Indian Patents
Title of Invention

BENZODIAZEPINE DERIVATIVES
Abstract The present invention relates to compounds of general formula (I) wherein X is a single bond or an ethynediyl group, wherein, in case X is a single bond, R?1¿ is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or cyano; In case X is an ethynediyl group, R?1¿ is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy; R?3¿ is a 5 or 6 membered aryl or heteroaryl which are optionally substituted. The compounds according to the present invention can be used for treating or preventing acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.
Full Text The present invention relates to compounds of general formula I

wherein
X is a single bond or an ethynediyl group, -wherein,
In case X is a single bond,
Rl is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or cyano;
In case X is an ethynediyl group,
Rl is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy;
R: is halogen; hydroxy; lower alkyl; lower halo-alkyl; lower alkoxy; hydroxymethyl; hydroxyethoxy, lower alkoxy-(ethoxy)n (n = 1 to 4); lower alkoxymethyl; cyanomethoxy; morpholine-4-yl;thiomorpholine-4-yl; l-oxothiomorpholine-4-yl; 1,1-dioxothiomorphoIine-4-yl; 4-oxo-piperidine-l-yI; 4-alkoxy-piperidine-l-yI; 4-hydroxy-piperidine-1-yl; 4-hydroxyethoxy-piperidine-l-yl; 4-lower alkyl-piperazine-1-yl; alkoxycarbonyl; 2-dialkylamino-ethylsulfanyl-; N,N-bis lower alkylamino lower alkyl; carbamoylmethyl; alkylsulfonyl; lower alkoxycarbonyl-lower alkyl; alkylcarboxy-lower alkyl; carboxy-lower alkyl; alkoxycarbonylmethylsulfanyl; carboxymethylsulfanyl; 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; carboxy-lower alkoxy; cyano-lower alkyl; 2,3-dihydroxy-lower alkoxy, carbamoylmethoxy;2-oxo-[l,3]-dioxolan-4-yl-lower alkoxy, (2-hydroxy-

lower alkyl)-lower alkyl amino; hydroxycarbamoyl-Iower alkoxy, 2,2-dimethyl-tetrahydro-[l,3]dioxolo[4,5c]-pyrrol-5-yl; lower alkoxy-carbamoyl-lower alkoxy; 3R-hydroxy-pyrrolidin-1-yl; 3,4-dihydroxy-pyrroIidin-l-yl; 2-oxo-oxazolidin-3-yl; lower alkyl-carbamoylmethoxy; or aminocarbamoyl-Iower alkoxy;
R3 is a 5 or 6 membered aryl or heteroaryl which are optionally substituted by
halogen; cyano; nitro; azido; hydroxy, carboxy, morpholine-4-carbonyl; carbamoyl; thiocarbamoyl; N-hydroxycarbamoyI; trimethylsilyl-ethynyl;
or lower alkyl; lower alkoxy; halo-lower alkyl; 4-lower alkyl-piperazine-1-carbonyl; lower alkylcarbamoyl which are optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated;
or an optionally substituted five-membered aromatic heterocycle, which maybe optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated, or lower alkyl which is optionally substituted by halogen, amino, lower alkylamino, acylamino, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkoxyimino, carboxy which is optionally esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl which is optionally substituted by lower alkyl, or amidino which is optionally substituted by lower alkyl, -C(NRR")=NR" (where R, R" and R" are hydrogen or lower alkyl)
and their pharmaceutically acceptable addition salts.
It has surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.
In the central nervous system (CNS) die transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms Hgand-r. controlled ion channels. The metabotropic glutamate receptors (mGluR) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.

At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group 1, mGluR2 and mGIuR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGIuR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer"s disease, cognitive disorders and memory deficits.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are chronic and acute pain, Huntington"s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production, as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
Preferred compounds of formula I in the scope of the present invention are those in which R3 is phenyl substituted in meta position by cyano; halogen; or imidazolyl which is optionally substituted by lower alky or methylsulfanyl; 1,2,3-triazolyl; 1,2,4-triazolyl; or isoxazolyl which is optionally substituted by lower alkyl.
The following are examples of such compounds:
3-(8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H~benzo[b][l,4]diazepin-2-yl)-
benzonitrile;
3-[8-(4-Methyl-piperazin-l-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-
benzo[b][l,4]diazepin-2-yl]-benzonitrile;

3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b}[l,4]diazepin-2-yl)-benzonitri]e;
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b][l,4]4iazepin-7-ylsulfanyl] -acetic acid methyl ester;
2-[4-(3-Cyano-phenyl)-2-oxo-8-p}ienylethynyl-2,3-dihydro-lH-benzo[b]ll,4]dia2epin-7-yl]-acetamide; 3-(8-Metho^y-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]diazepiH-2-yl}-
benzonitrile; 3-(8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]dia2epin-2-yl)-
benzonitrile;
4-(3-Iodo-phenyl)-7-(2-methoxy-ethoxy)-8-phenyIethynyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-one;
4-(3-Imidazol-l-yl-phenyl)-7-{2-methoxy-ethoxy)-8-phenylethynyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-one;
[RS]-3-[4-Oxo-8-(2-oxo-[lf3]dioxolan-4-ylmethoxy)-7-phenylethynyl-4,5-dihydro-3H-
benzo[b][l,4]dia2epin-2-yl]-benzomtrile-,
7-Hydroxymethyl-4-(3-imidazol-l-yl-phenyl)-8-phenylethynyl-l,3-dihydro-
benzofb] [l,4]diazepin-2-one;
[4-(3-ImidaZol-l-yl-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-
benzo[b][l,4]diazepin-7-yloxy]-acetonitrile;
8-(4-Fluoro-phenylethynyl)-7-hydroxymethyl-4-(3-imidazol-l-yl-phenyl)-l,5-dihydro-
benzo[b][l,4]diazepin-2-one; 7-(2-Hydroxy-ethoxy)-4>{3-imidazoI-l-yl-phenyI)-8-phenylethynyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-one;
8-(4-Fluoro-phenyl)-7-[4-(2-hydroxy"ethoxy)-piperidin-l-yl]-4-(3-imidazoI-l-yl-
phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one;
8-(4-Fluoro"pKenylV7-hydrQxy-4-(3-im.idazol-l-yl-phenyl)-l,3-dib.ydro-
benzo[b][l,4]diazepin-2-one;
8-(2-Fluoro-phenyl)-7-methoxy-4-[3-(2-methyl-imidazol-l-yl)-phenyl]-l,3-tlihydro-
benzo [b] [ 1,4] diazepin-2-one; 8-(2-Fkoro-phenyl)-7-hydroxy-4-(3-[l,2,3]triazol-l-yl-phenyl)-l,3-dihydro-
benzo[b][l,4]diazepin-2-one; 8-C2-Fluoro-phenyl)-7-hydroxy-4-[3-(2-methyl-iinidazoI-l-ylJ-phenyl]-l,3-dibydro-
benzo[b] [l,4]diazepin-2-one; 8-(2-Fluoro-phenyl)-7-hydroxy-4-[3-(2-methylsulfanyl-imida2ol-l-yl)-phenyl]-l)3-
dihydro-benzo[b][l,4]diazepin-2-one;
8-(2]5-Difluoro-phenyI)-7-methoxy-4-{3-[l,2,3]triazol-l-yl-phenyl)-l,3-dihydro-
benzo[b] [l,4]diazepin-2-one;

8-(2-nuoro-phenyI)-7-hydroxy-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-l,3-dihydro-benzo [b] [ 1,4] diazepin-2-one;
3-[7-(2,5-Difluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yI]-benzonitrile;
8-(4-Fluoro-phenylethynyl)-7-hydroKy-4-(3-imidazol-l-yl-phenyl)-l,3-dihydro-benzo[b] [l,4]diazepin-2-one; and
8-(4-Huoro-phenylethynyl)-7-hydroxy-4-(3-[l,2,3]triazol-l-yl-phenyI)-l,3-dihydro-benzo[b][l,4]diazepin-2-one.
Compounds of formula I, wherein R3 is thiophenyl, preferably lhiophen-2-yl, which is optionally substituted by cyano or halogen; or R3 is pyridinyl, preferably pyridin-4-yl, which is optionally substituted in 2-position by cyano or halogen, or wheiein R3 is thiazolyl which is optionally substituted in 2-position with imidazolyl or 4-methyIimidazolyl, are also preferred.
The following compounds are particularly preferred:
5-[7-(2-Fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-
thiophene-2-carbonitrile;
2-[7-(2-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-lH-benzo[b][l,4]diazepin-2-yl]-
thiophene-3-carbonitrile;
4-[7-(2-Fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-
pyridine-2-carbonitrile;
4-[7-(4-Fluoro-phenylJ-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l>4]diazepin-2-yl]-
pyridine-2-carbonitrile;
4-[7-(2-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepm-2-yl]-
pyridine-2-carbonitrile; and
8-{2-Fluoro-phenyl)-4-[2-{4-methyl-imidazol-l-yl)-thiazol-4-yl]-l,3-dihydro-
benzo[b][l,4]diazepin-2-one.
All tautomeric forms of the compounds of the invention are also embraced herewith.
The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term "lower cycloalkyl" used in the present description denotes cyclic saturated hydrocarbon residues with 3-5 carbon atoms, preferably with 3 carbon atoms, such as cyclopropyl.

The term "lower alkoxy" denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term "halogen" embraces fluorine, chlorine, bromine and iodine.
The term "5 or 6 membered aryl or heteroaryl" embraces phenyl, thiophenyl, pyridine, partially hydrated pyridine.
The expression "five-membered aromatic heterocycle" embraces, furan, thiazol, imidazol, pyrazol, 1,3-thiazol, 1,3-oxazol, 1,2-oxazol, 1,2-thiazol, 1,2,3-triazol, 1,2,4-triazol, 1,2,4-oxadiazol, 1,2,3-oxadiazol, 1,2,4-thiadiazol, 1,2,3-thiadiazol and tetrazol.
The compounds of general formula I and their pharmaceutically acceptable salts can be manufactured according to the following methods:

According to scheme A, compounds of general formula I, in which X,R",R2 and R areas described above, can be prepared from compounds of general formula II via an acylation-deprotection-cyclization sequence:
For example reacting compounds of general formula II with a dioxinone IV, in which R is as described above, in an inert solvent such as toluene or xylene at elevated temperatures, preferably between 80 °C and 160 °C gives rise to compounds of general formula III.
Alternatively, compounds of general formula III can also be prepared by for example reaction of a compound of general formula II with a f3-ketoester (general formula IVa), in which R3 is as described above using the same conditions as described for the reaction with the dioxinones.

Afterwards, cleaving the BOC protecting group in compounds of general formula III and concomitant cyclization of the deprotected compound yields the desired compounds of general formula I. Any other suitable amino protecting group, such as e.g. Fmoc.or benzyloxycarbonyl (Z), can be alternatively used instead of the BOC group.
The deprotection-cyclization step can be carried out by treating the compounds of general formula III with for example a Bronsted acid such as trifluoroacetic acid in an inert solvent such as dichloromethane (DCM). The reaction is preferably carried out at temperatures between 06Cand 50 °C. It may be advantageous to use also anisoleor 1,3-dimethoxybenzene as a carbocation scavenger in the reaction mixture.


According to scheme B, compounds of general formula II in which R1 is as described above for compounds where X is a single bond and R2 is as described above, can be prepared by different routes depending on the nature of R1 from the iodo-compounds of general formula V, in which R is as described above. As shown in scheme B, the key steps are coupling reactions of Suzuki- and Stille-type in presence or absence of carbonmonoxide. The exact conditions for the respective compounds of general formula II can be found in the experimental part.
Compounds of general formula V, in which R2 is as described above, can be prepared by different routes depending on the individual residue R2:

As shown in scheme C, compounds of general formula Va, in which R2 is lower alkyl, halogen or alkoxycarbonyl, can be prepared from the known compounds of general formula XI by iodination and subsequent protection of the synthetic intermediates with general formula XII.
The iodination step can be carried out by for example using iodine monochloride in acetic acid in the presence of sodium acetate. The reaction can be for example carried out at temperatures between 20 °C and 80 °C
The protection of the amino function can be achieved by for example reacting compounds of general formula XII with di-tert.-butyl-carbonate in the presence of a base such as cesium carbonate. The reaction can be carried out in polar solvents such as acetone or butanone and the like at temperatures between 20 °C and 60 °C.
As shown in scheme D, compounds of general formula Vb and Vc, in which R2 is attached via a sulfur- or nitrogen-atom (R: represents for example morpholin-4-yl; thiomorpholino-4-yl; dialkylamino; carboxymethylsulfanyl etc), respectively, can be prepared from the intermediate XIII by a nucleophilic substitution reaction with the respective amines or mercaptanes in the presence of a suitable base.


The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like. The base can be selected from the sterically hindered amines such as Hunig"s base, alkoxides such as sodium methoxide and tert.-butoxide, or hydrides such as sodium hydride. The reaction can be performed at temperatures between 20 °C and 110 °C, depending on the individual compounds to be synthesized.
Compounds of general formula Vd in which R2 is attached via an oxygen atom (R2 represents for example lower alkoxy, lower halo-alkoxy, lower cydo-alkoxy, lower alkoxy-lower alkoxy; etc.) can be prepared as for example shown in scheme E:


by a nudeophilic aromatic substitution reaction with the respective alcohol in the presence of a suitable base and subsequent protection of the amino function. The base can be selected from the class of Bronsted bases such as potassium hydroxide and the like. The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like at temperatures between 20 °C and 100 °C.
The protection of the amino function can be achieved by for example reacting compounds of general formula XV with di-tert.-butoxy carbonate in the presence of abase such as cesium carbonate. The reaction can be carried out in polar solvents such as acetone or butanone and the like at temperatures between 20 °C and 60 °C.
Another method to achieve this protection step is to transform first the amino function in a compound with general formula XV into an isocyanate by reaction with phosgene or a phosgene equivalent in the presence of a suitable base, which is then treated with tert.-buty]-alcohol to give the desired compounds of general formula Vd.
Another suitable method to achieve this protection step is to transform first the amino function in a compound with general formula XV into the corresponding di*Boc compound by reaction with excess di-tert-butoxy carbonate in the presence of 4-dimethylaminopyridine (DMAP), which is then treated with 2 eq. TFA in dichloromethane to give the desired compounds of general formula Vd.

This reversal of steps, i.e. performing first the nucleophilic aromatic substitution on the key intermediate XTV and second protection of the amino-function as shown in synthetic scheme E can also be applied to those compounds with the general formula Vb and Vc (synthetic scheme D).
Yet another method of preparing compounds of the general formula Vd is using the O-atlyl compound XIX and perfoming a deallylation-alkylation sequence as outlined in scheme E. The deallylation is preferably carried out by transition-metal catalyzed isomerisation, e.g. in the presence of Rhodium(I)-salts like for example Wilkinson"s catalyst [(PPh3)3RhG] or Palladium (II)-salts such as [(PPb^PdCb], followed by aqueous acid hydrolysis of the resulting vinyl ether. An example for this procedure can be found in /. Org. Chem. 1973, 38,3224. The alkylation of the phenol XX to the desired compound of the general formula Vd can be carried out -with electrophilic reagents of the general formula R-X, in which R has the meaning of lower alkyl, lower alkenyl, alkyl acetate or benzyl and X represents a leaving group, for example iodide, bromide, methanesulfonate or tolylsulfonate, in a suitable solvent in the presence of a base. The reaction is preferably carried out in polar, aprotic solvents, for example chlorinated solvents such as dichloromethane, chloroform or dichloroethane, or amides, for example dirnethylformamide, dimethylacetamide and N-mediyl-pyrrolidone, or sulfoxides, for example dimethyl sulfoxide. The base can be selected from the sterically hindered amines such as Hiinig"s base, alkoxides such as sodium methoxide and tert-butoxide, hydrides such as sodium hydride, hydroxides such as potassium hydroxide, carbonates such as potassium carbonate or hydrogen carbonates such as potassium hydrogen carbonate. The reaction can be performed at temperatures between -20 °C and 80 °C, depending on the individual compounds to be synthesized. For the synthesis of an O-tert.-butyl compound with the general formula Vd the phenol XX can be treated with DMF-di-tert.-butylacetal in toluene or benzene at 80 °C as described in Synthesis 1983,135.


compounds of general formula Ve and Vf in which R2 is attached via a carbon atom (R2 represents for example lower alkyloxy-carbonyl-methyl; cyano-methyl, etc.) can be prepared from compound XIII or XIV by for example reaction with a malonic acid ester or -half-ester in the presence of a base followed by the removal of one of the alkyl carboxylates via decarboxylation. The exact reaction conditions vary with the identity of the individual compounds and are described in the examples.
The key intermediates XIII and XIV can be prepared as already described in scheme C.
For the one-carbon-moiety bearing compounds of the general formula Vh to VI, the synthesis starts from known methyl 3-amino-4-nitrobenzoate. Standard iodination as described in synthetic scheme C leads to the iodide XXI, which in turn can be protected with the Boc-group. The reduction of the methyl ester can for example be performed by treatment with lithium borohydride, sodium borohydride or diisobutylalumiiiumhydride in an aprotic solvent like for example THF, ether or toluene . The presence of an alcohol such as methanol, ethanol or isopropanol can be advantegous. The reduction is preferably carried out at temperatures between -20 °C and 0 °C. Further functionalization, like for example conversion into a chloride (Vk), of the resulting benzylic alcohol Vh follows

standard procedures known to someone skilled in the art. The exact reaction conditions vary with the identity of the individual compounds and are described in the examples.

