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HK1099014B - Malonamide derivatives blocking the activity of gama-secretase - Google Patents

Malonamide derivatives blocking the activity of gama-secretase Download PDF

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Publication number
HK1099014B
HK1099014B HK07105326.7A HK07105326A HK1099014B HK 1099014 B HK1099014 B HK 1099014B HK 07105326 A HK07105326 A HK 07105326A HK 1099014 B HK1099014 B HK 1099014B
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HK
Hong Kong
Prior art keywords
methyl
oxo
malonamide
pentafluoro
dibenzo
Prior art date
Application number
HK07105326.7A
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Chinese (zh)
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HK1099014A1 (en
Inventor
Alexander Flohr
Guido Galley
Roland Jakob-Roetne
Eric Argirios Kitas
Jens-Uwe Peters
Wolfgang Wostl
Original Assignee
F. Hoffmann-La Roche Ag
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Priority claimed from PCT/EP2004/009700 external-priority patent/WO2005023772A1/en
Publication of HK1099014A1 publication Critical patent/HK1099014A1/en
Publication of HK1099014B publication Critical patent/HK1099014B/en

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Description

Malonamide derivatives blocking the activity of gamma-secretase
The present invention relates to malonamide derivatives of the formula and pharmaceutically acceptable suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof:
wherein
R1Is one of the following groups:
R2is lower alkyl, lower alkynyl, - (CH)2)n-O-lower alkyl, - (CH)2)n-S-lower alkyl, - (CH)2)n-CN、-(CR’R”)n-CF3、-(CR’R”)n-CHF2、-(CR’R”)n-CH2F、-(CH2)n-C (O) O-lower alkyl, - (CH)2)n-halogen, or is- (CH)2)n-cycloalkyl, optionallyIs substituted by one or more groups selected from phenyl, halogen or CF3Substituted with the substituent(s);
r', R "are independently from n and independently from each other hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy;
R3、R4independently of one another, hydrogen, lower alkyl, lower alkoxy, phenyl or halogen;
R5is hydrogen, lower alkyl, - (CH)2)n-CF3Or- (CH)2)n-a cycloalkyl group;
R6is hydrogen or halogen;
R7is hydrogen or lower alkyl;
R8is hydrogen, lower alkyl, lower alkynyl, - (CH)2)n-CF3、-(CH2)n-cycloalkyl or- (CH)2)n-phenyl, optionally substituted with halogen;
R9is hydrogen, lower alkyl, -C (O) H, -C (O) -lower alkyl, -C (O) -CF3、-C(O)-CH2F、
-C(O)-CHF2-C (O) -cycloalkyl, -C (O) - (CH)2)n-O-lower alkyl,
-C(O)O-(CH2)n-cycloalkyl, -C (O) -phenyl, optionally substituted by one or more groups selected from halogen or
-C (O) O-lower alkyl,
or is-S (O)2-lower alkyl, -S (O)2-CF3、-(CH2)n-cycloalkyl or is- (CH)2)n-phenyl, optionally substituted with halogen;
n is 0, 1, 2, 3 or 4.
The term "lower alkyl" as used herein denotes a saturated straight or branched alkyl group containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred lower alkyl groups are those containing 1 to 4 carbon atoms.
The term "lower alkynyl" as used herein denotes an unsaturated straight or branched carbon chain containing 2 to 7 carbon atoms and containing at least one triple bond.
The term "cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms.
The term "halogen" denotes chlorine, iodine, fluorine and bromine.
The term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above and is attached through an oxygen atom.
Expression "- (CR' R")n- "may be, for example, -CH2-、-CH2-CH2-、-CH2-CH2-CH2-、-CH2-CF2-、-CH2-CH2-CF2-、-CH2-CH2-CH(OCH3)-、-CH2CH (OH) -or-C (CH)3)2-CH(OH)-。
The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
It has been found that the compounds of formula I are inhibitors of gamma-secretase (secretase) and 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 years. AD is pathologically characterized by the deposition of amyloid in the brain in extracellular plaques and intracellular neurofibrillary tangles. Amyloid plaques are mainly composed of amyloid peptides (Abeta peptides) derived from β -Amyloid Precursor Protein (APP) through a series of proteolytic cleavage steps. Several forms of APP have been identified, the most abundant of which are proteins of 695, 751 and 770 amino acids in length. They are all produced from a single gene by differential splicing. The Abeta peptides are derived from the same domain of APP, but differ at their N-and C-termini, the main species being 40 and 42 amino acids in length.
The Abeta peptide is produced by APP through the sequential action of 2 proteases called β -and γ -secretases. The β -secretase enzyme first cleaves in the extracellular domain of APP outside the transmembrane domain (TM) to produce an APP C-terminal fragment containing the TM-and cytoplasmic domains (CTF β). CTF β is a substrate for γ -secretase, which cleaves at several adjacent positions within the TM to produce a β peptide and cytoplasmic fragments. Most Abeta peptides are 40 amino acids long (a β 40), with a few species carrying 2 additional amino acids at their C-terminus. The latter is presumed to be the more pathogenic amyloid peptide.
The beta-secretase enzyme is typically an aspartyl protease. Gamma-secretase has proteolytic activity and consists of several proteins, the exact composition of which is not completely understood. However, presenilins (presenilins) are essential components of this activity and may represent a new group of atypical aspartyl proteases that cleave within the TM of their substrates and are themselves heterotopic (polytopic) membrane proteins. Other essential components of gamma-secretase may be nicastrin and the products of aph1 and pen-2 genes. Substrates of the demonstrated gamma-secretase are the APP and Notch receptor family proteins, however, gamma-secretase has an unfixed substrate specificity and can also cleave membrane proteins unrelated to APP and Notch.
Gamma-secretase activity is absolutely required for Abeta peptide production. This has been demonstrated by genetic means, i.e., partial excision of the presenilin gene and by low molecular weight inhibitory compounds. Since the production and deposition of Abeta is the ultimate cause of the disease, either according to the amyloid hypothesis or AD, selective and potent inhibitors of γ -secretase are believed to be useful in the prevention and treatment of AD.
Thus, the compounds of the present invention are useful for the treatment of AD by blocking γ -secretase activity and reducing or preventing the formation of various amyloid-derived (amyloidogenic) Abeta peptides.
A large body of literature describes recent knowledge about gamma-secretase inhibition, such as the following publications:
nature Reviews/Neuroscience, Vol.3, 4/281 in 2002;
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, 5.2001, 459-;
FEBS Letters，483，(2000)，6-10；
science, Vol.297, 353-356, 7 months 2002; and
Journ.of Medicinal Chemistry，Vol.44，No.13，2001，2039-2060。
the invention relates to the use of compounds of general formula I per se, of compounds of formula I and of their pharmaceutically acceptable salts for producing medicaments for the treatment of diseases which are associated with gamma-secretase inhibition, to methods for the production thereof, to medicaments based on the compounds of the invention and to methods for the production thereof, and to the use of compounds of formula I for controlling or preventing Alzheimer's disease.
Another object of the present invention is all forms of optically pure enantiomers, racemates or diastereomeric mixtures of compounds of formula I.
Preferred compounds of the formula I are those in which R is1Is a) and R2To be optionally CF3Substituted- (CH)2)nCycloalkyl, such as the following compounds:
N-Cyclopropylmethyl-2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives(azepine) -7-yl) -malonamide; or
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (1-trifluoromethyl-cyclopropylmethyl) -malonamide.
Preferred compounds are further those wherein R is1Is a) and R2Is lower alkyl, - (CH)2)n-O-lower alkyl or- (CH)2)n-S-lower alkyl, for example the following compounds:
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-methoxyethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-methylthioethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3-methoxy-propyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -malonamide.
Preferred compounds are further those wherein R is1Is a) and R2Is- (CR 'R')n-CF3Or- (CR 'R')n-CHF2For example:
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoroethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide;
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide,
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (4, 4, 4-trifluoro-butyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide;
n- (5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
2-methyl-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(-) -2-methoxy-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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 [ ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide,
n- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-7-yl) -2-fluoro-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -propanedi-N-butylAn amide;
n- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- (5-isopropyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -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)]Aza derivatives-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 [ ]]Aza derivatives-7-yl]-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)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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 [ b, d ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
Another preferred group of compounds are those wherein R is1Is c) and R2Is- (CR 'R')n-CF3For example, the following compounds:
2-methyl-N- (1-methyl-2-oxo-5-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide;
n- ((3S) -5-benzoyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-fluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-chloro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (3, 5-difluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b [ -b ]][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
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]Diaza derivatives-1-carbonyl } -benzoic acid methyl ester;
n- ((3S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [5- ((3S) -4-fluoro-benzyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-chloro-benzoyl) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- ((3S) -1-methyl-2-oxo-5-trifluoromethanesulfonyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- [ (3S) -1-methyl-2-oxo-5- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (2-methoxy-acetyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (S) -5-methanesulfonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -5-trifluoromethanesulfonyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-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][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester malonamide;
n- [ (S) -5-cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamino]-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester;
n- [ (S) -5-acetyl-1-isopropyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide; or
N- ((S) -5-acetyl-1-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
Preferred compounds are further those wherein R is1Is b), for example:
2-methyl-N- (3-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ d)]Aza derivatives-1-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide.
Preferred compounds are furthermore those in which R is1Is d), for example:
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide(oxepine) -10-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide; or
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide-10-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
One embodiment of the invention is a compound of the general formula and pharmaceutically acceptable suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof:
wherein
R1Is one of the following groups:
R2is lower alkyl, lower alkynyl, - (CH)2)n-O-lower alkyl, - (CH)2)n-S-lower alkyl, - (CH)2)n-CN、-(CR’R”)n-CF3、-(CR’R”)n-CHF2、-(CH2)n-C (O) O-lower alkyl, - (CH)2)n-halogen, or is- (CH)2)n-cycloalkyl, optionally substituted by one or more substituents selected from phenyl, halogen or CF3Substituted with the substituent(s);
r', R "are independently from n and independently from each other hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy;
R3、R4independently of one another, hydrogen, lower alkyl, phenyl or halogen;
R5is lower alkylOr- (CH)2)n-a cycloalkyl group;
R6is hydrogen or halogen;
R7is hydrogen or lower alkyl;
R8is hydrogen, lower alkyl, lower alkynyl or- (CH)2)n-a cycloalkyl group;
R9is hydrogen, lower alkyl, -C (O) -lower cycloalkyl,
-(CH2)n-cycloalkyl, phenyl, -c (o) -phenyl, optionally substituted by one or more groups selected from halogen or
-C (O) O-lower alkyl,
or (CH) optionally substituted by halogen2)n-a phenyl group;
n is 0, 1, 2, 3 or 4.
The compounds of general formula I of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods well known in the art, for example, by a method comprising:
a) reacting a compound of formula II
With a compound of the formula III,
NH2R2 III
to obtain a compound of formula I:
wherein R is1-R4Have the meaning as described above;
and, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
Detailed descriptions can be found below and in examples 1-121. The starting materials of formula IV are known compounds or can be prepared by methods well known in the art. The amines of formulae VI and III are commercially available products or can be prepared by methods described in the literature.
Scheme 1
In this scheme, R1And R2As described below and R10And R11Independently lower alkyl.
According to scheme 1, compounds of formula I can be prepared as follows:
to compounds of formula V, e.g. 2-methyl-malonic acid mono-tert-butyl ester, and amines of formula VI, e.g. 7-amino-5-methyl-5H, 7H-dibenzo [ b, d ]]Aza derivativesTo a cooled solution of the-6-one in THF was added hydroxybenzotriazole, diisopropylethylamine and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, and the mixture was stirred at room temperature overnight. The solvent was evaporated, the residue washed, dried and purified in a conventional manner.
