, MS: m/e = 527.3 (M+H+), was prepared in analogy to example 32 from 2-methoxymethyl-pyrrolidin. Example 73 The title compound, MS: m/e = 613.3 (M+H+), was prepared in analogy to example 32 from 7,8-dichloro-l,2,3,4-tetrahydro-isoquinoline. Example 74 The title compound, MS: m/e = 494.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and benzyl-methyl-amine. Example 75 The title compound, MS: m/e = 511.4 (M+H+), was prepared in analogy to example 32 from azepane. Example 76 The title compound, MS: m/e = 457.5 (M+H+), was prepared in analogy to example 32 from dimethylamine. Example 77 The title compound, MS: m/e = 590.4 (M+H+), was prepared in analogy to example 32 from 7-nitro-1,2,3,4-tetrahydro-isoquinoline. Example 78 The title compound, MS: m/e = 606.5 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and l-cyclopropyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline. Example 79 The title compound, MS: m/e = 579.3 (M+H+), was prepared in analogy to example 32 from 7-chloro-l,2,3,4-tetrahydro-isoquinoline. Example 80 The title compound, MS: m/e = 523.3 (M+H+), was prepared in analogy to example 32 from furan-2-ylmethyl-methyl-amine. Example 83 The title compound, MS: m/e = 527.4 (M+H+), was prepared in analogy to example 32 from 2-methoxymethyl-pyrrolidin. Example 88 The title compound, MS: m/e = 563.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 6-fluoro-2,3,4,5-tetrahydro-lH-pyrido [4,3-b ] indole. Example 92 The title compound, MS: m/e = 529.4 (M+H+), was prepared in analogy to example 32 from2-methylaminomethyl-l,3-dioxolane. Example 97 The title compound, MS: m/e = 527.3 (M+H+), was prepared in analogy to example 32 from 4-hydroxymethylpiperidine. Example 98 The title compound, MS: m/e = 563.4 (M+H+), was prepared in analogy to example 32 from L-phenylalanine-tert-butylester hydrochloride and 8-fluoro-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. Example 99 d) N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl propyl-malonate. Example 100 a) N-(3,5-Difluoro-benzyl)-2-isopropyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl isopropyl-malonate. Example 101 N-(3,5-Difluoro-benzyl)-N'-[2-(3,4-dihydro-lH-isoquinoUn-2-yl)-l-(lH-indol-3-ylmethyl)-2-oxo-ethyl]-2-ethyl-malonamide a) N-(3,5-Difluoro-benzyl')-2-ethyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl ethyl-malonate. a) N-(3,5-Difluoro-benzyl)-2-allyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl allyl-malonate. Example 103 N-(3,5-Difluoro-benzyl)-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-fluoro-2-methyl-malonamide Example 104 N-(3,5-Difluoro-benzyl)-N'-[2-(3,5-dihydro-lH-isoquinolin-2-yl)-l-(lH-indol-3-ylmethyl)-2-oxo-ethyl]-malonamide Example 105 N-(3,5-Difluoro-benzyl-N'[2-(3,5-dihydro-lH-isoquinolin-2-yl-l-(lH-indol-3-ylmethyl)-2-oxo-ethyl]-2,2-dimethyl-malonamide a) N-(3,5-Difluoro-benzyl')-2,2-dimethyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl 2,2-dimethyl-malonate. Example 106 The title compound, MS: m/e = 525.1 (M+H+), was prepared in analogy to example 16 from 3-amino-7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodia2epin-2-one. Example 107 The title compound, MS: m/e = 519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodia2epin-2-one and N-(3,5~ difluoro-benzyl)-2-propyl-malonamic acid. Example 108 The title compound, MS: m/e = 533.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-tert-butyl~malonamicacid. Example 109 The title compound, MS: m/e = 519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-isopropyl-malonamicacid. Example 110 The title compound, MS: m/e = 505.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l74-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-ethyl-malonamicacid. Example 111 The title compound, MS: m/e = 495.3 (M+H+), was prepared in analogy to example 16 from 3-amino- 1,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid. Example 112 The title compound, MS: m/e = 464.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl~5H,7H-dibenzo[b,d]azepin-6-one. Example 113 The title compound, MS: m/e = 482.