Title of Invention

MALONAMIDE DERIVATIVES

Abstract A description is given of radiation-sensitive compositions composed of a binder component and low-odor polymeric reaction products composed of the reaction product of aldehydes and 5 ketones.
Full Text


MALONAMIDE DERIVATIVES BLOCKING THE ACTIVITY OF GAMMA-SECRETASE
The invention relates to malonamide derivatives of formula

wherein
R1 is one of the following groups

R2 is lower alkyl, lower alkinyl, -(CH2)n-O-lower alkyl, -(CH2)n -S-lower alkyl, -(CH2)n-CN, -(CR'R")CF3, -(CRTOn-CHF* -(CRTOn-CHUF, -(CH2)n-C(O)O-lower alkyl, -(CH2)n-halogen, or is -(CH2)n-cydoalkylJ optionally substituted by one or more substituents, selected from the group consisting of 10 phenyl, halogen or CF3;
R',R" are independently from n and from each other hydrogen, lower alkyl, lower aikoxy, halogen or hydroxy,
R3, R4 are independently from each other hydrogen, lower alkyl, lower alkoxy, phenyl or halogen;

VO 2005/023772 PCT/EP2004/009700
R5 is hydrogen, lower alkyl, -(CH2)n-CF3 or -(CH2)a-cyclo alkyl; R6 is hydrogen or halogen;
R7 is hydrogen or lower alkyl;
R is hydrogen, lower alkyl, lower alkinyl, -(CH2)n-CF3, -(CH2)n-cydo alkyl or -(CEb-phenyl, optionally substituted by halogen;
R9 is hydrogen, lower alkyl, -C(O)H, -C(O)4ower alkyl, -C(O)-CF3, -C(O)-CH2F, -C(O)-CHF2, -C(0)-cycloalkyl, -C(O)-(CH2)n-O-lower alkyl, -C(O)O-(CH2)n-cydoalkyl, -C(O)-phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen or -C(O)O-lower alkyl, or is »S(O)2-lower alkyl, -S(O)2-CF3, -(CH2)n-cycloalkyl or is -(CH2)a- phenyl, optionally substituted by halogen;
n is 0, 1, 2, 3 or 4;
and to phaxmaceutically suitable acid acidition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof.
As used herein, the term "lower alkyl" denotes a saturated straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyi, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
As used herein, the term 'lower alkinyl11 denotes a unsaturated straight- OT branched-carbon chain containing from 2 to 7 carbon atoms and containing at least one triple bond.
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.

WO 2005/023772 PCT/EP2004/009700
The expression "-(CR'R")n-a maybe, for example -CH2-3 -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CFr, -CH2-CH2-CF2-, -CH2^H2-CH(OCH3)-, -CH2CH(OH)- or -C(CH3)2-CH(OH)-.
The term "pharmaceutically acceptable acid acidition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulforic acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acidand the like.
It has been found that the compounds of general formula I are y-secretase
inhibitors and the related compounds may be 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 neuro fibrillary tangles. The amyloid plaques are
mainly composed of amyloid peptides (Abeta peptides) which originate from the β-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 spedes are of 40 and 42 amino-acidlength.
Abeta peptides are produced from APP through the sequential action of 2
proteolytic enzymes termed p- 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). CTFJ3 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 (Ap40), a minor spedes carries 2 aciditional arnino acids at its C-tenninus. Latter is supposed to be the more pathogenic amyloid peptide.
The p-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 aphla and penta 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/Neuroscdence, 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 Journ. of Medicinal Chemistry, VoL 44, No. 13,2001, 2039-2060.
Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I 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 formula I 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 formula I.
Preferred compounds of formula I are those, wherein R is a) and R2 is -(CH2)n-cycloaIkyl, optionally substituted by CF3, for example the following compounds:

N-cyclopropylmethyl-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide or
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(1-ixifluoromethyl-cyclopropylmethyl)-malonamide,
Preferred compounds are further those, wherein R1 is a) and R2 is lower alkyl, -(CH2)n-0-lower alkyl or -(CH2)n-S-lower alkyl, for example the following compounds:
2-methyl-N-(5-me1hyl-6-oxo-6,7-dihydro-5H-diben2o[b,d]azepin-7-yl)-N'-(2-methoxyethyi)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-NI-(2-m ethylthio ethyl-malonamide,
2-methy1-N-(5-methyl-6-oxo-6,-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3-methoxy-propyl)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b)d]a2epin-7-yl)-N'-propyl-malonamide or
2-fluoro-2-methyl-N-(3-methyl-butyl)-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide.
Preferred compounds are further those, wherein R is a) and R is -(CR'R")n-CF3 or -(CR'R"-CHFf2 for example
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,2-
trifluoroethyl)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,3-
trifluoro-propyl) -malonamide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(2,2,2-trifluoro-ethyl)-malonamide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-diben2o[b,d] (2,2,3,3,3-pentafluoro-propyl-malonamide,
2-fluoro-2-metiyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(3>3)4,4-tetrafluoro-butyl)-malonamxde3
2-fluoro-2-metiyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b>d]azepin-7-yl)-N!-
(4,4,4-trifluoro-butyl)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'- (4,4,4-
trifluoro-3-methoxy-butyl)-malonamide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-
(3,3,4,4-tetrafluoro-bu1yl)-malonamide,
N-(5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-mehtyl-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,

2-methyl-N-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-7l)-N'-(2,2,3,3,3-pentafiuoro-propyl)-malonamide,
N-((S)-6-oxo-6,7-dihydro-5H--dibenzo [b,d] azepin-7-yl)-N'- (2,2,3,3,3-pentafluoor-
propyl)-malonamide,
2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'- (2,2,3,3,3--
pentafluoro-propyl)-malonamide,
(-)-2-methoxy-N-(6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'- (2,2,3,3,3-
pentafluoro-propyl)-malonamide,
(2R)-2-fluoro-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2S)-2-fluoro-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H--dibenzo [b,d] azepin-7-yl)-N'
(2,2,3,3,3-pentafiuoro-propyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]a2epin-7-yl)-2-
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]a2epin-7-yl_-2,2-
dimethyl-N'-(2,2>3)3>3-pentafluoro-propyi)-malonamideJ
(R)-N-((S)-5-cydopropyimethyl-6-oxo-6,7-idhydro-5H-dibenzo[b,d]azepin-7-yl)-2-
fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonanamide,
N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b3d]azepin-7-yl)-2-
methoxy-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N- ((S) -5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl) -N' -
(3,3,4,4,4-pentafluoro-butyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-mehtyl-
N'-(3,3,4,4,4-pentafluoro7bu1yl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-
dimethyl-N'-3,3,4,4,4-pentafluoro-butyl-malonamide,
(R)-N-((S)-5-qrdopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
fluoro-2-methyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide,
N-(5-isopropyl-6-oxo-6,7-dihydro-5H-dibenzo[b>d]azepin-7-yl)-2-methyl-N'-(2,2,3,3,3-
pentafluoro-propyl-malonamide,
N-(5-isopropyl-6-oxo-6J-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-

pentafluoro-propyl)-malonamide,
2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2R)-2-fluoro-2-methyl-N- [ (S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d] azepin-7-
yi]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2S)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-
yl}-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
2-methoxy-N-((S)-5-methyl--6-oxo-6,7-dihydro-5H-dibenzo[b,d] azepin-7-N'-(3,3,4,4,4-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,4,4,4-
pentafluoro-butyl)-malonamide or
2,2-dimethylyl-N-[(S)-6-oxo-5-(2,2-trifluoro-ethyl)-6,7-dihydro-5H-
dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide.
A further preferred group of compounds is those, wherein R is c) and R is -(CR'R")n-CF3 for example the following compounds:
2-methyl-N-(l-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-lH-benzo[b] [1,4] diazepin-3-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide,
N-((3S)-5-benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyi)-malonamide, N-[(3S)-5-(4-fluoro-benzoyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyI)-malonamide, N-[(3S)-5-(4-chloro-benzoyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo [b] [ 1,4] diazepin-3-yl] -2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide? N-[(3S)-5-(3,5-difluoro-benzoyi)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyi)-malonamide, 4-{(3S)-5-methyl-4-oxo-3-[2-(2,2,3,3,3-pentafluoro-propyicarbamoyl)-propionylamino]-2,3,4,5-tetrahydro-benzo[b][l,4]diazepine-l-carbonyl}-benzoic acid methyl ester,
N-((3S)-5-acetyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2 methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide, N-[5-((3S)-4-fluoro-benzyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyI)-malonamide, N-[(3S)-5-(4-chloro-benzoyl)-l-cyclopropylmethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo [b] [1,4] diazepin-3-yl] -2-methyl-NI-(2,2,3,3,3-pentafluoro-propyl)-malonamide, (2RS)-methyl-N-((3S)-l-methyl-2-oxo-5-trifluoromethanaesulfonyl-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,

(2RS)-methyl-N-[(3S)-l-methyl-2-oxo-5-(2,2,2-trifluoro-acetyl)-2,3,4,5,-tetrahydro-1H-
benzo[b][l,4]dia2epin-3-yl]-N'-(2,2,3,3,3-pentafluoxo-propyl)-malonamide,
N-[(3S)-l-methyl-2-oxo-5-(2,2,2-trifluoro-acetyl)-2,3,4,5,-tetrahydro-1H-
benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-[(S)-5-methanesulfonyl-2-oxo-5-(2,2,2-trifluoro-acetyl)-2,3,4,5,-tetrahydro-1H-
benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentofluoro-propyI)-malonamide,
(2RS)-methyl-N-[(S)-2-oxo-l-(2,2,2-trifluoro-ethyl)-5-trifluoromethanesulfonyl-
2,3,4,5-tetxahydro-lH-benzo[b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide,
5-methyl-4-oxo-(3S)-[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-
propionylamino]-2,3,4,5-tetrahydro-benzo[b] [l,4ldiazepine-l-carboxylic acid
cydopropylmethyl estermalonamide,
N-[(S)-5-cyclopropanecarbonyi-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4>5-tetxahydro-lH
benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamideJ
4-oxo-(3S)-[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionylamino]-5-(2,2,2-
trifluoro-ethyI)-2,3,4,5-tetrahydro-ben2o[b][l,4]diazepine-l-carboxylicacid
cyclopropylmethyl ester,
N-[(S)-5-acetyl-l-isopropyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-
(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide or
N-((S)-5-acetyl-l-benzyl-2-oxo-2,3,4,3-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-
(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide.
Preferred compounds are further those, wherein R1 is b), for example 2-methyl-N-(3-methy!-2-oxo-2,3,4,3-tetrahydro-lH-benzo[b][l,4]diazepin-1-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide.
Preferred compounds of formula I are further those, wherein R is d), for example 2-methyl-N-(ll-oxo-1041-dihydxo-dibenzo[b,f]oxepin-10-yl)-N'-(2,2,2-trifluoro-ethyi)-malonamide or 2-methyl-N-(ll-oxo-10,ll-dihydro-dibenzo[b,f]oxepin-10-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide.
One embodiment of the invention are compounds of the general formula

wherein
R is one of the following groups

R~ is lower alkyl, lower alkinyl, -(CK2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-CN, -(CR'R")nCF3, -(CR'R'VCHF,, -(CH2)n-C(O)O-lower alkyl, -(CH2)n-halogen, or is -(CHo2-cycloalkyl, optionally substituted by one or more substituentSj selected from the group consisting of phenyl, halogen or CF3;
R',R" are independently from n and from each other hydrogen, lower allcyl, lower alkoxy, halogen or hydroxy;
R33 R4 are independently from each other hydrogen, lower alkyl, phenyl or halogen;
R5 is lower alkyl or -(CH)2-cycloalkyl;
R6 is hydrogen or halogen;
R7 is hydrogen or lower alkyl;
R8 is hydrogen, lower alkyl, lower alkinyl or -(CH)2-cydoalkyl;
R9 is hydrogen, lower alkyl, -C(O)-lower alkyl, -C(O)-lower cydoalkyl,
-(CH2)n-cycloalkyl, phenyl, -C(O)-phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen or -C(0)0-lower alkyl, or is (CHVphenyl, optionally substituted by halogen;

n is 0,1, 2, 3 or 4;
and pharmaceutically suitable acid acidition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof.
The present compounds of formula I 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 R1 - R4 have the meaning as described above, and
if desired, converting the compounds obtained into pharmaceutically acceptable acid acidition salts.
The detailed description can be found below and in Examples 1 - 121. The starting material of formula IV are known compounds or may be prepared by methods well-known in the art. The amines of formulas VI and III are commercial available products or can be prepared by methods described in the literature.

Scheme 1

In this scheme R1 and R2 are as described below and R10 and Ru are independently lower alkyl.
In accordance with scheme 1 a compound of formula I maybe prepared as follows:
To a cooled solution of a compound of formula V, for example 2-methyl-malonic acid mono-tert-butyl ester and and an amine of formula VI, for example 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one in THF is acided hydroxybenzotriazole, diisopropylethylamine and N-(3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride, and the mixture is stirred overnight at r.t The solvent is evaporated, the residue is washed, dried and purified in usual manner.
Then TFA (trifluoroacetic acid) is acided to the obtained solution of formula VII, for example 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-diben2o[b,d]azepin-7-yl)-malonamic acid tert-butyl ester in dichloromethane, and the mixture is stirred at art overnight The mixture is then taken up in more dichloromethane, washed and dried After evaporation of the solvent, a compound of formula II, for example 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamic acid

is obtained. This obtained compound and a compound of formula III, for example cyclopropylmethylamine are placed in a disposable polypropylene tube and dissolved in DMR TPTU (2-(2-pyridon-l-yI)-l,l,3,3-tetxamethyl uranium tetrafluoroborate) is acided, and the mixture is shaken overnight at r.t The obtained compound of formula I is isolated and purified in conventional manner.


Compounds of formula I maybe converted to a corresponding acid acidition salt The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfaric acid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, dtric acid, benzoic acid, dnnamic 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 acidacided in a similar solvent The temperature is maintained between 0 °C and 50 °C. The resulting salt predpitates spontaneously or maybe brought out of solution with a less polar solvent
The acidacidition salts of compounds of formula I 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 formula I and their pharmaceutically usable acidition 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 accordance with the test given hereinafter.
Description of γ-secretase assay
The activity of test compounds can be evaluated in assays which measure the proteolytic deavage of suitable substrates by γ-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 γ-secretase activity can also be determined in
cell-free in vitro a says 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 spedfic

BLISA 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 γ-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 truncated APP fragment which results after y-secretase
cleavage of the extracellular domain and which constitutes the y-secretase substrate. The assay principle is described in Li YMetal,PNAS 97(11), 6138-6143 (2000).Hek293 cells are mechanically disrupted and the microsomal fraction is isolated by differential centrifiigation. 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 IC so Table 1




The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceuticafly inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceuticafly acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based
on the inhibition of the γ-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 maybe 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)

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 equipment
4. acid item 5 and mix for three minutes; compress on a suitable press.
Capsule Formulation
Item Ingredients mg/capsule

Manufacturing Procedure
1. Mix items 1,2 and 3 in a suitable mixer for 30 minutes.
2. acid items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.

Example 1
N-Cyclopropylmethyl-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
a) 2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic
acid tert-butyl ester
To a cooled solution (0 °C) of 2-methyl-malonic acid mono-tert-butyl ester (L01 g, 5.79 mmol) and 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one (1.15 g, 4.83 mmol) in THF (8 ml) was added hydroxybenzotriazole (652 mg, 4.83 mmol), diisopropylethylamine (624 mg, 4.83 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (925 mg, 4.83 mmol), and the mixture was stirred overnight at art The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e = 395.3 (M+H+), (920 mg, 48 %) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2CI2).
b) 2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzor [b,d]azepin-7-ylVmalonamic
acid
TFA (3 ml) was added to a solution of 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid tert-butyl ester (920 mg, 2.33 mmol) in dichloromethane (3 ml) and the mixture was stirred at art overnight The mixture was then taken up in more dichloromethane, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e = 339.3 (M-f H+), (580 mg, 73 %) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2CI2).
c)N-Cvclopropvlmethvl-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl) malonamide
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and cyclopropylmethylamine (5 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2ml). TPTU (2-(2-pyridon-l-yl)1,1,3,3-tetramethyl uronium tetrafluoroborate, 19mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t The title compound, MS: m/e = 392.2 (M+PT+), 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, X = 230 inn, flow rate 40 ml/min).