TFA (trifluoroacetic acid) is then added to the obtained compound of formula VII, e.g. 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl) -propionamide tert-butyl ester in dichloromethane, andthe mixture was stirred at room temperature overnight. The mixture was then dissolved in more dichloromethane, washed and dried. After evaporation of the solvent, the compound of the formula II is obtained, for example 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl) -malonamic acid. The compound obtained and the compound of formula III, e.g. cyclopropylmethylamine, are placed in a disposable polypropylene test tube and dissolved in DMF. TPTU (2- (2-pyridinone-1-yl) -1, 1, 3, 3-tetramethylurantetrafluoroborate) was added and the mixture was shaken at room temperature overnight. The compound of formula I obtained is isolated and purified in a conventional manner.
The compounds of formula I can be converted into the corresponding acid addition salts. The conversion is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Generally, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, and the like, and the acid is added in a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be brought out of solution using a less polar solvent.
The acid addition salts of the compounds of formula I can be 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 addition salts have valuable pharmacological properties. In particular, it has been found that the compounds of the present invention can inhibit gamma-secretase.
The compounds were studied according to the tests given below.
Description of the Gamma-secretase assay
The activity of a test compound can be evaluated in assays that measure gamma-secretase activity to proteolytically cleave an appropriate substrate. These assays may be cellular assays in which, for example, a substrate for gamma-secretase is fused in its cytoplasmic domain to a transcription factor. Cells are transfected with such fusion genes and reporter genes whose expression is enhanced by transcription factors, such as luciferase. Cleavage of the fusion substrate by gamma-secretase allows expression of the reporter gene to be monitored in a suitable assay. The gamma-secretase activity can also be determined in cell-free in vitro assays, in which, for example, cell lysates containing the gamma-secretase complex are incubated with a suitable APP-derived substrate, which is cleaved to the Abeta peptide. The amount of peptide produced can be determined using a specific ELISA assay. Neuronal derived cell lines secrete Abeta peptides, which can be determined using specific ELISA assays. Treatment with compounds that inhibit γ -secretase results in a reduction in secreted Abeta, thereby providing a measure of inhibition.
In vitro assays for gamma-secretase activity use HEK293 membrane fraction as a source of gamma-secretase and a recombinant APP substrate. The latter consists of the C-terminal 100 amino acids of human APP fused to the 6 histidine tail for purification, which is expressed in E.coli using a regulatable expression vector, such as pEt 15. This recombinant protein corresponds to a truncated APP fragment, which is produced after cleavage of the extracellular domain by gamma-secretase and constitutes the gamma-secretase substrate. The principle of the test is described in PNAS97(11), 6138-. Hek293 cells were mechanically disrupted and the microsomal fraction was isolated by differential centrifugation. The membrane was dissolved in detergent (0.25% CHAPSO) and incubated with APP substrate. The Abeta peptide produced by gamma-secretase cleavage of the substrate was detected by a specific ELISA assay as described (Brockhaus M et al, Neuroreport, 9(7), 1481-1486 (1998)).
Preferred compounds exhibit IC50< 0.1. mu.M. Some data on gamma-secretase inhibition are described in the following table:
TABLE 1
Example number In vitro IC Example number In vitro IC
1 0.09 70 0.006
4 0.02 71 0.011
5 0.071 72 0.005
6 0.031 73 0.008
8 0.015 74 0.001
13 0.02 75 0.002
14 0.037 76 0.004
21 0.03 77 0.05
23 0.018 78 0.002
24 0.005 79 0.006
26 0.056 80 0.003
28 0.073 81 0.025
29 0.06 82 0.009
30 0.079 83 0.020
35 0.012 84 0.007
36 0.006 85 0.003
37 0.013 86 0.047
38 0.02 87 0.017
39 0.09 88 0.05
40 0.07 89 0.020
43 0.03 95 0.071
44 0.03 98 0.080
49 0.033 99 0.059
50 0.043 101 0.040
51 0.019 106 0.090
65 0.006 108 0.046
66 0.017 109 0.048
67 0.004 113 0.030
68 0.008 115 0.067
69 0.002 121 0.038
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, parenterally, for example in the form of injection solutions.
The compounds of formula I may be processed with pharmaceutically inert inorganic or organic carriers to prepare pharmaceutical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid 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 gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
Furthermore, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as well as a process for their preparation, 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.
According to the present invention, the compounds of formula I and their pharmaceutically acceptable salts are useful for the control or prevention of diseases, such as alzheimer's disease, based on gamma-secretase inhibition.
The dosage can vary within wide limits and will, of course, be adjusted in each particular case to the individual requirements. In the case of oral administration, the dosage for an adult may be from about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses and, in addition, the upper limit may be exceeded when this is found to be necessary.
Tablet (Wet granulation)
Item(s) Components mg/tablet
5mg 25mg 100mg 500mg
1. Compound 525100500 of formula I
2. Lactose anhydrous DTG 12510530150
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline cellulose 303030150
5. Magnesium stearate 1111
Total 167167167831
Preparation procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. The granules were dried at 50 ℃.
3. The particles are passed through a suitable milling apparatus.
4. Add 5 items and mix for 3 minutes; compressed on a suitable tablet press.
Capsule preparation
Item(s) Components mg/granule capsule
5mg 25mg 100mg 500mg
1. Compound 525100500 of formula I
2. Aqueous lactose 159123148-
3. Corn starch 25354070
4. Talc 10151025
5. Magnesium stearate 1225
Total 200200300600
Preparation procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
Example 1
N-Cyclopropylmethyl-2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
a) 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -propionamide Tert-butyl ester
To 2-methyl-malonic acid mono-tert-butyl ester (1.01g, 5.79mmol) and 7-amino-5-methyl-5H, 7H-dibenzo [ b, d ]]Aza derivativesTo a cooled (0 ℃) solution of-6-one (1.15g, 4.83mmol) in THF (8ml) were added hydroxybenzotriazole (652mg, 4.83mmol), diisopropylethylamine (624mg, 4.83mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (925mg, 4.83mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and dried (Na)2SO4). After evaporation of the solvent, the residue was purified by chromatography (silica gel, MeOH, CH)2Cl2) To give the title compound, MS: 395.3(M + H)+)，(920mg，48％)。
b) 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -propionamide Acid(s)
TFA (3ml) was added to 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-Yl) -propionamide tert-butyl ester (920mg, 2.33mmol) in dichloromethane (3ml) and the mixture was stirred at room temperature overnight. The mixture was then dissolved in more dichloromethane, washed with water and dried (Na)2SO4). After evaporation of the solvent, the residue was purified by chromatography (silica gel, MeOH, CH)2Cl2) The title compound was obtained, MS: 339.3(M + H)+)，(580mg，73％)。
c) N-Cyclopropylmethyl-2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -malonamide
Mixing 2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamic acid (20mg, 0.059mmol) and cyclopropylmethylamine (5mg, 0.059mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2- (2-pyridinone-1-yl) -1, 1, 3, 3-tetramethylurantetrafluoroborate, 19mg, 0.065mmol) was added and the mixture was shaken at room temperature overnight. By automatic preparative HPLC (YMC Combiprep C18 column 50X20mm, solvent gradient 5-95% CH in 0.1% TFA (aq.) over 6 min3CN, λ 230nm, flow rate 40ml/min) the title compound was isolated from the reaction mixture, MS: 392.2(M + H)+)。
Example 2
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -ethyl-malonamide
The title compound was prepared from ethylamine in analogy to example 1, MS: 366.2(M + H)+)。
Example 3
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -propargyl-malonamide
The title compound was prepared from propargylamine in analogy to example 1, MS: 376.3(M + H)+)。
Example 4
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-diphenylAnd [ b, d ]]Aza derivatives-7-yl) -N' - (2-methoxyethyl) -malonamide
The title compound was prepared from 2-methoxyethylamine in analogy to example 1, MS: 396.3(M + H)+)。
Example 5
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -propyl-malonamide
The title compound was prepared from propylamine in analogy to example 1, MS: 380.3(M + H)+)。
Example 6
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-methylthioethyl) -malonamide
The title compound was prepared from 2-methylthioethylamine in analogy to example 1, MS: 412.3(M + H)+)。
Example 7
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -cyclobutyl-malonamide
The title compound was prepared from cyclobutylamine in analogy to example 1, MS: 392.3(M + H)+)。
Example 8
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3-methoxy-propyl) -malonamide
The title compound was prepared from 3-methoxypropylamine in analogy to example 1, MS: 410.3(M + H) M/e+)。
Example 9
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -cyanomethyl-malonamide
The title compound was prepared from aminoacetonitrile in analogy to example 1, MS: 377.3(M + H)+)。
Example 10
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' -cyclopropyl-malonamide
The title compound was prepared from cyclopropylamine in analogy to example 1, MS: 378.3(M + H)+)。
Example 11
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-cyanoethyl) -malonamide
The title compound was prepared from 3-aminopropionitrile in a similar manner to example 1Substance, MS: m/e 391.2(M + H)+)。
Example 12
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-ethoxyethyl) -malonamide
The title compound was prepared from 2-ethoxyethylamine in analogy to example 1, MS: 410.3(M + H) M/e+)。
Example 13
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoroethyl) -malonamide
The title compound was prepared from 2, 2, 2-trifluoroethylamine in analogy to example 1, MS: 420.2(M + H) M/e+)。
Example 14
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 3-trifluoro-propyl) -malonamide
The title compound was prepared from 3, 3, 3-trifluoropropylamine in analogy to example 1, MS: 434.3(M + H)+)。
Example 15
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The title compound was prepared from 2, 2, 3, 3, 3-pentafluoropropylamine in analogy to example 1, MS: 470.1(M/+ H)+)。
Example 16
[2- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-ylcarbamoyl) -propionylamino]-tert-butyl acetate
The title compound was prepared from tert-butyl glycinate in analogy to example 1, MS: 452.3(M + H)+)。
Example 17
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 3-trifluoro-2-hydroxy-propyl) -malonamide
The title compound was prepared from 3-amino-1, 1, 1-trifluoro-2-propanol in analogy to example 1, MS: 450.2(M + H) M/e+)。
Example 18
N- (2, 2-difluoro-3-phenyl-cyclopropylmethyl) -2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
The title compound was prepared from C- (2, 2-difluoro-3-phenyl-cyclopropyl) -methylamine in analogy to example 1, MS: 504.3(M + H) M/e+)。
Example 19
N- (2, 2-difluoro-cyclopropylmethyl) -2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
The title compound was prepared from C- (2, 2-difluoro-cyclopropyl) -methylamine in analogy to example 1, MS: 428.2(M + H)+)。
Example 20