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepm-6-one and N-(3,5-di£iuoro-benzyl)-2-fluoro-2-methyl-malonamic acid. Example 114 The title compound, MS: m/e = 491.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid. Example 115 The title compound, MS: m/e = 478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyI)-2-ethyl-malonamic acid. Example 116 The title compound, MS: m/e = 468.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid. Example 117 The title compound, MS: m/e = 478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H, 7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2,2-dimethyl-malonamicacid. Example 118 The title compound, MS: m/e = 492.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid. Example 119 The title compound, MS: m/e = 539.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-benzyl-malonamic acid. Example 120 The title compound, MS: m/e = 506.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-tert-butyl-malonamic acid. Example 121 The title compound, MS: m/e = 450.2 (M4-H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-malonamic acid. Example 122 a) N-(4-Methoxy-benzyl)-2-methvI-malonamic acid The tide compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 458.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-methoxy-benzyl)-2-methyl-malonamic acid. Example 123 a) N-Benzyl-2-methyl-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 428.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-benzyl-2-methyl-malonamic acid. Example 124 a) N-(3,4-Dimethoxv-benzyl)-2-methyl-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,4-dimethoxy-benzyl)-2-methyl-malonamic acid. Example 125 a) N-(4-Fluoro-benzyl)-2-methyl-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound., MS: m/e = 446.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-fluoro-benzyl)-2-methyl-malonamic acid. Example 126 a) 2-Methyl-N-(3-methyl-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 442.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-methyl-benzyl)-malonamic acid. Example 127 a) 2-Methyl-N- (4-methyl-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 441.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]-azepin-6-one and 2-methyl-N-(4-methyl-benzyl)-malonamic acid. Example 128 a) 2-Methyl-N-(4-chloro-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 462.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(4-chloro-benzyl)-malonamic acid. Example 129 a) 2-Methyl-N-(3-5-dichloro-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 496.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid. Example 130 a) 2-Methyl-N-(3-fluoro-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 446.2 (M+H+), was prepared in analogy to example 16 from 7-amino~5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-fluoro-benzyl)-malonamic acid. Example 131 a) 2-Methyl"N-(3,5-dimethoxv-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamic acid. Example 132 a) 2-Methyl-N-f3-trifluoromethyl-benzyl)"malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 496.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N~(3-trifluoromethyl-benzyl)-malonamicacid. Example 133 a) 2-Methyl-N-(2,5-difluorO'benzyl)-malonamic acid The tide compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 464.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,5-difluoro-benzyl)-malonamic acid. Example 134 a) 2-Methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid The title compound was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1). The title compound, MS: m/e = 482.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid. Example 135 The title compound, MS: m/e = 485.4 (M+H+)? was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(4-methoxy-benzyl)-malonamicacid. Example 136 The title compound, MS: m/e = 455.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-benzyl-malonamic acid. Example 137 The title compound, MS: m/e = 515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3,4-dimethoxy-benzyl)-malonamicacid. Example 138 The title compound, MS: m/e = 473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l)4-benzodiazepin-2-one and 2-methyl-N-(4-fluoro-benzyl)-malonamicacid. Example 139 The title compound, MS: m/e = 468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(4-methyl-benzyl)-malonamicacid. Example 140 The title compound, MS: m/e = 468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3-methyl-benzyl)-malonamicacid. Example 141 The tide compound, MS: m/e = 489.