Example 2
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-ethyl-malonamide
The title compound, MS: m/e = 366.2 (M+H+), was prepared in analogy to example 1 from ethylamine.
Example 3
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-propargyl-malonamide
The title compound, MS: m/e = 376.3 (M+H+), was prepared in analogy to example 1 from propargylamine.
Example 4
2-Methyl-N- (5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d) azepin-7-yl)-N'- (2-methoxyethyl)-malonamide
The title compound, MS: m/e = 3963 (M+K+), was prepared in analogy to example 1 from 2-methoxyethylamine.
Example 5
2"Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-propyl-malonamide
The title compound, MS: m/e = 380.3 (M+H+), was prepared in analogy to example 1 from propylamine.
Example 6
2-Methyl-N-(5-metuhyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2-methylthioethyl)-malonamide
The title compound, MS: m/e = 412.3 (M+H+), was prepared in analogy to example 1 from 2-Methylthioetylamine.
Example 7
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-cyclobutyl-malonamide
The title compound, MS: m/e = 392.3 (M+H+), was prepared in analogy to example 1 from cydobutylamine.
Examples
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3-methoxy-propyl)-malonamide
The title compound, MS: m/e = 410.3 (M+H+), was prepared in analogy to example 1 from 3-methoxypropylamine.

Example 9
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-cyanomethyl-malonamide
The titie compound, MS: m/e = 377.3 (M+H+), was prepared in analogy to example 1 from aminoacetonitrile.
Example 10
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-cyclopropyl-malonamide
The title compound, MS: m/e = 378.3 (M+H+), was prepared in analogy to example 1 ■ from cydopropylamine.
Example 11
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-cyanoethyl)-malonamide
The title compound, MS: m/e = 391.2 (M+H+), was prepared in analogy to example 1 from 3-aminopropionitrile.
Example 12
2-Methyl-N- (5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N' - (2-ethoxyethyl)-malonamide
The title compound, MS: m/e = 410.3 (M+H+), was prepared in analogy to example 1 from 2-ethoxyethylamine.
Example 13
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,2-trifluoroethyl)-malonamide
The tide compound, MS: m/e = 420.2 (M+H+), was prepared in analogy to example 1 from 2,2,2-trifluoroethylamine.
Example 14
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,3-trifluoro-propyl)-malonamide
The tide compound, MS: m/e = 434.3 (M+H+), was prepared in analogy to example 1 from 3,3,3-trifluoropropylamine.
Example 15
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The tide compound, MS: m/e = 470.1 (M+H+), was prepared in analogy to example 1 from 2,2,3,3,3-pentafluoropropylamine.

Example 16
2-(5-Me1thyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)carbomyl-propionylainino] - acetic acid tert-butyl ester
The title compound, MS: m/e = 452.3 (M+H+), was prepared in analogy to example 1 from tert-butyl glycinate.
Example 17
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,3-trifluoro-2-hydroxy-propyl)-malonamide
The title compound, MS: m/e = 450.2 (M+H+), was prepared in analogy to example 1 from 3-amino-l,l,l-trifluoro-2-propanoL
Example 18
N-(2,2-Difluoro-3-phenyl-cyclopropyimethyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
The title compound, MS: m/e = 504.3 (M+H+), was prepared in analogy to example 1 from C-(2,2-difluoro-3-phenyl-cyclopropyl)-methylamine.
Example 19
N-(2,2-Difluoro-cyclopropylmethyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide
The title compound, MS: m/e = 428.2 (M+H+), was prepared in analogy to example 1 fromC-(2,2-difluoro-cydopropyl)-methylamine.
Example 20
2-Me1thl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide a) 2-Methvl-malonic acid monoethyl ester
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) 2-Methyl-N-92,2,2-trifluoro-ethyl)-inalonamic acid ethyl ester
To a solution of 1.56 g (10.6 mmol) methyl-malonic acidmonoethyl ester in 20 ml of tetrahydrofuran 1.06 g (10.6 mmol) of 2,2,2-txifluoroethylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HC1 (50 ml) and afterwards 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 column filtration (hexane/ethyl acetate = 2:1) to yield 1.48 g (61 %) of the title compound as white crystalline solid. MS m/e (%): 226,1 (M-H+, 100).
c) 2-Methyl-N-(2,2,2-trifluoro-ethyl)-malonarnic acid
To a solution of 1.48 g (6.52 mmol) 2-Methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofuran e, 20 ml of water and 1.09 g (26 mmol) of lithium hydroxide were added and the mixture was stirred overnight at room temperature. 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 give 1.09 g (84 %) of the title compound as a white solid. MS m/e (%): 197,9 (M-H+, 100).
d)2-Methvl-N-(3-methyl-2-oxo-2,3,4,5-tetrahvdro-lH-benzord]azepin-l-yl)N'-(2,2,2-trifluoro-ethyl-malonamide
To a solution of 0.066 g (0.3 mmol) 2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 2 ml of tetrahydrofuran 0.057 g (0.3 mmol) of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one, 0.058 g (0.3 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 0.040 g (0.3 mmol) of 1-hydroxyhenzotrizole hydrate and 0.116 g (0.9 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Then 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 NaHCO3 solution, dried ((MgSO4). ) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate = 3:1) to yield 0.10 g (89 %) of the diastereomeric mixture of title compound as white solid.

MS m/e (%): 372,1 (M+H*, 100).
Example 21
2-Methyl-N-(l-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-3-amino-l-methyl-5-phenyl-l,3,4,5-tetrahydro-benzo[b] [l,4]diazepin-2-one instead of (RS)-l-amino-3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one diethyl methyl-malonate in step d). MS m/e (%): 449.1 (M+H+, 100).
Example 22
N-(5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-phenyl-N'-(2,2,2-trifluoro-ethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl phenylmalonate instead of diethyl methyl-malonate in step a) and (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 482.1 (M+H+, 100).
Example 23
2-Fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)=N'-(2,2,2-trifluoro-ethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a) and (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step
d).
MS m/e (%): 438.3 (M+H+, 100).
Example 24
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), pentafluoropropylamine instead of 2,2,2-trifluoroethyl-amine in step b) and (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). i MS m/e (%): 488.2 (M+H+, 100).

Example 25 2-Methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)
N'-(2,2,3,3,3-pentafluoro-propyI)-malonamide
a) (S)-3-Amino-l-methyl-l,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-lH-ben2o[b] [1,4] diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at -75 °C 18 ml (IS mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at -75 °C the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried ((MgSO4). ). After evaporation of the solvent 20 ml of dichlorometane and 20 ml of trifluoracetic acid was added and the mixture was stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then ethylacetate was added and the mixture was extracted two times with water. The aqueouos phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried ((MgSO4). ) and evaporated. The residue was purified by column chromatography (dichloromethane/methanol = 9:1) to yield 2.1 g (65 %) of (S)-3-amino-l-methyl-l,3,4,5-tetrahydro-benzo[b][l,4] diazepin-2-one. MS m/e (%): 192.2 (M-H+, 100).
b) 2-Methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-
N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using pentafluoropropylamine instead of 2,2,2-trifluoroethyl-amine in step b) and (S)-3-amino-l-methyl-l,3,4,5-tetrahydro-benzo[b] [l,4]diazepin-2-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step
d).
MS m/e (%): 421.2 (M-H+, 100).
Example 26
N-((3S)-5-benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl) 2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
To a solution of 0.2 g (0.47 mmol) of 2-methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]dia2epin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3 ml of dichloromethane 0.096 g (0.95 mmol) of triethylamine and 0.08

mg (0.57 mmol) of benzoylchloride were added. The mixture was stirred for 20 min at room temperature. Hydrochloric acid (10 ml of a 1 N solution) was added and the mixture was extracted two times with dichloromethane. The combined organic layers were extracted with IN sodiumbicarbonate solution, dried ((MgSO4). ) and concentrated in vacuo. The remaining oil was purified by column chromatography to yield 0.15 g (60 %) of a white foam. MS m/e (%): 527.3 (M+H+, 100).
Example 27
N-((3S)-5-benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl) 2,2-dimethyl-N'-(2,2,2-trifIuoro-ethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 25 using diethyl 2,2-dimethylinalonate instead of diethyl methyl-malonate and 2,2,2-trifluoroethylamine instead of pentafluoropropylamine in step b) followed by the reaction with benzoylchloride as described in example 26. MS m/e (%): 491.3 (M+H+, 100).
Example 28
N-[(3S)-5-(4-Fluoro-benzoyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-2-methyl-N!-(2>2,3,3,3-pentafluoro-propyl)-malonamide The title compound was obtained in comparable yields according to the procedures described for example 26 using 4-fluorobenzoylchloride instead of benzoylchloride. MS m/e (%): 545.3 (M+H+, 100).
Example 29
N-[(3S)-5-(4-Chloro-benzoyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo [b] [ 1,4] diazepm-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 26 using 4-chlorobenzoylchloride instead of benzoylchloride. MS m/e (%): 561.4 (M+H+, 100).
Example 30
N-((3S)-5-(3,5-Difluoro-benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl) benzo (b] [ 1,4] diazepm-3-yl]-2-methyl-N'-92,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 26 using 3,5-difluorobenzoylchloride instead of benzoylchloride. MS m/e (%): 563.4 (M+H+, 100).
Example 31
2-Fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,3-trifluoro-2-hydroxy-1,l-dimethyl-propyl) -malonamide

The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and rac-3-amino-l, I,l-txifluoro-3-methyl-2-butanol instead of (RS)-l-axnino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 496.2 (M+H+, 100).
Example 32
2-Fluoro-N-(2-fluoro-ethyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b)d]azepin-6-one instead of 2,2,2-trifluoroethyiamine in step b) and 2-fluoroethylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 402,2 (M+H+, 100).
Example 33
N-(2,2-Difluoro-ethyl)-2-fluoro-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 2,2-difluoroethylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 420.1 (M+H+, 100).
Example 34
2-Fluoro-N-(2-cis-fluoro-cyclopropyl)-2-methyl-Nl-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and cis-2-fluorocyclopropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 414.2 (M+H+, 100).

Example 35 2-Fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)N'-
(3,3,4,4-tetrafluoro-butyi)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fiuoro-2-methylinalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H--dibenzo[b)d]a2epin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 3,3,4,4-tetrafluorobutylamide (available from the corresponding bromide via the Phthalimide method according to Jacobs et al: J.Med.Chem.1994, 37,1282) instead of (RS)-l-amino-3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 484.2 (M+H+, 100).
Example 36
2-Fluoro-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(4,4,4-trifluoro-butyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-diben2o[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 4,4,4-trifluorobutylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-onein step d). MS m/e (%): 466.2 (M+H+, 100).
Example 37
2-Huoro-2-methyl-N-(3-methyl--butyl)-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonaniide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 3-methyl-butylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 426.2 (M+H+, 100).
Example 38
2-Fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(l-trifluoromethyl-cyclopropylmethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2-fluoro-2-methylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 1-trifluormethyl-

cydopropylmethylamine (available from the corresponding alcohol via the Phthalimide method according to Jacobs et al: J.Med.Chem.1994, 37,1282) instead of (RS)-l-amino-3-methyl-1,3,4,5-tetrahydro-benzo(d)azepin-2-one in step d). MS m/e (%): 478.1 (M+H+, 100).
Example 39
4-{(3S)-5-Methyl-4-oxo-3-[2-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionylamino]-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepine-l-carbonyl}-benzoic acid methyl ester
The title compound was obtained in comparable yields according to the procedures described for example 26 using 4-(methoxycarbonyI)-benzoychloride instead of benzoylchloride. MS m/e (%): 583.3 (M+H+, 100).
Example 40
N-((3S)-5-Acetyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1h-benzo(b)(1,4)diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The tide compound was obtained in comparable yields according to the procedures described for example 26 using acetylchloride instead of benzoylchloride. MS m/e (%): 465,2 (M+H+, 100).
Example 41
2-Methyl-N-(ll-oxo-10,ll-dmydro-dibenzo[b,f]oxepin-10-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide
a) (RS)-ll-Amino-llH-dibenzo[b,f]oxepin-10-one hydrochloride To a solution of 1.85 g (8.77 mmol) 1 lH~dibenzo[b,f]oxepin-10-one in 4 ml of toluene at -20 °C 2.5 g (21.9 mmol) of potassium tertbutoxide was added. The solution was saturated with N2. After stirring for 15 min 1.2g (10.5 mmol) of isoamyl nitrite was added. After stirring overnight at room temperature the solution was cooled at 0 °C for 15 min water (80 ml), acetic acid (4 ml) and ethyl acetate (80 ml) were added. The aqueouos phase was extracted with ethyl acetate. The combined organic layers were reextracted with water and dried ((MgSO4). ). After evaporation of the ethyl acetate the resulting slurry of the oxim in toluene was cooled to 0 °C during an hour and filtered. The solid material was dissolved in tetrahydrofurane (20 ml), 8 ml 1M hydrochloric acid in tetrahydrofurane and 20 ing of platinum oxide were added The reaction mixture was flushed with N2 and subjected to a hydrogen atmosphere of 50 psi at room temperature. After stirring overnight with hydrogen atmosphere the formed precipitate was collected by filtration, washed with tetrahydrofurane and recrystallised from a methanol tetrahydrofurane mixture to yield 0.9 g of white crystals (Fp.215-217 °C)

b)2-Methyl-N-(11-oxo-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-N'-(2,2,2-trifluoro-
ethyl)-malonamide
The title compound was obtained in comparable yields according to the procedures
described for example 20 using (RS)-ll-amino-llH-dibenzo[b,f]oxepin-10-one instead
of (RS)-l-amino-3-meth)d-l,3,4,5-tetrahydro-ben2o[d]azepin-2-one in step d).
MS m/e (%): 407.3 (M+H+, 100).
Example 42
b)2-Methyl-N-(11-oxo-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-N'-(2,2,2-trifluoro-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using 2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine in step b) and (RS)-ll-amino-llH-diben2o[b,f]oxepin-10-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 457.4 (M+H+, 100).
Example 43
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(4,4,4-trifluoro-3-methoxy-butyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 4,4,4-trifluoro-3-methoxy-butylamine (available from 4,4,4-trifluoro-3-methoxybutaneamide via lithium aluminiumhydride reduction according to Jacobs et al: J.Med.Chem.1994, 37,1282) instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 476.3 (M-H+, 100).
Example 44
2-Fluoro-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,4,4-tetrafluoro-butyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-5-methyl-5H,7H-diben2o[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 3,3,4,4-tetrafluorobutylamine (available from the corresponding bromide via the Phthalimide method according to Jacobs et al: J.Med.Chem.1994, 37,1282) instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 464.2 (M-H+, 100).

Example 45
N-(3-Isoproporl-propyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-5-methyl-5H,7H-diben2o[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 3-Isopropoxy-propylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 436.3 (M+H+, 100).
Example 46
N-((3S)-l-Cydopropylmethyl-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide The title compound was obtained in comparable yields according to the procedures described for example 25 using cydopropylmethyl bromide instead of methyl iodide in step a). MS m/e (%): 463.5 (M+H+, 100).
Example 47
N-((3S)-l,5-Dimethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) ((3S)-l-Methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b)(l,4)diazepin-3-yl)-carbamic
acid tert-butyl ester
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [1,4] diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at -75 °C 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofiirane) was added. After stirring for 30 min at -75 °C the mixture was allowed to reach room
temperature and 3.07 g (21.6 mmol) of methyl iodide was added The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried ((MgSO4). ) to yield 4.95 g (94 %) of (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam. MS m/e (%): 292.0 (M+H+,100).
b) (SV3-Axnino-l,5-dimethyl-l,3,4,5-tetrahydro-benzo[b) (l,4)diazepin-2-one
To 0.29 g (1 mmol) of (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo(b)(1,4)diazepin-3-yl)-carbamic acid tert-butyl ester in dimethylformamide (3 ml) 0.46 g (3.33 mmol) of

potassium carbonate and 0.17 g (1.2 mmol) of methyl iodide were added and the mixture was stirred at room temperature overnight Water (10 ml) was added and the mixture was extracted two times with ethyl acetate (10 ml each). The combined organic layers dried ((MgSO4). and purified by column chromatography (hexane / ethyl acetate = 1:1) to yield 0.19 g (62 %) of a white solid. This compound was dissolved in a mixture of 2 ml of dichlorometane and 2 ml of trifluoro acetic acid and stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then dichloromethane was added and the mixture was extracted with sodium bicarbonate solution. The organic phase was dried ((MgSO4). ) and evaporated to yield 0.12 g of (S)-3-amino-l,5-dimethyl,l,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-2-one as a light yellow solid. MS m/e (%): 206,4 (M+H+, 100).
c)N-((3S)-l,5-Dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures
described for example 20 using pentafluoropropylamine instead of 2,2,2-trifluoroethyl-
amine in step b) and (S)-3-amino-l,5-dimethyl-l,3,4,5-tetrahydro-
benzo[b] [1,4]diazepin-2-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-
benzo[d]azepin-2-one in step d).
MS m/e (%): 437.5 (M+H+, 100).
Example 48 N-((3S)-5-Cyclopropylmethyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo [b] [ 1,4] diazepm-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures
described for example 47 using cydopropylmethyl bromide instead of methyl iodide in
step b).
MS m/e (%): 477.3 (M+H+, 100).
Example 49
N-[5-((3S)-4-Fluoro-benzyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo|b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafIuoro-propyl)-malonamide The title compound was obtained in comparable yields according to the procedures described for example 47 using 4-fluorobenzyl bromide instead of methyl iodide in step
b).
MS m/e (%): 531.3 (M+H+, 100).