2-methyl-N- (3-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ d)]Aza derivatives-1-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide
a) 2-methyl-malonic acid monoethyl ester
To a solution of 6.44g (115mmol) potassium hydroxide in 200ml ethanol was added 20.0g diethyl methyl-malonate (115mmol) and the mixture was refluxed for 4 hours. After cooling, the reaction mixture is concentrated on a rotary evaporator, 50ml of water are added and the mixture is extracted with diethyl ether (50ml × 2). The aqueous solution was acidified with 4M hydrochloric acid and extracted with ethyl acetate (50 ml. times.3). The combined organic layers were dried (MgSO)4) 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- (2, 2, 2-trifluoro-ethyl) -malonamic acid ethyl ester
To a solution of 1.56g (10.6mmol) of methyl-malonic acid monoethyl ester in 20ml of tetrahydrofuran were added 1.06g (10.6mmol) of 2, 2, 2-trifluoroethylamine, 2.05g (10.6mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 1.44g (10.6mmol) of 1-hydroxybenzotriazole hydrate and 2.75g (21.2mmol) of N, N-diisopropyl-ethylamine. The mixture was stirred at room temperature for 18 hours. Will be provided withThe mixture was poured onto 0.5N HCl (50ml) and extracted with dichloromethane (50 ml. times.3) after that. With 0.5NNaHCO3The combined organic layers were extracted with aqueous solution and dried (MgSO)4) And evaporated on a rotary evaporator. The residue was purified by column filtration (hexane/ethyl acetate 2: 1) to give 1.48g (61%) of the title compound as a white crystalline solid. MS m/e (%): 226.1 (M-H)+，100)。
c) 2-methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid
To a solution of 1.48g (6.52mmol) 2-methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid ethyl ester in 40ml tetrahydrofuran were added 20ml water and 1.09g (26mmol) lithium hydroxide and the mixture was stirred at room temperature overnight. After concentration in vacuo, water (50ml) was added and the mixture was extracted with dichloromethane (30 ml. times.3). The aqueous phase was acidified with 8N hydrochloric acid and extracted with dichloromethane (30 ml. times.4). The combined organic layers from the second extraction were dried (MgSO)4) And evaporated in vacuo to give 1.09g (84%) of the title compound as a white solid. MS m/e (%): 197, 9(M-H)+，100)。
d) 2-methyl-N- (3-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ d)]Aza derivatives -1-yl) -N' - (2, 2, 2- Trifluoro-ethyl) -malonamide
To a solution of 0.066g (0.3mmol) 2-methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid in 2ml tetrahydrofuran was added 0.057g (0.3mmol) (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives-2-one, 0.058g (0.3mmol) N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 0.040g (0.3mmol) 1-hydroxybenzotriazole hydrate and 0.116g (0.9mmol) N, N-diisopropyl-ethylamine. Mixing the mixtureStirred at room temperature for 18 hours. 0.5N HCl (5ml) was then added and the mixture was extracted with dichloromethane (5 ml. times.3). With 0.5N NaHCO3The combined organic layers were extracted with aqueous solution and dried (MgSO)4) And evaporated on a rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate 3: 1) to give 0.10g (89%) of the diastereomeric mixture of the title compound as a white solid. MS m/e (%): 372, 1(M + H)+，100)。
Example 21
2-methyl-N- (1-methyl-2-oxo-5-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide
The procedure as described in example 20 was followed, using (RS) -3-amino-1-methyl-5-phenyl-1, 3, 4, 5-tetrahydro-benzo [ b ] in step d)][1，4]Diaza derivatives-2-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 449.1(M + H)+，100)。
Example 22
N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-phenyl-N' - (2, 2, 2-trifluoro-ethyl) -malonamide
The procedure described in example 20 was followed using diethyl phenylmalonate instead of diethyl methyl-malonate in step a) and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ]]Aza derivatives-6-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step d)]Aza derivatives-6-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure as described in example 20Using diethyl 2-fluoro-2-methyl-malonate instead of diethyl methyl-malonate in step a), pentafluoropropylamine instead of 2, 2, 2-trifluoroethylamine in step b), and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step d)]Aza derivatives-6-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 488.2(M + H)+，100)。
Example 25
2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -3-amino-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-ketones
To 5.0g (18mmol) of (S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] at-75 deg.C][1，4]Diaza derivativesTo a solution of tert-butyl (3-yl) -carbamate in 80ml of tetrahydrofuran was added 18ml (18mmol) of a solution of lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran). After stirring at-75 ℃ for 30 minutes, the mixture was brought to room temperature and 3.07g (21.6mmol) of methyl iodide were added. The mixture was stirred at room temperature for 2.5 hours and concentrated in vacuo. Subjecting the residue to 1M NaHSO4The solution was partitioned with ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO)4). After evaporation of the solvent, 20ml of dichloromethane and 20ml of trifluoroacetic acid were added and the mixture was stirred at room temperature for 2.5 hours. For work-up, the mixture was concentrated in vacuo, then ethyl acetate was added and the mixture was extracted twice with water. The aqueous phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried (MgSO)4) And evaporated. The residue was purified by column chromatography (dichloromethane/methanol ═ 9: 1) to give 2.1g (65%) of (S) -3-amino-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b%][1，4]Diaza derivatives-2-ketones. MS m/e (%): 192.2 (M-H)+，100)。
b) 2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3- Base) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure as described in example 20 was followed, using pentafluoropropylamine instead of 2, 2, 2-trifluoroethylamine in step b), and (S) -3-amino-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b ] in step d)][1，4]Diaza derivatives-2-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 421.2 (M-H)+，100)。
Example 26
N- ((3S) -5-benzoyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
To a solution of 0.2g (0.47mmol) 2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivativesTo a solution of (E) -3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide in 3ml of dichloromethane were added 0.096g (0.95mmol) of triethylamine and 0.08mg (0.57mmol) of benzoyl chloride. The mixture was stirred at room temperature for 20 minutes. Hydrochloric acid (10ml of a 1N solution) was added and the mixture was extracted twice with dichloromethane. The combined organic layers were extracted with 1N sodium carbonate solution and dried (MgSO)4) And concentrated in vacuo. The remaining oil was purified by column chromatography to give 0.15g (60%) of a white foam. MS m/e (%): 527.3(M + H)+，100)。
Example 27
N- ((3S) -5-benzoyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2, 2-dimethyl-N' - (2, 2, 2-trifluoro-ethyl) -malonamide
The title compound was obtained in comparable yields according to the procedures described for example 25 using diethyl 2, 2-dimethylmalonate instead of diethyl methylmalonate and 2, 2, 2-trifluoroethylamine instead of pentafluoropropylamine in step b) and subsequently reacted with benzoyl chloride as described in example 26. MS m/e (%): 491.3(M + H)+，100)。
Example 28
N- [ (3S) -5- (4-fluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b][1，4]Diaza derivatives-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-fluorobenzoyl chloride instead of benzoyl chloride. MS m/e (%): 545.3(M + H)+，100)。
Example 29
N- [ (3S) -5- (4-chloro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-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-chlorobenzoyl chloride instead of benzoyl chloride. MS m/e (%): 561.4(M + H)+，100)。
Example 30
N- [ (3S) -5- (3, 5-difluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b [ -b ]][1，4]Diaza derivatives-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 3, 5-difluorobenzoyl chloride instead of benzoyl chloride. 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)]Aza derivatives-7-yl) -N' - (3, 3, 3-trifluoro-2-hydroxy-1, 1-dimethyl-propyl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, rac-3-amino-1, 1, 1-trifluoro-3-methyl-2-butanol instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] is used in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2-fluoroethylamine in step d) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ]]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2-difluoroethylamine in step d) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ]]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 420.1(M + H)+，100)。
Example 34
2-fluoro-N- (2-cis-fluoro-cyclopropyl) -2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, cis-2-fluorocyclopropylamine instead of (RS) in step d)-1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, 3, 4, 4-tetrafluorobutylamine (obtained from the corresponding bromide by the phthalimide method of Jacobs et al, J.Med.chem.1994, 37, 1282) is used in step d) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (4, 4, 4-trifluoro-butyl) -malonamide
Following the procedure described in example 20, in step (iii)Using diethyl 2-fluoro-2-methyl-malonate instead of diethyl methyl-malonate in step a), and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 4, 4, 4-trifluorobutylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 466.2(M + H)+，100)。
Example 37
2-fluoro-2-methyl-N- (3-methyl-butyl) -N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 3-methyl-butylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (1-trifluoromethyl-cyclopropylmethyl) -malonamide
Following the procedure described in example 20, diethyl 2-fluoro-2-methyl-malonate was used in step a) instead of diethyl methyl-malonate and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, 1-trifluoromethyl-cyclopropylmethylamine (obtained from the corresponding alcohol by the phthalimide method of Jacobs et al, J.Med.chem.1994, 37, 1282) is used in step d) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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]Diaza derivatives-1-carbonyl } -benzoic acid methyl ester
The title compound was obtained in comparable yields according to the procedures described for example 26 using 4- (methoxycarbonyl) -benzoyl chloride instead of benzoyl chloride. MS m/e (%): 583.3(M + H)+，100)。
Example 40
N- ((3S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 acetyl chloride instead of benzoyl chloride. MS m/e (%): 465.2(M + H)+，100)。
EXAMPLE 41
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide-10-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide
a) (RS) -11-amino-11H-dibenzo [ b, f)]Oxygen oxide -10-keto hydrochloride
To-20 ℃ 1.85g (8.77mmol) of 11H-dibenzo [ b, f ]]Oxygen oxideTo a solution of (E) -10-ketone in 4ml of toluene was added 2.5g (21.9mmol) of potassium tert-butoxide. With N2The solution was saturated. After stirring for 15 minutes, 1.2g (10.5mmol) of isoamyl nitrite were added. After stirring at room temperature overnight, the solution was cooled at 0 ℃ for 15 minutes, and water (80ml), acetic acid (4ml) and ethyl acetate (80ml) were added. The aqueous phase was extracted with ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO)4). After evaporation of the ethyl acetate, the resulting slurry of oxime in toluene was cooled to 0 ℃ over 1 hour and filtered. The solid material was dissolved in tetrahydrofuran (20ml), and 8ml of tetrahydrofuran containing 1M hydrochloric acid and 20mg of platinum oxide were added. With N2The reaction mixture was washed and placed under a hydrogen atmosphere at 50psi at room temperature. After stirring overnight under hydrogen atmosphere, the precipitate formed was collected by filtration, washed with tetrahydrofuran and recrystallized from a methanol tetrahydrofuran mixture to give 09g of white crystals (Fp.215-217 ℃ C.).