According to scheme G, compounds of general formula II in which R1 is as described above for compounds where X is an ethynediyl group can be prepared by different routes from the iodo-compounds V, depending on the nature of Rl and R2 As shown in scheme G, the transformation can for example be carried out
a) by directly attaching the R"-alkynediyl-substituent to a compound of general formula V
via a Sonogashira-type coupling followed by the reduction of the nitro group or
b) by two stepwise Sonogashira-type couplings, in which first trimethylsilyl-acetylene is
coupled to a compound of general formula V to yield, after deprotection with sodium
hydroxide in methanol, the intermediate XVIII which then can be transformed via a
second Sonogashira-type coupling with the appropriate reactant R"-I, R"-Br or R1-
OSO2CF3 and reduction of the nitro group to the desired compounds of general formula II.
I


According to Scheme H, the dioxinones and fi-keto esters building blocks with the general formula IV and IVa can be prepared by methods known to someone skilled in the art from the corresponding carboxylic acid derivatives R3-COR, i.e. free adds, methyl or ethyl esters and acid chlorides. The exact conditions for the corresponding compounds can be found in the experimental part.
Another synthetic route to prepare compounds of general formula I in which R1, R~ and X have the meaning as described above and R3 is a carbamide of general formula C(0)NR4R5, in which R* and R5 is hydrogen, lower alkyl or R4 and R5 together form a morpholino-residue or a N-methyl-piperazine, is outlined in scheme I:


The exact conditions for the respective compounds can be found in the experimental part.
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula 1. The compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer"s disease, cognitive disorders and memory deficits. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spina] cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are acute and chronic pain, Huntington"s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of formula 1 and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. 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 gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection

solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, 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 can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, -with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
The present invention relates also to the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind.
The compounds of the present invention are group II mGlu receptor antagonists. The compounds show activities, as measured in the assay described below, of 50 ujvi or less, typically 3 |iM or less, and ideally of 0.5 uM or less. In the table below are described some specific pKi values of preferred compounds.






f3Hl-LY354740 binding on mGlu2 transfected CHO cell membranes
Transfectiort and cell culture
cDNA encoding the rat mGlu2 receptor protein in pBluescript II was obtained from Prof. S. Nakanishi (Kyoto, Japan), and subcloned into the eukaryotic expression vector pcDNA I-amp from Invitrogen (NV Leek, The Netherlands). This vector construct (pcDlmGR2) was co-transfected with a psvNeo plasmid encoding the gene for neomycin resistance, into CHO cells by a modified calcium phosphate method described by Chen & Okayama (1988). The cells were maintained in Dulbecco"s Modified Eagle medium with reduced L-glutamine {2 mM final concentration) and 10% dialysed foetal caif serum from Gibco BRL (Basel, Switzerland). Selection was made in the presence of G-418 (1000 ug/ml final). Clones were identified by reverse transcription of 5 ug totaj RNA, followed by PCR using mGlu2 receptor specific primers 5"-atcaagcttgggtttctggcactg-3" and 5"-agcatcactgtgggtggcataggagc-3" in 60 mM Tris HC1 (pH 10), 15 mM (NH^SO*, 2 mM MgCU, 25 units/ml Taq Polymerase with 30 cycles annealing at 60 °C for 1 min., extention at 72 °C for 30 s, and 1 min. 95 °C denaturation.
Membrane preparation
Cells, cultured as above, were harvested and washed three times with cold PBS and frozen at -80 °C. The pellet was resuspended in cold 20 mM HEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with a polytron (Kinematica, AG, Littau, Switzerland) for 10s at 10 OOOrpm. After centrifiigation for 30 min. at 4 °C, the pellet was washed once with the same buffer, and once with cold 20 mM HEPES-NaOH buffer containing 0.1 mM EDTA, {pH 7.4). Protein content was measured using the Pierce method (Socochim, Lausanne, Switzerland) using bovine serum albumin as standard.
[5HJ-LY354740 binding
After thawing, the membranes were resuspended in cold 50mM Tris-HCl buffer containing
2 mM MgCU and 2 mM CaCl2, (pH 7) (binding buffer). The final concentration of the

membranes in the assays was 25 ag protein/ml. Inhibition experiments were performed with membranes incubated with 10 nM [3H]-LY354740 at room temperature, for 1 hour, in presence of various concentrations of the compound to be tested. Following the incubations, membranes were filtered onto Whatmann GF/C glass fiber filters and washed 5 times with cold binding buffer. Non specific binding was measured in the presence of 10 uM DCGIV. After transfer of the filters into plastic vials containing 10 ml of Ultima-gold scintillation fluid (Packard, Zurich, Switzerland), the radioactivity was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zurich, Switzerland).
Data analysis.
The inhibition curves were fitted with a four parameter logistic equation giving IC50
values, and Hill coefficients.
EXAMPLES
The following examples relate to the preparation of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters (Synthetic Scheme C):
General procedure A
Preparation of 4-iodo-2-nitroaniIines by iodination of 2-nitroani!ines [according to
Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983,36,2317-25]
To a stirred solution of the 2-nitroaniline {1.0 mol} in HOAc (500 mL) containing anhydrous NaOAc (93-103 g, 1.125-1.25mol), iodine monochloride (59-66mL, I.I25-I.25 mol) in HOAc (300 mL) was added over 60 min. The reaction mixture was heated to the given temperature until thin layer chromatography (tic) indicated complete conversion of the starting material, stirred for another 30 min at 23 °C, then diluted slowly with H2O (1000 mL) which caused the separation of the crystalline product. Stirring was continued for 1 h and the product was filtered off, washed free of HOAc and dried in vacuum at 60 °C.
Example Al
5-Chloro-4-iodo-2-nitro-phenylamine
Prepared from 5-chloro-2-rutroaniline by iodination with iodine monochloride in HOAc/NaOAc according to the general procedure A (80 °C). Obtained as an orange solid.
MS (EI) 298 (M+) and 300 [
Example A2 4-Iodo-5-methyl-2-nitro-phenylamine
Prepared from 5-methyl-2-nitroaniline by iodination with iodine monochloride in HOAc/NaOAc according to the general procedure A (80 °C). Obtained as a red solid.
MS (EI) 278 (M+); mp 154 °C (dec).
Example A3
5-Amino-2-iodo-4-nitrobenzoic acid methyl ester
Prepared from 3-amino-4-nitrobenzoic acid methyl ester (22.25 g, {CAS-No. [99512-09-1]; prepared in two steps as follows: 3-hydroxy-4-nitrobenzoic acid (30 g, 164 mmol), NHjCl (21.93 g, 410 mmol) in 25% aq. NH3 (180 ml) was heated in a steel autoclave at 160 °C for 7 h (internal pressure: 23 bar). Cooled to 23 °C and evaporated to dryness. Taken up in H20 (200 mL), adjusted pH with cone. H:S04 to pH 1, saturated with NaCI and extracted with EtOAc (6 x 750 mL), dried combined organic layer over MgS04. Filtration and removal of the solvent in vacuum left the sufficiently pure 3-amino-4-nitrobenzoic acid (22.26 g, 75 %) as an orange solid. This material was suspended in MeOH (500 mL), cone. H2S04 (3 mL) was added and the mixture was heated to 65 °C for 2.5 days. The solvent was removed in vacuum, the solid residue taken up in EtOAc, washed with sat. NaHCCVsol. and brine, followed by drying over MgS04. Removal of the solvent left the sufficiently pure 3-amino-4-nitrobenzoic acid methyl ester (22.25 g, 93 %) as an orange solid.} by iodination with iodine monochloride in HOAc/NaOAc according to the general procedure A (35 °C). Obtained as an orange solid (29.3S g, SO %).
MS (El) 322 (M+); mp 168 eC (dec).
General procedure B:
Preparation of {2-nitro-phenyl)-carbamic acid tert.-butyl esters from 2-nitroanilines
Method a: To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0 °C was added a solution of the 4-iodo-2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 4-iodo-2-nitropbenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert.-BuOH in CHiCh for 2.5 h. Removal of the solvent left an orange solid which

was purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Method b: To a mixture of the 4-iodo-2-nitroaniline (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 ml) was dropwise added a solution of Boc20 (37.8 g, 173 mmol) in 2-butanone (170 mL) and the resulting mixture was stirred at 52 "C for 26 h. The solvent was removed in vacuum, the residue was treated with a mixture of H2O (240 mL) and MeOH (240 mL) and extracted with hexane (3 x 500 mL). The combined hexane layer was washed with brine (200 mL) and all aqueous layers were reextracted with hexane (300 mL). All combined hexane layers were dried over MgSO,,, filtered and the solvent was removed in vacuum to give an orange solid, which was purified by silica gel column chromatography with hexane/EtOAc to give the (4 -iodo-2-mtro- phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Method c: To a solution of the 4-iodo-2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23 °C was dropwise added within 70 min a solution of Boc20 (246 g, 1128 mmol) in THF (500 mL) and stirring was continued at 23 °C for 75 min. The entire mixture was evaporated to dryness and dried at HV to leave a dark brown solid (253.59 g). This material was dissolved in DCM (1200 mL), cooled to 0 °C and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h, poured into icecold sat, NaHC03-sol., extracted with DCM, washed with brine and dried over MgS04. Removal of the solvent in vacuum left a dark brown solid (199.71 g) which was coated on silica gel and purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Example Bl
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester
Prepared the isocyanate from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (7.0 g, 23.45 mmol) with diphosgene (2.12 mL, 17.6 mmol) in EtOAc (30 mL), followed by treatment with tert.-BuOH (100 mL) in CH2G2 (100 mL) according to the general procedure B (method a). Obtained as a yellow solid (7.1 g, 76 %).
MS (El) 398 (M+) and 400 [(M+2)*]; mp 82-84 °C.
Example B2
(4-Iodo-5-methyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester

Prepared the isocyanate from 4-iodo-5-methyI-2-nitro-phenylamine (Example A2) (13.51 g, 48.6 mmol) with diphosgene (4.4 mL, 36.4 mmol) in EtOAc (50 mL), followed by-treatment with terL-BuOH (150 mL) and CH2C12 (150 mL) according to the general procedure B (method a). Obtained as a yellow solid (14.1 g, 77%).
MS (EI) 378 (M+); mp 99-100 °C.
Example B3
5-tert-Butoxycarbonylamino-2-iodo-4-nitro-ben2oic acid methyl ester
Prepared the isocyanate from 5-amino-2-iodo-4-nitro-benzoic acid methyl ester (Example A3) (5.5 g, 17 mmol) with diphosgene (1.55 mL, 13 mmol) in EtOAc (135 tnL), followed by treatment with tert-BuOH (20 mL) and CH2CI2 (70 mL) according to the general procedure B (method a). Obtained as a yellow solid (5.2 g, 72 %).
MS (ISP) 440 [(M+NH4)+]; mp 126 °C.
Example B4
(5-Allyloxy-4-iodo-2-nitro-phenyI)-carbamic acid tert.-butyl ester
Prepared the isocyanate from 5-allyIoxy-4-iodo-2-nitro-phenylamine (Example El) (9.0 g, 28.2 mmol) with diphosgene (2.6 mL, 21.2 mmol) in EtOAc (150 mL), followed by treatment with tert.-BuOH (80 mL) and CH:CI2 (80 mL) according to -the general procedure B (method a). Obtained as a yellow solid (9.16 g, 77 %).
MS (ISP) 421 [(M+H)+J and 438 [(M+NH4)+j; mp 93-95 °C.
Example B5
(4-Iodo-5-methoxy-2-nitro-phenyl)-carbamic acid tert.-butyl ester
Prepared the isocyanate from 4-iodo-5-methoxy-2-nitro-phenylamine (Example E2) (2.85 g, 9.69 mmol) with diphosgene (0.88 mL, 7.27 mmol) in EtOAc (52 mL), followed by treatment with tert.-BuOH (25 mL) and CH2CI2 (25 mL) according to the general procedure B (method a). Obtained as a yellow solid (3.0 g, 79 %).
MS(EI)394(M+);mpl71°C.

Example B6
[4-Iodo-5-(2-methoxy-ethoxy)-2-nitro- phenyl] -carbamic acid tert.-butyl ester
Prepared the isocyanate from 4-iodo-5-(2-methoxy-ethoxy)-2-nitro-phenylamine (Example E3) (2.73 g, 8.08 mmol) with diphosgene (0.8 mL, 6.06 mmol) in EtOAc (50 mL), followed by treatment with tert.-BuOH (25 mL) and CH2C12 (25 ml) according to the general procedure B (method a). Obtained as a yellow solid (3.0 g, 86 %).
MS (ISP) 439 [(M+H)+], 456 [(M+NH4)+] and 461 [(M+Na)+j; mp 109-111 °C.
Example B7
[4-Iodo-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-phenyl]-carbamic acid tert.-butyl ester
Prepared the isocyanate from 4-Iodo-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-phenylamine (Example E4) (8.0 g, 17 mmol) with diphosgene (1.54 mL, 13 mmol) in EtOAc (100 ml), followed by treatment with tert.-BuOH (25 mL) and CH2CI2 (25 ml) according to the general procedure B (method a). Obtained as a yellow oil (8.6 g, 89 %).
MS(ISP)588[(M+NH^.
Example B8
(RS)-[5-(2,2-Dimethyl-[1.3]dioxolan-4-ylmethoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from (RS)-5-(2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-2-nitro-4-phenylethynyl-phenylamine (Example K14) (2.678 g, 5.7 mmol), Cs2C03 (2.23 g, 6.8 mmol) and Boc20 {152 g, 7.0 mmol) in 2-butanone (36.5 ml) at 52 "C according to the general procedure B (method b). Obtained as a yellow foam (2.0 g, 75 %).
MS (ISP) 469 [(M+H)*] and 486 [(M+NH4)+); mp 32 °C.
Example B9 fVe (R=CN: R"=Boc11
(5-Cyanomethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester
Prepared the isocyanate from (5-amino-2-iodo-4-nitro-phenyl)-acetonitrile (Example Vf (R-CN; R"=H» (5.15 g, 17 mmol) with diphosgene (2.05 mL, 17 mmol) in BtOAc (150

mL), followed by treatment with tert-BuOH (25 ml) and CHJCIJ (25 mL) according to the general procedure B (method a). Obtained as a yellow solid (4.0 g, 58 %).
MS (ISN) 402 [(M-H)-]; mp 124-126 °C.
Example BIO
[5-(2-tert.-Butoxy-ethoxy)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester
Prepared the di-Boc-compound from 5-(2-tert.-butoxy-ethoxy)-4-iodo-2-nitro-phenylamine (Example E6) (13.9 g, 36.6 mmol) and Boc^O (16.35 g, 75 mmol), followed by treatment with 2 eq. TFA in CH2CI2 according to the general procedure B (method c). Obtained as a yellow solid (14.96 g, 85 %).
MS (ISP) 481 [(M+H)+j; mp 113-116 °C.
Example Bll
[4-Iodo-5-(4-methoxy-bertzyioxy)-2-nitro-phenyl]-carbamic acid tert.-butyl ester
Prepared the di-Boc-compound from 4-iodo-5-(4-methoxy-benzyloxy)-2-nitro-phenylamine (Example E7) (2.88 g, 7.20 mmol) and Boc20 (3.30 g, 15.12 mmol), followed by treatment with 2 eq. TFA in CH2Q2 according to the general procedure B (method c). Obtained as a waxy yellow solid (1.74 g).
MS (ISN) 499 f (M-H)"].
The following procedures relate to the preparation of those (4-k>do-2-nitro-phenyl)-carbamic acid tert.-butyl esters bearing nitrogen substituents in the 5-position (Scheme D).
General procedure C:
Preparation of 5-N-substituted-(4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters:
Method a: from (5-chloro-4-iodo-2-nitxo-phenyl)-carbamic acid tert-butyl ester
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) was stirred
with the desired amine optionally with toluene or DMSO and/or DIPEA at temperature
from 23 CC to 100-130 °C until tic indicated complete disappearance of the chloride. The
reaction was cooled to 23 °C poured into ice-water, the precipitate was filtered off, washed
with water and dried in vacuum. In cases were the product did not precipitate, the mixture
was extracted with EtOAc, washed with water and brine, dried over Na2S04. Filtration and
removal of the solvent in vacuum left a crude product, which was purified by silica gel
column chromatography with hexane/EtOAc to give the pure title compound.

Method b: from 5-chloro-4-iodo-2-nitro-phenylamine
A mixture of 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (1.49 g, 5.0 mmo!), the desired amine (6-25 mmol) and an appropriate base, like for example NaHC03, KaC03, Et3N or DIPEA (10-15 mmol) was stirred in DMSO, DMF or toluene {20-50 mL) at 60-130 °C until tic indicated complete disappearance of the chloride. The reaction was cooled to 23 °C poured into ice-water, neutralized with IN HC1, the precipitate was filtered off, washed with water and dried in vacuum. In cases were the product did not precipitate, the mixture was extracted with EtOAc, washed with water and brine, dried over NazS04. Filtration and removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with hexane/EtOAc to give the pure title compound. Protection of the amino-group was achieved by following the general procedure B.
Example CI
[4-Iodo-5-(4-methyl-pipera2in-l-yl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (2.39 g, 6.0 mmol) and 1-methylpiperazine (1.60 mL, 15 mmol) in toluene (4.5 mL) at 110 °Cfor 18 h according to the genera! procedure C (method a). Obtained as a yellow solid (2.2 g).
MS (ISP) 463 [(M+H)T]; mp 134-136 °C.
Example C2
(4-Iodo-2-nitro-5-thiomorpholin-4-yl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl )-carbamic acid tert.-butyl ester (Example Bl) (2.0 g, 5.0 mmol) and thiomorpholine (2.6 mL) in toluene (3.8 mL) DIPEA (1.7 mL) at 115 °C for 48 h according to the genera! procedure C (method a). Obtained as a yellow solid (1.1 g).
MS (ISP) 466 [(M+H)*]; mp 132-134°C.
Example C3
(4-Iodo-5-morpholin-4-yl-2-nitro-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (2.0 g, 5.0 mmol) and morpholine (10 mL) at reflux for 3 h according to the general procedure C (method a). Obtained as a yellow solid (0.805 g).

MS (ISP) 450 [(M+H)*l; mp 43-44 °C.
Example C4
[5-(l,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-iodo-2-nitro-phenyl]-carbamicacidtert.-but)d ester
Prepared from (5-chloro-4-iado-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (3.0 g, 7.53 mmol), l)4-dioxa-8-aza-spiro(4,5)decane (4.82 mL, 37.63 mmol) and DIPEA (2.58 mL, 15.0 mmol) in toluene (4 mL) at reflux for 6 h according to the general procedure C (method a). Obtained as an orange solid (4.0 g).
MS (ISP) 506 [(M+H)+]; mp 132-134 °C.
Example C5
[4-Iodo-5-(4-methoxy-piperidin-l-yl)-2-nitro-phenyl]-carbamic acid tert-butyl ester
Prepared from 5-chloro-4-io4o-2-nitro-phenylamine (Example Al) (6.91 g, 23.15 mmol), 4-methoxypiperidine (4.0 g, 34.73 mmol) and NaHC03 (5.83 g, 69.45 mmol) in DMSO (230 mL) at 100 °C according to the general procedure C (method b). The obtained brown solid (7.95 g) was converted to the title compound according to the general procedure B (method c). Obtained as a yellow solid {6.55 g).
MS (ISP) 478 [(M+HH; mp 133-135 °C.
Example C6
{5-[(2-Hydroxy-ethyl)-methyl-amino]-4-iodo-2-nitro-phenyl}-carbamic acid tert-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (1.99 g, 5.0 mmol) and 2.methyhminoethano] (2.00 mL, 25.0 mmol) in DMSO (2.5 mL) at 23 °C according to the general procedure C (method a). Obtained as a yellow gum (1.88 g).
MS(ISP)438[(M+H)+j.
Example C7
[5-(4-Hydroxy-piperidin-l-y])-4-iodo-2-nitro-phenyl]-carbamic acid tert-butyl ester

Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (1.99 g, 5 mmol) and 4-hydroxypiperidine (2.53 g, 25 mmol) in DMSO (2-5 mL) at 23 6C according to the general procedure C (method a). Obtained as a yellow solid (1.88 g).
MS (EI) 463 (M+); mp 58-60 °C.
Example C8
{5-[4-(2-Hydroxy-ethoxy)-piperidin-l-yl]-4-iodo-2-nitro-phenyl}-carbamicacidtert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (2.2 g, 5-5 mmol))4-(2-hydroxyethoxy)piperidine {CAS-No. [40256-14-2]} (800 mg, 5.5 mmol) and Et3N (2.3 mL, 16.5 mmol) in DMSO (2.3 mL) at 23 °C according to the general procedure C (method a). Obtained as a yellow solid (1.65 g).
MS (EI) 507 (M+); mp 64-65 °C.
Example C9
[5-(cis-3,4-Dihydroxy-pyiTolidin-l-yl)-4-iodo-2-nitro-phenyI]-carbamic acid tert.-butyl ester
Prepared in two steps as follows: (5-chloro-4-iodo-2-nitro-phenyI)-carbamic acid tert.-butyl ester (Example Bl) (8.73 g, 21.9 mmol) was reacted with 3-pyrroline (2.0 mL, 26.3 mmol, 70% pure, contains 30% pyrrolidine), Et3N (9.12 mL, 65.7 mmol) in DMSO (14 mL) and EtOH (5 mL) at 23 °C according to the general procedure C (method a) to give a 7:3 mixture of [5-(2,5-dihydro-pyrrol-l-yl)-4-iodo-2-nitro-phenyl]-carbamiC acid tert.-butyl ester and (4-iodo-2-nitro-5-pyrrolidin-l-yl-phenyl)-carbamic acid tert"butyl ester Obtained as a yellow solid (8.57 g). Part (4.31 g) of this material was dihydroxylated by reaction with NMO (1.2S g, 11.0 mmol}, 2.5% Os04 in t-BuOH (1 mL.O.I mmol) and K20s04 (40 mg, 0.1 mmol) in acetone (250 mL) and H20 (100 mL) at 23 °C for 6 days. Obtained the title compound as an amorphous yellow substance (2.50 g).
MS(ISP)466[(M+H)+].
Example ClO
[5-(2-Hydroxy-ethylamino)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester

Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (3.99 g, 10 mmol) and ethanolamhe (3.01 mL, 50 mmol) In DMSO (20 mL) at 23 °C according to the general procedure C (method a). Obtained as a yellow solid (4.53 g).
MS (ISP) 424 f(M+H)+]; mp 130-148 °C.
Example Cll
[5-((R)-3"Hydroxy-pyrroiidin-l-yI)-4-iodo-2-nitro-phenyI]-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl), (R)-3-hydroxypyrrolidine hydrochloride and Et3N in DMSO at 23 °C according to the general procedure C (method a). Obtained as a yellow solid (3.153 g).
MS (ISP) 450 [(M+H)+]; mp 158 °C (dec).
The following procedures relate to the preparation of those (4-iodo-2-mtro-phenyl)~ carbamic acid tert.-butyl esters bearing sulfur substituents in the 5-position (Synthetic Scheme D):
General procedure D:
Preparation of 5- S -substituted- (4-iodo-2-nitro-phenyi)-carbamic acid tert-butyl esters from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester To a solution of the thiol (2.2 mmol) in DMF was added NaOMe-sol. (5.4M in MeOH, 0.41 mL, 2.2 mmol) followed by (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (797 mg, 2.0 mmol) and stirring was continued at 23 °C until tic indicated complete disappearance of the chloride. Poured into ice-cold 5% citric acid, extracted with EtOAc, washed with sat. NaHC03-sol., brine, dried over MgS04. Removal of the solvent left an orange oil, which was purified by silica gel column chromatography with hexane/EtOAc to give the pure title compound.
Example Dl
[5-(2-Dimethylamino-ethylsulfanyl)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (399 mg, 1.0 mmol), 2-dimethylaminoethanolethiol hydrochloride (312 mg, 2.2 mmol) and NaOMe solution 5.4M in MeOH (0.8 mL, 8.8 mmol) in DMF (2 mL) according to the general procedure D. Obtained as a yellow solid (306 mg).

MS (ISP) 468 J(M+H)*3; mp 144 °C.
Example D2
(5-tert.-Butoxycarbonylarnino-2-iodo-4-nitro-phenylsulfanyl)-acetic acid methyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (797 mg, 2.0 mmol), methyl thioglycolate (0.2 mL, 2.2 mmol) and NaOMe solution 5.4M in MeOH (0.41 mL, 2.2 mmol) in DMF (2 mL) according to the genera) procedure D. Obtained as a yellow solid (847 mg).
MS (EI) 468 (MT); mp 110-112 °C.
The following procedures relate to the preparation of those (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters bearing oxygen substituents in the 5-position (Scheme E):
General procedure E:
Preparation of 5-0-substituted-4-iodo-2-nitro-phenylarnines from 5-chloro-4-iodo-2-
nitro-phenylamine
To a suspension of KOH (85 %, 3.62-7.96 g, 55-121 mmol) in DMSO (50 mL) was added
the alcohol (125-500 rnmol) and the mixture was stirred at 23 °C until all KOH had
dissolved. 5-ChIoro-4-iodo-2-nitro-phenylamine (Example AI) (15.0 g, 50 mmol) was
added in small portions and the resulting dark red clear solution was stirred at 23-60 °C
until tic indicated complete disappearance of the chloride. Poured into ice-cold IN HC1 or
ice-cold sat. NH4Cl-sol., extracted with EtOAc or CHC13, washed with IN HC1 or sat.
NH4CI-S0I. and brine, dried over MgS04. Removal of the solvent left a dark red solid,
which was purified by silica gel column chromatography to give the pure title compound.
Example El
5-AUyloxy-4-iodo-2-nitro-phenylamine
Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (35.0 g, 50 mmol), • allyl alcohol (50 mL) and KOH (7.96 g, 121 mmol) in DMSO (50 mL) according to the general procedure E. Obtained as an orange solid (9.38 g).
MS(EI)320(M+);mp74°C.
Example E2
4-Iodo-5-methoxy-2-nitro-phenyIamine
1

Prepared from 5-cHoro-4-iodo-2-nitro-phenylamine (Example Al) (2.98 g, 10 mmol), methanol (10 mL) and KOH (1.45 g, 22 mmol) in DMSO (10 mL) according to the general procedure E. Obtained as an orange solid (2.9 g).
MS (ISP) 295 [(M+H)+] and 312 [(M+NH*)*]; mp 189 °C.
Example E3
4-Iodo-5-(2-methoxy-ethoxy)-2-nitro-phenylamine
Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (2.98 g, 10 mmol), 2-methoxyethanol (7.9 ml, 100 mmol) and KOH (1.45 g, 22 mmol) in DMSO (8 mL) according to the general procedure E. Obtained as an orange solid (2.8 g).
MS (ISN) 337 [(M-H)-]; mp 121-122 °C.
Example £4
4-Iodo-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-phenylamine
Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (9.48 g, 32 mmol), tetraethyleneglycol monomethyl ether (19 g, 91 mmol) and KOH (2.31 g, 35 mmol) in DMSO (25 mL) at 60 °C according to the general procedure E. Obtained as a red oil (8.4 g).
MS (ISP) 471 [(M+Hf].
Example E5
(R.S)-5-(2>2-Dimethyl-[l,3]dioxolan-4-ylmethoxy)-4-iodo-2-nitro-phenylamine
Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (4.48 g, 15 mmol), D,L-a,fJ-isopropylidene-glyceroi (10 mL, SI mmol) and KOH (1.01 g, 18 mmol) in DMSO (10 mL) at 23 °C according to the general procedure E. Obtained as a yellow solid {4.9 g).
MS (ISN) 393 [(M-H)"]; mp 151 °C.
Example E6
5-(2-tert.-Butoxy-ethoxy)-4-iodo-2-nitro-phenylamine

Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (14.9 g, 50 mmol), 2-tert.-butoxyethanol (29.5 g, 250 mmol) and KOH (3.99 g, 60 mmol) in DMSO (25 mL) at 23 °C according to the general procedure E. Obtained as a yellow solid (14.3 g).
MS (ISP) 381 [(M+H)*]; mp 144-146 °C.
Example E7
4-Iodo-5-(4-methoxy-benzyloxy)-2-nitro-phenylamine
Prepared from 5-chloro-4-iodo-2-nitro-phenylamine (Example Al) (5.97g, 20 mmol), 4-methoxybenzyl alcohol (4.98 mL, 40 mmol) and KOH (1.58 g, 24 mmol) in DMSO (30 mL) at 23 °C according to the general procedure E. Obtained as a yellow-brown solid (2.94 S)-
MS (ISN) 399 [(M-H)"J; mp 183 DC.
The following examples relate to the preparation of (5-tert.-butoxycarbonylamino-2-iodo-4-nitro-phenyl)-acetic acid methyl ester and (5-cyanomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Synthetic Scheme F);
Example XVI t R=CO,Me: R"=Me: R"=Bod
2-(5-tert.-Butoxycarbonylamino-2-iodo-4-nitro-phenyl)-rnalonic acid dimethyl ester
To a solution of KOBut (0.56 g, 5.02 mmol) in DMSO (3 ml) was added dimethyl malonate (0.58 mL, 5.02 mmol) followed by {5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (1.00 g, 2.51 mmol) and the resulting dark red clear solution was stirred at 100 °C until tic indicated complete disappearance of the chloride. Poured into ice-cold 5% citric acid (100 mL), extracted with EtOAc (2 x 100 mi), washed with brine, dried over MgSO.i. Removal of the solvent left a yellow oil, which was purified by silica gel column chromatography with hexane/EtO Ac 4:1 to give the pure title compound as a yellow gum (1.13 g, 91 %).
MS (ISP) 512 [(M+NH4)+] and 517 [(M+Na)+}-
Example XVII (R=CN: R1=Et; R"=H1
(RS)-{5-Amino-2-iodo-4-nitro-phenyI)-cyano-acetic acid ethyl ester

Prepared as described for example XVI from 5-crdoro-4-iodo-2-nitro-phenylamine (Example Al) (14.9 g, 50 mmol), ethyl cyanoacetate (14.7 mL, 100 mmol) and KOBut (11.2 g, 100 mmol) in DMSO (60 mL) at 100 °C for 2h. Obtained as a dark brown gum.
MS (EI) 375 (M+).
Example Ve m=CO?Me; R"=Boc)
(5-tert.-Butoxycarbonylamino-2-iodo-4-nitro-phenyl)-acetic acid methyl ester
A mixture of 2-(5-tert.-butoxycarbonylamino-2-iodo-4-nitro-phenyl)-malonic acid dimethyl ester (Example XVI (R=CO:Me; R"=Me; R"=Boc)) (3.34 g, 6.76 mmol), LiCl (573 mg, 13.52 mmol) and H20 (0.122 mL, 6.76 mmol) in DMSO (46 mL) was stirred at 100 °C for 7 h. Poured into ice-water, extracted twice with EtOAc, washed with brine, dried over MgS04. Removal of the solvent left a yellow oil, which was purified by silica gel column chromatography with hexane/EtOAc 9:1 to give the pure title compound as a yellow solid {1.37 g, 47 %).
MS (EI) 436 (M+); mp 93 °C.
Example Vf(R=CN;R"=m
(5-Amino-2-iodo-4-nitro-phenyl) -acetonitrile
Prepared as described for example Ve from (RS)-(5-amino-2-iodo-4-nitro-phenyl)-cyano-acetic acid ethyl ester (Example XVII (R=CN; R"=Et; R"=H)) (20.62 g, 55 mmol) and LiCl (9.33 g, 220mmol) in DMSO (370 mL) and H20 (4.4 mL) at 120 °C for 2.5 h. Obtained as a green-brown solid.
MS (EI) 303 (M^mp 145-183 °C.
The following examples relate to the preparation of (5-hydroxymethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester, the corresponding THP-ether, as well as the (5-dimethylaminomethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester via the intermediate chloride (Synthetic Scheme F):
Example Vh
(5-Hydroxymethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester

UBH4 (0.32 g, 14.78 mmol) was added to a solution of 5-tert.-butoxycarbonylamino-2-iodo-4-nitxo-benzoic acid methyl ester (Example B3) (3.12 g, 7.39 mmol) and MeOH (0.6 mL, 14.78 mmol) in THF (44 mL) at 0 DC. The reaction mixture was stirred at 0 °C for 15 min. Poured into 5% citric acid, extracted twice with EtOAc, washed with sat. NaHC MS (ISP) 412 [(M+NH4}*j; mp >250 °C.
Example Vi
(RS)-[4-Iodo-2-nitro-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-carbamicacidtert.-butyl ester
To a mixture of (5-hydroxymethyi-4-iodo-2-niDro-phenyl)-carbamic acid tert.-butyl ester (Example Vh) (394 mg, 1.0 mmol) and 3,4-dihydro-2H-pyran (0.11 mL, 1.2 mmol) in DCM (5 mL) at 0 °C was added p-TsOH.H20 (ca. 5 mg) and the reaction was stirred at 0 °C for 1 h. Diluted with EtOAc, washed with sat. NaHC03-sol. and brine, dried over MgSO^. Removal of the solvent in vacuum left a yellow oil, which was purified by silica gel column chromatography with hexane/EtOAc 9:1 to give the pure title compound as a yellow gum (470 mg, 98 %).
MS(ISN)477[(M-Hr].
Example VI
(5-Dimethylaminomethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester
To a mixture of (5-hydroxymethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Vh), LiCl {3 eq.) and pyridine (2 eq,) in DMF at 0 °C was added methanesulfonyl chloride (1.5 eq.) and the reaction was stirred at 23 °C for 24 h. Me2NH in EtOH (10 eq.) • was added and stirring was continued for 24 h. Diluted with EtOAc, washed with sat. NaHCOVsol. and brine, dried over MgSO*. Removal of the solvent in vacuum left a yellow oil, which was purified by silica gel column chromatography with cyclohexane/EtOAc 3:1 to give the pure title compound as a yellow oil (421 mg).
MS (ISP) 422 [(M+H)+J.

The following examples relate to the preparation of (2-armno-4-aryl-phenyl)-carbamic
acid tert-butyl esters, [2-amino-4-(2-alkenyI)-phenyl]-carbarnic acid tert.-buty] esters and (2-amino-4-aroyl-phenyl)-carbamic acid tert.-butyl esters in regioisomerically pure fashion (Synthetic Scheme B):
General procedure F:
Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl esters by direct Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl esters with arylboronic acids A mixture of the {4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester (3.0 mmol), the arylboronic acid (4.5 mmol) and PdCl2(PPh.3)2 (2 moI%) was refluxed in 1,4-dioxane (25 mL) and 2M Na2C03-sol. (7.5 mL) [or alternatively with 1M NaHC03-sol. (7.5 mL), LiCI (6.0 mmol) and (Ph3P)4Pd (3 mol%) in DME (30 mL); also possible with EtjN (9.0 mmol), Pd(OAc)2 (3 mol%), PPh3 (6 mol%) in DMF (10 mL) at 100 °C] until tic indicated complete conversion of the iodide. The mixture was transferred into a separating funnel, H20 (25 mL) was added and the product was extracted with ether or EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO}. Removal of the solvent left a brown residue, which was purified by silica gel column chromatography with cyclohexane/ether or cyclohexane/EtOAc to give the tide compound.
Example Fl
(2-Chloro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (1.20 g, 3.00 mmol) and phenyl boronic acid (0.62 g, 3.30 mmol) according to the general procedure F. Obtained as a yellow oil (843 mg).
MS (EI) 348 (M+) and 350 [(M+2)+].
Example F2
(2-Methyl-5-nitxo-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (1.135 g, 3 mmol) and phenylboronic acid (630 mg, 3.3 mmol) according to the general procedure F. Obtained as a yellow oil (971 mg).
MS (EI) 328 (M*).

Example F3
RS)-f4"-nuoro-5-nitro-2-[4-(tetrahydro-pyran-2-^oxy)-piperidin-l-yl]-biphenyl-4-yl}-
:arbamic acid tert.-butyl ester
Prepared from (RS)-{4-iodo-2-nitro-5-[4-(tetrahydro-pyran-2-yloxy)-piperidin-l-yl]-:>heny]f-carbamic acid tert.-butyl ester [RO-69-4319/00Q, prepared from [5-(4-hydroxy-piperidin-l-yl)-4-iodo-2-nitro-phanyl]-carbamic acidtert.-butyl ester (Example C7) by treatment with 3,4-dihydro-2H-pyran and cat. Ts0H.H2O in DCM at 0 °C] (1-09 g, 2.0 mmol) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as an orange solid (894 mg).
MS (ISP) 516 [(M+H)*]; mp 144-146 eC.
Example F4
(RS)-(4"-FJuoro-5-nitro-2-j4-[2-(tetrahydro-pyrar)-2-yloxy)-ethoxy}-piperidin-l-y]}-biphenyl-4-yl)-carbamic acid tert-butyl ester
Prepared from (RS)-(4-iodo-2-nitro-5-{4-[2-{tetrahydro-pyran-2-yloxy)-edioxy]-piperidin-1-yl}-phenyl)-carbamic acid tert.-butyl ester [RO-69-4355/000, prepared from {5-[4-(2-hydroxy-ethoxy)-piperidin-l-yl]-4-iodo-2-nitro-phenyi}-carbamicacid tert.-butyl ester (Example C8) by treatment with 3,4-dihydro-2H-pyran and cat TSOH.H2O in DCM at 0 °C] (950 mg, 1.87 mmol) and 4-fluorophenylboronic acid (314 mg, 2.25 mmol) according to the general procedure F. Obtained as a viscous orange oil (930 mg).
MS (ISP) 560 [(M+H)+]; mp 144-146 °C.
Example F5
(RS)-[4"-Fluoro-5-nitro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-carbamic acid tert-butyl ester
Prepared from (RS)-[4-iodo-2-nitro-5-(tetrahydro-pyran-2-yloxymethyI)-phenyI]-carbamic acid tert.-butyl ester (Example Vi) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as an orange oil (1.24 g).
Example F6
(2-Cyanomethoxy-4"-fluoro-5-mtro-biphenyl-4-yl)-carbamic acid tert.-butyl ester

Prepared from (5-cyanomethoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example S2) (838 mg, 2.0 mmol) and 4-fluoTophenylboronic acid (392 mg, 2.8 mmol) according to the general procedure F. Obtained as a yellow solid (333 mg).
MS (ISP) 405 [(M+NH«)*]; mp 148 °C.
Example F7
(2-DimethyIaminomethy]-4"-fluoro-5-nitro-biphen)"l-4-yl)-carbamic acid tert.-butyl ester
Prepared from (5-dimethylaminomethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example VI) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid (1.01 g).
Example F8
[2-(2f2-Dimethyl-tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-5-yl)-4"-fluoro-5-mtro-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [5-(cis-2^-dimethyl-tetrahydro-[l,3]dioxolo[4J5-c]pyrrol-5-yl)-4-iodo-2-nitro-phenyl]-carbamic acid tert-butyl ester [RO-69-4741/000, prepared from [5-(cis-3,4-dihydroxy-pyrrolidin-l-yl)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example C9) by treatment with 2,2-dimethoxypropane and cat. TsOH.HjO in DMF at 23 °C] (845 mg, 1.67 mmol) and 4-fluorophenylboronic acid (327 mg, 2.34 mmol) according to the general procedure F. Obtained as a yellow solid (643 mg).
MS (ISP) 474 [(M+H)"*"]; mp 119 °C.
Example F9
(4"-FIuoro-2-methoxy-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-memoxy-2-nitro-phenyl)-carbamic acid tert.-butyi ester (Example B5) (3.68 g, 9.34 mmol) and 4-fluorophenylboronic acid (3.61 g, 25.8 mmol) according to the general procedure F. Obtained as a yellow solid (2.69 g).
MS (ISN) 361 [(M-H)-]; mp 250 °C.
Example FlO
[2-(l,4-Dioxa-8-a2a-spiro[4.5]dec-8-yl)-4"-fluoro-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester

Prepared from [5-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-jodo-2-nitro-pheny]]-carbaniic acid tert.-butyl ester (Example C4) (4.0 g, 7.02 mmol) and 4-fluorophenylboronic acid (1.33 g, 9.5 mmol) according to the general procedure F. Obtained as a yellow solid (2.43 g)-
mp213°C(dec). Example Fll
(4"-Fluoro-2-methyl-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (756 mg, 2.0 mmol) and 4-fluorophenylboronic acid (420 mg, 3.0 mmol) according to the general procedure F. Obtained as an amorphous yellow substance (611 mg).
MS (ISN) 345 [(M-H)-].
Example F12
(4-tert.-Butoxycarbonyiammo-4"-fluoro-5-nitro-biphenyl-2-yIoxy)-aceticacidtert.-butyi ester
Prepared from (5-tert-butoxycarbonylamino-2-iodo-4-nitro-phenoxy)-acetic acid tert.-butyl ester (Example SI) (2.14 g, 4.33 mmol) and 4-fluorophenylboronic acid (728 mg, 5.2 mmol) according to the general procedure F. Obtained as an orange solid (1.80 g).
MS (ISN) 461 [(M-H)"]; mp 92-93 °C
Example F13
(2-CHoro-4"-fluoro-5-mtro~biphenyI-4-yI}-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamicacid tert.-butyl Mter (Example Bl) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid (625 mg).
MS (El) 366 (M+).
Example F14
[4"-Fluoro-2-(2-methoxy-ethoxy)-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester

Prepared from [4-iodo-5-(2-methoxy-ethoxy)-2-nitro-phenylJ-carbamic add tert.-buty] ester (Example B6) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid (1.833 g).
MS (EI) 406 (M+).
Example P15
[2-{2-tert.-Butoxy-ethoxy)-4"-fluoro-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [5-(2-tert.-butoxy-ethoxy)-4-iodo-2-nitro-pbenyl]-carbamic acid tert.-butyl ester (Example BIO) and 4-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid (735 mg).
MS(ISP)449[(M+Hf].
Example F16
[4"-Fluoro-5-nitro-2-(2-oxo-oxa2olidin-3-yI)-biphenyI-4-yI]-carbamicacidterL-butyI ester
Prepared from [4-iodo-2-mtro~5-(2-oxo-oxazolidin-3-yl)-phenyl]-carbamic acid tert-butyl ester [RO-69-6758/000, prepared from [5-(2-hydroxy-ethylamino)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example CIO) by treatment with 1,1"-carbonyldiimidazole in dioxane and then in pyridine with cat. DMAP each at 100 °C] (503 mg, 1.12 mmol) and 4-fluorophenylboronic acid (235 mg, 1.68 mmol) according to the general procedure F. Obtained as a yellow solid (310 mg).
MS (ISN) 416 [(M-H)1; mp 201 °C.
Example Fi7
(4"-Fluoro-2-methoxy-2" -methyl- 5 -nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methoxy-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B5) and 4-fluoro-2-methyl-phenylboronic acid according to the general procedure F. Obtained as a yellow solid (699 mg).
MS (EI) 376 (M+).