Example 50
N4(3S)-5-(4-Chloro-benzoyl)-l-cydopropylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-
benzo [b] [ 1,4] diazepin-3-yl] -2-methyl-N'- (2,2,3,3,3-pentafluoro-propyl)-malonamide The title compound was obtained in comparable yields according to the procedures described for example 26 using N-((3S)-l-cyclopropylmethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l>4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide instead of 2-methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l>4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide and using 4-chlorobenzoyi chloride instead of benzoyl chloride. MS m/e (%): 60L5 (M+H+, 100).
Example 51
N-(5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) 5-Cydopropylmethyl-5H ,JH-dibenzo [b,d) azepin-6-one
To a solution of 0.5 g (2.4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 6 ml of dimethylformamide at room temperature 0.143 g (3.58 mmol) of sodium hydride was added. After stirring for 1 hour at 60 °C 0.97 g (7.2 mmol) of cyclopropylmethyl bromide were added and stirring was continued at 60 °C overnight After cooling to room temperature the mixture was distributed between water and dichloromethane. The combined organic layers were reextracted with sodium sulphate solution and dried ((MgSO4). ). After concentration in vacuo the residue was purified by column chromatography (hexane / ethyl acetate = 1:1) to yield 0.6 g (95 %) of 5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one as a white crystalline compound. MS m/e (%): 264.1 (M+H+, 100).
b) (RS)-7-Amino-5-cyclopropylmethyl-5H,7H--dibenzo[b,d)azepin-6-one
To a solution of 0.3 g (1.14 mmol) 5-cydopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one in 5 ml of toluene 0.285 g (2.44 mmol) of isoamyl nitrite were added and the mixture was cooled to 0 °C A solution of 3.6 ml (1.83 mmol) of potassium bis(trimethylsilyl)amide (0.5 M in toluene) was added slowly and stirring was continued for 1 hour at this temperature. Sodium hydrogensulphate solution was added and the mixture was extracted two times with ethylacetate.
The combined organic layers were reextracted with water and dried ((MgSO4). ). After evaporation of the solvent 0.2 g of a white foam was obtained, that was dissolved in ethanol (5 ml). Palladium on carbon (90 mg) was added and the mixture was hydrogenated at 2.5 bar H2 pressure for 32 hours. The catalyst was filtered off and the

solvent was evaporated. The residue was partitioned between dichloromethane (5 ml)
and 4N hydrochloric acid (2 ml). The aqueouos solution was separated, set to basic pH
with sodium hydroxide and extracted 2 times with ethyl acetate. After drying ((MgSO4). )
and evaporation of the ethyl acetate 0.1 g (52 %) of an off-white solid material was
obtained.
MS m/e (%): 279.3 (M+H*, 100).
c)N-(5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N'-(2,23,33"pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using 2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine in step b) and (RS)-7-amino-5-cydopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 50S.4 (M-H+, 100).
Example 52
N-((3S)-l-Acetyl-4-oxo-2,3,4,5-te1rahydro-lH-benzo[b][l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide a) 5-Acetyl-3-amino-1,3,4,5-tetrahvdro-benzo[b) [1,40diazepin-2-one A solution of 0.5 g (1.8 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4] diazepin-3-yl)-carbamic acid tert-butyl ester in 1.7 ml of acetic anhydride is stirred for 3 hours at
65 °C. The mixture was put onto water (5 ml) and extracted two times with dichloromethane (10 ml each). The combined organic layers were dried ((MgSO4). ) and evaporated to yield 0.6 g of a light yellow foam. This compound was dissolved in a mixture of 2 ml of dichlorometane and 2 ml of trifluoracetic acid and stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then dichloromethane was added and the mixture was extracted with sodium bicarbonate solution. The organic phase was dried ((MgSO4). ) and evaporated to yield 0.31 g of (S)-l-acetyl-3-amino-1,3,4,5-tetrahydro-benzo(b)(l,4)diazepin-2-one as a light yellow solid. MS m/e (%): 220.4 (M+H+, 100).
b)N-(l-Acetyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2-methyl-N'-
(2,2,3,3,3-pentafluoro-propyl)malonamide
The title compound was obtained in comparable yields according to the procedures
described for example 20 using pentafluoropropylamine instead of 2,2,2-trifluoroethyl-

amine in step b) and (S)-l-acetyl3-amino-l,3,4,5-tetrahydro-ben2o[b][l,4]diazepin-2-
one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydroo-benzo[d]azepin-2-one in step d).
MS m/e (%): 449.2 (M+H+, 100).
Example 53
N-((3S)-5-Acetyl-l-cydopropylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 26 using N-((3S)-l-cydopropyimethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo|b][l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide instead of 2-methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-rnalonamide and using acetyl chloride instead of benzoyl chloride. MS m/e (%): 503.2 (M-H+, 100).
Example 54
N-(3-tert-butoxy-propyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 3-tert-butoxy-propylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 396.2 (M-C4+H+ 100); 452.2 (M+H+, 43).
Example 55
2-Methyl-N-((3S)-2-oxo-l-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazeoin-3-yI)-N'-(2,2,3,3>3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 25 using prop-2-ynyl bromide instead of methyl iodide in step a). MS m/e (%): 447.5 (M+H+, 100).
Example 56
N- ((3S)-5-Cydopropanecarbonyl- l-methyl-2-oxo-2,3,4,5-tetrahydro- 1H-benzo [b] [ 1,4] diazepm-3-yl)-2-methyl-N'- (2,2,3,3,3-pentafluoro-propyl)-malonamide The title compound was obtained in comparable yields according to the procedures described for example 26 using cyclopropanecarbonyl chloride instead of benzoylchloride. MS m/e (%): 491.5 (M+H 100).

Example 57
2-Ethyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl ethyl-malonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethyiamine in step b) and 2,2,3,3,3-pentafluoropropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 484.5 (M+H+, 100).
Example 58
2-Isopropyl-N- (5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl isopropyl-malonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 2,2,3,3,3-pentafiuoropropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d).
MS m/e (%): 498.5 (M+H+, 100).
Example 59
N-(3S)-5-Cyclopropylmethyl-2-oxo-1-propynyl-2,3,4,5-tetrahydro-1H
benzo[b][l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures
described for example 47 using prop-2-ynyl bromide instead of methyl iodide in step a)
and cyclopropylmethyl bromide instead of methyl iodide in step b).
MS m/e (%): 501.4 (M+H+, 100).
Example 60
N-((3S)-5-Cydopropanecarbonyl-2-oxo-l-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[b] [l,4]diazepin-3-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 26 using 2-methyl-N-((3S)-2-oxo-l-prop-2-ynyl-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide instead of 2-methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b] [l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide and using cyclopropanecarbonyl chloride instead of benzoyl chloride. MS m/e (%): 515.4 (M+H+, 100).

Example 61
N-(5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-peatafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl malonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-diben2o[b,d]azepm-6-one instead of 2,2,2-trifluoroethyiamine in step b) and 2,23,3,3-pentafluoropropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-ben2o[d]a2epm-2-one in step d). MS m/e (%): 456.5 (M+H+, 100).
Example 62
2)2-Dimethyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using diethyl 2,2-dimethylmalonate instead of diethyl methyl-malonate in step a), (RS)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 2,23,3,3-pentafluoropropyiamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetraliydro-benzo[d]azepin-2-one in step d). MS m/e (%): 484.5 (M+H+, 100).
Example 63
N-(3-Fluoro-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-3-fluoro-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one (prepared in the same manner as the 2-fluoroderivative in WO9932453) instead of 2,2,2-trifluoroethylamine in step b) and 2,2,3,33-pentafluoropropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 486.4 (M-H+, 100).
Example 64
N- (2-Fluoro-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using (RS)-7-amino-2-fluoro-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one instead of 2,2,2-trifluoroethylamine in step b) and 2,2,3,3,3-pentafluoropropylamine instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d).

MS m/e (%): 486.2 (M-tT, 100).
Example 65
2-Me%l-N-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) 5-(4-Methoxy-benzyl-5H,7H-dibenzo[b,d]azepin-6-one
To a solution of 0.82 g (4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 15 ml of dimethylformamide at room temperature 0.20 g (5 mmol) of sodium hydride 55% in oil was added After stirring for 30 min at room temperature 0.75 g (5 mmol) of p-methoxybenzyl chloride were added and stirring was continued at room temperature for 2 hours. For workup the mixture was distributed between water and ethyl acetate. The organic layer was re-extracted with 1 N hydrochloric acid and the aqueous layers were washed with ethyl acetate. The combined organic layers were dried ((MgSO4). ) and concentrated in vacuo. The residue was purified by column chromatography (hexane / ethyl acetate = 1:1) to yield 1.175 g (91%) of 5-(4-methoxybenzyl)-5H,7H-dibenzo[b,d]azepin-6-one as a colourless oil. MS m/e (%): 330.4 (M+H*, 100).
b) (RS)-7-Amino-5-(4-methoxy-benzyl-5H,7H-dibenzo[b,d)azepin-6-one
To a solution of 1.15 g (3.5 mmol) 5-(4-methoxybenzyl)-5H,7H-dibenzo[b,d]azepin-6-one in 15 ml of toluene 0.836 g (7 mmol) of isoamyi nitrite were added and the mixture was cooled to 0°C. A solution of 21.4 ml (10.5 mmol) of potassium bis(trimethylsilyl)amide (0.5 M in toluene) was added slowly and stirring was continued for 2 hours at this temperature. Sodium hydrogensulphate solution was added and the mixture was extracted two times with ethylacetate.
The combined organic layers were re-extracted with water and dried ((MgSO4). ). After evaporation of the solvent a solid was obtained, that was purified by column chromatography (dichloromethane / methanol = 95:5) to yield 1.03 g (81%) oxime. This compound was dissolved in ethanol (5 ml) and 1.5 ml of 2N hydrochloric acidwere added. Palladium on carbon (10%, Degussa 1835,100 mg) was added and the mixture was hydrogenated at 5 bar H2 pressure for 24 hours at room temperature. The catalyst was filtered off and the solvent was evaporated. The residue was partitioned between dichloromethane (5 ml) and 4N hydrochloric acid(2 ml). The aqueous solution was separated, set to basic pH with sodium hydroxide and extracted 2 times with ethyl acetate. After drying ((MgSO4). ) and evaporation of the ethyl acetate 0.8 g (63%) of a white solid material was obtained.

MS m/e (%): 345.3 (M+H+, 100).
c) (RS)-7-Amino-5H,7H-dibenzo[b,d) azepin-6-one
To a solution of 0.1 g (0.29 mmol) (RS)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d] azepin-6-one in 8 ml of dichloromethane at 0°C temperature 0.67 ml (8.7 mmol) of trifluoroacetic acidand 0.25 ml of trifiuoromethansulfonic acid (2.9 mmol) were added and the mixture was stirred for 4 hours at room temperature. After concentration of the mixture at 40°C in vacuo an aqueous NaHCo3 solution was added and the mixture extracted two times with ethyl acetate. The combined organic layers were dried ((MgSO4). ). After evaporation of the solvent a light yellow oil was obtained, that was used directly in the next step.
d) (RSV2-Methvl-N-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-
pentafluoro-propyl-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 20 using and 2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine in step b) and (RS)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one instead of (RS)-l-amino-3-methyl-l,3,4,5-tetrahydro-benzo[d]azepin-2-one in step d). MS m/e (%): 456.5 (M+H+, 100).
Example 66
N-((S)-6-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) (S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzof[b,d]azepin-6-one
Racemic (RS)-7-amino-5-(4-methoxy-benzyl)-5H,7H--dibenzo[b,d]azepin--6-one was
separated by chromatography on Chiralpak AD with isopopanol/heptane 1:3 as solvent
to yield
(S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one, [a] 589 = -146°
(l%in CHCI3)and (R)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one,
[a] 589 = +148° (1% in CHC13).
b))S)_-N-(6-oxo-6,7-dihvdro-5H-dibenzo[b,d1azepin-7-yl)N'-(2,2,3,3,3-pentafluoro-
propyl-malonamide
The methoxybenzyl group of (S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-
dibenzo[b,d]azepin-6-one was removed according to the method described in section c)
of example 65 and the resulting (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one was

coupled with N-(2,2,3,3,3-pentafluoro-propyI)-maIonamic acid according to the method described in section d) of example 65 to yield (S)-N-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide, [a] 589 = -79.7° (1% in MeOH), MS m/e (%): 442.4 (M+H+, 100).
Example 67
2,2-Dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-
pentafluoro-propyl)-malonamide
(S)- 7-Amino-5H,7H-dibenzo[b)d]azepin-6-one was coupled with 2,2-dimethyl-N-
(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples
65 and 66 to yield 2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d)azepin-7-
yl)-N'-(2,2,3,3,3-pentafluoro-propyi)-malonamide,
[a] 589 = -38.8° (1% in CHC13), MS m/e (%): 470.3 (M+H+, 100).
Example 68
(-)-2-Metfcoxy-N-((S)6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) 2-Methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid methyl ester
2-Methoxy-malonic acid xnonomethyl ester was coupled with 2,2,3,3,3-pentafluoro-
propylamine in analogy to the description in Example 73 to yield 2-methoxy-N-
(2,2,3,3,3-pentafluoro-propyl)-malonamic acid methyl ester as colourless oil,
MS m/e (%): 280.0 (M+H+, 100).
b) 2-Methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid
2-Methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid methyl ester
was saponified in analogy to the procedure of example 75b to yield 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid as white solid, MS m/e (%): 266.0 (M+H+, 100).
c) (-2-Methoxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin7-yl-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide
(S)-7-Amino-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples 65 and 66 to yield (-)-2-methoxy-N-(6-oxo-6,7-dihydro-5H-diben2o[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid,
[a] 589 = -87.6° (1% in MeOH), MS m/e (%): 472.0 (M+H+, 100),

Example 69
(2R)-2-Fluoro-2-lmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-maloiiainide
a)(2S)-2-fluoro-2-methyl-N-((S)-6-Cyclopropyllmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)
malonamic acid ethyl ester
In an analogous manner to that described in Example 1 a), the condensation of (S)-7-
amino-5H,7H-diben2o[b,d]azepin-6-one and (2S)- 2-fluoro-2-methyl-malonic acid
mono ethyl ester (96.9% e.e.) yielded the title compound as a white solid; MS: m/e =371
(M+H)+.
The (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester was obtained by
stereoselective hydrolysis of the corresponding diester by Candida cylindracea hydrolase
following the procedure described in J. Org. Chem. 1986, 51,1003-6.
b)(2S)-2-Fluoro-2-methyl-N-((SV6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-
malonamic acid
In an analogous manner to that described in Example WC b), the hydrolysis of the (2S)-
2-fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic
acid ethyl ester under basic conditions yielded the title compound as white foam;
MS: m/e =341 (M-H)".
c)(2R)-2-Fluoro-2-methvl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzorb,d1azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 1 c), the condensation of (2S)-2-
fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic
acid and 2,2,3,3,3-pentafluoro-propylamine yielded the title compound as a white solid;
MS: m/e =474 (M+H)+; optical integrity 96.4% i.e..
Example 70
(2S)-2-Fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5H,7H-dibenzo[b,d] azepin-6-one and (2S)-2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid; MS: m/e =474 (M+H)+.

Example 71
N-((S)-5-Cyclopropyllmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-(2,2,3,3,3-pentafluoro-propyl)-mdonamide
a) (S)-7-amino-5-cvcIopropvlmethyl-5H,7H-dibenzo[b,d]azepin-6-one
(RS)-7-Amino-5-cydopropyImethyl-5H,7H-dibenzo[b,d]azepin-6-one was separated by
HPLC on Chiralpak AD with isopropanol/heptane 1:4 to give (S)-7-amino-5-cyclopropylmethyl5H,7H-dibenzo[b,d]azepin-6-one, [a] 589 = -162° (1% in MeOH), and(R)-7-amino-5-cydopropylmethyl-5H,7H-dibeiizo[b,d]azepin-6-one, [a] 589 = +163° (1% in MeOH).
Assignment of the absolute configuration by derivatisation with (-)-(S)-naproxen and x-ray analysis of the derivative (S)-N-((R)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-2-(6-methoxy-naphthalen-2-yl)-propionamide. A tetrahydrofurane solution of 0.05 g (0.18 mmol) (+)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was reacted overnight at room temperature with 0,04 g (0.18 mmol) (+)-(S)-naproxen, 0.03 g (0.18 mmol) 1-hydroxybenzotriazole, 0.063 l (0.36 mmol) diisopropylethylamine and 0.04 g (0.18 mmol) N-(3-dimethylaminopropyl)-N'-ethyl-carbodtimid-hydrochlorid. Extraction with 1 N aqueous hydrochloric acid/ dichloromethane and chromatography on silicagel yielded 0.09 g (97%) (S)-N-((R)-5-Cyclopropyllmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
yl)-2-(6-methoxy-naphthalen-2-yl)-propionamide as white solid which was crystallized from ethanol. mp.: 151-152 OQ MS m/e (%): 491.4 (M+H+, 100).
b)N-((S)-5-cvclopropy]methyl"6-oxo-6,7-dihydro-5H-dibenzo(b,,d]azepin-7-y1)-N' (2,2,3,3,3-pentafluoro-propyl)-malonamide
0.11 g(0.38 mmol) (S)-7-Amino-5-cyclopropylmethyl-5H,7H-dibenzo[bJd]azepin-6-one and 0.09 g (0.38 mmol) 3-oxo-3-(2,2,3,3,3-pentafluoro-propylamino)-propanoic acidin 10 ml tetrahydrofuran were reacted with 0.06 g (0.38 mmol) 1-hydroxybenzotriazole hydrate, 0.13 ul (0.76 mmol) diisopropylethylamine and 0.7 g (0.38 mmol) N-(3-dimethylaminopropyl-N'-ethyl-carbodiimid-hydrochlorid at 0°C for 4 hours. After stirring at room temperature over night the solvent was removed by distillation and the residue purified by chromatography on silicagel with heptane/ ethylacetate (gradient 100-0/0-100) to yield 0.17 g (89%) N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-rnalonamide as white solid. [a] 589 = -63.9° (1% in CHC13), MS m/e (%): 496.3 (M+H+, 100).