b) 2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide -10-yl) -N' - (2, 2, 2-trifluoro- Ethyl) -malonamide
Following the procedure described in example 20, in step d) (RS) -11-amino-11H-dibenzo [ b, f)]Oxygen oxide-10-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 407.3(M + H)+，100)。
Example 42
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide-10-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure described in example 20 was followed, using 2, 2, 3, 3, 3-pentafluoropropylamine in place of 2, 2, 2-trifluoroethylamine in step b), and (RS) -11-amino-11H-dibenzo [ b, f ] in step d)]Oxygen oxide-10-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS (Mass Spectrometry) m/e(％)：457.4(M+H+，100)。
Example 43
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (4, 4, 4-trifluoro-3-methoxy-butyl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, 4, 4, 4-trifluoro-3-methoxy-butylamine (obtained from 4, 4, 4-trifluoro-3-methoxybutyramide by lithium aluminium hydride reduction of Jacobs et al, J.Med.chem.1994, 37, 1282) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] amine in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 476.3 (M-H)+，100)。
Example 44
2-fluoro-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, 3, 4, 4-tetrafluorobutylamine is used in step d) (by Jacobs et al, J.MChem.1994, 37, 1282 phthalimide method, obtained from the corresponding bromide) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 464.2 (M-H)+，100)。
Example 45
N- (3-isopropoxy-propyl) -2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use 3-isopropoxy-propylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 436.3(M + H)+，100)。
Example 46
N- ((3S) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 cyclopropylmethyl bromide instead of methyl iodide in step a).MS m/e(％)：463.5(M+H+，100)。
Example 47
N- ((3S) -1, 5-dimethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3-yl) -carbamic acid methyl ester Tert-butyl ester
To 5.0g (18mmol) of (S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] at-75 deg.C][1，4]Diaza derivativesTo a solution of tert-butyl (3-yl) -carbamate in 80ml of tetrahydrofuran was added 18ml (18mmol) of a solution of lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran). After stirring at-75 ℃ for 30 minutes, the mixture was brought to room temperature and 3.07g (21.6mmol) of methyl iodide were added. The mixture was stirred at room temperature for 2.5 hours and concentrated in vacuo. The residue was partitioned between 1M NaHSO4Between the solution and ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO)4) This gave 4.95g (94%) (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester as a white foam. MS m/e (%): 292.0(M + H)+，100)。
b) (S) -3-amino-1, 5-dimethyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]IIAza derivatives-2-ketones
To a solution containing 0.29g (1mmol) of (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivativesTo dimethylformamide (3ml) of tert-butyl (3-yl) -carbamate were added 0.46g (3.33mmol) of potassium carbonate and 0.17g (1.2mmol) of methyl iodide and the mixture was stirred at room temperature overnight. Water (10ml) was added and the mixture was extracted twice with ethyl acetate (10ml each). The combined organic layers were dried (MgSO)4) And purified by column chromatography (hexane/ethyl acetate 1: 1) to give 0.19g (62%) of a white solid. The compound was dissolved in a mixture of 2ml dichloromethane and 2ml trifluoroacetic acid and stirred at room temperature for 2.5 hours. For work-up, the mixture is concentrated in vacuo, then dichloromethane is added and the mixture is extracted with sodium bicarbonate solution. The organic phase was dried (MgSO)4) And evaporated to give 0.12g of (S) -3-amino-1, 5-dimethyl-1, 3, 4, 5-tetrahydro-benzo [ b ]][1，4]Diaza derivatives-2-ketone as a pale yellow solid. MS m/e (%): 206.4(M + H)+，100)。
c) N- ((3S) -1, 5-dimethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3- 2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure as described in example 20 was followed, using pentafluoropropylamine instead of 2, 2, 2-trifluoroethylamine in step b), and (S) -3-amino-1, 5-dimethyl-1, 3, 4, 5-tetrahydro-benzo [ b ] in step d)][1，4]DinitrogenHetero compound-2-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 437.5(M + H)+，100)。
Example 48
N- ((3S) -5-cyclopropylmethyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 cyclopropylmethyl bromide instead of methyl iodide in step b). MS m/e (%): 477.3(M + H)+，100)。
Example 49
N- [5- ((3S) -4-fluoro-benzyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 4-fluorobenzyl bromide instead of methyl iodide in step b). MS m/e (%): 531.3(M + H)+，100)。
Example 50
N- [ (3S) -5- (4-chloro-benzoyl) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 26, N- ((3S) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide instead of 2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide using 4-chlorobenzoyl chloride instead of benzoyl chloride to obtain the title compound in comparable yields. MS m/e (%): 601. 5(M + H)+，100)。
Example 51
N- (5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) 5-Cyclopropylmethyl-5H, 7H-dibenzo [ b, d ]]Aza derivatives -6-ketones
0.5g (2.4mmol) of 5H, 7H-dibenzo [ b, d ] at room temperature]Aza derivativesTo a solution of the-6-ketone in 6ml of dimethylformamide was added 0.143g (3.58mmol) of sodium hydride. After stirring at 60 ℃ for 1 hour,0.97g (7.2mmol) of cyclopropylmethyl bromide was added and stirring was continued at 60 ℃ overnight. After cooling to room temperature, the mixture was partitioned between water and dichloromethane. The combined organic layers were re-extracted with sodium sulfate solution and dried (MgSO)4). After concentration in vacuo, the residue was purified by column chromatography (hexane/ethyl acetate 1: 1) to give 0.6g (95%) of 5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ]]Aza derivatives-6-ketone as white crystalline compound. MS m/e (%): 264.1(M + H)+，100)。
b) (RS) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
To a solution of 0.3g (1.14mmol) of 5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ]]Aza derivativesTo a solution of-6-one in 5ml of toluene was added 0.285g (2.44mmol) of isoamyl nitrite and the mixture was cooled to 0 ℃. 3.6ml (1.83mmol) of a solution of potassium bis (trimethylsilyl) amide (0.5M in toluene) are slowly added and stirring is continued at this temperature for 1 hour. Sodium hydrogen sulfate solution was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO)4). After evaporation of the solvent, 0.2g of a white foam was obtained, which was dissolved in ethanol (5 ml). Palladium on carbon (90mg) was added and the mixture was heated at 2.5 bar H2The mixture was hydrogenated under pressure for 32 hours. The catalyst is filtered off and the solvent is evaporated. The residue was partitioned between dichloromethane (5ml) and 4N hydrochloric acid (2 ml). The aqueous solution was separated, brought to basic pH with sodium hydroxide and extracted 2 times with ethyl acetate. Drying (MgSO)4) And evaporation of the ethyl acetate gave 0.1g (52%) of an off-white solid. MS m/e (%): 279.3(M + H)+，100)。
c) N- (5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -2-methyl -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure described in example 20 was followed, using 2, 2, 3, 3, 3-pentafluoropropylamine in place of 2, 2, 2-trifluoroethylamine in step b), and (RS) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] in step d)]Aza derivatives-6-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 508.4 (M-H)+，100)。
Example 52
N- ((3S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) 5-acetyl-3-amino-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-ketones
0.5g (1.8mmol) of (S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivativesA solution of-3-yl) -carbamic acid tert-butyl ester in 1.7ml acetic anhydride was stirred at 65 ℃ for 3 hours. The mixture was poured onto water (5ml) and extracted twice with dichloromethane (10ml each time). The combined organic layers were dried (MgSO)4) And evaporated to give 0.6g of a pale yellow foam. The compound was dissolved in a mixture of 2ml dichloromethane and 2ml trifluoroacetic acid and stirred at room temperature for 2.5 hours. For work-up, the mixture is concentrated in vacuo, then dichloromethane is added and the mixture is extracted with sodium bicarbonate solution. The organic phase was dried (MgSO)4) And evaporated to give 0.31g of (S) -1-acetyl-3-amino-1, 3, 4, 5-tetrahydro-benzo [ b ]][1，4]Diaza derivatives-2-ketone as a pale yellow solid. MS m/e (%): 220.4(M + H)+，100)。
b) N- (1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3-yl) -2-methyl -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure as described in example 20 was followed, using pentafluoropropylamine instead of 2, 2, 2-trifluoroethylamine in step b), and (RS) -1-acetyl-3-amino-1, 3, 4, 5-tetrahydro-benzo [ b ] in step d)][1，4]Diaza derivatives-2-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 449.2(M + H)+，100)。
Example 53
N- ((3S) -5-acetyl-1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 26, N- ((3S) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide instead of 2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide using acetyl chloride instead of benzoyl chloride, to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use 3-tert-butoxy-propylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 396.2 (M-C)4H9+H+，100)；452.2(M+H+，43)。
Example 55
2-methyl-N- ((3S) -2-oxo-1-prop-2-ynyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 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-cyclopropanecarbonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-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 benzoyl chloride. MS m/e (%): 491.5(M + H)+，100)。
Example 57
2-ethyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
According to example 20, ethyl-malonic acid diethyl ester is used instead of methyl-malonic acid diethyl ester in step a), and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] is used in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2, 3, 3, 3-pentafluoropropylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 484.5(M + H)+，100)。
Example 58
2-isopropyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 20, isopropyl-malonic acid diethyl ester was used instead of methyl-malonic acid diethyl ester in step a) and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2, 3, 3, 3-pentafluoropropylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 498.5(M + H)+，100)。
Example 59
N- ((3S) -5-cyclopropylmethyl-2-oxo-1-prop-2-ynyl-2, 3,4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-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-cyclopropanecarbonyl-2-oxo-1-prop-2-ynyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 26, 2-methyl-N- ((3S) -2-oxo-1-prop-2-ynyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] was used][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide instead of 2-methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide using cyclopropanecarbonyl chloride instead of benzoyl chloride gave the title compound in comparable yields. MS m/e (%): 515.4(M + H)+，100)。
Example 61
N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 20, diethyl malonate was used in place of methyl-diethyl malonate in step a) and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2, 3, 3, 3-pentafluoropropylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. 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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 20, diethyl 2, 2-dimethyl-malonate was used in place of methyl-malonate in step a) and (RS) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in step b)]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2, 3, 3, 3-pentafluoropropylamine in step d) instead of (RS) 1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ],]aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 484.5(M + H)+，100)。
Example 63
N- (3-fluoro-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-3-fluoro-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one (prepared in the same way as the 2-fluoro derivative in WO 9932453) instead of 2, 2, 2-trifluoroethylamine, 2, 2, 3, 3, 3-pentafluoropropylamine is used in step d) instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] amine]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 486.4 (M-H)+，100)。
Example 64
N- (2-fluoro-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 20, in step b) (RS) -7-amino-2-fluoro-5-methyl-5H, 7H-dibenzo [ b, d ] was used]Aza derivatives-6-one instead of 2, 2, 2-trifluoroethylamine, use of 2, 2, 3, 3, 3-pentafluoropropylamine instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d ] in step d)]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 486.2 (M-H)+，100)。
Example 65
2-methyl-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a)5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
To 0.82g (4mmol) of 5H, 7H-dibenzo [ b, d ] at room temperature]Aza derivativesTo a solution of-6-one in 15ml of dimethylformamide was added 0.20g (5mmol) of sodium hydride (55% in oil). After stirring for 30 minutes at room temperature, 0.75g (5mmol) of p-methoxybenzyl chloride was added and stirring was continued for 2 hours at room temperature. For work-up, the mixture was partitioned between water and ethyl acetate. The organic layer was re-extracted with 1N hydrochloric acid and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried (MgSO)4) And concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate 1: 1) to give 1.175g (91%) of 5- (4-methoxybenzyl) -5H, 7H-dibenzo [ b, d ]]Aza derivatives-6-ketone as colorless oil. MS m/e (%): 330.4(M + H)+，100)。
b) (RS) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
To a solution of 1.15g (3.5mmol) of 5- (4-methoxybenzyl) -5H, 7H-dibenzo [ b, d ]]Aza derivativesTo a solution of-6-one in 15ml of toluene was added 0.836g (7mmol) of isoamyl nitrite and the mixture was cooled to 0 ℃. A solution of 21.4ml (10.5mmol) of potassium bis (trimethylsilyl) amide (0.5M in toluene) was added slowly and stirring continued at this temperature for 2 hours. Sodium hydrogen sulfate solution was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO)4). After evaporation of the solvent, a solid was obtained which was purified by column chromatography (dichloromethane/methanol 95: 5) to yield 1.03g (81%) of oxime. This compound was dissolved in ethanol (5ml) and 1.5ml of 2N hydrochloric acid was added. Palladium on carbon (10%, Degussa 1835, 100mg) was added and the mixture was cooled to room temperature and 5 bar H2Hydrogenation under pressure for 24 hours, filtering off the catalyst and evaporating the solvent. The residue was partitioned between dichloromethane (5ml) and 4N hydrochloric acid (2 ml). The aqueous solution was separated, brought to basic pH with sodium hydroxide and extracted 2 times with ethyl acetate. After drying (MgSO)4) And after evaporation of the ethyl acetate 0.8g (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]Aza derivatives -6-ketones
To 0.1g (0.29mmol) of (RS) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d ] at a temperature of 0 deg.C]Aza derivativesTo a solution of the-6-ketone in 8ml of dichloromethane were added 0.67ml (8.7mmol) of trifluoroacetic acid and 0.25ml of trifluoromethanesulfonic acid (2.9mmol) and the mixture was stirred at room temperature for 4 hours. After concentrating the mixture at 40 ℃ in vacuo, NaHCO was added3Aqueous solution and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO)4). After evaporation of the solvent, a pale yellow oil was obtained which was used directly in the next step.
d) (RS) -2-methyl-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7- Base) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure described in example 20 was followed, using 2, 2, 3, 3, 3-pentafluoropropylamine in place of 2, 2, 2-trifluoroethylamine in step b), and (RS) -7-amino-5H, 7H-dibenzo [ b, d ] in step d)]Aza derivatives-6-one instead of (RS) -1-amino-3-methyl-1, 3, 4, 5-tetrahydro-benzo [ d]Aza derivatives2-ketone to obtain the title compound in comparable yields. MS m/e (%): 456.5(M + H)+，100)。
Example 66
N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
Separation of Racemic (RS) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d ] by Chiralpak AD chromatography using isopropanol/heptane 1: 3 as solvent]Aza derivatives-6-one to give (S) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d]Aza derivatives-6-ketone, [ alpha ]]589 ═ -146 ° (in CHCl)31%) and (R) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d ]]Aza derivatives-6-ketone, [ alpha ]]589 +148 ° (in CHCl)31% of the total).