Exampfe FI8
(2-tert.-Butoxy-4"-fluoro-5-nitro-biphenyI-4-yI)-carbamic acid tert.-butyl ester
Prepared from (5-tert.-butosy-4-iodo-2-nitro-phenyl)-carbarnic acid tert.-butyl ester (Example S4) (1.4 g, 3.21 mmol) and 4-fluorophenylboronic acid (0.67 g, 4.42 mmol) according to the general procedure F. Obtained as an amorphous yellow substance (1.2 g).
MS (EI) 404 (M+>.
Example Fl 9
(2-tert.-Butoxy-2"-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (5-tert.-butoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example S4) (1.4 g, 3.21 mmol) and 2-fluorophenylboronic acid (0.67 g, 4.83 mmol) according to the general procedure F. Obtained as an amorphous yellow substance (960 mg).
MS (EI) 404 (M+).
Example F20
(RS)-{4"-Fluoro-5-nitro-2-[(R)-3-(tetrahydro-pyran-2-yIoxy)-pyiToIidin-l-yI]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (RS)-{4-iodo-2-nitro-5-[(R)-3-(tetrahydro-pyran-2-yloxy)-pyrrolidin-l-yl]-phenyl}-carbamic acid tert-butyl ester [RO-69-6376/000, prepared from [5-((R)-3-hydroxy-pyrrolicun-l-yl)-4-Jodo-2-mtro-phenyl]-carbamic acid tert-butyl ester (Example Cll) by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H20 in DCM at 0 °C] and 4-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid (1-053 g).
MS(ISP)502[(M+Hf].
Example F21
(2"-Huoro-2-methoxy-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methoxy-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B5) (1.00 g, 2.54 mmol) and 2-fluorophenylboronic acid (0.60 g, 4.32 mmol)

iccording to the general procedure F. Obtained as an amorphous yellow substance (687 ng).
tfS (EI) 362 (M+).
Example F22
[2-(l,4-Dioxa-8-aza-spiro[4.5jdec-8-yI)-2"-fiuoro-5-nitro-biphenyI-4-yI]-carbamicacid tert.-butyl ester
Prepared from [5-(lJ4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example C4) (1.89 g, 3.47 mmol) and 2-fluorophenylboronic acid (0.63 g, 4.49 mmol) according to the general procedure F. Obtained as a yellow solid (1.46
g)-
MS (ISP) 474 [(M+H)+]; mp 164 °C.
Example F23
(2",5"-Difluoro-2-methoxy-5-nitro-biphenyl-4-yI)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methoxy-2-nitro-phenyi)-caibamic acid tert.-butyl ester (Example B5) (3.94 g, 10 mmol) and 2,5-difluorophenylboronic acid (2.21 g, 14 mmol) according to the general procedure F. Obtained as an amorphous yellow substance (1.05
g)-MS(ISN)379[(M-H)-].
Example F24
[2"~Fluoro-2-(2-methoxy-ethoxy)-5-nitro-biphenyl-4-yI]-carbamic acid tert.-butyl ester
Prepared from [4-iodo-5-{2-methoxy-ethoxy)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example B6) and 2-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow solid {3.63 g).
MS(ISN)405[(M-H)"].
Example F25
(RS)-[2"-Fluoro-5-nitro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-carbamic acid tert.-butyl ester

Prepared from (RS)-[4-iQdo-2-nitro-5-(tetrahydro-pyran-2-yloxymemyl)-phenyl]-carbamic acid tert.-butyl ester (Example Vi) and 2-fluorophenylboronic acid according to the general procedure F. Obtained as a yellow liquid {2.606 g).
MS(ISN)445[(M-H)"].
Example F26
[2"-Fluoro-2-(4-methoxy-benzyloxy)-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [4-iodo-5-(4-methoxy-benzyloxy)-2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example Bll) (1.69 g, 3.38 mmol) and 2-fluorophenylboronic acid (0.61 g, 4.39 mmol) according to the general procedure F. Obtained as a yellow foam (940 mg).
MS(ISP)469[(M+H)+],
Example F27
(2-terL-Butoxy-2",5"-difluoro-5-nitro-biphenyI-4-yl) -carbamic acid tert-butyl ester
Prepared from (5-tert.-butoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example S4) (3.00 g, 6.SS mmol) and 2,5-difluorophenylboronic acid (2.23 g, 14.1 mmol) according to the general procedure F. Obtained as an amorphous yellow substance (2.30
6)-
MS(1SN)421 l(M-H)"].
General procedure G:
Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl esters by Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters with bis(pinacolato)diboron and subsequent reaction with aryl halides
A mixture of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester {2.0 iamo]), bis(pinacolato)diboron (2.2 mmol), KOAc (6.0 mmol) and PdCl2(PPhj)2 (3 mol%) in 1,4-dioxane (25 mL) was stirred at 100 °C until tic indicated complete conversion of the iodide [cf. Terr. Lett. 1997, 38, 3841-3844). After addition of the aryl halide (4.0 mmol), PdCl2(PPh3)2 (3 mol%) and 2M Na2C03-sol. (7.5 ml) the mixture was stirred at 100 °C until tic indicated complete conversion of the intermediate boronic ester. The mixture was transferred into a separating funnel, H20 (30 mL) was added and the product was extracted with ether or EtOAc (3 x 50 mL). The combined organic layers were washed with

brine (100 mL) and dried over Na2S04. Removal of the solvent left a brown residue, which was purified by silica gel column chromatography with cyclohexane/ether or cyclohexane/EtOAc to give the title compound.
General procedure H:
Preparation of (4-aroyl-2-nitro-phenyl)-carbamic acid tert.-butyl esters by carbonylative Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters with aryl boronic acids
A mixture of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (1.0 mmol), aryl boronic acid (1.1 mmoi), K2C03 (3.0 mmol) and PdCI2(PPh3)2 (3 mol%) in anisole (6 ml) was stirred at 80 °C under a CO-atmosphere until thin layer chromatography indicated complete conversion of the iodide [cf. Tetr. Lett. 1993,34,7595-7598]. The mixture was transferred into a separating funnel, H^O (30 mL) was added and the product was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 ml) and dried over Na2S04. Removal of the solvent left a yellow residue, which was purified by silica gel column chromatography with or hexane/EtOAc to give the title compound.
Genera? procedure J:
Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl esters or (4-{alkenyl-, cycloalkenyl- or heterocycloaIkenyl}-2-nitro-phenyl)-carbamic acid tert.-butyl esters by Stille-couplingof (2-nitro-4-tributylstannanyl-phenyl)-carbamicacid tert.-butyl ester with aryl halides or vinyl trifiates or Stille-coupling of (4-iodo-2-nitrophenyl)-carbamic acid tert.-butyi ester with trialkylarylstannanes
A mixture of (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (525 mg, 1.0 mmol; prepared from the corresponding (4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester (Examples B) (10 mmol) by reaction with hexabutyldistannane (7.5 mL, 15 mmol) and Pd(PPh3}4 (116 mg, 0.1 mmol) in toluene (20 mL) at 60 °C for 5 days according to Bull. Chem. Soc. Jpn. 1983,56, 3855-3S56), aryl halide or vinyl triflate (0.95-6.0 mmol), anhydrous LiCl (126 mg, 3.0mmol) and Pd(PPh3)4 (5 mol°/o) in DME (3 mL) was stirred at 100 °C under argon atmosphere until tic indicated complete consumption of the stannane. The reaction was cooled to 23 °C, stirred with sat. aqueous KF-sol. (5 mL) for 45 min, filtered through celite, washed with ether and the filtrate was dried over MgS04-Removal of die solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with hexane/EtOAc to give the tide compound.

The following examples relate to the preparation of (2-amino-4-arylethynyl-phenyl)-carbamic acid tert.-butyl esters in regioisomerically pure fashion (Synthetic Scheme G):
General procedure K:
Preparation of (4-alkynyl-2-nitro-phenyl)-carbainic acid tert.-butyl esters by Sonogashira-
coupling of (4-iodo-2-ni£ro-phenyl)-carbamk acid tert.-butyl esters with acetylenic
compounds;
also Sonogashira-coupiing of (4-ethynyI-2-nitro-phenyl)-carbamic acid tert-butyl esters
with aryl halides;
and Sonogashira-coupiing of 8-iodo-4-aryl-l,3-dihydro-benzo[b][l,4]dia2epin-2-ones
with acetylenic compounds.
A mixture of the halide (3.0-4.5 mmol), acetylenic compound (3.0-4.5 mmol), EtjN (13.5
mmol), PdCl2(PPh3)2 (5 mol%) and PPh3 (2.5 mol%) in THF (12 ml) [with very insoluble
material DMF (up to 12 ml) could be added] was stirred for 20 min at 23 °C while being
purged with Argon. Cul (1.2 mol%) was added and stirring was continued at 60 °C under
Argon atmosphere until tic indicated complete conversion of the minor component [cf. /.
Org. Chem. 1998, 63,8551], The mixture was transferred into a separating funnel, 5% citric
acid (50 mL) was added and the product was extracted with EtOAc (2 x 100 ml). The
combined organic layers were washed with sat. NaHCOVsol. (50 mL) and brine (50 mL),
followed by drying over MgSO,]. Removal of the solvent left a yellow residue, which was
purified by silica gel column chromatography with hexane/EtOAc and/or triturated with
hexane or aqueous EtOH to give the title compound.
Example Kl
(5-ChIoro-2-nitro-4-phenyIethynyl-phenyI)-carbamic acid tert.-butyl ester
Prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Bl) (1.2 g, 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 mmol) according to the general procedure K. Obtained as a yellow solid (944 mg).
MS(ISN)371 [(M-H)"] and373 [(M-H+2)"];mp 166-167°C
Example K2
(5-Methyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-iodo-5-methyl-2-nitro-phenyI)-carbamic acid tert.-butyl ester (Example B2) (1.13 g, 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 mmol) according to the general procedure K. Obtained as a green-yellow solid (794 mg).
MS (EI) 352 (M+); mp 161-164 °C.
Example K3
[5-(4-Methyl-piperazin-l-yl)-2-mtro-4-phenylethynyl-phenyl]-carbamicacidtert.-butyl ester
Prepared from [4-iodo-5-(4-methyI-piperazin-l-yl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example Cl) (1.34 g, 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 mmol) according to the general procedure K. Obtained as a green-yellow solid (1.1 g).
MS (ISP) 437 [(M+H)*]; mp 170 °C
Example K4
(5-Morpholin-4-yl-2-mtro-4-phenylethynyl-phenyl)-carbamic add tert.-butyl ester
Prepared from (4-iodo-5-morpholin-4-yl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C3) (890 mg, 2.0 mmol) and phenylacetylene (0.33 mL, 3.0 mmol) according to the general procedure K. Obtained as an orange solid (580 mg).
MS (ISP) 424 [(M+H)+]; mp 190-191 °C.
Example K5
(2-Nitro-4-phenylethynyl-5-thiomorpholin-4-yI-phenyl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-2-nitro-5-thiomorpholin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example C2) (1.0 g, 2.15 mmol) and phenylacetylene (0.36 mL, 3.22 mmol) according to the general procedure K. Obtained as an orange solid (620 mg).
MS (ISP) 440 [(M+Hf ] and 462 [(M+Na)+]; mp 201 °C (dec).
Example K6
[5-(l,l-Dioxo-thiomorpholin-4-yl)-2-nitro-4-phenylethynyI-phenyl]-carbamic acid tert.-butyl ester

Prepared in two steps as followed:
To a solution of (4-iodo-2-nitro-5-thiomorphohn-4-yl-phenyl)-carbamic acid tert-butyl ester (Example C2) (465 mg, 1 mmol) in acetone (25 mL) and H20 (1 mL) 0.3M ammoniummolybdate sol. (0.3 mL) and 33% H202 (2.3 mL) were added at 0°C and mixture was stirred for 1 h at 23 °C. Obtained the [5-(l,l-dioxo-thiomorpholin-4-yl)-4-iodo-2-nitro-phenylj-carbamk add tert.-butyl ester (497 mg, 1.0 mmol) as an amorphous yellow material, which was reacted with phenylacetylene (0.17 mL, 1.5 mmol) according to the general procedure K. Obtained as a yellow solid (245 mg).
MS (ISP) 472 [(M+H)*]; mp 217-221 "C.
Example K7
[5-(l,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-nitro-4-phenylethynyl-phenyl]-carbamicacid tert.-butyl ester
Prepared from [5-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yI)-4-iodo-2-iu"txo-phenyl)-carbamic acid tert.-butyl ester (Example C4) (3.80 g, 7.53 mmol) and phenylacetylene (1.24 mL, 11.3 mmol) according to the general procedure K. Obtained as a orange solid (1.8 g).
MS (ISN) 478 [(M-H)"]; mp 179-180 °C.
Example K8
[5-(2-Dimethylamino-ethylsulfanyl)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [5-(2-dimethylamino-ethylsulfanyl)-4-iodo-2-nitro-phenyl]-carbamic acid terL-butyl ester (Example Dl) (721 mg, 1-54 mmol) and phenylacetylene (0.23 mL, 2.31 mmol) according to the general procedure K. Obtained as an amorphous yellow material (595 mg).
MS (ISP) 442 [(M+H)+]; mp 179-180 DC.
Example K9
{5-tert.-Butoxycarbonylamino-4-nitro-2-phenylethynyl-phenylsulfanyl)-acetic acid methyl ester

Prepared from (5-tert.-butoxycarbonylamino-2-iodo-4-nitro-phenylsulfanyl)-acetic acid methyl ester (Example D2) (780 mg, 1.67 mmol) and phenylacetylene (0.27 mL, 2.5 mmol) according to the general procedure K. Obtained as an orange solid (700 mg).
MS (ISP) 460 KM+KH*)*]; mp 125-127 °C.
Example KlQ
[5-(2-Methoxy-ethoxy)-2-nitro-4-phenylethyny!-phenyl]-carbamic acid tert.-butyl ester
Prepared from [4-iodo-5-(2-methoxy-etiioxy)-2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example B6) (876 mg, 2 mmol) and phenylacetylene (0.33 mL, 3 mmol) according to the general procedure K. Obtained as a yellow solid (569 mg).
MS (ISP) 413 [(M+H)+] and 430 [(M+NH*)*]; mp 118-119 °G
Example Kll
(5-Methoxy-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-methoxy-2-nitro-phenyI)-carbamic add tert.-butyl ester (Example B5) (1.18 g, 3.00 mmol) and phenylacetylene (0.58 mL, 4.5 mmol) according to the general procedure K. Obtained as a yellow solid (1.1 g).
MS(EI)368(M+);mpl29°C.
Example Kl2
[5-(2-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [4-iodo-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-phenyl]-carbamic acid tert.-hutyl ester (Example B7) (5.7 g, 10.0 mmol) and phenylacetylene (1.65 mL, 15 mmol) according to the general procedure K. Obtained as a yellow oil (5.2 g).
MS(ISN)543[(M-H)-].
Example K13
(5-tert.-Butoxycarbonylamino-4-nitro-2-phenylethynyl-phenoxy)-aceticacidtert.-butyl ester

Prepared from {5-tert.-butoxycarbonyIamino-2-iodo-4-nitro-phenoxy)-acetic acid tert.-butyl ester (Example SI) {1.46 g, 2.99 mmol) and phenylacetylene (0.49 mL, 4.49 mmol) according to the general procedure K. Obtained as a yellow solid (1.4 g).
MS (ISP) 486 KM+NH4)+V, mp 130 °C.
Example K14
(RS)-5-(2,2-Dimethyl-[l,3]dioxolan-4-ylmethoxy)-2-nitro-4-phenylethynyl-phenylamine
Prepared from {RS)-5-(2>2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-4-iodo-2-nitro-phenylamine {Example E5) (4.5 g, 11.4 mmol) and phenylacetylene (1.88 mL, 17.1 mmol) according to the general procedure K. Obtained as an orange solid (5.4 g).
MS (ISN) 367 [{M-H)-]; mp 147-149 °C.
Example K15
(5-tert-Butoxycarbonylamino-4-nitro-2-phenylethynyI-benzoic acid methyl ester
Prepared from 5-teit.-butoxycarbonylamino-2-iodo-4-nitro-benzoic acid methyl ester
(Example B3) (1.22 g, 2.89 mmol) and phenylacetylene (0.48 mL, 4.34 mmol) according to the general procedure K. Obtained as a yellow solid (793 mg).
MS (ISP) 397 [(M+H)+} and 414 [(M+NH4)+]; mp 173 °C
Example Kl 6
{5-tert.-Butoxycarbonylamino-4-nitro-2-phenylethynyl-pheny])-acetic acid methyl ester
Prepared from (5-tert.-butoxycarbonylamino- 2 -iodo-4-nitro-phenyl) -acetic acid methyl ester (Example Ve (R=C02Me; R"=Boc)) (1.32 g, 3.03 mmol) and phenylacetylene (0.5 mL, 4.55 mmol) according to the general procedure K. Obtained as a yellow solid (1.1 g).
MS (ISP) 411 [(M+H)+],428 [(M+NH4)+] and433 [(M+Na)+];mp 134 °C.
Example K17
(5-Cyanomethyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester

Prepared from (5-cyartomethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B9 [Ve (R=CN; R"=Boc)]) (3.97 g, 9.85 mmol) and phenylacetylene (3.24 mL, 29.56 mmol) according to the general procedure K. Obtained as an olive solid (1.6 g).
MS (ISP) 395 [(M+NH4)+]; mp 166 °C.
■ Example Kl 8
(RS)-[5-(23-Dihydroxy-propoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamit acid ten.-butyl ester.
Prepared from (RS)-[5-(2,3-dihydroxy-propoxy)-4-iodo-2-nitro-phenyl]-carbamicacid tert.-butyl ester (RO-68-5451/000 (3.23 g, 7.11 mmol); prepared from (5-allyk>xy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B4) (4.20 g, 10.0 mmol) by reaction with NMO (1.28 g, 11.0 mmol), Os04 2.5% in t-BuOH (1 mL, 0.1 mmol) and K2Os04 (40 mg, 0.1 mmol) in acetone (250 mL) and H20 (100 mL) at 23 °C for 6 days) and phenylacetylene (1.17 mL, 10.67 mmol) according to the general procedure K. Obtained as a yellow solid (2.74 g).
MS (ISP) 429 [ Example K19
(5-Hydroxymethyl-2-nitro-4-phenyletJiynyI-phenyl)-carbaniic acid tert.-butyl ester.
Prepared from (5-hydroxymethyl-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Vh) (2.61 g, 6.62 mmol) and phenylacetylene (1.10 mL, 9.93 mmol) according to the general procedure K. Obtained as a yellow solid (1.76 g).
MS (ISP) 386 [(M+NH4)+J; mp 177 °C (dec).
Example K20
[5-(4-Methoxy-piperidin-l-yI)-2-nitro-4-phenylethynyl-phenyI]-carbamicacidtert.-butyl ester.
Prepared from [4-iodo-5-(4-methoxy-piperidin-l-yl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example C5) (1.0 g, 2.1 mmol) and phenylacetylene (0.35 mL, 3.15 mmol) according to the general procedure K. Obtained as a yellow solid (799 mg).
mp 147-150 °C

Example K2l
(5-Cyanomethoxy-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert-butyl ester.
Prepared from (5-cyanomemoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example S2) (605 mg, 1.44 mmol) and phenylacetylene (0.24 mL, 2.16 mmol) according to the general procedure K. Obtained as a yellow solid (508 mg).
MS (EI) 393 (M+); mp 170 °C.
Example K22
E4-(4-FIuoro-phenylethynyI)-5-hydroxymethyI-2-nitro-phenyl]-carbamic acid tert.-butyl ester.
Prepared from (5-hydroxymethyl-4-iodo-2-nitro-phenyI)- carbamic acid tert.-butyl ester (Example Vh) (2.00 g, 5.07 mmol) and 4-fluorophenylacetylene (0.91 g, 7.61 mmol) according to the general procedure K. Obtained as a yellow solid (1.55 g).
MS (ISN) 385 [(M-H)"]; mp 198 °C.
Example K23
(RS)-{4-(4-Fluoro-phenylethynyl)-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino}-2-nitro-phenyl)-carbamic acid tert.-butyl ester.
Prepared from (RS)-(4-iodo-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino}-2-nitro-phenyl)-carbamic acid tert-butyl ester [RO-69-3820/000, prepared from {5-[(2-hydroxy-ethyl)-methyl-amino]-4-iodo-2-nitro-phenyl}-carbamic acid tert.-butyl ester (Example C6) by treatment with 3,4-dihydio-2H-pyran and cat. TsOH.H20 in DCM at 0 °C] (2.09 g, 4.01 mmol) and 4-fluorophenylacetylene (0.72 g, 6.02 mmol) according to the general procedure K. Obtained as a yellow-brown solid (1.84 g).
MS (ISP) 514 KM+Hrj; mp 134 °C. Example K24
(RS)-{2-Nitio-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyll-carbamic acid tert.-butyl ester.
Prepared from (RS)-{4-iodo-2-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy3-phenyl}-carbamic acid tert.-butyl ester (Example S3) (743 mg, 1.46 mmol) and phenylacetylene

(0.24 mL, 2.19 mmol) according to the general procedure K. Obtained as a yellow-brown viscous oil (429 mg).
MS (EI) 393 (M+).
Example K25
Prepared from [5-(2-tert.-butoxy-ethoxy)-4-iodo-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example BIO) (1.44 g, 3.0 mmol) and 4-fluorophenylacetylene (541 mg, 4.5 mmol) according to the general procedure K. Obtained as a yellow solid (777 mg).
MS (EI) 472 (M+); mp 96-98 °C.
Example K26
[5-tert.-Butoxy-4-(4-fiuoro-phenylethynyl)-2-nitro-phenyI]-carbamicacidtert.-butyl ester.
Prepared from (5-tert.-butoxy-4-iodo-2-nitro-phenyl}-carbamic acid tert-butyl ester (Example S4) (1.40 g, 3.21 mmol) and 4-fluorophenylacetylene (0.66 g, 5.46 mmol) according to the general procedure K. Obtained as a brown solid (520 mg).
MS(EI)428(M+);mp201°C.
General procedure L:
Preparation of the (2-amino-phenyl )-carbamic acid tert. -butyl esters by reduction of (2-
nitro-phenyl)-carbamic acid tert.-butyl esters;
Also preparation of 4-aryl-l,3-dihydro-benZo[b] [l,4]diazepin-2-ones by reduction and
concomitant cyclization of3-aryl-N-(2-nitro-phenyl)-3-oxo-propionamides
Method a: Catalytic hydrogenation
A mixture of the nitro compound (1.0 mmol) in MeOH or EtOH and THF (1:1 ca. 20 mL) and 10% Palladium on carbon (20 mg) or Raney-Ni (20 mg) was stirred vigorously at 23 °C under hydrogen atmosphere until tic indicated complete conversion. The catalyst was filtered off, washed thoroughly with MeOH or EtOH and THF (1:1), the solvent was removed in vacuum to give the title compound, which was generally pure enough for further transformations.

Method b: Reduction with SnCI:-2H20
A mixture of the nitro compound (1.0 mmol) and SnCI2-2H20 {5.0 mmol) was either stirred in EtOH (30 mL) at 70-80 °C or alternatively in pyridine (3 mL) and DMF (12 mL) at 23 °C under Argon atmosphere until tic indicated complete conversion [cf. Tetr. ten. 1984,25, 839]. The reaction mixture was brought to pH 8 by addition of sat. NaHC03-sol. and extracted with EtOAc (2 x 100 mL). The combined organic layer were washed with brine and dried over Na:S04. Removal of the solvent left a yellow solid, which - if necessary - can be purified by silica gel column chromatography.
Method c: Reduction with 2n and NR,C1
To a mixture of the nitro compound (1.0 mmol) in EtOH/THF/sat. NH4Cl-soI. (1:1:1,30 mL) was added Zinc dust (3.0 mmol) and the mixture was stirred at 70 6C under Argon atmosphere until dc indicated complete conversion. Aqueous workup as described in method b.
Method d: Reduction with Fe and HOAc
To a mixture of the nitro compound (1.0 mmol) in THF/H20 (4:1, 10-50 mL) was added Fe powder (6.0 mmol) and the mixture was stirred at 70 °C under Argon atmosphere until tic indicated complete conversion. Aqueous workup as described in method b.
Example LI
(2-Amino-4-iodo-5-thiomorpholin-4-yl-phenyI)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-2-nitro-5-thiomorpholin-4-yl-phenyI)-carbamic acid tert.-butyl ester (Example C2) (1.05 g, 2.25 mmo!) by reduction with SnCl2-2H20 (2.54 g, 11.3 mmol) according to the general procedure L (method b). Obtained as a light yellow soHd (993 mg).
MS (ISP) 436 [(M+H)+j; mp 125-127 °C.
Example L2
(2-Amino-4-iodo-5-morpholin-4-yl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (4-iodo-5-morpholin-4-yl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C3) (753 g, 1.65 mmol) by reduction with SnClr2H:0 (1.9 g, 8.27 mmol) according to the general procedure L (method b). Obtained as a yellow solid (696 mg).

MS (ISP) 420 [(M+H)*]; mp 139-143 °C.
Example L3
(2-Amino-5-chloro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from {5-cUoro-2-nitro-4-phenylethynyI-phenyl)-carbamic acid tert.-butyl ester (Example Kl) (742 mg, 2.0 mmol) by reduction with SnCl2-2H20 {2.245 g, 10 mmol) according to the general procedure L (method b). Obtained as an orange solid (483 mg).
MS (ISP) 343 [(M+H)+] and 345 [(M+2+H)+J.
Example L4
(2-Amino-5-methyl-4-phenylethynyl-phenyI)-carbamic acid tert.-butyl ester
Prepared from (5-methy!-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K2) (741 mg, 2.1 mmol) by reduction widi SnCl2-2H20 (2.37 g, 10.3 mmol) according to the general procedure L (methodb). Obtained as a light-brown solid (419 mg).
MS (ISP) 323 [(M+H)*]; mp 172-173 °C.
Example L5
[2-Amino-5-(4-methyl-pipera2in-l-yl)-4-phenylethynyl-phenyl]-carbamicacid tert.-butyl ester
Prepared from [5-(4-methyl-piperazin-l-yl)-2-nitro-4-phenykthynyl-phenyl]-carbamic acid tert.-butyl ester (Example K3) (1.08 g, 2.48 mmol) by reduction with SnCl2-2H20 (2.8 g, 12.4 mmo!) according to the general procedure L (method b). Obtained as an orange solid (1.0 g).
MS (ISP) 407 [(M+H)+j; mp 81-85 °C.
Example L6
(5-Amino-2-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-chloro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example Fl) (783 mg, 2.24 mmol) by reduction with SnCl2-2H20 (2.53 g, 11.2 mmol) according to the general procedure L (method b). Obtained as a yellow solid (684 mg).

MS (EI) 318 (M+) and 320 [(M+2)*]; mp 109-111 °C.
Example L7
(5-Ammo-2-methyI-biphenyi-4-yl)-carbamic acid terL-butyi ester
Prepared from (2-methyl-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F2) (921 mg, 2.8 mmol) by catalytic hydrogenation with Pd/C according to the general procedm-e L (method a). Obtained as a white solid (796 mg).
MS (EI) 298 (Mf); mp 122 6C.
Example L8
[2-Amino-5-(2-dimethylamino-ethylsulfanyl)-4-phenylethynyl-phenyl]-carbamicacid tert.-butyl ester
Prepared from [ 5- {2-dimethylamino-ethylsulfenyI)-2-nitro-4-phenylethynyl-phenyl] -carbamic acid tert.-butyl ester (Example K8) (551 mg, 1.25 mmol) by reduction with SnCl2-2H20 (1.41 g, 6.25 mmol) according to the general procedure L (method b). Obtained as an orange foam (510 mg).
MS (ISP) 412[(M+H)+];mp 115-117 °C.
Example L9
(4-Amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-phenylsulfanyl)-aceticacid methyl ester
Prepared from (5-tert.-butoxycarbonylamino-4-nitro-2 -phenylethynyl-phenyisulfanyl)-acetic acid methyl ester (Example K9) (634 mg, 1.43 mmol) by reduction with SnClvlH^O (1.62 g, 7.16 mmol) according to the general procedure L (method b). Obtained as an orange gum (590 mg).
MS (ISP) 413 [(M+H)+], 435 [(M+Na)+] and 451 [(M+K)+j.
Example LlO
(4-Amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-phenyl)-acetic acid methyl ester
Prepared from (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethynyl- phenyl) -acetic acid methyl ester (Example K16) (1.09 g, 2.66 mmol) by reduction with SnCl:-2H:0 (3.00 g,

13.28 mmol) according to the general procedure L (method b). Obtained as a light yellow solid (900 mg).
MS (ISP) 381 [(M+H)+] and 403 [(M+Na)+); mp 130 °C.
Example LI 1
[2-Amino-5-(2-methoxy-ethoxy)-4-phenyIethynyl-phenyl]-carbamic acid tert. -butyl ester
Prepared from [5-(2-methoxy-ethoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid terL-butyl ester (Example K10) (1.417 g, 3.44 mmol) by reduction with SnCl2-2H20 {3.88 g, 17.2 mmol) according to the general procedure L (method b). Obtained as an off-white solid (1.04 g).
MS (EI) 382 (M+); mp 105-107 °C.
Example LI2
(2-Amino-5-morpholin-4-yl-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-morpholin-4-yl-2-nitro-4-phenylethynyl-phenyl)-carbanuc acid tert.-butyl ester (Example K4) (563 mg, 1.329 mmol) by reduction with SnCl2-2HjO (1.5 g, 6.65 mmol) according to the general procedure L (method b). Obtained as a red-brown solid (488 mg).
MS (ISP) 394 [(M+H)*l; mp 174-176 °C.
Example LI 3
(2-Amino-5-methoxy-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-methoxy-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example Kll) (1.00 g, 2.71 mmol) by reduction with SnCl2-2H20 (3.06 g, 13.57 mmol) according to the general procedure L (method b). Obtained as a yellow solid (870 mg).
MS(EI)338(Mt);mpl58°C.
Example LI 4
4-Amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-benzoic acid methyl ester

Prepared from (5-tert.-butoxycarbonylamino-4-nitto-2-phenyIethynyl-benzoic acid methyl ester (Example K15) (754 mg, 1.90 mmol) by reduction with SnC!2-2H20 (2.15 g, 9.51 mmo!) according to the general procedure L (method b). Obtained as a pink solid (431 mg).
MS (EI) 366 (M+); mp 164 °C. Example LI5
[2-Amino-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example K12) (3.0 g, 5.51 mmol) by reduction with SnCl2-2H20 (6.2 g, 27.54 mmol) according to the general procedure L (method b). Obtained as a brown oil (2.9 g).
MS(ISP)515[(M+H)+].
Example L16
(4- Amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-phenoxy)-acetic acid tert. -butyl ester
Prepared from (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenoxy)-acetic acid tert.-butyl ester (Example K13) (1.32 g, 2.82 mmol) by reduction with SnCl2-2H20 (3.18 g, 14.10 mmol) according to the general procedure L (method b). Obtained as an amorphous orange material (1.2 g).
MS (ISP) 439 [(M+H)+] and461 [(M+Na)+].
Example LI7
(2-Ammo-5-cyanomethyl-4-phenyl ethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-cyanomethyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ■ ester (Example K17) (377 mg, 1.0 mmol) by reduction with SnCl:-2H:0 (1.13 g, 5.0 mmol) according to the general procedure L {method b). Obtained as an orange solid (338 mg).
MS (ISP) 348 [(M+Hf] and 370 [(M+Na)+]; mp 143 °C.

Example L18
[2-Amino-5-(lJ4-dioxa-8-aza-spiro[4.5}dec-8-yl)-4-phenylethynyl-phenyI]-carbamicacid tert.-butyl ester and [2-Amino-5-(4,4-diemoxy-piperidin-l-yl)-4-phenylethynyl:phenyl]-carbamic acid tert.-butyl ester
Prepared from [5-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-nitJo-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example K7) {1.73 g, 3.6 mmol) by reduction with SnCir2H:0 (4.0 g, 18.0 mmol) in EtOH according to the general procedure L (method b). Obtained as a brown solid (418 mg) and as dark brown solid (379 mg}, respectively.
MS (ISP) 450 [(M+H)*]; mp 79-82 °C; MS (ISP) 480 [(M+H)+].
Example LI9
[2-Amino-5-(l,l-dioxo-6-thiomorpholin-4-yI)-4-phenylethynyI-phenyl]-carbamicacid tert.-butyl ester
Prepared from [5-(l,l-dioxo-thiomorpholin-4-yl)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example K6) (235 mg, 0.5 mmol) by reduction with SnCl2-2H:0 (564 mg, 2.5 mmol) according to the general procedure L (method b). Obtained as a brown solid (418 mg, impure material, used directly in Example 6 without purification and characterization).
Example L20
[2-Amino-5-(2,2-dimethyl-[l,3}dioxolan-4-ylmethoxy)-4-phenylethynyl-phenyl]-tarbamic acid tert.-butyl ester
Prepared from (RS)-[5-(2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example B8) (1.90 g, 4.06 mmol) by reduction with SnCI2-2H;0 (4.6 g, 20.32 mmol) according to the general procedure L (method b). The crude product was reprotected by stirring with 2,2-dimethoxypropane (5 mL) and p-TsOH-H20 (1.1 eq) in DMF (5 mL) at 23 °C for 4 h. Obtained as a brown solid (1.1 g).
MS (ISP) 439 [(M+H)+], 461 [(M+Na)+} and 477 [(M+Kf].
Example L21
4-Amino-5-tert.-butoxycarbonylamino-2-iodo-benzoic acid methyl ester

Prepared from 5-tert.-butoxycarbonylamino-2-iodo-4-nitro-benzoic acid methyl ester (Example B3) (3.00 g, 7.11 mmol) by reduction with SnOj^O (8.02 g, 35.55 mmol) according to the general procedure L (method b). Obtained as a light red foam (1.9 g).
MS (ISP) 393 [(M+H)+i; mp 60-78 °C.
Example L22
[RS]-[2-Amino-5-(2-oxo-[l,3]dioxoIan-4-ylmethoxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [RS]-[2-Nitro-5-(2-oxo-[l,3]dioxolan-4-ylmethoxy)-4-phenylethynyI-phenyl]-carbamic acid tert.-butyl ester [RO-68-8108/000 (411 mg, 0.9 mrnol), prepared from (RS)- [5-(2,3-dihydroxy-propoxy)-2-nitro-4-phenylethynyl-phenyI] -carbamic acid tert.-butyl ester (Example K18) by treatment with l,l"-carbonylcaim.idazole in THF at 0 to 23 °C] by reduction with SnCl2"2H20 (1.02 g, 4.5 mmol) according to the general procedure L (method b). Obtained as an apricot solid (370 mg).
MS (ISP) 425 [(M+H)*]; mp 140 °C.
Example L23
(2-Amino-5-ethoxymethyl-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from carbonic acid 5-tert.-butoxycarbony!amino-4-nitro-2-phenylethynyl-berizyl ester methyl ester [RO-68-8481/000, prepared from (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K19) bytreatment with methyl chloroformate and Et3N in THE at 0 °C) by reduction with SnCl^HzO according to the general procedure L (method b). Obtained as an amorphous brown substance (139 mg).
MS(ISP)367[(M+H)+].
Example L24
2,2-Dimethy]-propionicacid4-amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-benzyl ester
Prepared from 2,2-dimethy3-propionic acid 5-tert-butoxycarbonylamino-4-nitro-2-phenylethynyl-benzyl ester [RO-68-9779/000, prepared from (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K19) by treatment with

pivaloyl chloride and cat. DMAP in pyridine at 0 to 23 °C] by reduction with SnC!2"2H20
according to the general procedure L (method b). Obtained as an amorphous yellow substance (182 mg).
MS(ISN)421 [(M-H)"].
Example L25
(RS)-[2-Amino-4-phenyIethyriyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-carbamic acid tert. -butyl ester
Prepared from (RS)-[2-nitro-4-phenylethynyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-carbamic acid tert-butyl ester [RO-69-2829/000, prepared from (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example Kl9) by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H20 in DCM at 0 °C] by reduction with SnCl2-2H:0 according to the general procedure L (method b). Obtained as a yellow solid (1.78 g).
MS (ISN) 421 [(M-H)"]; mp 158 °C.
Example L26
[2-Amino-5-(4-methoxy-piperidin-l-yl)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [5-(4-medioxy-piperidin-l-yl)-2-nitro-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example K20) (727 mg, 1.61 mmol) by reduction with SnCU"2H20 according to the general procedure L (method b). Obtained as a yellow solid (489 mg).
MS (ISP) 422 [(M+H)*]; mp 173-176 °C.
Example L27
(2-Amino-5-cyanomethoxy-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-cyanomethoxy-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert-butyl ester (Example K21) (395 mg, 0.91 mmol) by reduction with SnCV2H:0 according to the general procedure L (method b). Obtained as an amorphous yellow substance (219 mg).
MS(1SP)364[(M+H)+!.