Example 72
(R)-N-((S)-5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide and
Example 73
(S)-N-((S)-5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl"N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
0.15 g (0.54 mmol) (S)-7-amino-5-cyclopropylmetiiyi-5H,7H-dibenzo[b3d]azepin-6-one
and 0.13 g (0.54 mmol) 2-methyl-3-oxo-3-(2,2,3,3,3-pentafluoro-propylamino)-
propanoic acid in 13 ml tetrahydrofuran were reacted with 0.07 g (0.54mmol) 1-
hydroxybenzotriazole hydrate, 0.19 µl (1.08 mmol) diisopropylethylamine and 0.11 g
(0.54 mmol) N-(3-dimethylamnopropyl)-N'-ethyl-carbodimid-hydrochloride with
stirring at room temperature over night. Extraction with IN aqueous hydrochloric acid/dichloromethane and chromatography on silicagel with ethylacetate gave 0.22 g solid material which was separated by chromatography on Chiralpak AD with heptane/isopropanol 80/20 to yield 0.10 g (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide [a] 589 = -74.6° (1% in CHC13), MS m/e (%): 510.3 (M+H+, 100) as white solid and 0.09 g (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b3d]azepin-7-yl)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide [a] 589 = -63.8° (1% in CHC13), MS m/e (%): 510.3 (M+H+, 100) as white solid.
Example 74
N-((S)-5-Cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
(S)-7-amino-5-cycIopropylmethyl-SH,7H-dibenzo[b,d]azepin-6-one was coupled with
2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the
description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-
dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
as white solid.
[a] 589 = -60.4° (1% in CHC13), MS m/e (%): 524.3 (M+H+, 100).

Example 75
(R)-N-((S)-5-Cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
fluoro-2-methyl-malonamic acid ethyl ester
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]a2epin-6-one was coupled with (S)-2-fluoro-2-methyl-malonic acid monoethyl ester in analogy to the description in example 73 to yield (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonainic acid ethyl ester as colourless oil. MS m/e (%): 425.4 (M+H+, 100).
b) (S)-N-((S)-5-cyclopropyiinethvl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7"yl)-2-
fluoro-2-methyl-malonamic acid
0.22g (0.52 mmol) (S)-N-((S)«5-cyclopropylmethyl-6-oxo-6J7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid ethyl ester in 3 ml tetrahydrofarane was reacted with a solution of 0.02 g (0,52 mmol) lithium hydroxide monohydrate in 1 ml water at room temperature for 2 hours. Evaporation of the tetrahydrofurane, extraction with diethylether, acidification with 0.5 ml 1 N aqueous hydrochloric acid and extraction with ethylacetate gave 0.18 g (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6J7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl
malonamic acid as white solid. MS m/e (%): 397.4 (M+H+, 100).
c) (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide (S)-N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-meth^-malonamic acidwas coupled with 2,2,3,3,3-pentafluoropropylamine in analogy to the procedure described for RJR 7 to yield (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
[a] 589 = -45.7° (1% in CHC13), MS m/e (%): 528,2 (M+H+, 100).
Example 76
N-((S)-5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methoxy-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide

(S)-7-amino-5-cydopropydimethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyi)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-C7clopropylmethyl-6-oxo-6,7-dihydro-5H-
dibenzo[b4]azepin-7-yl)-2-methoxy-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamideas white solid.
[a] 589 = -105.5° (1% in MeOH), MS m/e (%): 526.3 (M+H+, 100).
Example 77
N- ((S)-5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
(S)-7-amino-5-cycloprop)imethyl-5H>7H-dibenzo[b,d]azepin-6-one was coupled with N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acidin analogy to the description in example 73 to yield N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide as white solid.
[a] 589 = -57.5° (1% in CHC13), MS m/e (%): 510.1 (M+H+, 100).
Example 78
N- ((S) -5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-2-methyl-N'- (3,3,4,4,4-pentafluoro-butyl)-malonamide
a) 2-Methyl-N-(3,3,4,4,4-pentafluoro-butyl-malonamic acid ethyl ester
2-Methyl-maIonic acidmonoethyi ester was coupled with 3,3,4,4,4-pentafluoro-
butylamine in analogy to the description in example 73 to yield 2-methyl-N-(3,3,4,4,4-
pentafluoro-butyl)-malonamic acid ethyl ester as colourless oil.
MS m/e (%): 292.1 (M+H+,100).
b) 2-Methyl-N-(3,3,4,4,4-pentafluoro-butyl)malonamic acid
2-Methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acidethyl ester was saponified in analogy to the procedure of example 75b to yield 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acidas white solid.
MS m/e (%): 262.1 (M-H+, 100).
c)N-((S)-5-Cyclopropylmethvl-6-oxo-6J-dihydro-5H-dibenzo[b,dlazepin-7-vD-2-methyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
(S)-7-amino-5-cyclopropylmethyl-5HJ7H-dibenzo[b,d]azepin-6-one was coupled with 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-

dibenzo[b,d]azepin-7-yl)-2-methyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malnamide
(epimers) as white solid
MS m/e (%): 524.2 (M+H+, 100).
Example 79
N-((S)-5-Cyclopropyimethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2 dunethyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with
2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acidin analogy to the description in example 73 to yield N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide (epimers) as white solid, [a] 589 = -64.9° (1% in CHC13), MS m/e (%): 533.3 (M+H+, 100).
Example 80
(R)-N-((S)-5-Cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-fluoro-2-methyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
fluoro-2-methyl-malonamic acidwas coupled with 3,3,4,4,4-pentafluoro-butylamine in
analogy to the procedure described for example 73 to yield (R)-N-((S)-5-
cyclopropylmeth}d-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl
N'-(3,3,4,4,4-pentafluoro-butyl-malonamide as white solid.
[a] 589 = -56.7 (1% in CHC13), MS m/e (%): 542.0 (M+H+, 100).
Example 81
N-(5-Isopropyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N!-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The title compound was obtained in comparable yields according to the procedures described for example 65 using and 2-iodopropane instead of p-methoxybenzyl chloride in step a) while step c) was omitted and directly continued with step d). MS m/e (%): 496.1 (M-H+, 100).
Example 82
N-(5-Isopropyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide

The title compound was obtained in comparable yields according to the procedures described for example 65 using and 2-iodopropane instead of p-methoxybenzyl chloride in step a) while step c) was omitted and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid was used instead of 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in step d). MS m/e (%): 510.3 (M-H+, 100).
Example 83
N-((S)-5-Me&yi-6-oxo-6,7-dihydrdro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3 pentafluoro-propyl)-malonamide
(S)-7-Amino-5-mediyl-5H,7H-diben2o[bJd]azepin-6-one was coupled with N-(2,2,3,3,3-pentafluoro-propyi)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-Methyl-6-oxo-6,7-dihydrdro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3 pentafluoro-propyl)-malonamide as white solid.
[a] 589 = -52.7° (1% in CHC13), MS m/e (%): 456.4 (M+H+, 100).
Example 84
2,2-Dimethyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyi)-malonamic acid in analogy to the description example 73 to yield 2,2-dimethyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d)azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
[a] 589 = -53.8° (1% in CHC13), MS m/e (%): 484.0 (M+H+, 100).
Example 85
(2R>2-Huoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-
yl] -N'- (2,2,3,3,3-pentafluoro-propyl)-malonamide
a) (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-
7-yl)malonamic acidethyl ester
In an analogous manner to that described in Example 1 a), the condensation of (S)-7-
amino-5-methyl-5H37H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-malonic
acid mono ethyl ester yielded the title compound as a colourless oil;
MS:m/e=385(M+H)+.

The (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester (optical integrity 91% e.e.) was obtained by stereoselective hydrolysis of the corresponding diester by Candida cylindracea hydrolase following the procedure described in J.Org.Chem. 1986, 51,1003-6.
bU2S)-2-Huoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin 7-yl)malonamic acid
A solution of 75 mg (0.2 mmol) of (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonainic acidethyl ester in 1 ml of tetrahydroforane was treated for 2 h at room temperature with a solution of 8 mg (0.2 mmol) of lithium hydroxide monohydrate in 0.5 ml of water. For the working-up, the tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous layer was extracted twice with 10 ml of diethylether. The combined organic layers were washed with 5 ml of water and, thereafter, the combined aqueous layers were acidified with 0.025 ml of hydrochloric acid (25%). Thereupon, the aqueous layer was extracted three times with 15 ml of ethyl acetate. The organic layers were washed with 15 ml of a saturated solution of sodium chloride, then combined, dried over sodium sulphate, and evaporated under reduced pressure. There were obtained 69 mg (99% of theory) of the title compound as a white foam; MS: m/e =355 (M-H)c)(2R)-2-Fluoro-2-methvl-N-(S)-5-methyl-6-oxo-6,7-dihydro-5H-
dibenzo)[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)_-malonamide
In an analogous manner to that described in Example 1 c), the condensation of (2S)-2-
fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-
malonamic acid and 2,2,3,3,3-pentafluoro-propylamine yielded the title compound as a
white foam; MS: m/e =488 (M+H)+; optical integrity 94% Ae.
Example 86
(2S)-2-Fluoro-2-raethyl-N-[(S)-5-methyl-(2RS)-2-Methyl--6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid; MS: m/e =488 (M+H)+.
The (2S)-2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid was obtained in a reaction sequence analogous to that leading to (2RS)-methyl-N-(2,2,2-

trifluoro-ethyl)-malonamic acid [Example 20 c)] by replacing (2RS)-methyl-malonic acid monoester by (2S)-2-fluoro-2-methyl-malonic acid monoester.
Example 87
2-Methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N' (2,2,3,3,3-pentafluoro-propyi)-malonamide
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield 2-methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[bJd]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid. [a] 589 = -71.8° (1% in CHC13), MS m/e (%): 486.4 (M+H+, 100).
Example 88
N-((S)-5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yI)-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
(S)-7-Amino-5-methyl-5H)7H-dibenzo[b)d]azepin-6-one was coupled with N-(3,3,4,4,4-
pentafluoro-butyl)-malonamic acid in analogy to the description example 73 to yield N-
((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,4,4,4-
pentafluoro-butyl)-rnalonamide as white solid,
[a] 589 = -51.4° (1% in CHC13)> MS m/e (%): 470.1 (M+H+, 100),
Example 89
2,2-Dimethyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyi)-6,7-diliydro-5H-dibenxo[b,d]azepin-7-yl]-N'-(2.2.3,3,3-pentafluoro-propyl)-malonamiide
a) 7-Amino-5-(2,212-trifluoro-etfaylV5H7H-diben2o[b>d]azepin-6-one
Racemic(RS)-7-amino-5-(2,2,2-trifluoro-etiyl)-5H,7H-dibenzo[b,d]azepin-6-one
separated by chromatography on Chiralpak AD with isopopanol/heptane 1:3 as solvent
to yield
(S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one
[a] 589 = -29° (1% in CHC13) and
(R)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one.
[a] 589 = +26° (1% in CHC13).
b)fS)-2,2-Dimethvl-N-(S)-6-oxo-5-(2,2,2-trifluoro-ethyl-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide

(S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one was coupled
with 2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the
description example 73 to yield (S)-2,2-dimethyl-N-[(S)--6-oxo-5-(2,2,2-trifluoro-ethyl)-
6,7-dihydro-5H-dibenzo(1,4]azepin-7-yl]--N'-(2,2,3,3,3-pentafluoro-propyi)-malonamide as white solid,
[a] 5S9 = -13.9° (1.1% in CHC13), MS m/e (%): 550.5 (M-H+, 100),
Example 90
(2RS)-2fluoro-2-Methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-
7-yl]-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-
amino-5-methyl-5H,7H-dibenzo[b,d]diazepin-6-one and (2RS)-2-fluoro-2-methyl-N-
(3,3,4,4,4-pentafluoro-butyi)-maIonamic acid yielded the title compound as a white
solid; MS: m/e =502 (M+H)+.
The (2RS)-2-fluoro-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid was
obtained in a reaction sequence analogous to that leading to (2RS)-methyl-N-(2,2,2-
trifluoro-ethyl)-malonamic acid [Example 20 c)] by replacing (2RS)-methyl-malonic
acid monoester by (2RS)-2-fluoro-2-methyl-malonic acid monoester and by replacing
2,2,2-trifluoro-ethylamine by 3,3,4,4,4-pentafluoro-butylamine [J.Fluorine Chemistry
55(1), 85 (1991)].
Examples 91 and 92
(2R)-2-Fluoro-2-metiyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-
yl]-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide and
(2S)-2-FIuoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d]azepin-
yl] -N'- (3,3,4'4,4-pentafluoro-butyl)-malonanmide
The separation of 0.2 g of the two isomers of (2RS)-2-fluoro-2-methyl-N-[(S)-5-methyl-
6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(3,3,4,4,4-pentafluoro-butyl)-
malonamide (Example WG) was performed on a preparative chiral HPLC column
(CHIRALPAK® AD, pressure: flow: 35 ml/min) using a 4:1 mixture of n-heptane and
isopropanol as the eluent There were obtained 23 mg [11% of theory, optical integrity
>99.5% d.eo MS: m/e =502 (M+H)+] of the first efuting isomer (2R)-2-FIuoro-2-methyl-
N-[(S)-5-me1hyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d]azepin-7-yl]-N'-(3,3,4,4,4
pentafluoro-butyl)-malonamide and 22 mg [11% of theory, optical integrity >99.5% d.e.,
MS: m/e =502 (M+H)+] of the later eluting isomer (2S)-2-fluoro-2-methyl-N- [(S)-5-
methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(3,3,4,4,4-pentafluoro-

butyl)-malonamide, each as a yellowish foam.
Example 93
(2RS)-2-Methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'
(3,3,4,4,4-pentafluoro-butyl)-malonamide
In an analogous manner to that described in Example 20 d)> the condensation of (S)-7-
amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2RS)-2-methyl-N-(3,3,4,4,4
pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid;
MS: m/e =484 (M+H)+.
The (2RS)-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid was obtained in a
reaction sequence analogous to that leading to (2RS)-methyl-N-(2,2>2-trifluoro-ethyl)-
malonamic acid [Example 20 c)] by replacing 2,2,2-trifluoro-ethylamine by 3,3,4,4,4-
pentafluoro-butylamine [J.Fluorine Chemistry 55(1), 85 (1991)].
Example 94
2,2-Dmethyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'
(3,3,4,4,4-pentafluoro-butyl)-malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]a2epin-6-onea nd2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid; MS: m/e =498 (M+H)+.
The 2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyi)-malonamic acid was obtained in a reaction sequence analogous to that leading to (2RS)-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid [Example 20 c)] by replacing (2RS)-methyl-malonic acid monoester by 2,2-dimethyl-malonic acid monoester and by replacing 2,2,2-trifluoro-ethylamine by 3,3,4,4,4-pentafluoro-butyiamine.
Example 95
(2RS)-Methyl-N-((3S)-l-methyl-2-oxo-5-trifluorome1tanesulfonyl-2>3,4>5-tetrahydro lH-benzo[b][l,4]diazeini-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 26, the reaction of (2RS)-methyl-
N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-N'_
(2,2,3,3,3-pentafluoro-propyl)-malonamide [Example 25] with trifluoromethanesulfonic
acid anhydride yielded the title compound as a white foam;
MS:m/e=555(M+H)+.