b) (S) -N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro- Propyl) -malonamide
(S) -7-amino-5- (4-methoxy-benzyl) -5H, 7H-dibenzo [ b, d ] was removed as described in example 65 part c)]Aza derivatives-methoxybenzyl of 6-one and the resulting (S) -7-amino-5H, 7H-dibenzo [ b, d ] according to the procedure described in example 65 part d)]Aza derivatives-6-one with N- (2)2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to obtain (S) -N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide, [ alpha ]]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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in examples 65 and 66]Aza derivativesCoupling of-6-one with 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give 2, 2-dimethyl-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide, [ alpha ]]589 ═ -38.8 ° (in CHCl)3Middle 1%), MSm/e (%): 470.3(M + H)+，100)。
Example 68
(-) -2-methoxy-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) Methyl ester of malonamic acid
Coupling 2-methoxy-malonic acid monomethyl ester with 2, 2, 3, 3, 3-pentafluoro-propylamine in analogy to the procedure described in example 73, to give 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid methyl ester as colorless oil, MS m/e (%): 280.0(M + H)+，100)。
b) 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid
Saponification of 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid methyl ester following a procedure analogous to example 75b gave 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid as a white solid, MS m/e (%): 266.0(M + H)+，100)。
c) (-) -2-methoxy-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7- Base) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in examples 65 and 66]Aza derivativesCoupling the (E) -6-ketone and 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to obtain (-) -2-methoxy-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid, [ alpha ]]589 ═ -87.6 ° (1% in MeOH), MS m/e (%): 472.0(M + H)+，100)。
Example 69
(2R) -2-fluoro-2-methyl-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (2S) -2-fluoro-2-methyl-N- [ (S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-C Amidoacid ethyl ester
(S) -7-amino-5H, 7H-dibenzo [ b, d) in a similar manner to that described in example 1a)]Aza derivativesCondensation of (2S) -2-fluoro-2-methyl-malonic acid monoethyl ester (96.9% e.e.) with (6-one) to give the title compound as a white solid; MS: 371(M + H) M/e+。
Stereoselective hydrolysis of the corresponding diester with Candida cylindracea hydrolase gave (2S) -2-fluoro-2-methyl-malonic acid monoethyl ester according to the procedure described in J.org.chem.1986, 51, 1003-6.
b) (2S) -2-fluoro-2-methyl-N- [ (S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives -7-yl]-C Amidoacids
(2S) -2-fluoro-2-methyl-N- [ (S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d) was hydrolyzed under basic conditions in a similar manner to that described in example WC b)]Aza derivatives-7-yl]-malonamic acid ethyl ester to give the title compound as a white foam; MS: 341M/e (M-H)-。
c) (2R) -2-fluoro-2-methyl-N- [ (S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives -7- Base of]-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) was reacted in a similar manner to that described in example 1c)]Aza derivatives-7-yl]Condensation of malonamic acid with 2, 2, 3, 3, 3-pentafluoro-propylamine to give the title compound as a white solid; MS: 474(M + H)+(ii) a Optical purity (optical integration) 96.4% d.e.
Example 70
(2S) -2-fluoro-2-methyl-N- [ (S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Reacting (S) -7-amino-5H, 7H-dibenzo [ b, d) in a similar manner as described in example 20d)]Aza derivativesCondensation of (2S) -2-fluoro-2-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid with (6-ketone to give the title compound as a white solid; MS: 474(M + H)+。
Example 71
N- ((S) -5-cyclopropylmethyl-6-oxo6, 7-dihydro-5H-dibenzo [ b, d ] s]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
Separation of (RS) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] by HPLC using isopropanol/heptane 1: 4 on Chiralpak AD]Aza derivatives-6-one to give (S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d]Aza derivatives-6-ketone, [ alpha ]]589 ═ -162 ° (1% in MeOH), and (R) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ═]Aza derivatives-6-ketone, [ alpha ]]589 ═ 163 ° (1% in MeOH).
Para-derivative (S) -N- ((R) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2- (6-methoxy-naphthalen-2-yl) -propionamide the absolute configuration was arranged and x-ray analyzed by derivatization with (-) - (S) -naproxen.
0.05g (0.18mmol) (+) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d]Aza derivativesA solution of the-6-one in tetrahydrofuran is reacted at room temperature overnight with 0.04g (0.18mmol) (+) - (S) -naproxen, 0.03g (0.18mmol) 1-hydroxybenzotriazole, 0.063. mu.l (0.36mmol) diisopropylethylamine and 0.04g (0.18mmol) N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide-hydrochloride. Extraction with 1N aqueous hydrochloric acid/dichloromethane and chromatography on silica gel gave 0.09g (97%) of (S) -N- ((R) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d%]Aza derivatives-7-yl) -2- (6-methoxy-naphthalen-2-yl) -propionamide as a white solid, which is crystallized from ethanol. mp.: 151 ℃ 152 ℃, MS m/e (%): 491.4(M + H)+，100)。
b) N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7- Base) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
0.11g (0.38mmol) of (S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] in 10ml of tetrahydrofuran at 0 DEG]Aza derivatives-6-one and 0.09g (0.38mmol) 3-oxo-3- (2, 2, 3, 3, 3-pentafluoro-propylamino) -propionic acid were reacted with 0.06g (0.38mmol) 1-hydroxybenzotriazole hydrate, 0.13. mu.l (0.76mmol) diisopropylethylamine and 0.7g (0.38mmol) N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide-hydrochloride for 4 hours. After stirring overnight at room temperature, the solvent was removed by distillation and the residue was purified by silica gel chromatography using heptane/ethyl acetate (gradient 100-0/0-100) to give 0.17g (89%) of N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ -63.9 ° (in CHCl)31%) MS m/e (%): 496.3(M + H)+，100)。
Example 72
(R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
0.15g (0.54mmol) of (S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] in 13ml of tetrahydrofuran]Aza derivatives-6-ketone and 0.13g (0.54mmol) 2-methyl-3-oxo-3- (2, 2, 3, 3, 3-pentafluoro-propylamino) -propionic acid were reacted with 0.07g (0.54mmol) 1-hydroxybenzotriazole hydrate, 0.19. mu.l (1.08mmol) diisopropylethylamine and 0.11g (0.54mmol) N- (3-dimethylaminopropyl) -N' -ethyl-carbodiimide-hydrochloride at room temperature overnight with stirring. Extraction with 1N aqueous hydrochloric acid/dichloromethane and chromatography on silica gel using ethyl acetate gave 0.22g of a solid which was isolated by chromatography on Chiralpak AD, heptane/isopropanol 80/20 to give: 0.10g of (R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl)-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide [ alpha ]]589 ═ -74.6 ° (in CHCl)3Middle 1%), MSm/e (%): 510.3(M + H)+100), as a white solid; and 0.09g of (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide [ alpha ]]589 ═ -63.8 ° (in CHCl)31%) MS m/e (%): 510.3(M + H)+100), as a white solid.
Example 74
N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of-6-one with 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ 60.4 ° (in CHCl)31%) MS m/e (%): 524.3(M + H)+，100)。
Example 75
(R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives -7-yl) -2- Fluoro-2-methyl-malonamic acid ethyl ester
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling the (S) -6-ketone and (S) -2-fluoro-2-methyl-malonic acid monoethyl ester to obtain (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-fluoro-2-methyl-malonamic acid ethyl ester as colorless oil. MS m/e (%): 425.4(M + H)+，100)。
b) (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -2- Fluoro-2-methyl-malonamic acid
0.22g (0.52mmol) of (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ] in 3ml of tetrahydrofuran are introduced]Aza derivatives-7-yl) -2-fluoro-2-methyl-malonamic acid ethyl ester with 0.02g (0.52mmol) lithium hydroxide monohydrate in 1ml waterThe solution of (2) was reacted at room temperature for 2 hours. Tetrahydrofuran is evaporated, extracted with diethyl ether, acidified with 0.5ml of 1N aqueous hydrochloric acid and extracted with ethyl acetate to give 0.18g of (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives -7-yl) -2- fluoro-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) according to a procedure analogous to that described for RJR7]Aza derivativesCoupling (R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d) with (E) -7-yl) -2-fluoro-2-methyl-malonamic acid and 2, 2, 3, 3, 3-pentafluoropropylamine]Aza derivatives-7-yl) -2-fluoro-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ 45.7 ° (in CHCl)31%) MS m/e (%): 528.2(M + H)+，100)。
Example 76
N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyloxy-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of-6-one with 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methoxy-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of the-6-ketone with N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide as a white solid. [ alpha ] to]589 ═ -57.5 ° (in CHCl)31%) MS m/e (%): 510.1(M + H)+，100)。
Example 78
N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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
In a similar manner as described in example 73, 2-methyl-malonic acid monoethyl ester was coupled with 3, 3, 4, 4, 4-pentafluoro-butylamine to give 2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid ethyl ester as colorless 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 acid ethyl ester was saponified in analogy to the procedure of example 75b to give 2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid as white solid. MS m/e (%): 262.1 (M-H)+，100)。
c) N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -2-methyl based-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivatives-6-one with 2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -propionylAmino acid coupling to obtain N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide (epimer) as a white solid. MS m/e (%): 524.2(M + H)+，100)。
Example 79
N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2, 2-dimethyl-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
(S) -7-amino-5-cyclopropylmethyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of-6-one with 2, 2-dimethyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2, 2-dimethyl-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide (epimer) as a white solid, [ alpha ]]589 ═ 64.9 ° (in CHCl)31%) MS m/e (%): 538.3(M + H)+，100)。
Example 80
(R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-fluoro-2-methyl-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
Following a procedure analogous to that described in example 73, (S) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivativesCoupling (R) -N- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ] is obtained by coupling (7-yl) -2-fluoro-2-methyl-malonamic acid with 3, 3, 4, 4, 4-pentafluoro-butylamine]Aza derivatives-7-yl) -2-fluoro-2-methyl-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide as a white solid. [ alpha ] to]589 ═ -56.7 ° (in CHCl)31%) MS m/e (%): 542.0(M + H)+，100)。
Example 81
N- (5-isopropyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Following the procedure described in example 65, using 2-iodopropane instead of p-methoxybenzyl chloride in step a), while eliminating step c), step d) was performed directly to give the title compound in comparable yields. MS m/e (%): 496.1 (M-H)+，100)。
Example 82
N- (5-isopropyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
The procedure described in example 65 was followed using 2-iodopropane instead of p-methoxybenzyl chloride in step a), with elimination of stepStep c), using 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid instead of 2-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid in step d), gives the title compound in comparable yields. MS m/e (%): 510.3 (M-H)+，100)。
Example 83
N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of the-6-ketone with N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ -52.7 ° (in CHCl)31%) 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)]Aza derivatives-7-yl) -N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] was reacted in a similar manner to that described in example 73]Aza derivativesCoupling of-6-one with 2, 2-dimethyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give 2, 2-dimethyl-N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ] a]Aza derivatives-7-yl) -N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ 53.8 ° (in CHCl)31%) MS m/e (%): 484.0(M + H)+，100)。
Example 85
(2R) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-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)]Aza derivatives -7-yl) -malonamic acid ethyl ester
(S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in a similar manner to that described in example 1a)]Aza derivativesCondensation of-6-ketone and (2S) -2-fluoro-2-methyl-malonic acid monoethyl ester to give the title compound as colorless oil; MS: 385(M + H)+。
The corresponding diester was stereoselectively hydrolyzed by Candida cylindracea hydrolase to give (2S) -2-fluoro-2-methyl-malonic acid monoethyl ester (optical purity 91% e.e.) according to the procedure described in J.org.chem.1986, 51, 1003-6.
b) (2S) -2-fluoro-2-methyl-N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives -7-yl) -malonamic acid
75mg (0.2mmol) of (2S) -2-fluoro-2-methyl-N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ] are reacted at room temperature with a solution of 8mg (0.2mmol) of lithium hydroxide monohydrate in 0.5ml of water]Aza derivativesA solution of-7-yl) -malonamic acid ethyl ester in 1ml of tetrahydrofuran was treated for 2 hours. For working up, tetrahydrofuran was evaporated under reduced pressure and the remaining aqueous layer was extracted twice with 10ml of diethyl ether. The combined organic layers were washed with 5ml of water, after which the combined aqueous layers were acidified with 0.025ml of hydrochloric acid (25%). Then, the aqueous layer was extracted three times with 15ml of ethyl acetate. The organic layers were washed with 15ml of saturated sodium chloride solution and then combined, dried over sodium sulfate and evaporated under reduced pressure. 69mg (99% of theory) of the title compound are obtained as a white foam; MS: 355(M-H) M/e-。
c) (2R) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives -7-yl]-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) in a similar manner to that described in example 1c)]Aza derivativesCondensation of-7-yl) -malonamic acid and 2, 2, 3, 3, 3-pentafluoro-propylamine to give the title compound as a white foam; MS: (488) m/eM+H)+(ii) a Optical purity 94% d.e.