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(4-chloro-benzyl)-malonamicacid. Example 142 The title compound, MS: m/e = 523.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid. Example 143 The title compound, MS: m/e = 473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3-fluoro-benzyl)-malonamicacid. Example 144 The title compound, MS: m/e = 515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamicacid. Example 145 The title compound, MS: m/e = 523.4 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(3-trifluoromethyl-benzyl)-malonamicacid. Example 146 The title compound, MS: m/e = 491.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(2, 5-difluoro-benzyl)-malonamic acid. Example 147 The title compound, MS: m/e = 509.3 (M+H+), was prepared in analogy to example 16 from 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamicacid. Example 148 The tide compound, MS: m/e = 480.3 (M+H+), was prepared in analogy to example 16 from 2-amino-2'-benzyl-N-methylacetanilide. Example 149 The tide compound, MS: m/e = 533.4 (M+H+), was prepared in analogy to example 16 from2-amino-4'-chloro-N-methyl-2'-(phenylthio)acetanilide. Example 150 The title compound, MS: m/e = 528.4 (M+H+), was prepared in analogy to example 16 from 2-amino-2'-benzoyl-4-chloro-N-methylacetanilide. Example 151 the mixture was shaken overnight at r.t. The title compound, MS: m/e = 446.2 (M+H-f), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50 x 20mm, solvent gradient 5 - 95 % CH3CN in 0 J % TFA(aq) over 6.0 min, x = 230 nm, flow rate 40 ml/min). Example 152 The tide compound, MS: m/e = 462.2 (M+H+), was prepared in analogy to example 151 from 2-chlorobenzylamine. Example 153 The tide compound, MS: m/e = 442.3 (M+H+), was prepared in analogy to example 151 from 2-methylbenzylamine. Example 154 The title compound, MS: m/e = 458.3 (M+H+), was prepared in analogy to example 151 from 2-methoxybenzylamine. Example 155 The tide compound, MS: m/e = 496.3 (M+H+), was prepared in analogy to example 151 from 2-trifluoromethylbenzylamine. Example 156 The title compound, MS: m/e = 458.3 (M+H+), was prepared in analogy to example 151 from 3-methoxybenzylamine. Example 157 The title compound, MS: m/e = 462.2 (M+H+), was prepared in analogy to example 151 from 3-chlorobenzylamine. Example 158 The title compound, MS: m/e = 496.3 (M+H+), was prepared in analogy to example 151 from 4-trifluorobenzylamine. Example 159 Example 160 Solid phase synthesis was performed on a benzhydrylamine polystyrene resin, functionalized with an Fmoc-amide linker, p-[(R,S)-a-l-(9H-fluoren-9- 9-Fmoc-aminoxanthen-3-yloxy-methyl resin (Sieber Amide resin; Calbiochem-Novabiochem AG) (5 g, 0.52 mmol/g loading) was treated with 20 % piperidine/DMF (50 ml, 10 min) and then washed (3 x alternating DMF/isopropanol). (2S-cis)-5-(9H-Fluoren-9-yl)methoxycarbonylamino-4-oxo-l,2,4,5,6,7-hexahydro-azepino[3,2,l-hi]indole-2-carboxylic (1.83 g, 3.9 mmol), TPTU (1.2 g, 3.9 mmol), diisopropylethylamine (3 ml, 17.6 mmol) and DMF (10 ml) were added to the resin. Coupling was allowed to proceed for 1 h ( Ninhydrin test: negative) and the resin was filtered and washed as before. Fmoc group removal was followed by t-Boc group amine protection using t-Boc anhydride (5.7 g, 26 mmol) diisopropylethylamine (2.2. ml, 13 mmol) in 12 ml dichloromethane. The washed, dried resin was treated with trifluoroacetic anhydride (1.8 ml, 13 mmol), pyridine ( 2.1 ml, 26 mmol) in 15 ml dichloromethane for 16 h at room temperature. The filtrate was collected and the resin washed (CH2CI2,2x10 ml). The combined organic fractions were washed with 5 % NaHCO3, dried (MgSO4) filtered and concentrated under reduced pressure yielding a crude oil which was purified by flash chromatography (ethyl acetate-n-hexanes 1:3); 0.71 g; MS: 328.3 (MH+(20 %)); 228.2 (MH+-Boc(100)). concentrated under reduced pressure and concentrated another two times from acetonitrile. The hydrochloride salt (ca. 20 mg) was dissolved in 1 ml DMF and the pH of the solution was adjusted to 8. Malonic acid derivative, (41 mg, 0.17 mmol) TPTU (50 mg, 0.17 mmol) diisopropylethylamine (87µl , 0.51 mmol) in 0,5 ml DMF were added and the reaction mixture was shaken for 1 h. The reaction mixture was acidified with acetic acid, concentrated to a smaller volume and directly purified by prep.RP(C18)HPLC: 14.5 mg, MS: 581.1 (MH+(100 %)); Example 163 Example 164 The title compound was obtained in comparable yields according to the procedures described for example 162 using malonic acid derivative N-(3,5-difluorobenzyl)-2,2-dimethyl-malonamic acid instead of derivative N-(3,5-difluorobenzyl)-2-methyl-malonamic acid: 15.0 mg, MS: 595.1 (MH+(100 %)); Example 165 The title compound was obtained in comparable yields according to the procedures described for example 162 using 4-fluorophenylacetic acid instead of thiophene-2-acetic acid and malonic acid derivative N-(3,5-difluorobenzyl)-2,2-dimethyl-malonamic acid instead of N-(3,5-difluorobenzyl)-2-methyl-malonamic acid: 5.4 mg, MS: 607.1 (MH+(100%)); Example 167 The title compound, MS: m/e = 442.3 (M+H+), was prepared in analogy to example 166 from 2-phenethylamine. Example 168 N-[2-(4-Fluoro-phenyl)-etiiyl]-2-methyl-N,-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide The title compound, MS: m/e = 460.3 (M+H+), was prepared in analogy to example 166 from 4-fluorophenethylamine. Example 169 The title compound, MS: m/e = 476.2 (M+H+), was prepared in analogy to example 166 from 4-chlorophenethylamine. Example 170 The title compound, MS: m/e = 460.3 (M+H+), was prepared in analogy to example 166 from 3-fluorophenethylamine. Example 171 The title compound, MS: m/e = 429.3 (M+H+), was prepared in analogy to example 166 from 3-aminomethylpyridine. Example 172 The title compound, MS: m/e = 429.3 (M+H+), was prepared in analogy to example 166 from 2-aminomethylpyridine. Example 173 The title compound, MS: m/e = 418.3 (M+H+), was prepared in analogy to example 166 from 2-aminomethylfurane. Example 174 The title compound, MS: m/e = 429.3 (M+H+), was prepared in analogy to example 166 from 4-aminomethylpyridine. Example 175 The title compound, MS: m/e = 432.3 (M+H+), was prepared in analogy to example 166 from 5-methylfurfurylamine. Example 176 The title compound, MS: m/e = 484.3 (M+H+), was prepared in analogy to example 166 from 3-aminomethylbenzothiophene. Example 177 The title compound, MS: m/e = 442.3 (M+H+), was prepared in analogy to example 166 from (R)-(+)-l-phenylethylamine. Example 178 The title compound, MS: m/e = 472.3 (M+H+), was prepared in analogy to example 166 from N-benzylethanolamine. Example 179 The title compound, MS: m/e = 442.3 (M+H+), was prepared in analogy to example 166 from N-methylbenzylamine. Example 180 The title compound, MS: m/e = 481.3 (M+H+), was prepared in analogy to example 166 from N-benzyl-aminoacetonitrile. Example 181 The title compound, MS: m/e = 468.3 (M+H+), was prepared in analogy to example 166 from 1,2,3,4-tetrahydro-naphthalen-l-yl-amine. Example 182 The title compound, MS: m/e = 454.3 (M+H+), was prepared in analogy to example 166 from 1-aminoindane. Example 183 The title compound, MS: m/e = 490.3 (M+H+), was prepared in analogy to example 166 from 4,6-difluoro- 1-aminoindane. Example 184 The title compound, MS: m/e = 470.4 (M+H+), was prepared in analogy to example 166 from 2-amino-l-indanol. Example 185 The title compound, MS: m/e - 454.3 (M+H+), was prepared in analogy to example 166 from 2-aminoindane. Example 186 The title compound, MS: m/e = 504.3 (M+H+), was prepared in analogy to example 166 from C-(2,2-difluoro-l-phenyl-cyclopropyl)-methylamine. Example 187 The title compound, MS: m/e = 450.3 (M-H+), was prepared in analogy to example 166 from (RS)-2,2- dimethyl-[1,3]dioxolan-4-ylmethylamine. Example 188 The title compound, MS: m/e = 420.2 (M-H+), was prepared in analogy to example 166 from(RS)-tetrahydro-furan-2-ylmethylamine. Claims 1. Compounds of the general