Example L28
(RS)-[2-Amino-4-(4-fluoro-phenylethynyl)-5-(tetrahydro-pyran-2-yloxyinethyl)-phenyI]-carbamic add tert.-butyl ester
Prepared from (RS)-[4-(4-fiuoro-phenylethynyl)-2-nitro-5-(tetrahydro-p)Tan-2-yloxymethyI)-phenyl]-carbamic acid tert.-butyl ester [RO-69-3877/000, prepared from [4-{4-fluoro-phenylethynyl)-5-hydroxymethyl-2-nitro-phenyl]-carbamic acid tert.-butyl ester {Example K22) by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H20 in DCM at 0 °C] by reduction witfi SnCl2"2H20 according to the genera] procedure L (method b). Obtained as an amorphous light brown substance (990 mg).
MS (ISP) 441 [(M+H)+].
Example L29
(RS)-(2-Amino-4-(4-fluoro-phenyIethynyl)-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethyl] -amino}-phenyl)-carbamic acid tert.-butyl ester
Prepared from (RS)-(4-(4-fluoro-phenylethynyI)-5-!methyl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino}-2-nitro-phenyl)-carbamic acid terL-butyl ester (Example K23) (1.79 g, 3.49 mmol) by reduction with SnCI;2H20 according to the general procedure L (method b). Obtained as an amorphous light brown substance (1.20 g).
MS(ISP)484[(M+H)+].
Example L30
(RS)-{2-Amino-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-carbamic acid tert.-butyl ester
Prepared from (RS)-[2-nitro-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-carbamic acid tert.-butyl ester (Example K24) (420 mg, 0.87 mmol) by reduction with SnCl2"2H:0 according to the general procedure L (method b). Obtained as a light brown solid (346 mg).
MS(ISP)453[(M+Hf].

Example L31
(RS)-{5-Amino-4"-fiuoro-2-[4-(tetrahydro-pyran-2-yloxy)-piperidin-l-yl]-biphenyl-4-yI}-carbamic acid tert.-butyl ester
Prepared from (RS)-{4"-fiuoro-5-nitro-2-[4-(tetrahydro-pyran-2-yloxy)-piperidin-l-yl]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example F3) (845 mg, 1.64 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light gTeen solid (758 mg).
MS (ISP) 486 [(M+H)+]; mp 157-161 °C.
Example L32
[2-Amino-5-(2-tert.-butoxy-ethoxy)-4-(4-f3uoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester
Prepared from [5-(2-tert.-butoxy-ethoxy)-4-(4-fluoro-phenylethynyl)-2-nitro-phenyl] -carbamic add tert.-butyl ester (Example K25) (744 mg, 1.57 mmol) by reduction with SnCl2"2H:0 according to the general procedure L (method b). Obtained as a light yellow solid (575 mg).
MS (ISP) 443 [(M+Hf]; mp 149-150 °C.
Example L33
(RS)-(5-Amino-4"-fluoro-2-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-piperidin-l-yl}-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (RS)-(4"-fluoro-5-nitro-2-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-piperidin-l-yl}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F4) (900 mg, 1.61 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light brown foam (779 mg).
MS (ISP) 530 [(M+HD; mp 56-58 °C.
Example L34
(RS)-E5-Amino-4"-fluoro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-carbamic acid tert-butyl ester

Prepared from (RSJ-[4"-fluoro-5-nitxo-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example F5) by reduction with SnCIj"2H20 according to the general procedure L (method b). Obtained as an orange solid (1.15 g).
mp 139-142 °C.
Example L35
(5-Amino-2-cyanomethoxy-4"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-cyanomethoxy-4"-fiuoro-5-nitro-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example F6) (310 mg, 0.8 mmol) by redaction with SnCl;"2H:0 according to the general procedure L (method b). Obtained as a light brown solid (220 mg).
MS (ISN) 356 [(M-H)"]; mp 118-119 °C.
Example L36
(5-Amino-2-dimediylaminometJiyl-4,-fluoro-biphenyl-4-yl)-carbamic acid tert. -butyl ester
Prepared from (2-dimethylaminometiiyl-4"-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F7) by reduction with SnClv2H20 according to the general procedure L (method b). Obtained as a yellow solid (908 mg).
mp 97-125 °C.
Example L37
[5-Amino-2-(2,2-dimethyl-tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-5-yl)-4"-fluoro-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [2-(2,2-dimethyl-tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-5-yl)-4"-fluoro-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F8) (610 mg, 1.29 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as an off-white foam (578 mg).
MS(ISP)444[(M+H)+1.
Example L38
(5-Amino-4"-fluoro-2-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester

Prepared from (4"-fluoro-2-memoxy-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F9) (2.64 g, 7.29 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method aj. Obtained as an off-white solid (2.36 g).
MS (ISP) 333 [(M+H)*]; mp 155 °C (dec).
Example L39
[5-Amino-2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4"-fluoro-biphenyl-4-ylj-carbamicacid tert.-butyl ester
Prepared from [2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4"-fluoro-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example FlO) (2.4 g, 5.0 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a green solid (2-37 g).
MS(ISP)444((M+H)+].
Example L4Q
(5-Amino-4"-fluoro-2-methyl-biphenyI-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4"-fiuoro-2-methyl-5-nitro-biphenyl-4-yl)-carbarnic acid tert.-butyl ester (Example Fll) (560 mg, 1.62 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light brown solid (512 mg).
MS (ISP) 317 [(M+HH; mp 112 °C.
Example L41
(5-Amino-4-tert.-butoxycarbonylamino-4"-fiuoro-biphenyl-2-yloxy)-acetic acid tert.-butyl ester
Prepared from (4-tert.-butoxycarbonylamino-4"-fluoro-5-nitro-biphenyl-2-yloxy)-acetic acid tert.-butyl ester (Example F12) (2.29 g, 4.95 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a dark blue solid (2.14
g)-
MS (ISP) 433 [(M+H)*]; mp 30-33 °C.

Example L42
(5-Amino-2-chloro-4"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-cHoro-4"-£Iuoro-5-nitro-biphenyI-4-yl)-carbamic acid tert.-butyl ester (Example F13) by reduction with SnClv2H20 according to the genera] procedure L (method b). Obtained as a light red solid (544 mg).
MS(ISP)337[{M+Hrj.
Example L43
[5-Amino-4"-fluoro-2-(2-methoxy-ethoxy)-biphenyI-4-yl]-carbamic add tert.-butyl ester
Prepared from [4"-fluoro-2-(2-methoxy-ethoxy)-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F14) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light brown solid (1.652 g).
MS(ISP)377[(M+H)+].
Example L44
[5-Amino-2-(2-tert.-butoxy-ethoxy)-4"-£luoro-biphenyl-4-yl]-carbamicacidtert.-butyl estei
Prepared from [2-(2-tert.-butoxy-ethoxy)-4"-fluoro-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F15) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a purple solid (547 mg).
MS (ISP) 419 [(M+H)+]; mp 133 °C (dec).
Example L45
[5-Amino-4"-fiuoro-2-(2-oxo-oxazolidin-3-yl)-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [4"-fluoro-5-nitro-2-(2-oxo-oxazolidm-3-yl)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F16) (280 mg, 0.67 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a yellow solid (277 mg).
MS (ISP) 388 [(M+H)+J; mp 210 °C.

Example L46
(5-AminD-4"-fluoro-2-methoxy-2"-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (4,-fluoro-2-rnethoxy-2"-methyl-5-nitro-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example F17) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a brown solid (588 mg).
MS (ISP) 347 [(M+H)+].
Example L47
(5-Amino-2-tert.-butoxy-4"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-tert.-butoxy-4"-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F18) (1.15 g, 2.84 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a pink solid (747 mg).
MS (ISP) 375 [(M+HD; mp 139 °C.
Example L48
(5-Amino-2-tert.-butoxy-2"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-tert.-butoxy-2"-fluoro-5-nitro-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example F19) (930 mg, 2.3 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a pink solid (649 mg).
MS (ISP) 375 KM+H)+]; mp 130 °C.
Example L49
(RS)-{5-Amino-4"-uuoro-2-((R)-3-(tetrahydro-pyran-2-yIoxy)-pyrrolidin-l-yl]-biphenyl-4-ylJ-carbamic acid tert-butyl ester
Prepared from (RS)-(4"-fluoro-5-nitro-2-[(R)-3-(tetrahydro-pyran-2-yloxy)-pyrrolidin-l-yl]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example F20) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a dark green solid {852 mg).
MS(ISP)472[(M+Hr],

Example L50
(5-Amino-2"-fiuoro-2-memoxy-biphenyl-4-y])-carbamic acid tert.-butyl ester
Prepared from (2"-fluoro-2-methoxy-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F21) (649 mg, 1.79 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light brown solid (352 mg).
MS (ISP) 333 [(M+H)+]; mp 161 °C.
Example L51
[5-Amino-2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yt)-2"-fluoro-biphenyl-4-yl]-carbamicacid tert.-butyl ester
Prepared from [2-(l,4-dioxa-S-aza-spiro[4.5]dec-8-yl)-2"-fluoro-5-nitro-biphenyI-4-yl]-carbamic acid tert-butyl ester (Example F22) (1.39 g, 2.94 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a light beige solid (1.01 g).
MS (ISP) 444 [(M+H)+i; mp 198 °C.
Example L52
(5-Amino-2",5"-difluoro-2-methoxy-biphenyI-4-y!)-carbamic acid tert.-butyl ester
Prepared from (2",5"-difluoro-2-methoxy-5-nitro-biphenyI-4-yl)-carbamic acid tert.-butyl ester (Example F23) (1.05 g, 2.76 mmol) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a beige solid (618 mg).
MS (ISN) 349 ((M-H)"]; mp 144 °C.
Example L53
[5-Amino-2"-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from [2"-fluoro-2-(2-methoxy-ethoxy)-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F24) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as a purple solid (2.581 g).

Example L54
(RS)-[5-Amino-2"-fluoro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yI]-carbamic acid tert.-butyl ester
Prepared from (RS)-[2"-£luoro-5-nitro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-carbamk acid tert.-butyl ester (Example F25) by reduction with SnCl2"2H20 according to the general procedure L (method b). Obtained as a yellow liquid (2.676 g).
MS(ISP)439[(M+Na)+].
Example L55
[5-Amino-2"-fluoro-2-(4-methoxy-benzyloxy)-biphenyl-4-yl]-carbamicacid tert.-butyl ester
Prepared from [2"-fluoro-2-(4-methoxy-benzyIoxy)-5-nitro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example F25) (0.90 g, 1.92 mmol) by reduction with SnCl^HzO according to the general procedure L (method b). Obtained as a beige solid (719 mg).
MS(ISP)439[(M+H)+].
Example L56
(5-Amino-2-tert.-butoxy-2",5"-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (2-tert.-butoxy-2",5"-difluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example F27) by catalytic hydrogenation with Pd/C according to the general procedure L (method a). Obtained as an amorphous grey-blue substance (2.37 g).
MS(ISP)393[(M+H)+],
Example L57
[2-Amino-5-tert.-butoxy-4-(4-fluoro-phenylethynyl)-phenyl] -carbamic acid tert.-butyl ester
Prepared from [5-tert.-butoxy-4-(4-fluoro-phenylethynyl}-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example K26) (649 mg, 1.51 mmol) by reduction with SnCk2H;0 according to the general procedure L (method b). Obtained as a light yellow solid (410 mg).

MS (ISPJ 399 ICM+H)*1; mp 183 °C.
The following examples relate to the preparation of the ethyl or tert.-butyl 3-aryI-3-oxo-propionates (general formula Vila), which serve as building blocks in the synthesis of the target compounds (Synthetic Scheme H):
General procedure M
Method a) Preparation of ethyl or tert.-butyl 3-aryI-3-oxo-propionates
The ethyl or tert.-butyl 3-aryl-3-oxo-propionates were prepared from the aryl acid chlorides and ethyl or tert.-butyl malonate potassium salt [CAS-no. 6148-64-7 and 75486-33-8] with Et3N and MgC!; in CH3CN at 0 °C to 23 °C according to Synthesis 1993,290, If the free aryl carboxylic acid was employed in this reaction, it was activated by treatment with ethyl chloroformate and Et3N in THF/CH3CN at 0 °C prior to reaction with the malonate salt
Method b) Preparation of tert.-butyl 3-aryl-3-oxo-propionates
The tert.-butyl 3-aryl-3-oxo-propionates were alternatively prepared from the methyl or ethyl aryl esters by treatment with lithium tert.-butyl acetate [ prepared by treatment of tert.-butyl acetate with lithium diisopropylamide in THF at -78 °C] in the presence of lithium tert.-butoxide according to Synthesis 1985, 45. If the product contained residual starting material after workup, thus could be removed by selective saponification with LiOH in THJ/MeOH/HzO at 23 °C.
Method c) Preparation of 3-aryI-3-oxo-propionic acids
The 3-aryl-3-oxo-propionic acids were prepared from the aryl acid chlorides and bis(trimethylsilyl)malonate with Et3N and LiBr in CH3CN at 0 *C according to Synth. Commun. 1985,15, 1039 (method cl) or with n-BuLi in ether at -60 °C to 0 °C according to Synthesis 1979, 787 (method c2).
Example Ml
3-Oxo-3-(3-[l,2,4]triazol-4-yl-phenyl)-propionic acid ethyl ester.

RO-71-2790/000

Prepared from 3- [lf2,4]triazol-4-y!-benzoic acid [RO-71-1432/000, prepared by reaction of 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 120 °C] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with Et3N and MgCU in CH3CN according to general procedure M (method a). Obtained as a white solid (5.74 g).
MS (EI) 259 (NT).
Example M2
3-Oxo-3-(3-[ 1,2,3]triazol-l-yl-phenyl)-propionic acid ethyl ester.
Prepared from 3-[l,2,3]triazol-l-yl-benzoic acid [RO-71-3703/000, prepared by reQuxing of methyl 3-azidobenzoate [CAS-No. 93066-93-4] in trimethylsilylacetylene, followed by saponification with aqueous NaOH in reftuxing EtOH] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with EtjN and MgCh in CH3CN according to general procedure M (method a). Obtained as a light yellow solid (2.22 g).
MS (El) 259 (M+); mp 72-74 QC.
Example M3
3-(3-Cyano-phenyI)-3-oxo-propionic acid tert-butyl ester.
Prepared from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a light brown oily semisolid.
MS (EI) 245 (Mf).
Example M4
3-(3-Imidazol-l-yl-phenyl)-3-oxo-propionic acid tert.-bury! ester.Prepared from methyl 3-(lH-£midazol-l-yl)benzoate [prepared from 3-(lH-imidazol-l-yl)ben2oic add {J- Med. Chem. 1987,30,1342; CAS-No. [108035-47-8] by refluxing in cone. H2S04/MeOH] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as an orange-brown oil.
MS(1SP)2S7[(M+H)*].
Example M5
3-(2-Imida2ol-l-yl-pyTidin-4-yl)-3-oxo-propionic acid tert.-butyl ester.
Prepared from 2-imidazol-l-yl-isonicotinoyl chloride hydrochloride [prepared by reaction of tert.-butyl 2-chloroisonicotinoale with imidazole and NaH in DMF at 80 "C, treatment with formic acid at 50 °C and reaction with thionylchloride in toluene at 100 "C] and tert.-butyl malonate potassium salt with EtsN and MgCU in CH3CN according to general procedure M (method a). Obtained as a brown solid (10.8 g).
MS (EI) 287 (M*); mp 80 °C (dec).
Example M6
3-Oxo-3-(3-[l,2,4]triazol-l-yl-phenyl)-propionic acid tert.-butyl ester.
Prepared from methyl 3-[ l,2,4]tria2ol-l-yl-benzoate [CAS-No. 167626-27-9] by treatment v."ith lithium tert.-butyl acetate according to general procedure M (method b). Obtained as an orange liquid (2.41 g).
MS(E!)287(M*).
Example M7
3-[3-(4-Methyl-imidazol-l-yl)-phenyI]-3-oxo-propiomc acid tert.-butyl ester.
Prepared from methyl 3-(4-methyl-imidazol-l-yl)-benzoate [RO-69-6483/000, prepared the corresponding acid from 3-isothiocyanatobenzoic acid and 2-aminopropionaldehyde dimethyl acetal according to /. Med. Chem. 1987,30,1342, followed by reSuxing in cone. HiSO^/MeOH] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a yellow-brown oil {10.69 g).
MS (EI) 300 (M*).