Example 86
(2S) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Reacting (S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d) in a similar manner to that described in example 20d)]Aza derivativesCondensation of-6-ketone and (2S) -2-fluoro-2-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give the title compound as a white solid; MS: m/e 488(M + H)+。
(2S) -2-fluoro-2-methyl-N- (2, 2, 3, 3-pentafluoro-propyl) -malonamic acid was obtained by a reaction sequence analogous to that which gave (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ] ], replacing (2RS) -methyl-malonic acid monoester with (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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in a similar manner to that described in example 73]Aza derivativesCoupling of-6-one with 2-methoxy-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give 2-methoxy-N- ((S) -5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid. [ alpha ] to]589 ═ -71.8 ° (in CHCl)31%) MS m/e (%): 486.4(M + H)+，100)。
Example 88
N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
(S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d ] in a similar manner to that described in example 73]Aza derivativesCoupling of the-6-ketone with N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide as a white solid. [ alpha ] to]589 ═ 51.4 ° (in CHCl)31%) MS m/e (%): 470.1(M + H)+，100)。
Example 89
2, 2-dimethyl-N- [ (S) -6-oxo-5- (2, 2, 2-trifluoro-ethyl) -6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) 7-amino-5- (2, 2, 2-trifluoro-ethyl) -5H, 7H-dibenzo [ b, d]Aza derivatives -6-ketones
Separation of Racemic (RS) -7-amino-5- (2, 2, 2-trifluoro-ethyl) -5H, 7H-dibenzo [ b, d ] by chromatography on Chiralpak AD using isopropanol/heptane 1: 3]Aza derivatives-6-ketone to give: (S) -7-amino-5- (2, 2, 2-trifluoro-ethyl) -5H, 7H-dibenzo [ b, d]Aza derivatives-6-ketone, [ alpha ]]589 ═ 29 ° (in CHCl)31%) and (R) -7-amino-5- (2, 2, 2-trifluoro-ethyl) -5H, 7H-dibenzo [ b, d ]]Aza derivatives-6-ketone, [ alpha ]]589 ═ 26 ° (in CHCl)31% of the total).
b) (S) -2, 2-dimethyl-N- [ (S) -6-oxo-5- (2, 2, 2-trifluoro-ethyl) -6, 7-dihydro-5H-dibenzo [b，d]Aza derivatives -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 ] in a similar manner to that described in example 73]Aza derivativesCoupling the (E) -6-ketone and 2, 2-dimethyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to obtain (S) -2, 2-dimethyl-N- [ (S) -6-oxo-5- (2, 2, 2-trifluoro-ethyl) -6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide as a white solid, [ alpha ]]589 ═ -13.9 ° (in CHCl)31.1%) MS m/e (%): 550.5 (M-H)+，100)。
Example 90
(2RS) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
Reacting (S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d) in a similar manner to that described in example 20d)]Aza derivativesCondensation of (6-one) with (2RS) -2-fluoro-2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give the title compound as a white solid; MS: m/e 502(M + H)+。
(2RS) -2-fluoro-2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid [ J.fluorine Chemistry, 55(1), 85(1991) ] was obtained by replacing (2RS) -methyl malonate monoester with (2RS) -2-fluoro-2-methyl malonate monoester and 2, 2, 2-trifluoro-ethylamine with 3, 3, 4, 4, 4-pentafluoro-butylamine according to a reaction sequence analogous to that leading to (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ].
Examples 91 and 92
(2R) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide and
(2S) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
Using a preparative chiral HPLC column (AD, pressure: flow rate: 35 ml/min), 0.2g of (2RS) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ] using a 4: 1 mixture of N-heptane and isopropanol as eluent]Aza derivatives-7-yl]Two isomers of-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide (example WG). 23mg [ 11% of theory, optical purity > 99.5% d.e., MS: m/e 502(M + H)+]First eluting isomer (2R) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide and 22mg [ 11% of theory, optical purity > 99.5% d.e., MS: m/e 502(M + H)+]Late eluting isomer (2S) -2-fluoro-2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d [ ]]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide, which is a yellow foam.
Example 93
(2RS) -2-methyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
Reacting (S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d) in a similar manner to that described in example 20d)]Aza derivativesCondensation of (2RS) -2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid with (6-one to give the title compound as a white solid; MS: m/e-484 (M + H)+。
(2RS) -2-methyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid was obtained by a reaction sequence analogous to that for the formation of (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ] by replacing 2, 2, 2-trifluoro-ethylamine with 3, 3, 4, 4, 4-pentafluoro-butylamine [ J.fluorinine Chemistry, 55(1), 85(1991) ].
Example 94
2, 2-dimethyl-N- [ (S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl]-N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide
Reacting (S) -7-amino-5-methyl-5H, 7H-dibenzo [ b, d) in a similar manner to that described in example 20d)]Aza derivativesCondensation of-6-ketone with 2, 2-dimethyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid to give the title compound as a white solid; MS: m/e 498(M + H)+。
2, 2-dimethyl-N- (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamic acid was obtained by a reaction sequence analogous to that for the formation of (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ] ] by substituting 2, 2-dimethyl-malonic acid monoester for (2RS) -methyl-malonic acid monoester and 3, 3, 4, 4, 4-pentafluoro-butylamine for 2, 2, 2-trifluoro-ethylamine.
Example 95
(2RS) -methyl-N- ((3S) -1-methyl-2-oxo-5-trifluoromethanesulfonyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(2RS) -methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted in a similar manner as described in example 26][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide [ example 25]Reaction with trifluoromethanesulfonic anhydride to give the title compound as a white foam; MS: m/e 555(M + H)+。
Example 96
N- ((3S) -5-formyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 26, (2RS) -methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is acylated with acetic anhydride and formic acid][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide to give the title compound as a pale yellow foam; MS: 451(M + H) M/e+。
Example 97
N- [ (3S) -5- (2-fluoro-acetyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 26, (2RS) -methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] was acylated with fluoroacetyl chloride][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide to give the title compound as a pale yellow foam; MS: m/e 483(M + H)+。
Example 98
(2RS) -methyl-N- [ (3S) -1-methyl-2-oxo-5- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Acylation of (2RS) -methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] with trifluoroacetic anhydride in a similar manner to that described in example 26][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide to give the title compound as a white foam; MS: 519(M + H)+。
Example 99
N- [ (3S) -5- (2-methoxy-acetyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 26, (2RS) -methyl-N- ((3S) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] was acylated with methoxyacetyl chloride][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide to give the title compound as a pale 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 ]][1，4]Diaza derivatives-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]Diaza derivatives -2-keto salts Acid salts
(S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b) was reacted with 2, 2, 2-trifluoroethyl trifluoromethanesulfonate in a similar manner to that described in example 25a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester alkylation followed by acid catalyzed cleavage of the tert-butoxycarbonyl group to give the title compound as a yellow solid.
b) (2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [b][1，4]Diaza derivatives -3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -3-amino-1- (2, 2, 2-trifluoro-ethyl) -1, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner to that described in example 20d)][1，4]Diaza derivatives-2-keto hydrochloride and (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b]]Condensation to give the title compound as a white solid; MS: 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]Diaza derivatives -3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted in a similar manner to that described in example 26][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide was reacted with methanesulfonic anhydride to give the title compound as a off-white amorphous mass; 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-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted in a similar manner to that described in example 26][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide was reacted with trifluoromethanesulfonic anhydride to give the title compound as a white amorphous material; MS: 623(M + H) M/e+。
Example 102
(2RS) -methyl-N- [ (S) -2-oxo-5- (2, 2, 2-trifluoro-acetyl) -1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted in a similar manner to that described in example 26][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide was reacted with trifluoroacetic anhydride to give the title compound as a pale yellow solid; MS: 587(M + H)+。
Example 103
(S) -N- (5-methanesulfonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3-yl) -carbamic acid Tert-butyl ester
(S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted with methyl iodide as described in example 25a)][1，4]Diaza derivativesAlkylation of tert-butyl (3-yl) -carbamate, chromatography on silica gel using a 3: 1-n-heptane mixture with ethyl acetate as eluent to give (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester as a light yellow foam; MS: 292(M + H) M/e+。
b) [ (S) -5-methanesulfonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives -3- Base of]-carbamic acid tert-butyl ester
A mixture of 623mg (3.4mmol) of methanesulfonic anhydride and 0.12ml (0.7mmol) of N-ethyl-diisopropylamine is cooled to 0 ℃ and treated with 200mg (0.7mmol) of (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] b][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester in 2ml dichloromethane. The reaction mixture was warmed to room temperature and stirred over 18 hours. For working up, the reaction mixture is cooled to 0 ℃ and treated with saturated sodium carbonate solution. The organic layer was separated, washed with saturated ammonium hydrochloride solution and water, finally dried over sodium sulfate and evaporated. For purification, the crude material was chromatographed on silica gel using 96: a mixture of 4-dichloromethane and ethyl acetate was used as eluent. 100mg (40% of theory) of ((S) -5-methanesulfonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] are obtained][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester as a white foam; MS: 370(M + H) M/e ═ e+。
c) (S) -3-amino-5-methanesulfonyl-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-keto salts Acid salts
100mg (0.27mmol) of ((S) -5-methanesulfonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is treated with 0.22ml of hydrochloric acid][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester in 5ml dioxane and heated at 50 ℃ in a sealed flask for 1 hour. For working up, the solvent is evaporated under reduced pressure and the residue is azeotropically distilled with toluene. After drying under reduced pressure, quantitative yield of (S) -3-amino-5-methanesulfonyl-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b ] was obtained][1，4]Diaza derivatives-2-keto hydrochlorideAs a pale yellow solid; MS: m/e 270(M + H)+。
d) (S) -N- (5-methanesulfonyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives -3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -3-amino-5-methanesulfonyl-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner as described in example 20d)][1，4]Diaza derivatives-2-keto hydrochloride with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white foam; MS: m/e 501(M + H)+。
Example 104
N- [ (S) -5- (2, 2-dimethyl-propionyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-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-1H-benzo [ b)][1，4] Diaza derivatives -3-yl]-carbamic acid tert-butyl ester
Acylation of (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b) with pivaloyl chloride in a similar manner as described in example 103b)][1，4]DinitrogenHetero compound-3-yl) -carbamic acid tert-butyl ester to give the title compound as a white solid; MS: m/e 376(M + H)+。
b) (S) -3-amino-5- (2, 2-dimethyl-propionyl) -1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]IINitrogen is present inHetero compound -2-keto hydrochloride
Cleaving [ (3S) -5- (2, 2-dimethyl-propionyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b) in a similar manner as described in example 103c)][1，4]Diaza derivatives-3-yl]-tert-butoxy-carbonyl of tert-butyl carbamate to give the title compound as a white solid; MS: m/e 276(M + H)+。
c) N- [ (S) -5- (2, 2-dimethyl-propionyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4] Diaza derivatives -3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 20d), ((S) -3-amino-5- (2, 2-dimethyl-propionyl) -1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b)][1，4]Diaza derivativesCondensation of-2-keto hydrochloride with N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give the title compound as a white foam; MS: 493(M + H)+。
N- (2, 2, 3, 3-pentafluoro-propyl) -malonamic acid was obtained by replacing (2RS) -methyl-malonic acid monoester with malonic acid monoester according to a reaction sequence analogous to that which gave (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ] ].