formula benzo[b]thiophenyl, tetrahydronaphthyl, indanyl, 2,2-dimethyl-[l,3]dioxolanyl or tetrahydrofuranyl; R1 and R1' are the same or different and are hydrogen, lower alkyl, halogen, benzyl or lower alkenyl; (R2) 1,2,3 is independently from each other hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R3 - is phenyl or benzyl, which are unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen or cyano, or is - lower alkyl, - two hydrogen atoms. or is a mono-, di or tricyclic group, unsubstituted or substituted by R to R °, and which groups may be linked by -N(CH3)(CH2)0,1,2, to the -C(O) -group in formula IB, selected from the group consisting of wherein (R5)1,2 is independently from each other hydrogen, halogen, lower alkyl or -(CH2)1,2,OH; R6 is hydrogen, halogen or lower alkoxy; R7 is hydrogen or -CH2OCH3; R8 is hydrogen or halogen; R is hydrogen, lower alkoxy, lower alkyl or amino; (R10) 1,2,3 is independently from each other hydrogen, lower alkyl, lower alkoxy, lower cycloalkyl, halogen, hydroxy, =0, amino, nitro, -CH2CN, -OCH2C6H5, R14 is hydrogen, lower alkyl, -(CH2)2OH or -(CH2)2CN; and to pharmaceutically suitable acid addition salts thereof. 2. Compounds of the general formula wherein R1 and R1' are the same or different and are hydrogen, lower alkyl, halogen, benzyl or lower alkenyl; (R )1,2,3 is independently from each other hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R3 is phenyl or benzyl, which are unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen or cyano, or is - lower alkyl, - two hydrogen atoms, -(CH2)1,2-S-Iower alkyl, - (CH2)1,2-cycloalkyl, - (CH2)1,2-OH, - CH2OCH2-phenyl, or the groups R4 is lower alkoxy, - mono-or dialkyl amino, -N(CH3)(CH2)1,2-C=CH, or is a mono-, di or tricyclic group, unsubstituted or substituted by R5 to R10 , and which groups may be linked by -N(CH3)(CH2)0,1,2, to the -C(O) -group in formula IB, selected from the group consisting of wherein (R5 )1,2 is independently from each other hydrogen, halogen, lower alkyl or -(CH2)l,2OH; R is hydrogen, halogen or lower alkoxy; R7 is hydrogen or -CH2OCH3; R8 is hydrogen or halogen; R9 is hydrogen, lower alkoxy, lower alkyl or amino; wherein X is -CH2, -S(0)2 or -C(O)-; R11 is hydrogen or lower alkyl; " is hydroaxyl or haloacyl and pharmaceutically suitable acid addition salts thereof. 3. Compounds of formula IA in accordance with claim 2, 4. Compounds of formula IA in accordance with claim 3, wherein 7. Compounds of formula IA in accordance with claim 6, which compounds are 9. Compounds of formula IA in accordance with claim 8, wherein the compounds are N-(3,5-difluoro-benzyl)-2-ethyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H- benzo[e] [l,4]diazepin-3-yl)-malonamide or 14. Compounds of formula IB in accordance with claims 1 or 2. 15. Compounds of formulas IA or IB in accordance with claims 1 or 2, wherein at least one of (R 2)1,2,3 is fluoro. 16. A process for preparing a compound of formulas IA or IB as defined in claims 1-15, which process comprises with a compound of formula to a compound of formula wherein the substituents are described in claim 1, or b) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are described in claim 1, c) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are described in claim 1, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. 17. A compound according to any on of claims 1 - 15, whenever prepared by a process as claimed in claim 16 or by an equivalent method. 18. A medicament containing one or more compounds as claimed in any one of claims 1-15 and pharmaceutically acceptable excipients. 19. A medicament according to claim 18 for the treatment of Alzheimer's disease. 20. The use of a compound in any one of claims 1 - 15 for the manufacture of medicaments for the treatment of Alzheimer's disease.

Documents:

1782-chenp-2005-abstract.pdf

1782-chenp-2005-claims.pdf

1782-chenp-2005-correspondnece-others.pdf

1782-chenp-2005-description(complete).pdf

1782-chenp-2005-form 1.pdf

1782-chenp-2005-form 26.pdf

1782-chenp-2005-form 3.pdf

1782-chenp-2005-form 5.pdf

1782-chenp-2005-form18.pdf

1782-chenp-2005-pct.pdf