Example 96
N-((3S)-5-Formyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-
(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 26, the acylation of (2RS)-methyl-
N-((3S)-l-methyl-2-oxo-2,3,4,5-teixahydro-lH-benzo(b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide with acetic acid anhydride and formic acid yielded the title compound as a light yellow foam; MS: m/e =451 (M-H)+.
Example 97
N-[(3S)-5-(2-Fluoro-acetyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide
In an analogous manner to that described in Example 26, the acylation of (2RS)-methyl-
N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-N'-
(2,2,3,3 ,3-pentafluoro-propyl)-malonamide with fluoroacetyl chloride yielded the title
compound as a light yellow foam; MS: m/e =483 (M+H)+.
Example 98
(2RS)-Methyl-N-[(3S)-l-methyl-2-oxo-5-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-
benzo[b](l,4]diazepin-3-yl]-N'-(2,2,3,3,3-pentafluoro-propyI)-maIonamide
In an analogous manner to that described in Example 26, the acylation of (2RS)-methyl-
N-((3SH-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide with trifluoroacetic anhydride yielded the title compound as a white foam; MS: m/e =519 (M+H)+.
Example 99
N-[(3S)-5-(2-Methoxy-acetyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 26, the acylation of (2RS)-methyl-N-((3S)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide with methoxyacetyl chloride yielded the title compound as a light yellow foam; MS: m/e =495 (M+H)+.

Example 100
N-[(S)-5-Methanesulfonyl-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H
benzo[b][l,4]diazepin-3-yl)-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a)(S)-3-amino-1(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one and one hydrochloride
In an analogous manner to that described in Example 25 a), the alkylation of (S)~(2-oxo-2,3,4,5-te1xahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acidtert-butyl ester by 2,2,2-trifluoroethyl triflate followed by the acid catalysed deavage of the tert-butoxycarbonyl group yielded the title compound as a yellow solid.
bU2Methyl-N-(S)2-oxo-l-(2,2,2-trmuoro-ethyl)-2,3,4,5-tetrahvdro-lH-
benzo(b)(1,4)diazepin-3-yl1-N'-(2,2,3,3,3-pentafluoro-propyl-malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-
amino-l-(2,2,2-trifluoro-ethyl)-l,,4,5-tetrahydro-benzo[b][l,4]diazepin-2-one
hydrochloride and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid[see
Example 25 b)] yielded the title compound as a white foam;
MS:m/e=491(M+H)+.
c)N-((S)-5-Methanesulfonyl-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H benzo[b)(1,4)diazepin-3-vl-(2RSVmethvl-N'-(2,2,3,3,3-pentafluoro-propvi)-
malonamide
In an analogous manner to that described in Example 26, the reaction of (2RS)-methyl-
N-[(S)-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-
yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide with methanesulfonic acidanhydride
yielded the title compound as an off-white amorphous material;
MS: m/e =567 (M-H)+
Example 101
(2RS)-Methyl-N-[(S)-2-oxo-1-(2,2,2-trifluoro-ethyl)-5-trifluoromethanesulfonyl-
2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yI]-N'-(2,2,3,3,3-pentafluoro-propyI)- malonamide
In an analogous manner to that described in Example 26, the reaction of (2RS)-methyl-
N-[(S)-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-
yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide with trifluoromethanesulfonic acid

anhydride yielded the title compound as an white amorphous material; MS: m/e =623 (M+H)+.
Example 102
c)(2RS)-methyl-N-2-oxo-(2,2,2-trifluoro-acetyl)-1-(2,2,2-trifluoro-ethyl)-2,3,4,5 tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 26, the reaction of (2RS)-methyl-N-((S)-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl
yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide with trifluoroacetic acid anhydride yielded the title compound as a light yellow solid; MS: m/e =587 (M+H)+.
Example 103
(S)-N-(5-Methanesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl)-(2RS)-methyl-N'-(2,2,3,3,3-pentfluoro-propyl)-
malonamide
a)(S)-(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester
The alkylation of the(S)-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4] diazepin-3-yl)-carbamic acid tert-butyl ester with methyliodide, as described in Example 25 a), yielded, after chromatography on silica gel using a 3:l-mixture of n-heptane and ethyl acetate as the eluent, the (S)-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a light yellow foam; MS: m/e =292 (M+H)+.
b) ((S)-5-Methanesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4] diazepin-3-yl)-carbamic acid tert-butyl ester
A mixture of 623 mg (3.4 mmol) of methanesulfomc acid anhydride and 0.12 ml (0.7 mmol) of N-ethyi-diisopropylamine was cooled to 0°C and treated with a solution of 200 mg (0.7 mmol) of (S)-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 2 ml of dichloromethane. The reaction mixture was left to warm to room temperature and stirred during 18h. For the working-up, the reaction mixture was cooled to 0°C and treated with a saturated solution of sodium carbonate. The organic layer was separated, washed with a saturated solution of ammonium hydrochloride and water, finally dried over sodium sulphate and evaporated.

For purification, the crude material was chromatographed on silical gel using a 96:4-mixture of dichloromethane and ethyl acetate as the eluent There were obtained 100 mg (40% of theory) of the ((S)-5-methanesulfonyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbainic acidtert-butyl ester as a white foam; MS:m/e=370(M+H)+.
c) (S)3-Amino-5-methanesulfonyl-1-methyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin 2-one hvdrochloride
A solution of 100 mg (0.27 mmol) of ((S)-5-methanesulfonyi-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 5 ml of dioxane was treated with 0.22 ml of hydrochloric acid and heated in the sealed flask at 50°C for 1 hour. For the working-up, the solvent was evaporated under reduced pressure and the residue submitted to a azeotropic distillation with toluene. After drying under reduced pressure, the (S)-3-amino-5-methanesulfonyl-l-methyl-l,3,4,5-tetrahydro-benzo[b] [l,4]diazepin-2-one hydrochloride was obtained in quantitative yield as a light yellow solid; MS: m/e =270 (M+H)+.
c) (S)3-Amino-5-methanesulfonyl-1-methyl-2,3,4,5-tetrahydro-1H benzo[b][l,4]diazepin-3-yl)-(2RS)methvl-N'-(2,2,3,3,3-pentafluoro-propyl)
malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-
amino-5-methanesulfonyl-l-methyl-l,3,4,5-tetrahydro-benzo[b][l,4]diazepin-2-one
hydrochloride and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see
Example 25 b)] yielded the title compound as a white foam;
MS: m/e =501 (M+H)+.
Example 104
N-[(S)-5-(2,2-Dimethyl-propionyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yi]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide a)((3S)-5-(2,2-Dimethyl-propionyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl-carbamic acidtert-butyl ester
In an analogous manner to that described in Example 103b), the acylation of (S)-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester with pivaloyl chloride yielded the title compound as a white solid; MS: m/e =376 (M+H)+.

b) fS)-3-Amino-5-(2,2-dimethyl-propionyl)-l-methyl-1,3,4,5-tetrahydro-
benzo(b)(1,4)diazepin-2-one hvdrochloride
In an analogous manner to that described in Example 103c), the cleavage of the tert-
butoxy-carbonyl group of the [(3S)-5-(2,2-dimethyl-propionyl)-l-methyl-2-oxo-2,3,4,5'
tetrahydro-lH-benzo[b] [l,4)diazepin-3-yl)-carbamic acid tert-butyl ester yielded the
title compound as a white solid;
MS: m/e =276 (M+H)+.
N-((S)-5-(2,2-dimethyl-propinyl)-I-methyl-2-oxo-2,3,4,5-tetrahydro-1H
benzo[b](1,4)diazepin-3-yl1-N'-(2,2,3,3,3-pentafluoro-propYlVmalonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-
amino-5-(2,2-dimeythyl-propionyl)-1-methyl-1,3,4,5-tetrahydro-benzo(b))(1,4)
2-one hydrochloride and N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the
title compound as a white foam;
MS: m/e =493 (M+H)+.
The N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid was obtained in a reaction
sequence analogous to that leading to (2RS)-methyl-N-(2,2,2"trifluoro-ethyl)-malonamic acid [Example 20 c)] by replacing (2RS)-methyl-malonic add monoester by malonic acid monoester.
Example 105
N-((S)-5-(2,2-dimethyl-propinyl)-I-methyl-2-oxo-2,3,4,5-tetrahydro-1H benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-
amino-5-(2,2-dime1hyl-propionyl)-l-methyl-l,3,4,5-tetrahydro-benzo[b3[l,4]
2-one hydrochloride and {2RS)-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid
[Example 20 c)] yielded the title compound as a white foam; MS: m/e =507 (M-hH)+.
Example 106
5-Methyl-4-oxo- (3S)- [ (2RS)- (2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionylamino]-2,3,4,5-tetrahydro-benzo[b] [l,4]diazepine-l-carboxylic acid
cyclopropylmethyl estermalonamide
a) (S)-3-tert-Butoxycarbonvlainino-5-methyl-4-oxo-2,3,4,5-tetrahydro-
benzo(b) [1,4) diazepine-1-carboxylic acid cyclopropvlmethyl ester

A solution of 350 mg (1.2 mmol) of (S)-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester [Example 103a) in 10 ml of N,N-dimethylformamide was treated successively with about 1 g of solid carbon dioxide, 237 mg (1.7 mmol) of bromomethyl-cyclopropane, and 626 mg (1.9 mmol) of cesium carbonate. The reaction mixture was stirred in a sealed flask at 80°C during the weekend For the working-up, the solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of 30 ml of ethyl acetate and 10 ml of water. The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure. For the purification, the crude compound was chromatographed on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent There were obtained 410 mg (87% of theory) of the (S)-3-tert-butoxycarbonylamino-5-methyl-4-oxo-2>3J4,5-tetrahydro-benzo[b] [l,4)diazepine-l-carboxylic acid cyclopropylmethyl ester as a white gum; MS: m/e =579 (M+OAc)+.
(S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-1-carboxylic
acid cyclopropylmethyl ester hydrochloride
In an analogous manner to that described in Example 103c), the cleavage of the tert-
butoxy-carbonyl group of the (S)-3-tert-butoxycarbonylamino-5-methyl-4-oxo-2,3,4,5-
tetrahydro-benzo(b)(1,4) diazepine-l-carboxylic acid cyclopropylmethyl ester yielded the
title compound as a light yellow foam.
c)5-Methyl-4-oxo-(3S)[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyI)-propionvlamino)-2,3,4,5-tetrahydro-benzo(b)(l,4)diazepine-l-carboxylic acid cyclopropylmethyl estermalonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepine- 1-carboxylic acid cyclopropylmethyl ester hydrochloride and (2RS)-methyl-N-(2,2,2-trifluoro-ethyl)-inalonamic acid [Example 20 c)] yielded the title compound as a white solid; MS: m/e =579 (M+OAc)+.
Example 107
N-((S)-5-acetyl-2-oxo-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo [b] [ 1,4] diazepin-3-yl]-2-methyl-N'-2,2,3,3,3-pentafluoro-propyl)-malonamide
((S)-2-oxo-1-(2,2,2-triflouo-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl yl)-carbamic acid tert-butyl ester

In an analogous manner to that described in Example 25 a), the allegation of the {S)-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [1,4] diazepin-3-yl)-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl triflate, yielded, after chromatography on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent, the title compound as a white solid; MS: m/e =360 (M+H)+.
b) [(S)-5-Acetyl-2-oxo-l-(2,2,2-trifluoro-ethvl-2,3,4,5-tetrahydro-lH-
benzo(b) (l,4)diazepin-3-yl)-carbamic acid tert-butvi ester
In an analogous manner to that described in Example 103b, the acylation of the [{S)-2-
oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-
carbamic acid tert-butyl ester with acetic acid anhydride yielded the title compound as a
white solid;
MS: m/e =419 (M+NH4)+.
c) (S)-5-Acetyl-3-amino-l-(2,2,2-trifluoro-ethyl)-l,3,4,5-tetrahydro-
benzo(b) (l,4)diazepin-2-one hydrochloride
In an analogous manner to that described in Example 103c, the cleavage of the tert-butoxycarbonyl group of the [(S)-5-acetyl-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-lH-benzo[b][l,4]dia2epin-3-yl]-carbamic acid tert-butyl ester by hydrochloric acid yielded the title compound as a light yellow solid; MS: m/e =302 (M+H)+.
d)N4(S)-5-Acetyl-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-lH-
benzo(b)(1,4)diazepin-3-yl)-(2RS)-methvl-N'-(2,2333-pentafluoro-propyl)-
malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-5-
acetyl-3-amino-l-(2,2,2-trifluoro-ethyl)-l,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one
hydrochloride and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see
Example 25 b)] yielded the title compound as a white solid; MS: m/e =533 (M-J-H)+-
Example 108
N-[(S)-5-Cyclopropanecarbonyl-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H
benzo[b] [l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide a) [(S)-5-Cyclopropanecarbonyl-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahvdro-lH-benzofbl [l,4]diazepin-3-yl) -carbamic acid tert-butyl ester

In an analogous manner to that described in Example 103b> the acylation of the [(S)-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl) carbamic acid tert-butyl ester [Example 107b] with cyclopropane-carbonyl chloride yielded the title compound as a yellow solid; MS: m/e =428 (M+H)+.
b)(S)-3-Amino-5-cyclopropanecarbonyl-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro
benzo(b)(1,4) diazepin-2-one hvdrochloride
In an analogous manner to that described in Example 103c, the cleavage of the tert-
butoxycarbonyl group of the [(S)-5-cydopropanecarbonyl-2-oxo-l-(2,2,2-trifluoro-
ethyl)-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)carbamic acid tert-butyl ester
by hydrochloric add yielded the title compound as a yellow solid; MS: m/e =328
(M+H)+.
c)N-(S)-5-cyclopropanecarbonyl-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro
lH-benzo(b)(1,4)diazepin-3-y1)-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyI)-
malonamide
In an analogous manner to that described in Example 20 d), the condensation of (S)-5-
acetyl-3-arnmo-l-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one
hydrochloride and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see
Example 25 b)] yielded the title compound as a white solid;
MS: rn/e =559 (M+H)+.
Example 109
4-Oxo-(3S)-[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionyiamino]-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b] [l,4]diazepine-l-carboxylic acid cyclopropylmethyl ester
a) (SV3-tert-Butoxycarbonylamino-4-oxo-5-(2,2,2-tifluoro-ethylV2,3,4,5
benzo(b) ( l,4]diazepine-l-carboxylic acid cyclopropylmethyl ester
In an analogous manner to that described in Example 106a, the reaction of [(S)-2-oxo-l-
(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-carbamic acid
tert-butyl ester [Example 107b] with carbon dioxide and bromomethyl-cydopropane in
presence of cesium carbonate yielded the title compound as a white foam; MS: m/e =475
(M+NH4)+.
b)(S)-3-Amino-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo(b)(1 4)diazepine-l-carboxylic acid cydopropvlmethyl ester hydrochloride

In an analogous manner to that described in Example 103c, the cleavage of the tert-butoxycarbonyl group of the (S)-3-tert-butoxycarbonyiamino-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b] [l,4]diazepine-l-carboxylic acid cyclopropylmethyl ester by hydrochloric acid yielded the title compound as a yellowish foam which was engaged in the next step without further purification and characterisation.
c) 4-oxo-(3SV[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamovlVpropionyl)amino)-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahvdro-ben2of(b)(1,4)diazepine-l-carboxylic acid cyclopropylmethyl ester
In an analogous manner to that described in Example 20 d), the condensation of the (S)-3-Amino-4-oxo-5-(2,2,2-trifluoro-ethyi)-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepine-1-carboxylic acid cyclopropylmethyl ester hydrochloride and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a light yellow solid; MS: m/e =647 (M+OAc)+.
Example 110
-(2RS)-N-((S)-acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2,2 yl]-2-fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-inalonainide
N-((S)-acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-carbamic acid tert-butyl ester
In an analogous manner to that described in Example 103b, the acylation of (S)-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [1,4] diazepin-3-yl)-carbamic acid tert-butyl ester [Example 103a) with acetic acid anhydride yielded the title compound as a white solid; MS: m/e =334 (M+H)+.
b)(S)-5-Acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one hydrochloride
In an analogous manner to that described in Example 103c, the cleavage of the tert-butoxy-carbonyl group of the [(S)-5-acetyl-l-methyl-2-oxo-2,3>4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl]-carbamic add tert-butyl ester yielded the title compound as a light yellow solid; MS: m/e =234 (M+H)+.
c)(2RS)-N-((S)-5-Acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin 3-yl-2-fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide

In an analogous manner to that described in Example 20 d), the condensation of (S)o-(S)-5-acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one and
and 2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white foam; MS: m/e =483 (M+H)+.
The (2RS)-2-fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid was obtained in a reaction sequence analogous to that leading to (2RS)-methyl-N-(2,2,2-txifluoro-ethyl)-malonamic acid [Example 20 c)] by replacing (2RS)-methyl-malonic acid monoester by (2RS)-2-fluoro-2-methyl-malonic acid monoester.
Example 111
N-((S)-acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2,2 dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) (S)-l-Acetyl-4-oxo-2,3,4,5-tetrahvdro-lH-benzo (b)[l,4)diazepin-3-yl)-carbamic acid
tert-butyl ester
In an analogous manner to that described in Example 52 a), the acetylation of (S)-(2-
oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4] diazepin-3-yl)-carbamic acid tert-butyl ester
with acetic acid anhydride yielded the title compound as a grey solid; MS: m/e =320
(M+H)+.
b)(S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one and
In an analogous manner to that described in Example 25 a), the alkylation of the (S)-l-acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester with ethyl iodide, followed by the acid catalysed cleavage of the tert-butoxycarbonyl group yielded the title compound as a yellowish waxy solid [MS: m/e =248 (M+H)+] which was engaged in the next step without further purification.
N-((S)-acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2,2 2,2-dimethvl-N'-(2,2,3,33-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-l-ethyl-l,3,4,5-tetrahydro-benzo[b] [l,4]diazepin-2-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid; MS: m/e =493 (M+H)+

Example 112
N-((S)-5-Acetyl-1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl (2RS)-methyl-N'(2,2,3,3,3-pentafluoro-propyl)-malonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one and
(2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)"malonamic add [see Example 25 b)] yielded the title compound as a white solid; MS: m/e =479 (M+H)+.
Example 113
N-((S)-5-Acetyl-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl (2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
a) (S)-5-Acetyl-3-amino-l-isopropyl-1,3,4,5-tetrahydro-benzo[b)(1,4)diazepin-2-one In an analogous manner to that described in Example 25 a), the alkylation of the (S)-l-acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester with 2-iodo-propane, followed by the acid catalysed cleavage of the tert-butoxycarbonyl group yielded the title compound as a yellowish waxy solid [MS: m/e =262 (M+H)+] which was engaged in the next step without further purification.
N-((S)-5-Acetyl-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl
vll-(2RSVmethvl-N'-(2,2,3,3,3-pentafluoro-propvlVmalonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-l-isopropyl-l,3,4,5-tetrahydro-benzo[b][l,4]diazepin-2-oneand (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e =493 (M+-H)+.
Example 114
N-((S)-acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2,2
dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl-malonamide
a) (S)-5-Acetyl-3-amino-l-benzyl-13,4,5-tetrahvdro-benzo[b)[l,4)diazepin-2-one In an analogous manner to that described in Example 25 a), the alkylation of the (S)-l-acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-butyl ester with benzylbromide, followed by the acid catalysed cleavage of the tert-butoxycarbonyl group yielded the title compound as a light yellow solid [MS: m/e =310 (M+H)+] which was engaged in the next step without further

purification.
b)N-[(S)-l-Acetyl-1-benzyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)
2,2-dimethyl-N'-(2,2,3,3,3-pentafluoro-propvl)-maIonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of
(S)-5-acetyl-3-amino-1-benzyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-2-one and 2,2-
dnnethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded
the title compound as a white solid; MS: m/e =553 (M-H)'.
Example 115
N-((S)-5-Acetyi-l-ben2yl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl) (2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-maIonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-l-benzyi-1,3,4,5-te1xahydro-benzo[b][l,4]dia2epin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e =539 (M-H)',
Example 116
N-[(S)-5-Acetyl-l-(4-fluoro-benzyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-2,2-dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonanmide
a)(S)-5-Acetyl-3-amino-(4-fluoro-benzyl-1,3,4,5-tetrahydro-benzo(b)(1,4)diazepin
In an analogous manner to that described in Example 25 a), the alkylation of the (S)-l-
acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)-carbamic acid tert-
butyl ester with 4-fluoro-benzyibromide, followed by the acid catalysed cleavage of the
tert-butoxycarbonyl group yielded the title compound as a white foam
[MS: m/e =328 (M+H)+] which was engaged in the next step without further
purification.
blN4(SV5'Acetvl-l-(4-fluoro-benzvl-2-oxO"2,3,4,5-tetrahydro-lH-
benzo[b)(1,4)diazepin-3-yl)-2,2-dimethvl-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of
(S)-5-acetyl-3-ambo-l-(4-fluoro-benzyl-l,3,4,5-tetrahydro-benzon(b)][l,4]diazepin-2-
one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25

b)] yielded the title compound as a white solid; MS: m/e =571 (M-H)Example 117
N-((S)-5-Acet7l-l-(4-fluoro-benzyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl)-(2RS)-niethyl-N'-(2,2,3,3,3-peritafluoro-propyl)-
malonamide
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S) -5-acetyl-3-amino-1 -(4-fluoro-benzyi-13,4,5-tetrahydro-benzo [b] [ 1,4] diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e =557 (M-H)-.
Examples 118 and 119
N-[(S)-l-Acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-(2Ror 2S) methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide and
N-[(S)-l-Acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-(2S or 2R)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
The separation of 0.2 g of the two isomers of N-[(S)-l-acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,3,3,3-pentafluoro-propyl)-malonamide (Example 52) was performed on a preparative chiral HPLC column (CHIRALPAK® AD, pressure: 15 bar, flow: 35 ml/min) using a 4:1 mixture of n-heptane and isopropanol as the eluent There were obtained 77 mg [35% of theory, optical integrity ,99.5% d.e. MS: m/e =449 (M-H)*] of the first eluting isomer (+)-N-[(S)-l-acetyl-4-oxo-2,3,4,5-tetrahydro-lH-benzo[b3 [l,4]diazepin-3-yl]-(2R or 2S)-methyl-N!-(2,2,3,3,3-pentafluoro-propyl)-malonamide and 77 mg [35% of theory, optical integrity 99.4% d.e., MS: m/e =449 (M-H)~] of the later eluting isomer (-)-N-[(S)-l-acetyi-4-oxo-2,3,4,5-te1xahydro-lH-benzo[b][14]diazepin-3-yl]-(2Sor2R)-metiyl-NI-(2,2,3,3,3 pentafluoro-propyl)-malonamide, each as a white solid.
Examples 120 and 121
N-[(S)-5-Acetyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-(2R-
or 2S)-methyl-N'-(2,2'3'3,3-pentafluoro-propyl)-malonamide and
N-[ (S)-S-Acetyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-(2R-or 2R)-methyl-N'-(2,,3,3,3-pentafluoro-propyl)-malonamide

The separation of 0.6 g of the two isomers of N-[(S,-5-acefyl-l-methyl-2-oxo-2,3,4,5--
tetxahydro-lH-benzo[b][l,4]diazepin-3-yl,-(2RS,-methyl-N'-(2,2,3,3,3-pentafluoro
propyl,-malonamide (Example 40, was performed on a preparative chiral HPLC column
(CHIRALPAK® AD, pressure: 15 bar, flow: 35 ml/min, using a 4:1 mixture of n-heptane
and isopropanol as the eluent There were obtained 220 mg (36.7% of theory, optical
integrity ,99.5% d.e., of the first eluting isomer (+,-N-[(S,-5-acetyl-l-methyl-2-oxo-
23A5-tetrahy pentafluoro-propyl,-malonamide and 247 mg (41.2% of theory, optical integrity ,99.5%
d.e., of the later eluting isomer (-,-N-[(S,-5-acetyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-
lH-benzo[b] [l,4]diazepin-3-yl]-(2S or 2R,-methyl-N'-(2,3,3,3-pentafauoro-propyl,-
malonamide, each as a white solid.
In analogy to the described examples the following compounds have been prepared:
Example 122
2,2-Dimethyl-N-((S,-6-oxo-6,7-dihydro-5H-dibenzo(b,d,azepin-7-yl,-N'-(2,2,3,3,3 pentafluoro-butyl,-malonamide, MS: m/e (%, = 484.5 (M+H,+, 100.
Example 123
(R,-2-Fluoro-2-methyl-N-((S,-6-oxo-6J-dihydro-5H-dibenzo[b5d]azepin-7-yl,-N!-(3,3,4,4,4-pentafluoro-butyl,-malonamide
Example 124 (3,3,4,4,4-pentafluoro-butyl,-carbamicacid(S,-l-((S,-6-oxo-6,7-dihydro-5H-
dibenzo [b,d] azepin-7-ylcarbamoyl,-ethyl ester MS: m/e (%, = 488.5 (M+H,+, 100.
Example 125 (R,-2-Fluoro-2-methyl-N-((S,-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-
yl,-N'-(3,3,3-trifluoro-propyi,-malonamide
The title compound [MS m/e (%,: 452.3 (M+H+,, 100,]was prepared in analogy to example 14 from 3,3,3-trifluoropropylamine and (2S,-2-fluoro-2-methyl-N-((S,-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl,-malonamicadd.


Claims 1. Compounds of the general formula

wherein
R1 is one of the following groups

R is lower alkyl, lower alkinyl, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower allkyl -(CH2)n-CN, -(CR'R")nCF3 -(CR'R")nCHF2 -(CR'R")n-CH2F, -(CH2)n-C(0)0-lower alkyl, -(CH2)n-halogen, or is -(CH2)n-cycloalkyl, optionally substituted by one or more substituents, selected from the group consisting of phenyl, halogen or CF3;
R',R" are independently from n and from each other hydrogen, lower alkyl, lower allcoxy, halogen or hydroxy;
R3, R4 are independently from each other hydrogen, lower alkyl, lower alkoxy, phenyl or halogen;
R5 is hydrogen, lower alkyl, -(CH2)n-CF3 or -(CH2)n-cycloalkyl; R° is hydrogen or halogen;

R7 is hydrogen or lower alkyl;
R8 is hydrogen, lower alkyl, lower allkinyl, -(CH2)n-CF3, (CH2)n-cycloalkyl or -(CH2)n-phenyl, optionally substituted by halogen;
R9 is hydrogen, lower alkyl, -C(O)H, -C(O)-lower alkyl, -C(O)-CF3, -C(O)-CH2F, -C(O)-CHF2, -C(O)-cycloalkyl, -C(0)-(CH2)n-O-lower alkyl, -C(0)0-(CH2)n-cycloaIkyl, -C(O)-phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen or -C(O)O-lower alkyl, or is -S(O)2-lower alkyl, -S(O)2-CF3) -(CH2)n-cyclo alkyl or is -(CH2)n- phenyl, optionally substituted by halogen;
n is 0,1,2,3 or 4;
and to pharmaceutically suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof.
2. Compounds of the general formula
wherein
R1 is one of the following groups

R2 is lower alkyl, lower alkinyl, -(CH2)n-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-CN, -(CR'R")n-CPs, -(CR'R")n-CHF2, -(CH2)n-C(O)O-lower alkyl,

-(CH2)n-halogen, or is -(CH2)D-cydoalkyl, optionally substituted by one or more substituents, selected from the group consisting of phenyl, halogen or CF3;
R',R" are independently from n and from each other hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy;
R, R are independently from each other hydrogen, lower alkyl, phenyl or halogen;
R5 is lower alkyl or -(CH)2-cycIoalkyl;
R is hydrogen or halogen;
R is hydrogen or lower alkyl;
R8 is hydrogen, lower alkyl, lower alkinyl or -(CH)2-cycloalkyl;
► R9 is hydrogen, lower alkyl, -C(O)-lower alkyl, -C(O)4ower cycloalkyl,
-(CH2)n-cycloalkyl, phenyl, -C(O)-phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen or -C(O)O-lower alkyl, or is (CH)2-phenyl, optionally substituted by halogen;
n is 0,1,2,3 or 4;
and pharmaceutically suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof.
3. Compounds of formula I in accordance with claim 1, wherein R1 is a).
4. Compounds of formula I in accordance with claim 3, wherein R is
-(CH2)n-cycloalkyl, optionally substituted by CF3.
5. Compounds of formula I in accordance with claim 4, wherein the compounds
are

N-cyclopropylmetkyl-2-methyl-N'(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonanude or 2-fluoro-2-metliyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(1-trifluoromethyl-cyclopropylmethyl)-malonamide.
6. Compounds of formula I in accordance with, daim 2, wherein R2 is lower alkyl,
-(CH2)n-O-lower alkyl or -(CH2)n-S-lower alkyl.
7. Compounds of formula I in accordance with claim 6, wherein the compounds
are
2-methyI-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl)-N'-(2-
methoxyethyl-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2-
methylthioethyl) -malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3-
methoxy-propyl)-malonamide,
2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yi)-N'-propyl-
malonamide or
2-fluoro-2-methyl-N-(3-methyl-butyl)-N'-(5-methyl-6-oxo-6,7-dihydro-5H-
dibenzo[b,d] azepin-7-yl)-malonamide.
8. Compounds of formula I in accordance with claim 2, wherein R is
-(CR'R")n-CF3 or -(CR'R")n-CHF2.
9. Compounds of formula I in accordance with claim 8, wherein the compounds
are 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,2-
trifluoroethyl)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-(3,3,3-
trifluoro-propyl)-malonarnide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yI)-N'-
(2,2,2-trifluoro-ethyl)-malonamide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d] azepin-7-yl)-N]'
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
2-fluoro-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(3,3,4,4-tetrafluoro-butyl)-malonamide,

2-fluoro-2-methyI-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-
(4,4,4-trifluoro-butyl)-malonamide,
2-methyl-N-(5-methyl-6-oxo-6,7-dihydro(b,d)azepin-7-yl)-N'-(4,4,4-
trifluoro-3-methoxy-butyyl-malonamide,
2-fluoro-2-methyI-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-
(3,3,4,4-tetrafluoro-butyl-malonamide,
N-(5-cydopropylmethyl-6-oxo-6,7-dihydro-5-5H-dibenzo[b,d]azepin-7-yl)-N-
(2,2,3,3,3-pentafluoro-propyl-malonamide,
2-methyl-N-(6-oxo-6,7-dihydro-5H-benzo[b,d]azepin-7-yl)-N'-(2,2,3,3 pentafluoro-propyl-malonamide,
N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,2,3,3,3-pentafluoro-
propyl-malonamide,
2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2
pentafluoro-propyl)-malonamide,
(-)-2-methoxy-N-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'--(2,2,3,3,3-
pentafluoro-propyl)-malonamide,
(2R)-2-fluoro-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl-malonamide,
(2S)-2-fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydxo-5H-dibenzo[b,d]azepin-7-yl)-2
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo|b,d]azepin-7-yl)-2,2-
dimethyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo|b,d]azepin-7-yl)-2-
fluoro-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-cyclopropylmetiiyl-6-oxo-6,7-diliydro-5H-dibenzo[b,d]azepin-7-yl)-2-
methoxy-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d)azepin-7-yl)-N'-
(3,3,4,4,4-pentafluoro-butyl)-malonamide,
N-((S)-5-cydopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-
N'-3,3,4,4,4-pentafluoro-butyl)-malonamide,
N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-

dimethyl-N'3,3,4,4,4-pentafluoro-butyl-malonamide,
(R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-2-
fluoro-2-methyl-N'-(3,3,4,4,4-pentafluoro-butyl)-malonamide,
N-(5-isopropyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-2-N'-(2,2,3,3,3-
pentafluoro-propyl)-malonamide,
N- (5-isopropyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d] azepin-7-yl -2,2-dimethyl-N' -
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-(5-isopropyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-2-N'-(2,2,3,3,3-
pentafluoro-propyl)-malonamide,
2,2-dimethyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2R)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-
yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2S)-2-fluoro-2-methyl-N-[(S)-5-methy-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-
yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
2-methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydxo-5H-dibenzo[b,d]azepin-7-yl)-N'-
(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(3,3,4,4,4-
pentafluoro-butyl)-malonamide or
2,2-dimethyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-
dibenzo[bJd]azepin-7-yi]-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide.
10. Compounds of formula I in accordance with claim 1, wherein R1 is b).
11. Compounds of formula I in accordance with daim 10, wherein the compound
is
2-methyl-N-(3-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[d]azepin-l-yl)-N'-(2,2,2-
trifluoro-ethyl)-malonamide.
12. Compounds of formula I in accordance with claim 1, wherein R1 is c).
13. Compounds of formula I in accordance with claim 12, wherein R is
-(CR'R")n-CF3.
14. Compounds of formula I in accordance with claim 13, wherein the
compounds are
2-methyl-N-(l-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yI)-N'-(2,2,2-trifluoro-ethyl)-malonamide,