Example 105
N- [ (3S) -5- (2, 2-dimethyl-propionyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -3-amino-5- (2, 2-dimethyl-propionyl) -1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner to that described in example 20d)][1，4]Diaza derivatives-2-keto hydrochloride with (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c)]Condensation to give the title compound as a white foam; MS: 507(M + H) M/e+。
Example 106
5-methyl-4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamino]-2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester malonamide
a) (S) -3-tert-Butoxycarbonylamino-5-methyl-4-oxo-2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -1-Carboxylic acid cyclopropylmethyl ester
350mg (1.2mmol) of (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is treated with approximately 1g of carbon dioxide solid, 237mg (1.7mmol) of bromomethyl-cyclopropane and 626mg (1.9mmol) of cesium carbonate in that order][1，4]Diaza derivatives-3-Yl) -carbamic acid tert-butyl ester [ example 103a]Solution in 10ml of N, N-dimethylformamide. The reaction mixture was stirred in a sealed flask at 80 ℃ over the weekend. For working up, the solvent is evaporated under reduced pressure and the residue is dissolved in a mixture of 30ml of ethyl acetate and 10ml of water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. For purification, the crude compound was chromatographed on silica gel using a 3: 1-mixture of heptane and ethyl acetate as eluent. 410mg (87% of theory) of (S) -3-tert-butoxycarbonylamino-5-methyl-4-oxo-2, 3, 4, 5-tetrahydro-benzo [ b ] are obtained][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester, as a white gum; MS: m/e 579(M + OAc)+。
b) (S) -3-amino-5-methyl-4-oxo-2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -1-Carboxylic acid cyclopropane Methyl ester hydrochloride
Cleavage of (S) -3-tert-Butoxycarbonylamino-5-methyl-4-oxo-2, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner to that described in example 103c)][1，4]Diaza derivatives-tert-butoxy-carbonyl of cyclopropylmethyl 1-carboxylate to give the title compound as a pale yellow foam.
c) 5-methyl-4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamide Base of]-2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -1-carboxylic acid cyclopropylmethyl ester malonamide
(S) -3-amino-5-methyl-4-oxo-2, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner to that described in example 20d)][1，4]Diaza derivatives1-Carboxylic acid cyclopropylmethyl ester hydrochloride with (2RS) -methyl-N- (2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c)]Condensation to give the title compound as a white solid; MS: m/e 579(M + OAc)+。
Example 107
N- [ (S) -5-acetyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives -3- Base of]-carbamic acid tert-butyl ester
In an analogous manner to that described in example 25a), (S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is reacted with 2, 2, 2-trifluoroethyl trifluoromethanesulfonate][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester alkylation using 98: after chromatography on silica gel using a mixture of 2-dichloromethane and methanol as eluent, the title compound was obtained as a white solid; MS: m/e 360(M + H)+。
b) [ (S) -5-acetyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]II Aza derivatives -3-yl]-carbamic acid tert-butyl ester
Acylation of [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] with acetic anhydride in a similar manner as described in example 103b][1，4]Diaza derivatives-3-yl]-tert-butyl carbamate to give the title compound as a white solid; MS: m/e ═ 419(M + H)4)+。
c) (S) -5-acetyl-3-amino-1- (2, 2, 2-trifluoro-ethyl) -1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-keto hydrochloride
(S) -5-acetyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is cleaved with hydrochloric acid in a similar manner to that described in example 103c][1，4]Diaza derivatives-3-yl]-tert-butoxy-carbonyl of tert-butyl carbamate to give the title compound as a light yellow solid; MS: 302(M + H) M/e ═ e+。
d) N- [ (S) -5-acetyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4] Diaza derivatives -3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 20d), (S) -5-acetyl-3-amino-1- (2, 2, 2-trifluoro-ethyl) -1, 3, 4, 5-tetrahydro-benzo [ b)][1，4]Diaza derivatives-2-keto hydrochloride with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white solid; MS: 533(M + H) M/e+。
Example 108
N- [ (S) -5-cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) [ (S) -5-Cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [b][1，4]Diaza derivatives -3-yl]-carbamic acid tert-butyl ester
In a similar manner to that described in example 103b, the [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4,5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]Tert-butyl carbamate [ example 107b]To give the title compound as a yellow solid; MS: 428(M + H) M/e+。
b) (S) -3-amino-5-cyclopropanecarbonyl-1- (2, 2, 2-trifluoro-ethyl) -1, 3, 4, 5-tetrahydro-benzo [ b][1，4]II Aza derivatives -2-keto hydrochloride
(S) -5-Cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ] is cleaved with hydrochloric acid in a similar manner to that described in example 103c][1，4]Diaza derivatives-3-yl]-tert-butoxy-carbonyl of tert-butyl carbamate to give the title compound as a yellow solid; MS: 328(M + H) M/e ═ e+。
c) N- [ (S) -5-cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [b][1，4]Diaza derivatives -3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
In a similar manner to that described in example 20d), (S) -5-acetyl-3-amino-1- (2, 2, 2-trifluoro-ethyl) -1, 3, 4, 5-tetrahydro-benzo [ b)][1，4]Diaza derivatives-2-keto hydrochloride with (2RS) -methyl-N-, (2RS)2, 2, 3, 3, 3-Pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white solid; MS: m/e ═ 559(M + H)+。
Example 109
4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamino]-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives-1-Carboxylic acid cyclopropylmethyl ester
a) (S) -3-tert-Butoxycarbonylamino-4-oxo-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [b][1，4]Diaza derivatives -1-Carboxylic acid cyclopropylmethyl ester
In a similar manner to that described in example 106a, [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]Tert-butyl carbamate [ example 107b]With carbon dioxide and bromomethyl-cyclopropane in the presence of cesium carbonate to give the title compound as a white foam; MS: m/e is 475(M + NH)4)+。
b) (S) -3-amino-4-oxo-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -1-Carboxylic acid cyclopropylmethyl ester hydrochloride
In a similar manner as described in example 103cBy cleaving (S) -3-tert-butoxycarbonylamino-4-oxo-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b ] with hydrochloric acid][1，4]Diaza derivatives-tert-butoxy-carbonyl of cyclopropylmethyl 1-carboxylate to give the title compound as a yellow foam, which was used in the next step without further purification and characterization.
c) 4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamino]-5-(2，2，2- Trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -1-Carboxylic acid cyclopropylmethyl ester
(S) -3-amino-4-oxo-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b) in a similar manner to that described in example 20d)][1，4]Diaza derivatives1-Carboxylic acid cyclopropylmethyl ester hydrochloride with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a pale yellow solid; MS: 647(M + OAc)+。
Example 110
(2RS) -N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2-fluoro-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives -3- Base of]-carbamic acid tert-butyl ester
Acylation of (S) - (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] with acetic anhydride in a similar manner to that described in example 103b][1，4]Diaza derivatives-3-Yl) -carbamic acid tert-butyl ester [ example 103a]To give the title compound as a white solid; MS: m/e is 334(M + H)+。
b) (S) -5-acetyl-3-amino-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-keto hydrochloric acid Salt (salt)
Cleavage of [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] in an analogous manner to that described in example 103c][1，4]Diaza derivatives-3-yl]-tert-butoxy-carbonyl of tert-butyl carbamate to give the title compound as a light yellow solid; MS: 234(M + H) M/e+。
c) (2RS) -N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Dinitrogen Hetero compound -3-yl]-2-fluoro-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
According to the followingIn an analogous manner to that described in example 20d), (S) -5-acetyl-3-amino-1-methyl-1, 3, 4, 5-tetrahydro-benzo [ b)][1，4]Diaza derivativesCondensation of-2-keto hydrochloride with 2-fluoro-2-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give the title compound as a white foam; MS: m/e 483(M + H)+。
(2RS) -2-fluoro-2-methyl-N- (2, 2, 3, 3-pentafluoro-propyl) -malonamic acid was obtained by replacing (2RS) -methyl-malonic acid monoester with (2RS) -2-fluoro-2-methyl-malonic acid monoester according to a similar reaction sequence leading to (2RS) -methyl-N- (2, 2, 2, 2-trifluoro-ethyl) -malonamic acid [ example 20c ] ].
Example 111
N- [ (S) -5-acetyl-1-ethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives -3-yl) -carbamic acid methyl ester Tert-butyl ester
(S) - (2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] using acetic anhydride in a similar manner to that described in example 52a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester acetylation to give the title compound as a grey solid; MS: 320(M + H) M/e ═ 320+。
b) (S) -5-acetyl-3-amino-1-ethyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-ketones
(S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] was reacted with ethyl iodide in a similar manner to that described in example 25a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester alkylation followed by acid catalyzed cleavage of the tert-butoxycarbonyl group to give the title compound as a yellow waxy solid [ MS: m/e 248(M + H)+]It was used in the next step without further purification.
c) N- [ (S) -5-acetyl-1-ethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3- Base of]-2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1-ethyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivativesCondensation of-2-ketone with 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid to give the title compound as a white solid; MS: 493(M + H)+。
Example 112
N- ((S) -5-acetyl-1-ethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1-ethyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-one with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white solid; MS: m/e as 479(M + H)+。
Example 113
N- [ (S) -5-acetyl-1-isopropyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -5-acetyl-3-amino-1-isopropyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-ketones
(S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b) with 2-iodo-propane in a similar manner to that described in example 25a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester alkylation followed by acid catalyzed cleavage of the tert-butoxycarbonyl group to give the title compound as a yellow waxy solid [ MS: m/e & 262(M + H)+]It was used in the next step without further purification.
b) N- [ (S) -5-acetyl-1-isopropyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives -3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1-isopropyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-keto with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b]]Condensation to give the title compound as a white solid; MS: 493(M + H)+。
Example 114
N- [ (S) -5-acetyl-1-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -5-acetyl-3-amino-1-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives -2-ketones
(S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] using benzyl bromide in a similar manner to that described in example 25a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butylalkyl esterThe conversion followed by acid-catalyzed cleavage of the tert-butoxycarbonyl group gave the title compound as a pale yellow solid [ MS: m/e 310(M + H)+]It was used in the next step without further purification.
b) N- [ (S) -5-acetyl-1-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives -3- Base of]-2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-one with 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white solid; MS: m/e 553(M-H)-。
Example 115
N- ((S) -5-acetyl-1-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-one with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b)]Condensation to give the title compound as a white solid; MS: 539(M-H)-。
Example 116
N- [ (S) -5-acetyl-1- (4-fluoro-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
a) (S) -5-acetyl-3-amino-1- (4-fluoro-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b)][1，4]Diaza derivatives -2-ketones
(S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] using 4-fluoro-benzyl bromide in a similar manner to that described in example 25a)][1，4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester alkylation followed by acid catalyzed cleavage of the tert-butoxycarbonyl group to give the title compound as a white foam [ MS: 328(M + H) M/e ═ e+]It was used in the next step without further purification.
b) N- [ (S) -5-acetyl-1- (4-fluoro-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Dinitrogen Hetero compound -3-yl) -2, 2-dimethyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1- (4-fluoro-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-one with 2, 2-dimethyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b]Condensation to give the title compound as a white solid; MS: 571(M-H)-。
Example 117
N- ((S) -5-acetyl-1- (4-fluoro-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
(S) -5-acetyl-3-amino-1- (4-fluoro-benzyl-1, 3, 4, 5-tetrahydro-benzo [ b ] is reacted in a similar manner as described in examples 20d) and 27][1，4]Diaza derivatives-2-keto with (2RS) -methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamic acid [ see example 25b]Condensation to give the title compound as a white solid; MS: m/e 557(M-H)-。
Examples 118 and 119
N- [ (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2R or 2S) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide and
n- [ (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2S or 2R) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Using a preparative chiral HPLC column (AD, pressure: 15 bar, flow rate: 35 ml/min), 0.2g of N- [ (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] were isolated using a 4: 1 mixture of n-heptane and isopropanol as eluent][1，4]Diaza derivatives-3-yl]Two isomers of ((2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide (example 52) 77mg [ 35% of theory, optical purity > 99.5% d.e., MS: M/e 449(M + H)+]First eluting isomer (+) -N- [ (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b [ -b [ ]][，4]Diaza derivatives-3-yl]- (2R or 2S) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide and 77mg [ 35% of theory, optical purity > 99.4% d.e., MS: m/e 449(M + H)+]The late eluting isomer (-) -N- [ (S) -1-acetyl-4-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]- (2S or 2R) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide, all as white solids.