Example M8
3-[3-(2-Methyl-imidazol-l-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester.
Prepared from ethyl 3-(2-methyl-iniidazo!-l-yl)-benzoate[RO-69-7480/000, prepared by reaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloride in EtOH at 0 °C, direct treatment with aminoacetaldehyde diethyl acetal in EtOH at 23 °C, follwed by addition of cone. H2SO4 and reQuxing.] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a brown oil (9.66 g).
MS(ISN)299[(M-H)"].
Example M9
3-[3-(2,4-Dimethyl-iinidazol-l-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester.
Prepared from ethyl 3-(2,4-dimethyl-imida2oI-l-yI)-benzoate [RO-71-0583/000, prepared by reaction of ethyl 3-aminoben2oate with ethyl acetimidate hydrochloride in EtOH at 0 "C, direct treatment with 2-aminopropionaldehyde dimethyl acetal in EtOH at 23 "C, follwed by addition of cone. H2S04 and refluxing.] by treatment with lithium tert.-butyl acetate according to genera! procedure M (method b). Obtained as a yellow-brown oO (6.00 g).
MS(ISN)313[(M-Hri.
Example M10
3-(2-Cyano-pyridin-4-yI)-3-oxo-propionic acid tert.-butyl ester.
Prepared from 2-cyano-isonicotimc acid ethyl ester [CAS-No. 58481-14-41 by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a light brown solid (7.70 g).
MS(ISN)245[(M-H)-].
Example Mil
3-Oxo-3-(3-[l,2,4]triazol-4-yI-phenyl)-propionic acid tert.-butyl ester.
Prepared from methyl 3-[ 1,2,4]triazol-4-yl-ben2oate [prepared by reaction of 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 120 °C, followed by esterification with cone. H2SO4 in refluxing MeOH] by treatment wth

lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a light yellow gum (870 mg).
MS(ISN)286[(M-H)"].
Example Ml2
3-[3-(2-Methoxymethylsu]fanyl-imidazol-i-yl)-phenyl]-3-oxo-propionicacidtert.-butyl ester.
Prepared from ethyl 3-(2-methoxymethylsiilfanyl-imidazol-l-yI)-benzoate [prepared by esterification of 3-(2-methoxymethylsulfanyI-imidazol-l-yl)-ben2oic acid [CAS-No. 108035-46-7] with cone. H2SO4 in EtOH, followed by treatment Mth chloromethylmethyl ether and NaH in THF/DMF] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as an orange oil (1.82 g).
MS (EI) 362 (M*).
Example M13
3-[3-(2-Methylsulfanyl-imidazol-l-yl)-phenylj-3-oxo-propionic acid tert.-butyl ester.
Prepared from ethyl 3-(2-methylsu}fanyl-imidazol-l-yl)-ben2oate [prepared by esterification of 3-(2-methoxymethylsulfanyl-imida2ol-l-yl)-ben2oic acid [CAS-No. 108035-46-7] with cone. H2SO4 in EtOH, followed by treatment methyl iodide and NaH in THF/DMF] by treatment with lithium tert.-butyl acetate according to general procedure M {method b). Obtained as a light brown oil (4.41 g).
MS(ISP)333[(M+Hr].
Example M14
3-[3-{3-Methyl-isoxa2o!-5-yI)-phenyl]-3-oxo-propionic acid tert.-butyl ester.
Prepared from ethyl 3-(3-methyI-isoxazol-5-yl)-ben2oate [prepared by reaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixture of NCS, acetaldoxime, EtsN and cat. amount of pyridine in CHCI3 at 50 "C according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a yellow solid (2.54 g).
MS (ISP) 302 [(M+H)*]; mp 50-56 °C.

Example Ml5
3-Oxo-3-(3-tetra2ol-l-yl-phenyl)-propiomc acid ethyl ester.
Prepared from 3-tetra2ol-l-yl-benzoic acid [CAS-No. 204196-80-5] by activation with ethyl chloroformate/EtsN and reaction with ethyl malonate potassium salt with EtjN and MgCb in CHsCN according to general procedure M (method a). Obtained as a hght yellow solid (211 mg).
MS (EI) 260 (M^).
Example M16
3-(3-ChlorO"thiophen-2-yl)-3-oxo-propionic acid ethyl ester
Prepared from 3-chIoro-2-thiophenecarbonyl chloride [CAS-No. 86427-02-3] by reaction with ethyl malonate potassium salt with EtjN and MgC^ in CH3CN according to general procedure M (method a). Obtained as a brown oil (6.84 g).
MS (EI) 232 (M*) and 234 [(M+2)^j.
Example M17
3-(5-Cyano-thiophen-2-yl)-3-QXO-propionic add tert.-butyl ester
Prepared from ethyl 5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a yellow solid (6.66 g).
MS(EI)251(M^);mp78=C.
Example Ml8
3-(5-Cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester
Prepared from 5-cyano-2-fluoro-benzoyl chloride [prepared from the corresponding acid [CAS-No. 146328-87-2] by treatment with SOCU, cat. DMF in toluene at 80 "C] by reaction with ethyl malonate potassium salt with EtjN and MgCb in CH3CN according to general procedure M (method a). Obtained as a light yellow solid (3.S5 g).
MS (EI) 235 (M*); mp 55-60 "C.

Example M19
3-(2-Imidazol-l-yl-thia2ol-4-yl)-3-oxo-propionic acid tert.-butyl ester
Prepared from ethyl 2-imidazoM-yl-thiazole-4-carboxylate [CAS-No. 256420-32-3] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as an orange oil (12.0 g).
Example M20
3-[2-(4-Methyl-imidazol-l-y!)-thia2ol-4-yI]-3-oxo-propionic acid tert.-butyl ester
Prepared from ethyl 2-(4-methyI-imidazol-l-y!)-lhiazole-4-carboxylate [prepared from ethyl 2-amino-4-thia2olecarboKylate (CAS-No. [256420-32-3]) by the following synthetic sequence: 1.) NaH, 2-isothiocyanato-l,l-dimethoxy-propane, DMF, 23 °C; 2.) aq. H2SO4, reflux; 3.) EtOH, cone. H.SO^, 23 °C; 4.) 30% HiOj, HOAc, 23 "C] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a brown oil (8.73 g).
MS (EI) 307 (M*).
Example M21
3-[3-(l-MethyI-lH-imidazol-2-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester
Prepared from ethyl 3-(l-methyl-lH-imidazol-2-yl)ben2oate [CAS-No. 168422-44-4] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Obtained as a light yellow liquid (1.26 g).
MS (ISP) 301.3 [(M+H)^].
The following examples relate to the preparation of the 6-aryl-2,2-dimethyl-[l,3]dioxin-4-ones (general formula VII), which serve as building blocks in the synthesis of the target compounds (Synthetic Scheme H):
General procedure K
Preparation of 6-3ryl-2,2-dimethyI-[l,3]dioxin-4-ones
Method a)

The 6-aryl-2,2-diraethyl-[l,3]dioxin-4-ones were prepared from 3-aryI-3-oxo-propionic adds and catalytic amount of cone. HiSO* or trifluoroacetic acid (TFA) in isopropenyl acetate at 23 "C according to Chem. Pharm. Bull. 1983,31,1896. The final products were purified by silica gel column chromatography with hexane/EtOAc.
Method b)
The 6-aryl-2,2-dimethyI-[l,3]dioxin-4-ones were prepared from the tert.-buty! 3-aryl-3-oxo-propionates by treatment with trifluoroacetic anhydride (TFAA) in a mixture of TFA and acetone at 23 "C according to Tetrahedron Lett. 1998, 39, 2253. The final products were if necessary purified by silica gel column chromatography with hexane/EtOAc.
Example Nl
2,2-Dimethyl-6-thiophen-2-yl-[l,3]dioxin-4-one.
The 3-oxo-3-thiophen-2-yl-propionic acid was prepared from thiophene-2-carbonyl chloride (5.3 mL, 50 mmol) and bis(triniethylsilyl}malonate (25.6 mL, 100 mmol) with n-BuLi C1.6M in hexane, 62.5 mL) in ether at -60 "C to 0 "C according to the general procedure M (method c2). The crude material (7.88 g) was transformed into the title compound by stirring in isopropenyl acetate and TFA according to the general procedure N (method a). Obtained as a yeUow solid (4.09 g).
MS (EI) 210 (M""); mp42 "C (dec).
Example N2
6-(3-Chloro-thiophen-2-yl)-2,2-dimethyl-[l,3]dioxin-4-one.
The 3-(3-chIoro-thiophen-2-yI)-3-oxo-propionic acid was prepared from 3-chloro-thiophene"2-carbonyl chloride {7.82 g, 43.2 mmol) andbis(trimethyUilyl)malonate (11.6 mL, 45.4 mmol) with Et3N (12.65 mL, 90.7 mmol) and LiBr (3.53 g, 47.5 mmol) in CHjCN at 0 °C according to general procedureM (method cl). The crude material (5.69 g) was transformedinto the tide compound by stirring in isopropenyl acetate and cone. HiSO^ according to general procedure N (method a). Obtained as an orange solid (2.3 g).
MS (EI) 244 (M*) and 246 [(M+2)""]; mp 88-89 "C (dec).
Example N3
6-{3-Cyano-thiophen-2-yl)-2,2-dimethyl-[l,3]dioxin-4-one.

The 3-(3-cyano-thiophen-2-yl)-3-oxo-propiomc acid was prepared from 3-cyano-thiophene-2-carbonyl chloride (24.33 g, 140.6 mmol) and bisCtrimethylsilyl}malonate (38.0 mL, 147.7 mmol) with EtsN (41 mL, 295.4 mmol) and LiBr (13.5 g. 154.7 mmol) in CH3CN at 0 "C according to genera] procedure M (method cl). The crude material (24.8 g) was transformed into the title compound by stirring in isopropenyl acetate and cone. H2SO4 according to general procedure N (method a). Obtained as an orange solid (5.6 g).
MS (EI) 235 (M*); mp 116-120 °C (dec).
Example N4
3-(2,2-Dimethy!-6-oxo-6H-[l,3]dioxin"4-yl)-benzonitrile.
The 3-(3-cyano-phenyl)-3-oxo-propionic acid was prepared from 3-cyanobenzoyl chloride (828 mg, 5 mmol) and bis(trimethylsilyl)malonate (2.56 ml, 10 mmol) with n-BuLi (1-6M in hexane, 6.25 mL) in ether at —60 °C to 0 "C according to general procedure M (method c2). The crude material (1.04 g) was transformed into the title compound by stirring in isopropenyl acetate and TFA according to general procedure N (method a). Obtained as a light yellow solid (0.8 g).
MS (EI) 229 (M*); mp 138 X (dec).
Example "N 5
2,2-Dimethyl-6-(3-trifluoromethyl-phenyl)-ll,3]dioxin-4-one.
The 3-oxo-3-(3-trifluoromethyl-pheny])-propionic acid was prepared from 3-trifluoromethylbenzoyl chloride (10 mL, 67.6 mmol) and bis(trimethylsilyl)malonate (18.2 mL, 71 mmol) with EtjN (20 mL, 142 mmo!) and LiBr (6.46 g, 74.4 mmol) in CH3CN at 0 "C according to general procedure M (method cl). The crude material (7.0 g of the obtained 15.4 g) was transformed into the tide compound by stirring in isopropenyl acetate and cone. H2SO4 according to general procedure N (method a). Obtained as a Ught yellow solid (5.3 g).
MS (EI) 272 (M^); mp 77-78 "C (dec).
Example N6
6-(3-Chloro-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one.

The 3-(3-chloro-phenyl)-3-oxo-propiomc add was prepared from 3-chloroben2oyl
chloride (11 mL, 85.7 mmol) and bis(tximethyIsi!yl)malonate (23.0 mL, 90.0 mmol) with EtjN (25 mL, 180 mmol) and LiBr (8.19 g, 94.3 mmol) in CHjCN at 0 "C according to general procedure M (method cl). The crude material (17.1 g) was transformed into the title compound by stirring in isopropeny! acetate and cone. HzSO^ according to general procedure N (method a). Obtained as a yellow-brown solid (8.0 g).
MS (EI) 238 (M*) and 240 [(M+2)""]; mp 87-88 °C (dec).
Example N7
6-(3-Iodo-phenyl)-2,2-dimethyl-[l,3jdioxin-4-one.
The 3-(3-iodo-pheny!)-3-oxo-propionic acid was prepared from 3-iodobenzoyl chloride (21.0 g, 78.8 mmol) and bis(trimethylsilyl)malonate (21.0 mL, 82.8 mmol) with EtsN (23 mL, 165.5 mmol) and LiBr (7.54 g, 86.7 mmol) in CHjCN at 0 "C according to general procedure M (method cl). The crude material (21.9 g) was transformed into the title compound by stirring in isopropenyl acetate and cone. H2SO4 according to general procedure N (method a). Obtained as a yellow solid (9.6 g).
MS (EI) 330 (M^); mp 79-80 "C (dec).
Example N8
2,2-Dimethyl-6-(3-triQuoromethoxy-phenyl)-[l,3]dioxin-4-one.
The 3-oxo-3-(3-tri£Iuoromethoxy-phenyl)-propionic acid was prepared from 3-trifluoromethoxybenzoyl chloride and bis(trimethylsilyl)malonate with EtjN and LiBr in CH3CN at 0 °C according to general procedure M (method cl). The crude material was transformed into the title compound by stirring in isopropenyl acetate and cone. H2SO4 according to genera! procedure N (method a). Obtained as an orange solid (2.27 g).
MS (EI) 288 (M*); mp 49-54 "C (dec).
Example N9
2,2-Dimethy!-6-pyridin-4-yl-[l,3]dioxin-4-one.
Prepared from 3-oxo-3-pyridin-4-yl-propionic acid [prepared from 4-acetylpyridine, magnesium methyl carbonate and CO2 in DMF at 120 "C according to Journal of Antibiotics

1978,31, 1245] by treatment with acetone, TFA and TFAA according to general procedure N (method b). Obtained as a white solid (1.3 g).
MS (EI) 205 CM^)
Example NlO
5-(3-ImidazoI-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one.
The 3-(3-iinida2ol*l-yl-phenyl)-3-oxo-propionic add was prepared from 3-(lH-imida2ol-l-yl)benzoyI chloride hydrochloride [preparedby treatment of 3-(lH-imida2ol-l-j^Dbenzoic acid (/. Med. Chem. 1987,30,1342; CAS-No. [108035-47-8] with SQCh) and bis(trimethylsilyI)malonate with EtjN and LiBr in CH3CN at 0 "C according to general procedure M (method cl). The crude material was transformed into the tide compound by stirring in isopropeny! acetate and cone. H2SO4 according to general procedure N (method a). Obtained as an orange semisolid (617 mg).
MS (EI) 270 (M*).
Example Nl]
2,2-Dimethyl-6-(3-methoxy-phenyI)-[i,3]dioxin-4-one.
The 3-(3-methoxy-phenyl)-3-oxo-propionic acid was prepared from 3-methoxyben2oyl chloride (10.3 g, 60.4 mmol) and bis(trimethylsilyl)malonate (16.2 ml, 63.4 minol) with EtjN (17.7 ml, 127 mmol) and LiBr (5.77 g, 66.4 mmol) in CH3CN at 0 °C according to general procedure M (method cl). The crude material (6.38 g) was transformed into the title compound by stirring in isopropenyl acetate and cone. H2SO4 according tC) general procedure N (method a). Obtained as a yellow oil (640 mg).
MS (ISP) 235 [(M+H)*! and 252 [(M+NH4)*].
Example Nl2
2,2-Dimethy!-6-(3-nitro-phenyl)-[l,3]dioxin-4-one.
The 3-(3-nitTO-phenyl)-3-oxo-prop!onic acid tert.-butyl ester was prepared frQm 3-nitrobenzoyl chloride (2.71 g, 14.6 mmol) and tert.-but>-l malonate potassium salt (6.0 g, 30.0 mmol) with EtjN (4.5 mL, 32.2 mmol) and MgCb (3.48 g, 36.52 mmol) iri CH3CN according to genera! procedure M (method a). The crude material (3.88 g) was

transformed into the title compound by stirring in TFAyacetone with TFAA according to general procedure N (method b). Obtained as a yellow solid (2.76 g).
MS (EI) 249 (M""); mp 110-117 "C.
Example NI3 -
2,2-Dimethyl-6-C3-[l,2,4]tria2oI-l-yl-phenyl)-[l,3]dioxin-4-one.
The3-oxo-3-(3-[l,2,4]tria2o!-l-yl-phenyI)-propionicacidtert.-butyl ester [RO-69-3506/000] was prepared from 3-[l,2.4]triazol-l-yl-ben2oic acid methyl ester [CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetate according to general procedure M (method b). Prepared from (Example M6) by stirring in TFA/acetone v-ith JFAA according to general procedure N (method b). Obtained as a yellow solid (539 ing).
MS (EI) 27i (M"").
Example Nl4
6-(2-Imidazol-l-yl-pyridin-4-yl)-2,2-dimethyI-[l,3]dioxin-4-one.
Prepared from 3-(2-imidazol-l-y!-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example M5) by stirring in TFA/acetone with TFAA according to general procedure N (method b). Obtained as a brown solid (10.8 g).
MS (EI) 271 (M*); mp 151 °C (dec).
Example Nl 5
2,2-Dimethyl-6-[3-(2-methyl-imidazol-l-yl)-phenyl]-[l,3]dioxin-4-one.
I Prepared from 3-[3-(2-methyl-imidazol-l-yl)-phenyIj-3-oxo-propionic acid tert-butyl ester (Example M8) by stirring in TFA/acetone with TFAA according to general procedure N (method b). Obtained as a beige solid (2.13 g).
MS (EI) 284 (M-^); mp 122 °C.
Example N16
i 4-(2^-Dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-pyridine-2-carbonitrUe.

Prepared from 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic add tert.-butyl ester (Example MIO) by stirring in TFA/acetone with TFAA according to general procedure N (method b). Obtained as a brown solid {3.30 g).
MS (EI) 230 (M*); mp 132 °C (dec).
The following examples relate to the preparation of the 4,8-diaryl-l,3-dihydro-ben2D[b][l,4]d!a2epin-2-ones, respectively the 4-aryl-8-ary]ethynyl-1,3-dihydro-ben2o[b][l,4]dia2epin-2-ones andthe8-aroyl-4-aryl-l,3-dihydro-benzo[b][l,4]diazepin-2-ones in regioisomerically pure fashion (Synthetic Scheme A):
General procedure O:
Preparation of l2-[3-aryl-3-oxo-propionylamino]-4-aryl-phenyll-carbamic acid tert.-butyl ester by reaction of (2-amino-4-aryI-phenyl)-carbamic acid tert.-butyl esters with ethyl 3-aryl-3-oxo-propionates or 6-aryl-2,2-dimethyl-[l,3]dioxin-4-ones;
also 3-aryi-N-(2-nitro-4-aryl-phenyl)-3-oxo-propionamides by reaction of 2-nitro-4-aryl-phenylamines with 6-aryl-2,2-dimethyl-[ 1,3]dioxin-4-ones
A mixture of the (2-amino-4-aryl-phenyl)-carbamic acid tert-butyl ester or 2-riitro-4-aryl-phenylamine (1.0 mmol) and excess (1.2-1.5 mmol) of the ethyl 3-aryl-3-oxo-propionate [prepared from the aryl acid chloride and ethyl malonate potassium salt with EtsN and MgClz in CH3CN at 23 °C according to Synthesis 1993, 290] or 6-aryl-2,2-dimethy]-[l,3]dioxin-4-one was refluxed in toluene (8 mL) until tic indicated complete consumption of the amine. The solution was allowed to cool to 23 "C, whereupon the product generally crystallized (in cases where crystallization failed to appear it vas induced by addition of hexane). The solid was filtered off, washed with ether or mixtures of ether/hexane and dried in vacuum to give the {2-[3-aryl-3-oxo-propionylamino]-4-aryl-phenylj-carbamic acid tert.-butyl esters or 3-aryI-N-(2-nitro-4-aryI-phenyl)-3-oxo-propionamides, which was used direcdy in the following step or - if necessar>" - was purified by recrystallization or by silica gel column chromatography.
Example 01
{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-iodo-5-thiomorpholin-4-yI-phenyl}-carbamic acid tert.-butyl ester
Prepared from (2-amino-4-iodo-5-thiomorpholin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example LI) (653 mg, 1.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (690 mg, 2.25 mmol) according to the general procedure O. Obtained as a yellow solid (629 mg).