N-((3S)-5--benzyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-
2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-[(3S)-5-(4-fluoro-benzoyi)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H
benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide
N-[(3S)-5-(4-chloro-benzoyl-l-methyl-2-oxo-2,3,4,5-tetrahydro-1H
benzo [b] [ 1,4] diazepin-3-yl] -2-methyl-N'-(2,2,3,3,3-pentafluoro-propyl) -malonamide,
N-[(3S)-5-(3,5-difluoro-benzoyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo|^][l)4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentefluoro-propyl)-malonamide,
4-{(3S)-5-methyl-4-oxo-3-[2-(2>23,3)3-pentafluoro-propyicarbamoyi)-
propionyiamino]-2,3,4,5-tetrahydro-benzo(b)(1,4)diazepin-1-carbonyl)-benzoic acid
methyl ester,
N-((3S)-5-acetyl-l-methyl-2-oxo-2,3,4,5-te1xahydro-lH-benzo[b][l,4]diazepin-3-yl)-2-
methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
N-[5-((3S)-4-fluoro-benzyI)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafluoro-propyi)-malonam
N-[(3S)-5-(4-chloro-benzoyl)-l-cyclopropylmethyl-2-oxo-23,43-tetrahydro-lH-
benzo(b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2333-pentafluoro-propyl)-malonamide,
(2RS)-methyl-N-((3S)-l-methyl-2-oxo-5-trifluoromethanesulfonyl-2,3,4,5-tetrahydro-
lH-benzo[b][l,4]diazepin-3-yl)-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(2RS)-methyl-N-[(3S)-l-methyl-2-oxo-5-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H
benzo[b][l,4]diazepin-3-yl]-N'-(2,2,3,3,3-pentafuoro-propyl)-rnalonamide,
N-[(3S)-5-(2-methoxy-acetyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-1Hb
benzo|b][l,4]diazepin-3-yl]-(2RS)-methyl-lSr-(2,2,3,3,3-pentafluoro-propyl)-
malonamide,
N-[(S)-5-methanesdfonyl-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide,
(2RS)-methyl-N-[(S)-2-oxo-l-(2,2,2-trifluoro-ethyl)-5-trifluoromethanesulfonyl
2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl]-N'-(2,2,3,3,3-pentafluoro-propyl)-
malonamide,
5-methyl-4-oxo-(3S)-[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-
propionylamino]-2,3,4,5-tetrahydro-benzo[b] [l,4)diazepine-l-carboxylic acid
cydopropylmethyl estermalonamide,
N-[(S)-5-cyclopropanecarbonyl-2-oxo-l-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-lH-
benzo[b][l,4]diazepin-3-yl]-2-methyl-N'-(2,2,3,3,3-pentafuoro-propyl)-malonarm

4-oxo-(3S)-[(2RS)-(2,2,3,3,3-pentafluoro-propylcarbamoyi)-propionylamino]-5-(2,2,2, trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b] [l,4]diazepine-l-cafboxylic acid cydopropylmethyl ester,
N-[(S)-5-acetyi-l-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin (2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyI)-malonamide or
N-((S)-5-acetyl-l-benzyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-(2RS)-methyl-N'-(2,2,3,3,3-pentafluoro-propyl)-malonamide.
15. Compounds of formula I in accordance with claim 1, wherein R1 is d).
16. Compounds of formula I in accordance with claim 15, wherein the compounds
are
2-methyl-N-(ll-oxo-10,11-dihydro-dibenzo)[b,f]oxepin-10-yl)-N'-(2,2,2-trifluoro-ethyl)-malonamide or
l-methyl-N-(ll-oxo-10,11-dihydro-dibenzo(b,f)oxepin-10-yl)-N'-2,2,3,3,3-pentafluoro-propyl)-malonamide.
17. A process for preparing a compound of formula I as defined in claims
1-16, which process comprises
a) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein R1 - R4 have the meaning as described above, and

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
. 18. A compound according to any on of claims 1 — 16, whenever prepared by a process as claimed in claim 14 or by an equivalent method.
19. A medicament containing one or more compounds as claimed in any one of
claims 1-16 and pharmaceutically acceptable excipients.
20. A medicament according to claim 19 for the treatment of Alzheimer's disease.
21. The use of a compound in any one of claims 1-16 for the manufacture of
medicaments for the treatment of Alzheimer's disease.
22. The invention as hereinbefore described.
***
Dated this 7 day of March 2006



































Radiation-sensitive composition
The invention relates to a low-odor, radiation-sensitive composition composed of a binder and radiation-sensitive polymers, a process for preparation thereof, and the use thereof as low-5 volatility photoinitiator.
Radiation-curable coating materials have increasingly gained an importance within recent years, on account of the low VOC (volatile organic compounds) content of these systems. The film-forming components in the coating material are of relatively low molecular mass and
10 hence of low viscosity, so that there is no need for high fractions of organic solvents. Durable coatings are obtained by the formation, following application of the coating material, of a high molecular mass, polymeric network by means of crosslinking reactions initiated, for example, by UV light or electron beams. Formation of the network results in volume contraction, which is said in the literature to be a reason for the sometimes poor adhesion of radiation-curable
15 coating materials to different substrates [Surface Coatings International Part A, 2003/06, pp. 221-228].
The film-forming components are generally binders composed of polymers containing unsaturated moieties. A review article of the various polymers commonly employed today 20 appears in Ink World, July 2003, p. 14 f.
The binders crosslink, for example, by a radical or cationic mechanism. This reaction is initiated by UV light, by virtue of the presence of photosensitive compounds, known as photoinitiators, accompanied where appropriate by photosensitizers, which breakdown into free 25 radicals.
The photoinitiators commonly used today may come, for example, from the group of the benzophenones, ot-hydroxy ketones, a-amino ketones, monoacylphosphine oxides or bisacyl ketones. Relevant literature includes, for example, Journal of Coatings Technology, Vol. 65, 30 No. 819, April 1993, p. 49 ff., Surface Coatings International, 1999 (7), p. 344 ff., and Farbe und Lack, 7/97, p. 28 ff.

Radiation-sensitive compounds which may contain, where appropriate, an acetophenone submoiety, and polymeric derivatives containing acetophenone moieties, are described in EP 0 346 788, EP 0 377 199 and DE 102 06 987.
5 EP 0 346 788 describes ethylenically unsaturated, copolymerizable, radiation-sensitive organic compounds which carry at least one (meth)acrylic ester group. EP 0 377 199 describes UV-crosslinkable compositions based on (meth)acrylic ester copolymers.
Ester moieties are not stable to hydrolysis, and so there is a process of polymer degradation 10 which is promoted by hot, moist ambient conditions, especially in the presence of acidic or basic compounds.
The vinyl ether derivatives that are described in DE 102 06 987 can form hydroperoxides with atmospheric oxygen, and these hydroperoxides may then initiate unwanted premature 15 polymerization and lead to aging of the crosslinked polymers. The acid environment, moreover, does not assure stability.
Ketone-aldehyde resins are used in coating materials as, for example, unhydrolyzable additive resins, in order to enhance certain properties such as gloss, hardness or scratch resistance. On 20 account of their relatively low molecular weight customary ketone-aldehyde resins possess a low melt viscosity and solution viscosity and hence one of their uses in coating materials is as film-forming functional fillers.
Ketone-aldehyde resins normally possess hydroxyl groups and can therefore be crosslinked 25 only with, for example, polyisocyanates or amine resins. These crosslinking reactions are usually initiated and/or accelerated thermally.
Customary ketone-aldehyde resins are not suited to radiation-initiated crosslinking reactions in accordance with cationic and/or radical reaction mechanisms.
30 For this reason the ketone-aldehyde resins are usually used in radiation-curable coating systems as, for example, an additive film-forming component, but not as an additive crosslinking

component. Owing to the uncrosslinked fractions, coatings of this kind often possess poor resistance with respect, for example, to gasoline and other chemicals or solvents.
DE 23 45 624, EP 736 074, DE 28 47 796, DD 24 0318, DE 24 38 724 and JP 09143396 5 describe the use of ketone-aldehyde resins and ketone resins, e.g., cyclohexanone-formaldehyde resins, in radiation-curable systems. Radiation-induced crosslinking reactions of these resins are not described. Ketone-formaldehyde resins as photoinitiators are also not described.
The polymer-analogous reaction of cyclohexanone-formaldehyde resins with azo compounds is 10 described in Die Angewandte Makromolekulare Chemie, 168 (1989), p. 129 ff. The process is complicated for the industrial scale. Since azo compounds are used the preparation entails high safety impositions. Azo compounds, moreover, are thermally labile, and hence storage is complicated.
15 Journal of Applied Polymer Science, Vol.72 (1999), p. 927 ff. describes cyclohexanone-formaldehyde and acetophenone-formaldehyde resins which become photoactive by virtue of the attachment of 10 mol% of benzoin or benzoin butyl ethers. The synthesis is complicated, since it takes place over two stages which last more than 16 hours. There is no assurance of full conversion, and so volatile constituents may be present. Moreover, low molecular mass
20 fractions reduce the performance profile of high-grade coatings with respect to their mechanical properties.
It was an object of the present invention to prepare a radiation-sensitive composition comprising a binder component and low-odor, radiation-sensitive polymers which are suitable
25 as polymeric photoinitiators and possess a low volatility, are widely compatible with different raw materials and easy to incorporate, a process for preparing them, and their use for initiating the UV-light-induced, free-radical crosslinking reaction of coating materials, adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants. A further object was, through the use of these radiation-sensitive
30 polymers, to enhance the gloss, solvent and chemical resistance, and hardness of these systems.

Surprisingly it has proven possible to achieve this object, in accordance with the claims, through the provision of the radiation-sensitive composition of the invention, by preparing and using polymeric reaction products from aldehydes of the general formula I and ketones of the general formula E, with the use of further ketones if desired, in coating materials or adhesives, 5 for example.

10 where R = H, branched or unbranched alkyl radical having 1 to 12 carbon atoms, or aryl radical,
15
where Ri = unbranched alkyl radical having 1 to 12 carbon atoms and

25 where R3 to R7 = H, alkyl, OCH3, OC2H5, Cl, F, COCXQ-C3 alkyl). Additionally it is possible for R4 to R6 to be OH and/or SH.
The invention accordingly provides low-odor, radiation-sensitive, polymeric reaction products essentially comprising 30 the reaction product of
A) aldehydes of the general formula I


5 where R = H, branched or unbranched alkyl radical having 1 to 12 carbon atoms or aryl radical
and
B) at least one ketone of the general formula II

where Ri = unbranched alkyl radical having 1 to 12 carbon atoms

where the radicals R3 to R7 are H, alkyl, OCH3, OC2H5, Cl, F, COO(d^C3 alkyl), and R4 to Re are additionally OH and/or SH
25
and
C) if desired, a further, CH-acidic ketone
for use as polymeric photoinitiators of low volatility in radiation-curing coating materials, 30 adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants.

Aldehydes suitable as aldehyde component A) according to formula I include in principle branched or unbranched aldehydes, such as formaldehyde, benzaldehyde, acetaldehyde, n-butyraldehyde and/or iso-butyraldehyde, valeraldehyde and also dodecanal, for example. Generally speaking it is possible to use any of the aldehydes said in the literature to be suitable 5 for ketone-aldehyde resin syntheses. Preference is given, however, to using formaldehyde and benzaldehyde alone or in mixtures.
The required formaldehyde is normally used in the form of an approximately 20% to 40% strength by weight aqueous or alcoholic (e.g., methanolic or butanolic) solution. Other use 10 forms of formaldehyde, such as the use of para-formaldehyde or else trioxane, for example, are likewise possible.
Examples of ketones B) according to formula II include acetophenone and its ring-substituted derivatives, such as hydroxyl-, methyl-, ethyl-, tert-butyl- and cyclohexyl-acetophenone.
15
In addition to component B) it is also possible for further ketones C) to be present, in a
mixture, such as acetone, 4-tert-butyl methyl ketone, methyl naphthyl ketone, hydroxynaphthyl ketone, methyl ethyl ketone, heptan-2-one, pentan-3-one, methyl isobutyl ketone, propiophenone, cyclopentanone, cyclododecanone, mixtures of 2,2,4- and 2,4,4-
20 trimethylcyclopentanone, cycloheptanone and cyclooctanone, cyclohexanone and all alkyl-substituted cyclohexanones having one or more alkyl radicals containing in total from 1 to 8 carbon atoms, individually or in a mixture. Examples of alkyl-substituted cyclohexanones include 4-tert-amylcyclohexanone, 2-sec-butylcyclohexanone, 2-tert-butylcyclohexanone, 4-tert-butylcyclohexanone, 2-methylcyclohexanone and 3,3,5-trimethylcyclohexanone.
25
Benzoin and/or its alkyl ethers, such as methyl, ethyl, propyl and isobutyl ethers, for example, can be used as component C) in a minor proportion, up to a maximum of 9.9 mol%, based on ketone components B) and C).
30 In general, however, it is possible to use any of the ketones said in the literature to be suitable for synthesizing ketone resins and ketone-aldehyde resins, and generally all CH-acidic ketones, as additional ketone C).

Preference is given to reaction products of formaldehyde and/or benzaldehyde with acetophenone, hydroxyl-, methyl-, tert-butyl- and/or cyclohexyl-acetophenone and also, if desired, 4-tert-butyl methyl ketone, cyclohexanone, 4-tert-butylcyclohexanone, 3,3,5-trimethyl-cyclohexanone and/or heptanone.
5
The synthesis of the polymers from components A), B) and, where used, C) takes place in a condensation reaction in a manner known from the literature in a basic medium (Dieter Stoye, Werner Freitag, Lackharze, Chemie, Eigenschaften und Anwendungen [Resins for Coatings; Chemistry, Properties, and Applications], Carl Hanser Verlag, Munich, Vienna, 1996, p. 164
10 ff.; US-PS 2 540 885; US-PS 2 540 886; DE-PS 11 55 909; DL-PS 12 433; DE-PS 13 00 256; DE-PS 12 56 898; DE 33 24 287; DE 10 33 8580.0, EP 0 007 106; DE 12 65 415).
Reaction conditions: Solvent:
15 The reaction can be carried out using an auxiliary solvent. Alcohols such as methanol or ethanol, for example, have proven suitable. It is also possible to use water-soluble ketones as auxiliary solvents, such as methyl ethyl ketone or acetone, for example, which are then incorporated into the resin by reaction. Bases:
20 The products on which the invention is based are prepared from A), B) and, where used, C) using from 0.05 to 10 mol% (based on the ketone employed) of at least one base. Preference is given to (metal) hydroxides such as, for example, hydroxides of the cations NH4, Li, Na and/or K. Particular preference is given to using potassium hydroxide and/or sodium hydroxide.
25 Ratio of ketone to aldehyde component:
The ratio between the ketone component (total B)+C)) and the aldehyde component A) may vary between 1:0.9 to 1:4. A preferred ketone/aldehyde ratio, however, is from 1:1 to 1:2.5. The ketone component and the aldehyde component can be added as they are or in solvents as mentioned above or in aqueous form. Particular preference is given to using an aqueous or 30 alcoholic formaldehyde solution, trioxane and/or paraformaldehyde.
Ratio of ketone B) to component C):

Based on the total of the ketones B) and C) used, the ketone component B) may be present in the range from 10 to 100 mol%, preferably between 20 to 90 mol%, more preferably between 25 and 80 mol%. The ketone component C) can be used in the range from 0 to 90 mol%, preferably from 10 to 80 mol%, more preferably from 20 to 75 mol%. 5
Through the nature and the proportion of the components with respect to one another it is easily possible to vary properties such as, for example, solubility properties in solvents of different polarity, compatibilities with other raw materials, softening ranges, glass transition temperatures or further functionalities, such as OH groups, for example, which are needed for 10 the crosslinking of dual-cure systems composed of photopolymerizable binders, binders containing OH groups, and, for example, polyisocyanate crosslinkers.
The low odor, radiation-sensitive, polymeric reaction products of components A), B) and, where used, C), that are relevant to the invention, possess the following properties, depending 15 on identity and on the ratio between ketones B) and C) and aldehydes A):
• melting ranges between 30 and 160°C, preferably 40 and 150°C, more preferably 40 and
125°C,
• average molecular weights from 300 to 2000, more preferably from 400 to 1500 g/mol,

• color numbers (according to Gardner, 50% in ethyl acetate) of less than 5, preferably less
20 than 4, more preferably less than 3,
• OH numbers of between 0 and 250 mg KOH/g, preferably between 0 and 200 mg KOH/g.
The invention also provides for the use of the products according to the invention for initiating the UV-light~induced, free-radical crosslinking reaction of radiation-curable coating materials, 25 adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants.
It has been found that proportions of between 5% and 80% by mass, preferably between 10% and 70% by mass, more preferably between 15% and 60% by mass, based on the overall 30 formulation, are advantageous.