Examples 120 and 121
N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]- (2R or 2S) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide and
n- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]DinitrogenHetero compound-3-yl]- (2S or 2R) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide
Using a preparative chiral HPLC column (AD, pressure: 15 bar, flow rate: 35 ml/min), 0.6g of N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] are isolated using a 4: 1 mixture of n-heptane and isopropanol as eluent][1，4]Diaza derivatives-3-yl]Two isomers of- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide (example 40). 220mg (36.7% of theory, > 99.5% optical purity d.e.) of the first eluting isomer (+) -N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] are obtained][1，4]Diaza derivatives-3-yl]- (2R or 2S) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide and 247mg (41.2% of theory, optical purity > 99.5% d.e.) of the isomer (-) -N- [ (S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ] b which elutes after][1，4]Diaza derivatives-3-yl]- (2S or 2R) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide, all as white solids.
The following compounds were prepared in analogy to the above examples:
example 122
2, 2-dimethyl-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide, MS: m/e (%) ═ 484.5(M + H)+，100。
Example 123
(R) -2-fluoro-2-methyl-N- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide.
Example 124
(3, 3, 4, 4, 4-Pentafluoro-butyl) -carbamic acid (S) -1- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 3-trifluoro-propyl) -malonamide
In a similar manner 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)]Aza derivatives-7-yl) -propionamidoic acid the title compound was prepared [ MS m/e (%): 452.3(M + H)+，100)]。
TABLE 2

Claims (20)

1. A compound of the general formula or a pharmaceutically acceptable suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof:
wherein
R1Is one of the following groups:
R2is C1-7Alkyl radical, C2-7Alkynyl, - (CH)2)n-O-C1-7Alkyl, - (CH)2)n-S-C1-7Alkyl, - (CH)2)n-CN、-(CR’R”)n-CF3、-(CR’R”)n-CHF2、-(CR’R”)n-CH2F、-(CH2)n-C(O)O-C1-7Alkyl, - (CH)2)n-halogen, or is- (CH)2)n-C3-7Cycloalkyl, optionally substituted by one or more groups selected from phenyl, halogen or CF3Substituted with the substituent(s);
r ', R' are independent of n and independently of one another hydrogen, C1-7Alkyl radical, C1-7Alkoxy, halogen or hydroxy;
R3、R4independently of one another are hydrogen, C1-7Alkyl radical, C1-7Alkoxy, phenyl or halogen;
R5is hydrogen, C1-7Alkyl, - (CH)2)n-CF3Or- (CH)2)n-C3-7A cycloalkyl group;
R6is hydrogen or halogen;
R7is hydrogen or C1-7An alkyl group;
R8is hydrogen, C1-7Alkyl radical, C2-7Alkynyl, - (CH)2)n-CF3、-(CH2)n-C3-7Cycloalkyl or- (CH)2)n-phenyl, optionally substituted by halogen;
R9is hydrogen, C1-7Alkyl, -C (O) H, -C (O) -C1-7Alkyl, -C (O) -CF3、-C(O)-CH2F、-C(O)-CHF2、-C(O)-C3-7Cycloalkyl, -C (O) - (CH)2)n-O-C1-7Alkyl, -C (O) O- (CH)2)n-C3-7Cycloalkyl, -C (O) -phenyl, optionally substituted by one or more groups selected from halogen or-C(O)O-C1-7Substituted by alkyl, or-S (O)2-C1-7Alkyl, -S (O)2-CF3、-(CH2)n-C3-7Cycloalkyl or is- (CH) optionally substituted by halogen2)n-a phenyl group;
n is 0, 1, 2, 3 or 4.
2. A compound of formula I according to claim 1,
wherein
R1Is one of the following groups:
R2is C1-7Alkyl radical, C2-7Alkynyl, - (CH)2)n-O-C1-7Alkyl, - (CH)2)n-S-C1-7Alkyl, - (CH)2)n-CN、-(CR’R”)n-CF3、-(CR’R”)n-CHF2、-(CH2)n-C(O)O-C1-7Alkyl, - (CH)2)n-halogen, or is- (CH)2)n-C3-7Cycloalkyl, optionally substituted by one or more groups selected from phenyl, halogen or CF3Substituted with the substituent(s);
r ', R' are independent of n and independently of one another hydrogen, C1-7Alkyl radical, C1-7Alkoxy, halogen or hydroxy;
R3、R4independently of one another are hydrogen, C1-7Alkyl, phenyl or halogen;
R5is C1-7Alkyl or- (CH)2)n-C3-7A cycloalkyl group;
R6is hydrogen or halogen;
R7is hydrogen or C1-7An alkyl group;
R8is hydrogen, C1-7Alkyl radical, C2-7Alkynyl or- (CH)2)n-C3-7Cycloalkyl radicals；
R9Is hydrogen, C1-7Alkyl, -C (O) -C1-7Alkyl, -C (O) -C3-7Cycloalkyl, - (CH)2)n-C3-7Cycloalkyl, phenyl, -C (O) -phenyl, optionally substituted by one or more groups selected from halogen or-C (O) O-C1-7Alkyl, or (CH) optionally substituted by halogen2)n-a phenyl group;
n is 0, 1, 2, 3 or 4.
3. A compound of formula I according to claim 1, wherein R1Is a).
4. A compound of formula I according to claim 3, wherein R2Is optionally CF3Substituted- (CH)2)n-C3-7A cycloalkyl group.
5. A compound of formula I according to claim 4, wherein the compound is:
N-Cyclopropylmethyl-2-methyl-N' - (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -malonamide, or
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (1-trifluoromethyl-cyclopropylmethyl) -malonamide.
6. A compound of formula I according to claim 2, wherein R2Is C1-7Alkyl, - (CH)2)n-O-C1-7Alkyl or- (CH)2)n-S-C1-7An alkyl group.
7. A compound of formula I according to claim 6, wherein the compound is:
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-methoxyethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2-methylthioethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3-methoxy-propyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -malonamide.
8. A compound of formula I according to claim 2, wherein R2Is- (CR 'R')n-CF3Or- (CR 'R')n-CHF2。
9. A compound of formula I according to claim 8, wherein the compound is:
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoroethyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide;
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide;
2-fluoro-2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (4, 4, 4-trifluoro-butyl) -malonamide;
2-methyl-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (4, 4, 4-trifluoro-3-methoxy-butyl) -malonamide;
2-fluoro-N- (5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4-tetrafluoro-butyl) -malonamide;
n- (5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-7-yl) -2-fluoro-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide,
n- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (3, 3, 4, 4, 4-pentafluoro-butyl) -malonamide,
n- ((S) -5-cyclopropylmethyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-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)]Aza derivatives-7-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- (5-isopropyl-6-oxo-6, 7-dihydro-5H-dibenzo[b，d]Aza derivatives-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)]Aza derivatives-7-yl) -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)]Aza derivatives-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 [ ]]Aza derivatives-7-yl]-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)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide; or
N- ((S) -5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (3,4, 4, 4-pentafluoro-butyl) -malonamide.
10. A compound of formula I according to claim 1 or 3, wherein the compound is:
2-methyl-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- ((S) -6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-7-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(-) -2-methoxy-N- (6-oxo-6, 7-dihydro-5H-dibenzo [ b, d)]Aza derivatives-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)]Aza derivatives-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 [ ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide; or
2, 2-dimethyl-N- [ (S) -6-oxo-5- (2, 2, 2-trifluoro-ethyl) -6, 7-dihydro-5H-dibenzo [ b, d ]]Aza derivatives-7-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
11. A compound of formula I according to claim 1, wherein R1 is b).
12. A compound of formula I according to claim 11, wherein the compound is:
2-methyl-N- (3-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ d)]Aza derivatives-1-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide.
13. A compound of formula I according to claim 1, wherein R1Is c).
14. Compounds of formula I according to claim 13, wherein R2Is- (CR 'R')n-CF3。
15. A compound of formula I according to claim 14, wherein the compound is:
2-methyl-N- (1-methyl-2-oxo-5-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide;
n- ((3S) -5-benzoyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-fluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-chloro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (3, 5-difluoro-benzoyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b [ -b ]][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
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]Diaza derivatives-1-carbonyl } -benzoic acid methyl ester;
n- ((3S) -5-acetyl-1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [5- ((3S) -4-fluoro-benzyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (4-chloro-benzoyl) -1-cyclopropylmethyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- ((3S) -1-methyl-2-oxo-5-trifluoromethanesulfonyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- [ (3S) -1-methyl-2-oxo-5- (2, 2, 2-trifluoro-acetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (3S) -5- (2-methoxy-acetyl) -1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
n- [ (S) -5-methanesulfonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
(2RS) -methyl-N- [ (S) -2-oxo-1- (2, 2, 2-trifluoro-ethyl) -5-trifluoromethanesulfonyl-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-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][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester malonamide;
n- [ (S) -5-cyclopropanecarbonyl-2-oxo-1- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]-2-methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide;
4-oxo- (3S) - [ (2RS) - (2, 2, 3, 3, 3-pentafluoro-propylcarbamoyl) -propionylamino]-5- (2, 2, 2-trifluoro-ethyl) -2, 3, 4, 5-tetrahydro-benzo [ b][1，4]Diaza derivatives-1-carboxylic acid cyclopropylmethyl ester;
n- [ (S) -5-acetyl-1-isopropyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b ]][1，4]Diaza derivatives-3-yl]- (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide, or
N- ((S) -5-acetyl-1-benzyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)][1，4]Diaza derivatives-3-yl) - (2RS) -methyl-N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
16. A compound of formula I according to claim 1, wherein R1Is d).
17. A compound of formula I according to claim 16, wherein the compound is:
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide-10-yl) -N' - (2, 2, 2-trifluoro-ethyl) -malonamide; or
2-methyl-N- (11-oxo-10, 11-dihydro-dibenzo [ b, f)]Oxygen oxide-10-yl) -N' - (2, 2, 3, 3, 3-pentafluoro-propyl) -malonamide.
18. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 17, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
a) reacting a compound of formula II
With a compound of the formula III,
NH2R2 III
to obtain a compound of formula I:
wherein R is1-R4Has the meaning as defined in any one of claims 1 to 17;
and optionally converting the compound obtained into a pharmaceutically acceptable acid addition salt.
19. A medicament containing one or more compounds as claimed in any one of claims 1 to 17 and pharmaceutically acceptable excipients.
20. Use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of alzheimer's disease.
HK07105326.7A 2003-09-09 2004-08-31 Malonamide derivatives blocking the activity of gama-secretase HK1099014B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP03019683 2003-09-09
EP03019683.6 2003-09-09
PCT/EP2004/009700 WO2005023772A1 (en) 2003-09-09 2004-08-31 Malonamide derivatives blocking the activity of gama-secretase

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Publication Number Publication Date
HK1099014A1 HK1099014A1 (en) 2007-08-03
HK1099014B true HK1099014B (en) 2010-11-19

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