It has also emerged that the products according to the invention possess broad compatibility with different raw materials and are easy to incorporate.
Suitable binder components of the radiation-curable coating materials, adhesives, inks, gel
5 coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants
and/or insulants include in principle all of the unsaturated binders which are said to be suitable
in the literature and are amenable to a free-radical crosslinking reaction. Examples include
aromatic and aliphatic urethane acrylates, epoxy acrylates, polyester acrylates, acrylated
polyacrylates, polyether acrylates, unsaturated polyesters, alkyd resins, and acrylated ketone-
10 formaldehyde resins.
The radiation-curable coating materials, adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants may further comprise reactive diluents.
15
Compounds which can be used with preference as reactive diluents include acrylic acid and/or methacrylic acid, C1-C40 alkyl esters and/or cycloalkyl esters of methacrylic acid and/or acrylic acid, glycidyl methacrylate, glycidyl acrylate, 1,2-epoxybutyl acrylate, 1,2-epoxybutyl methacrylate, 2,3-epoxycyclopentyl acrylate and 2,3-epoxycyclopentyl methacrylate, and also
20 the analogous amides; styrene and/or its derivatives may also be present.
Particular preference is given to phenoxyethyl acrylate, ethoxyethoxyethyl acrylate, isodecyl acrylate and isobornyl acrylate.
25 A further preferred class of radiation-reactive solvents are di-, tri- and/or tetraacrylates and their methacrylic analogs, which originate formally from the reaction products of acrylic acid or methacrylic acid, respectively, and an alcohol component, with elimination of water. As the alcohol component customary for this purpose use is made, for example, of ethylene glycol, 172- and/or 1,3-propanediol, diethylene glycol, di- and tripropylene glycol, triethylene glycol,
30 tetraethylene glycol, 1,2- and/or 1,4-butanediol, 1,3-butylethylpropanediol, 1,3-methylpropanediol, 1,5-pentanediol, l,4-bis(hydroxymethyl)cyclohexane (cyclohexane-dimethanol), glycerol, hexanediol, neopentyl glycol, trimethylolethane, trimethylolpropane,

pentaerythritol, bisphenol A, B, C, F, norbornylene glycol, 1,4-benzyldimethanol, 1,4-benzyldiethanol, 2,4-dimethyl-2-ethylhexane-l,3-diol, 1,4- and 2,3-butylene glycol, di-6-hydroxyethylbutanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, decanediol, dodecanediol, neopentyl glycol, cyclohexanediol, triraethylolpropane, 3(4),8(9)-5 bis(hydroxymethyl)tricyclo[5.2.1.02'6]decane (Dicidol), 2?2-bis(4-hydroxycyclohexyl)propane, 2,2-bis[4-(B-hydroxyethoxy)phenyl]propane, 2-methylpropane-l,3-diol, 2-methylpentane-l,5-diol, 2?2,4(2,4,4)-trimethylhexane-1,6-diol, hexane-1,2,6-triol, butane-1,2,4-triol, tris(B-hydroxyethyl) isocyanurate, mannitol, sorbitol, polypropylene glycols, polybutylene glycols, xylylene glycol or neopentyl glycol hydroxypivalate, alone or in mixtures. 10
Particular preference is given, however, to dipropylene glycol diacrylate (DPGDA) and/or tripropylene glycol diacrylate (TPGDA), hexanediol diacrylate (HDDA), and trimethylolpropane triaciylate, alone or in a mixture.
15 In general, however, it is possible to use any of the reactive diluents said in the literature to be suitable for radiation-curable coating materials.
The radiation-curable coating materials, adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants can include, in
20 combination with the polymeric, photoreactive compounds of the invention, further, commercially customary photoinitiators and/or photosensitizers.
These are derived, for example, from the group of the phenylglyoxylates, benzophenones, a-hydroxy ketones, a-amino ketones, benzil dimethyl ketals, monoacylphosphines, tertiary amines, bisacylphosphines, metallocenes and/or bisacyl ketones.
25 Examples are 2,4,6-trimethylbenzoyldiphenylphosphine, a,a-dimethoxy-ot-hydroxyaceto-phenone, 2-methyl-1 -(4-methylthio)phenyl-2-morpholinopropan-1 -one, 1 -hydroxycyclohexyl phenyl ketone, 4-(4-methylphenylthiophenyl)phenylmethanone, phenyl tribromomethyl sulfone, 2-isopropylthioxanthone, 4-isopropylthioxanthone, benzophenone, ethyl 4-(dimethylamino)benzoate, methyl phenylglyoxylate, methyl benzoylbenzoate, diphenyl(3,4,6-
30 trimethylbenzoyl)phosphine oxide, and substituted benzophenones, such as 4-methylbenzo-phenone, alone or in a mixture.

The radiation-curable coating materials, adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants may also include auxiliaries and additives such as, for example, inhibitors, water and/or organic solvents, neutralizing agents, surface-active substances, oxygen scavengers and/or free-radical 5 scavengers, catalysts, light stabilizers, color brighteners, thixotropic agents, antiskinning agents, defoamers, antistats, thickeners, thermoplastic additives, dyes, pigments, flame retardants, internal release agents, fillers and/or propellants.
As well as the initiation of radiation-induced crosslinking reactions, the low-odor products 10 according to the invention also improve, in particular, the gloss, solvent and chemical resistance, and hardness of coating materials, adhesives, inks, gel coats, polishes, glazes, stains, pigment pastes, filling compounds, cosmetics articles, sealants and/or insulants.
Atmospheric oxygen is a quencher of free radicals and so slows down the UV-light-induced 15 crosslinking reaction; it may even lead to termination of the crosslinking of the polymers. In order to ensure effective curing in spite of this, present-day systems operate, for example, with large amounts of photoinitiator or else with waxes, which form a barrier layer between air and coating. A widespread method is that of curing in the absence of atmospheric oxygen, generally under an inert gas atmosphere, such as in a nitrogen, carbon dioxide or noble gas atmosphere, 20 for example. All of the methods described of complete curing are either expensive or lead to further disadvantages. In the case of using wax the surface is matt and must therefore be polished where appropriate. Waxes also hinder effective adhesion of subsequent coats to the surface.
25 It is particularly noticeable that the surface hardness of coating materials which have not been cured in the absence of oxygen is extremely high. It is therefore possible in the case of UV-light-induced curing to dispense with an inert gas atmosphere or with the waxes described.
The examples which follow are intended to illustrate the invention but not to restrict the scope 30 of its application:

Examples
Example 1: Preparation of the radiation-sensitive, polymeric reaction products
600 g of acetophenone, 108ml of methanol, 200 g of Cavasol W7M (methylated (3-5 cyclodextrin derivative, Wacker, Burghausen, DE) and 180 g of formalin (30% strength in water) are introduced to a three-necked flask and heated therein with stirring and under a nitrogen atmosphere to 50°C. 16 g of 25% strength sodium hydroxide solution are added, and the reaction mixture heats up to 70°C. Over 90 minutes 330 g of formalin (30% strength in water) are added and the reaction mixture is then heated to 95°C and held under reflux for 5 h. 10
The aqueous phase is separated from the resin phase and the resin is washed to neutrality with water at 100°C and freed in vacuo, at up to 150°C, from volatile constituents.
This gives a yellowish, clear and brittle resin which is soluble to 50% strength in methyl ethyl 15 ketone, acetone, ethyl acetate and xylene and possesses a softening point of48°C. The Gardner color number of a 50% strength solution in ethyl acetate is 2.2.



The solutions were applied to glass plates using a drawdown frame and exposed six times for 6 s (TECHNIGRAF UV4/120/2 80W). The pure solutions A, B and C do not form a crosslinked film.

1) in accordance with DIN EN ISO 1522
2) in the MEK test a cloth soaked with methyl ethyl ketone (MEK) is moved back and forth
(double rubs) over the surface under test between said surface and a 1 kg test cushion.
The number of rubs after which the coating changes is recorded.


What is claimed is:
1. A radiation-sensitive composition
composed of a binder component and low-odor polymeric reaction products composed of the reaction product of
A) aldehydes of the general formula I

where R = H, branched or unbranched alkyl radical having 1 to 12 carbon atoms or aryl radical
and
B) at least one ketone of the general formula II

where R\ = unbranched alkyl radical having 1 to 12 carbon atoms

where the radicals R3 to R7 are H, alkyl, OCH3, OC2H5, Cl, F, COO(C]-C3 alkyl), and R4 to R6 are additionally OH and/or SH

and C) if desired, a further, CH-acidic ketone.
2. A radiation-sensitive composition as claimed in claim 1,
wherein
formaldehyde, benzaldehyde, acetaldehyde, n-butyraldehyde and/or isobutyraldehyde, valeraldehyde and also dodecanal, alone or in combination, are used as aldehyde component A).
3. A radiation-sensitive composition as claimed in claim 1,
wherein
acetophenone and its ring-substituted derivatives, alone or in combination, are used as ketone component B).
4. A radiation-sensitive composition as claimed in claim 3,
wherein
hydroxyl-, methyl-, ethyl-, tert-butyl- or cyclohexyl-acetophenone, alone or in combination, are used as ring-substituted acetophenone derivatives.
5. A radiation-sensitive composition as claimed in claim 1?
wherein
acetone, 4-tert-butyl methyl ketone, methyl naphthyl ketone, hydroxynaphthyl ketone, methyl ethyl ketone, heptan-2-one, pentan-3-one, methyl isobutyl ketone, propiophenone, cyclopentanone, cyclododecanone, mixtures of 2,2,4- and 2,4,4-trimethylcyclopentanone, cycloheptanone, cyclooctanone, cyclohexanone and all alkyl-substituted cyclohexanones having one or more alkyl radicals containing in total from 1 to 8 carbon atoms, alone or in combination, are used as further CH-acidic ketone component under C).
6. A radiation-sensitive composition as claimed in claim 5,
wherein

4-tert-amylcyclohexanone, 2-sec-butylcyclohexanone, 2-tert-butylcyclohexanone, 4-tert-butylcyclohexanone, 2-methylcyclohexanone and 3,3,5-trimethylcyclohexanone, alone or in combination, are used as alkyl-substituted cyclohexanones.
7. A radiation-sensitive composition as claimed in claim 1, 5 and 6,
wherein
a maximum of up to 9.9 mol% of the ketone component C), based on the sum of B) and C), can be replaced by benzoin or alkyl ethers.
8. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
the polymeric reaction products of components A), B) and, where used, C) have melting ranges between 30 and 160°C, average molecular weights of from 300 to 2000, color numbers (according to Gardner, 50% in ethyl acetate) of less than 5 and OH numbers of between 0 and 250 mg KOH/g.
9. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
the polymeric reaction products of components A), B) and, where used, C) are present in proportions of from 5% to 80% by mass, based on the overall formulation, in the radiation-sensitive composition.
10. A radiation-sensitive composition as claimed in claim 1,
wherein
unsaturated binders amenable to a free-radical crosslinking reaction are used as binder component.
11. A radiation-sensitive composition as claimed in claim 1 and 10,
wherein
aromatic and aliphatic urethane acrylates, epoxy acrylates, polyester acrylates, acrylated polyacrylates, polyether acrylates, unsaturated polyesters, atkyd resins and acrylated ketone-formaldehyde resins, alone or in combination, are used as binder component.

12. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
the radiation-sensitive composition comprises reactive diluents.
13. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
acrylic acid, methacrylic acid, C1-C40 alkyl esters, cycloalkyl esters of methacrylic acid, acrylic acid, glycidyl methaciylate, glycidyl acrylate, 1,2-epoxybutyl acrylate, 1,2-epoxybutyl methaciylate, 2,3-epoxycyclopentyl acrylate, 2?3-epoxycyclopentyl methacrylate and also the analogous amides, styrene and its derivatives, di-, tri- and/or tetraacrylates and their methacrylic analogs, which result formally from the reaction products of acrylic acid or methacrylic acid, respectively, and an alcohol component, with elimination of water, alone or in combination, are used as reactive diluents.
14. A radiation-sensitive composition as claimed in claim 13,
wherein
ethylene glycol, 1,2- and/or 1,3-propanediol, diethylene glycol, di- and tripropylene glycol, triethylene glycol, tetraethylene glycol, 1,2- and/or 1,4-butanediol, 1,3 -butylethyl-propanediol, 1,3-methylpropanediol, 1,5-pentanediol, l,4-bis(hydroxymethyl)cyclohexane (cyclohexanedimethanol), glycerol, hexanediol, neopentyl glycol, trimethylolethane, trimethylolpropane, pentaerythritol, bisphenol A, B, C, F, norbornylene glycol, 1,4-benzyldimethanol, 1,4-benzyldiethanol, 2,4-dimethyl-2-ethylhexane-l,3-diol, 1,4- and 2,3-butylene glycol, di-B-hydroxyethylbutanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, decanediol, dodecanediol, neopentyl glycol, cyclohexanediol, trimethylolpropane, 3(4),8(9)-bis(hydroxymethyl)tricyclo[5.2.1.02'6]decane (Dicidol), 2,2-bis(4-hydroxycyclohexyl)propane, 2,2-bis[4-(B-hydroxyethoxy)phenyl]propane, 2-methylpropane-l,3-diol, 2-methylpentane-l,5-diol, 2,2,4(2,4,4)-1iimethylhexane-l,6-dioL, hexane-l?2,6-triol, butane-1,2,4-triol, tris(B-hydroxyethyl) isocyanurate, mannitol, sorbitol, polypropylene glycols, polybutylene glycols, xylylene glycol or neopentyl glycol hydroxypivalate, alone or in mixtures, are used as alcohol component for the reactive diluents.

15. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
the radiation-sensitive composition comprises further photoinitiators and/or photosensitizers.
16. A radiation-sensitive composition as claimed in any one of the preceding claims,
wherein
phenylglyoxylates, benzophenones, ot-hydroxy ketones, a-amino ketones, benzil dimethyl ketals, monoacylphosphines, tertiary amines, bisacylphosphines, metallocenes and bisacyl ketones, alone or in combination, are used as photoinitiators and/or photosensitizers.
17. A process for preparing a radiation-sensitive composition,
which comprises
using a binder component and low-odor polymeric reaction products composed of the reaction product of
A) aldehydes of the general formula I

where R = H, branched or unbranched alkyl radical having 1 to 12 carbon atoms or aryl radical
and
B) at least one ketone of the general formula II

where R1 = unbranched alkyl radical having 1 to 12 carbon atoms


where the radicals R3 to R7 are H, alkyl, OCH3, OC2H5, Cl, F, COO(C!-C3 alkyl), and R4 to R6 are additionally OH and/or SH and C) if desired, a further, CH-acidic ketone.
8. The use of a radiation-sensitive composition as claimed in any one of the preceding claims, in a coating material, adhesive, ink, gel coat, polish, glaze, stain, pigment paste, filling compound, cosmetics article, sealant and/or insulant.
^9. The use of a radiation-sensitive composition as claimed in claim 18, the composition further comprising as auxiliaries and additives inhibitors, water and/or organic solvents, neutralizing agents, surface-active substances, oxygen scavengers and/or free-radical scavengers, catalysts, light stabilizers, color brighteners, thixotropic agents, antiskinning agents, defoamers, antistats, thickeners, thermoplastic additives, dyes, pigments, flame retardants, internal release agents, fillers and/or propellants, alone or in combination.


Documents:

814-CHENP-2006 AMENDED PAGES OF SPECIFICATION 12-05-2011.pdf

814-CHENP-2006 AMENDED CLAIMS 12-05-2011.pdf

814-chenp-2006 amended pages of specification 27-06-2011.pdf

814-chenp-2006 correspondence others 27-05-2011.pdf

814-chenp-2006 form-1 12-05-2011.pdf

814-chenp-2006 form-3 12-05-2011.pdf

814-chenp-2006 form-3 27-05-2011.pdf

814-CHENP-2006 OTHER PATENT DOCUMENT 12-05-2011.pdf

814-CHENP-2006 POWER OF ATTORNEY 12-05-2011.pdf

814-chenp-2006 correspondence others 27-06-2011.pdf

814-CHENP-2006 EXAMINATION REPORT REPLY RECEIVED 12-05-2011.pdf

814-CHENP-2006 CORRESPONDENCE OTHERS 17-08-2010.pdf

814-CHENP-2006 CORRESPONDENCE OTHERS.pdf

814-CHENP-2006 CORRESPONDENCE PO.pdf

814-chenp-2006-abstract.pdf

814-chenp-2006-claims.pdf

814-chenp-2006-correspondnece-others.pdf

814-chenp-2006-description(complete).pdf

814-chenp-2006-form 1.pdf

814-chenp-2006-form 26.pdf

814-chenp-2006-form 3.pdf

814-chenp-2006-form 5.pdf

814-chenp-2006-pct.pdf


Patent Number 248400
Indian Patent Application Number 814/CHENP/2006
PG Journal Number 28/2011
Publication Date 15-Jul-2011
Grant Date 12-Jul-2011
Date of Filing 07-Mar-2006
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address Grenzacherstrasse 124, CH-4070 Basel
Inventors:
# Inventor's Name Inventor's Address
1 FLOHR, Alexander Passwangstrasse 3, CH-4153 Reinach
2 GALLEY, Guido Katzenbuckelweg 14, 79618 Rheinfelden
3 JAKOB-ROETNE, Roland Oberer Baselblick 37, 79594 Inzlingen
4 KITAS, Eric, Argirios Eichbergweg 4, CH-4147 Aesch
5 PETERS, Jens-Uwe Bertlingen 14, 79639 Grenzach-Wyhlen
6 WOSTL, Wolfgang Im Strick 2, 79639 Grenzach-Wyhlen
PCT International Classification Number C07K 1/06
PCT International Application Number PCT/EP2004/009700
PCT International Filing date 2004-08-31
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03019683.6 2003-09-09 EUROPEAN UNION