MSCISP)607[(M+Hr].
Example 02
{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-iodo-5-morpholin-4-yI-phenyI}-carbamic acid tert.-butyl ester
Prepared from {2-amino-4-iodo-5-morpholin-4-y!-phenyl)-carbamic add tert--biityl ester (Example L2) (690 mg, 1.65 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[i,3]dioxin-4-yl)-benzonitrile {Example N4) (566 mg, 2.47 mmol) according to the general procedure O. Obtained as an orange solid (523 mg).
MS (ISP) 591 [(M+H)""] and 613 [(M+Na)*].
Example 03
{2-Chloro-5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic add tert.-butyl ester
Prepared from {5-amino-2-ch]oro-biphenyI-4-yI)-carbamic add tert--butyl ester (Example L6) (652 mg, 2.05 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) {564 mg, 2.46 mmol) according to the general procedure O. Obtained as an off-white solid (725 mg).
MS{ISN)488[(M-H}-].
Example 04
[2-[3-(3-Cyano-phenyl)-3-cxo-propionylamino]-5-(2-dimethylamino-ethylsulfanyl)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-(2-dimethylamino-ethylsulfanyl)-4-phenylethynyl-phenyl]-caibamic acid tert.-butyl ester (Example L8) {206 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-ben2onitrile {Example N4) (138 mg, 0.6 mmol) according to the general procedure O. Obtained as a yellow solid (210 mg).
MS (ISP) 583 [(M+H)""]; mp 88 °C.
Example 05
{5-tert.-Butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2-phenylethynyl-phenylsulfanylj-acetic acid methyl ester

Prepared from {4-ammo-5-tert.-butoxycarbonyl2rnino-2-phenylethynyl-phenylsulfanyl)-acetic acid methyl ester (Example L9) (534 mg, 1.3 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (358 mg, 1.56 mmol) according to .the genera! procedure O, Obtained as a yellow foam (457 mg).
MS (ISP) 584 [(M+H)*], 601 [(M+NH4)*] and 605 [(M+Na)^]; mp 69-73 "C. Example 06
{5-tert.-Butoxycarbony!amino-4-[3-(3-cyano-phenyl)-3-oxo-propionyIamino]-2-phenylethynyl-phenyl}-acetic acid methyl ester
Prepared from (4-amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-phenyl)-acetic acid methyl ester {Example LIO) (721 mg, 2.0 mmol) and 3-{2,2-diniethy!-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (550 mg, 2.4 mmol) according to the general procedure O. Obtained as a light yellow soKd {886 mg).
MS (ISP) 552 [(M+H)""] and 569 [(M+NH*)^]; mp 138 °C.
Example 07
[2-[3-(3-Cyano-phenyl)-3-oKo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyJJ-carbamicacid tert.-butyl ester
Prepared from [2-amino-5-(2-methox)"-ethoxy)-4-phenykthynyl-phenyl]-carBamic acid tert.-butyl ester (Example LU) (415 mg, 1.09 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (373 mg, 1.63 mmol) according to the general procedure O. Obtained as a light yellow soHd (137 mg).
MS (ISP) 554 [(M+H)^l, 571 [(M+NH4)*] and 576 [(M+Na)^; mp 175-175 °C.
Example OS
{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-5-methoxy-4-phenylethynyi-phenylI-carbamic acid tert.-butyl ester
Prepared from (2-amino-5-methoxy-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example L12) (338 mg, 1.0 mmol) and 3-{2,2-dimethyl-6-oxo-6H-tl,3]dioxin-4-yl)-benzonitrile (Example N4) (252 mg, 1.1 mmol) according to the general procedure O. Obtained as a yellow solid (388 mg).

MS (ISP) 510 [(M+H)*], 527 [(M+NH4)*] and 532 [(M+Na)""]; mp 169 "C.
Example 09
5-tert.-Butoxycarbonylamino-4-[3-(3-cyano-phenyl}-3-oxo-propionylamino]-2-phenyleihynyl-benzoic acid methyl ester
Prepared from 4-amino-5-tert.-butoxycarbonyIamino-2-phenyIethynyI-benzoic add methyl ester (Example L14) (396 mg, 1.08 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (273 mg, 1.19 mmol) according to the general procedure O. Obtained as an off-while solid (540 mg).
MS (ISP) 538 [(M+H)*], 555 [(M-rNH4)*) and 560 [(M+Na)*j; mp 158 X (dec). Example 010
{2-[3-(3-Cyano-phenyl)-3-oxQ-propionylamino]-5-morpholin-4-yI-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester
Prepared from (2-amino-5-morpholin-4-yl-4-phenylethynyI-phenyl)-carbamic acid tert.-butyl ester (Example L12) (483 mg, 1.23 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4} (422 mg, 1.84 mmol) according to the genera! procedure O. Obtained as an amorphous orange material {375 mg).
MS (ISP) 565 [(M+H)^] and 587 [(M+Na)^].
Example Oil
[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-5-{2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-elhoxy}-ethQxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example L15) (514 mg, 1.0 mmol) and 3-{2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (344 mg, 1.5 mmol) according to the general procedure O. Obtained as a light yellow solid (353 mg).
MS (ISP) 686 [(M+H)""] and 703 [(M+NH4)^]; mp 135-136 "C.
Example 012
{5-tert.-ButoxycarbonyIamino-4-[3-(3-cyano-phenyl)-3-oxo-propionyiammo]-2-phenylethynyl-phenoxyl-aceticacid tert.-butyl ester

Prepared from (4-amino-5-tert.-butoxycarbonylammo-2-phenylethynyl-phenoxy)-acetic acid tert.-butyl ester (Example L16) (877 mg, 2.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[ l,3]dioxm-4-yI)-benzonitrile (Example N4) (504 mg, 2.2 mmol) according to the general procedure O. Obtained as a yellow solid (723 mg).
MS (ISP) 610 [(M+H)*], 627 [(M+NH4)""] and 632 [(M+Na)*]; mp 95 "C.
Example OI3
{5-Cyanomethyl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester
Prepared from (2-amino-5-cyanomethyl-4-phenyIethynyl-phenyI)-carbamic acid tert.-butyl ester (Example L17) (298 mg, 0.86 mmol) and 3-(2,2-dimethyl-6-oxo-6fi-[ l,3]dioxin-4-yI)-benzonitrile (Example N4) (218 mg, 0.95 mmol) according to the general procedure O. Obtained as a yellow solid (299 mg).
MS (ISP) 519 [(M+H)^], 536 [(M+NH4)*] and 541 [(M+Na)*]; mp 98 "C.
Example Ol4
[2-[3-(3-Cyano-pheny!)-3-oxo-propiony!amino]-5-(l,4-dioxa-8-aza-spiro[4.$ldec-8-yl)-4-pKen.yleth,YTvyl-ph.e,nyll-a.tba.mic add tert.-butyl ester
Prepared from [2-amino-5-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yI)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example L18) (393 mg, 0.87 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (301 mg, 1.31 mmol) according to the general procedure O. Obtained as an amorphous orange material (268 mg)-
MS (ISP) 621 [(M+H)""].
Example Ol5
[2-[3-(3-Iodo-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenylj-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]-cafbamic acid tert-butyl ester (Example Lll) (840 mg, 2.2 mmol) and 6-(3-iodo-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example N7) (780 mg, 2.36 mmol) according to the general procedure O. Obtained as a white solid (1.3 g).

MS (ISP) 655 [(M+H)""], 672 [(M+NH4r]. 677 [(M+Na)-"] and 693 [(M+K)^]; mp 172 °C.
Example 016
[2-[3-(3-Cyano-phenyI)-3-oxo-propionylamino]-5-(2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-4-phenyIethynyl-phenyl]-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-(2,2-dimethyl-[l,3] MS (ISP) 610 [(M+H)*], 627 [(M+NHi)""] and 632 [(M+Na)^]; mp 132-134 "C.
Example Ol7
5-tert.-Butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2-iodo-benzoic acid methyl ester
Prepared from 4-amino-5-tert.-butoxycarbonylamino-2-iodo-benzoic acid methyl ester (Example L21) (395 mg, 1.0 mmol) and3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (254 mg, 1.1 mmo!) according to the general procedure O. Obtained as an apricot solid (435 mg).
MS (ISP) 564 [(M+H)^], 581 [(M+NH4)^] and 586 [(M+Na)*j; mp 162-166 "C.
Example 018
[[2-[3-(3-Imidazol-l-yl-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester.
Prepared from [2-amino-5-(2-methoxy-ethox)")-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example Lll) (191 mg, 0.5 mmol) and 6-(3-imida2ol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) (135 mg, 0.5 mmol) according to the general procedure O. Obtained as a light brown waxy solid (206 mg).
MS (ISN) 593 [(M-H)"]-,mp 122-129 X.

Example OI9
[RS]-[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-5-(2-oxo-[l,3]dioxolai:-4-ylmethoxy)-4-phenylethynyl-phenyl]-carbamic acid ten.-butyl ester
Prepared from [RS]-[2-amino-5-(2-oxo-[l,3]dioxolan-4-ylmethoxy}-4-phenylethynyI-phenylj-carbamic acid tert.-butyl ester (Example L22) (346 mg, 0.82 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (206 mg, 0.9 mmol) according to the general procedure K. Obtained as a light yellow solid (433 mg).
MS (ISP) 594 [(M-H)""]; mp 181 "C.
Example 02Q
{2-[3-(3-Cyano-phenyl)-3-oxo-propiony!amino]-5-ethoxymethyl-4-phenylethynyl-phenyl}-carbamic add tert.-butyl ester
Prepared from (2-amino-5-ethoxymethyl-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example L23) (130 mg. 0.35 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yI)-ben2onitriie (Example N4) (80 mg, 0.35 mmol) according to the general procedure K. Obtained as an amorphous yellow substance (148 mg).
MS (ISP) 535 [(M-H)""].
Example 021
2,2-Dimethyl-propionicacid5-tert.-butoxycarbonylamino-4-[3-(3-cyano-phenyI)-3-oxo-propionylamino]-2-phenylethyny!-ben;yl ester.
Prepared from 2,2-dimethyl-propionic acid 4-amino-5-tert.-butoxycarbonylamino-2-phenylethynyl-benzyl ester (Example L24) (155 mg, 0.37 mmol) and 3-{2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (94 mg, 0.41 mmol) according to the general procedure K. Obtained as an amorphous light orange substance (184 rng).
MS (ISP) 611 [(M+NH4)^].
Example 022
(RS)-[2-[3-(3-Imidazol-l-yl-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-carbamic acid tert.-butyl ester.

Prepared from (RS)-[2-aniino-4-phenyIethynyI-5-(tetrahydro-pyran-2-yloxyinethyl)-phenylj-carbamic add tert.-butyl ester (Example L25) and 6-(3-imidazoI-l-yI-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) according to the general procedure .O. Obtained as an amorphous yellow substance (267 mg).
MSaSP)635[(M+H)1.
Example 023
[2-[3-(3-Imidazol-l-yI-phenyI)-3-oxo-propionyIamino]-5-(4-methoxy-piperidin-l-yl)-4-phenylethynyl-phenylj -carbamic acid tert.-buty! ester.
Prepared from [2-amino-5-(4-methoxy-piperidin-l-yl)-4-phenylethynyl-phenfll-carbamic acid tert-butyl ester {Example L26) (236 mg, 0.56 mmol) and 6-(3-iiiiidazol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) (151 mg, 0.56 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (253 mg).
MS(ISP)634[(M+H)1.
Example 024
"^2-\^S-(i-CyaTio-pVieny\V^-ox&-p^opioTi7larniiiol-S-(4-iutthoxy-piperidm-"l-y\)-4-phenylethynyl-phenylj-carbamic acid tert.-butyl ester.
Prepared from [2-amino-5-(4-methoxy"piperidin-l-yl)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example L26) (224 mg, 0.53 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzon!trile (Example N4) (125 mg, 0.53 mmol) according to the general procedure O. Obtained as a yellow foam (274 mg).
MS(ISN)591 [(M-H)"]-,mp 97-100 "C.
Example 023
f5-Cyanomethoxy-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylaminoj-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester.
Prepared from (2-ammo-5-cyanomethoxy-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example U7) and 6-(3-imidazol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) according to the general procedure O. Obtained as an amorphous yellow substance (169 mg).

MS(ISP)576[{M+Hr].
Example 026
{5-Cyanomethoxy-2-[3-(3-cyano-phenyl)-3-oxo-propionyIammol-4-phenyIethynyl-phenyl}-carbamic acid tert.-butyl ester.
Prepared from {2-ammo-5-cyanomethoxy-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example L27) {80 mg, 0.22 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1.3]dioxin-4-yI)-benzonitrile {Example N4) (55 mg, 0.24 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (96 mg).
MS(ISN)533[(M-H)"l.
Example 027
{RS)-[4-(4-Fluoro-phenylethynyl)-2-[3-{3-irmdazol-l-yl-phenyl)-3-oxo-
propionylamino]-5-(tetrahydro-pyTan-2-yloxymethyl)-phenyl]-carbamicacidtert.-butyl
ester.
Prepared from (RS)-[2-amino-4-(4-fluoro-phenylethynyl)-5-{tetrahydro-pyTan-2-yloxymethyl)-phenyl]-carbaniic acid tert.-butyl ester (Example L28) and 6-(3-imidazol-l-yVpheny\)-2,2-diine^yl-^\,Sidio"xin-4-cint (Example "NlO^accoiding to ^htgen«Tzl procedure O. Obtained as an amorphous yellow substance (990 mg).
MS(ISN)651 [(M-H)-].
Example 028
(RS)-(4-(4-Fluoro-phenylethynyl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-5-{methyl-[2-(tetrahydro-pyTan-2-yloxy)-ethyl]-amino!-phenyl)-
carbamic acid tert.-butyl ester
Prepared from (RS)-(2-amino-4-(4-fluoro-phenylethynyl)-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethylj-aminol-phenyl)-carbamic acid tert.-butyl ester (Example L29) (242 mg, 0.5 mmol) and 6-(3-imidazol-l-y3-phenyI)-2,2-dimethyl-[l,3ldioxin-4-one (Example NIG) (135 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance {198 mg).
MS(1SN)694[(M-H)"J.

Example 029
{5-{4,4-Diethoxy-piperidm-l-yI)-2-[3-(3-imida2ol-l-yl-phen>"l)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic add tert.-butyl ester
Prepared from [2-amino-5-(4,4-diethoxy-piperidin-l-yl)-4-phenyiethynyI-phenyI]-carbamic acid tert.-butyl ester {Example L18) (321 mg, 0.67 mmol) and6-(3-imida2oI-l-y!-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) (240 mg, 0.89mmol) according to the general procedure O. Obtained as an orange foam (295 mg).
MS(ISP)692[(M+H)""].
Example 03Q
(RS)-(2-[3-(3-Imidazol-l-yl-pbenyl)-3-oxo-propionylamino]-4-phenyIethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-carbamic acid tert.-butyl ester
Prepared from (RS)-[2-amiiio-4-phenyIethyny]-5-[2-(tetrahydro-pyraii-2-yloxy)-ethoxy]-phenyl}-carbamic acid tert.-butyl ester (Example L30) (346 mg, 0.76 mmol) and 6-(3-imidazol-l-yl-phenyl)-2,2-dimethyi-[l,3]dioxin-4-one (Example NlO) (300 mg, 1-li mmol) according to the general procedure O. Obtained as a yellow foam (196 mg).
MS(1SP}665[(M+H)""].
Example 031
(RS)-l4"-Fluoro-5"[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-2-[4-{tetrahydro-pyran-2-yloxy)-piperidin-l-yl]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (RS)-[2-amiao-4-(4-fluoro-phenylethynyl)-5-(tetrahydro-pyr2n-2-yloxymethyl)-phenyl]-carbamic acid tert.-butyl ester (Example L2S) and 6-(3-imida2ol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) according to the general procedure O. Obtained as a yellow solid (282 mg).
MS (ISP) 698 [(M+H)*]; mp 129-132 "C.
Example 032
{5-(2-tert.-Butoxy-ethoxy)-4-(4-fluoro-phenylethynyl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester

Prepared from [2-ainino-5-(2-tert.-butoxy-ethoxy)-4-(4-fluoro-phenylethynyl)-pheny]]-carbamic acid tert.-butyl ester (Example L32) (560 mg, 1.27 mmol) and6-(3-imid22ol-l-yl-phenyl}-2,2-dimethyI-[l,3]dioxin-4-one (Example NIO) (413 mg, 1.53 mmol) according to the general procedure O. Obtained as a yellow solid (507 mg).
MS (ISP) 655 [(M+H)*l; mp 62-65 "C.
Example 033
(RS)-(4"-Fluoro-5-f3-(3-imidazol-l-yI-phenyl)-3-oxo-propionylaniino]-2-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-piperidin-l-yI}-biphenyl-4-yl)-carbamicacidtert.-butyl ester
Prepared from (RS)-(5-amino-4"-fluoro-2-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-piperidin-l-y]}-biphenyI-4-yl)-carbamic acid terL-butyl ester (Example L33) and 6-(3-imida2ol-l-yl-pheny!)-2,2-diinethyl-[l,3]dioxin-4-one (Example NlO) according to the genera] procedure O. Obtained as a yellow solid (473 mg).
MS (ISP) 742 [(M+H)^]; mp 57-58 "C.
Example 034
(RS)-[4"-Fluoro-5-l3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionylamino]-2-(tetrahydro-pyTan-2-yloxymethyl)-biphenyl-4-yl] -carbamic acid tert.-butyl ester
Prepared from (RS)-[5-amino-4"-fiuoro-2-(tetrahydro-pyran-2-y]oxymethyl)-biphenyl-4-yl]-carbamic acid tert-butyl ester (Example L34) and 6-(3-imidazol-l-yI-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) according to the general procedure O. Obtained as a light yellow solid (330 mg).
Example 035
{2-Cyanomethoxy-4"-fluDrD-5-[3-(3-imid32ol-l-y\-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-cyanomethoxy-4"-fluoro-biphenyI-4-yl)-carbamic acid tert.-butyl ester (Example L35) (190 mg, 0.53 mmol) and 6-(3-imida2ol-l-y!-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) (164 mg, 0.61 mmo!) according to the general procedure O. Obtained as a yellow gum (90 mg).
MS (ISP) 570 UM+H)*).

Example 038
{2-Dimethy]aminomethyl-4"-fluoro-5-[3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionylamino] -biphenyI-4-yI}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-dimethylaminomethyl-4"-fiuoro-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example L36) and 6-(3-imidazol-l-yI-phenyl)-2,2-dimethyl"[13]dioxin-4-one (Example NIO) according to the general procedure O. Obtained as a light yellow solid (329 mg).
Example 037
{2-(2,2-Dimethyl-tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-5-yi)-4"-fiuoro-5-[3-£3-iinidazol-l-yl-pbenyi)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from [5-amino-2-(2,2-dimethyl-tetrahydro-[l,3]dioxoIo[4,5-c]pyrfol-5-yl)-4"-fluoro-biphenyI-4-yl]-carbamic acid tert.-butyl ester (Example L37) (465 mg, 1-05 mmol) and6-(3-iraidazol-I-yl-phenyl}-2,2-dimethyl-[l,3ldioxin-4-one (Example NIO) (314 mg^ 1.16 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (540 mg).
MS(ISN)654[(M-H)-].
Example 038
f4"-Fluoro-5-[3-(3-imidazo!-l-yl-phenyl)-3-oxo-propionylamino]-2-methoxy-biphenyl-4-yli-carbamic add t,ert.-butyl ester
Prepared from (5-amino-4"-£luoro-2-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L38) (332 mg, 1.0 mmol) and 6-(3-imidazol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NIO) (270 mg, 1.0 mmol) according to the general procedure O. Obtained as an amorphous brown substance (328 mg).
MS (ISN) 543 [(M-H)"].
Example 039
{2-(I,4-Dioxa-8-a2a-spiro[4.5ldec-8-yl)-4"-fluoro-5-[3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionyIamino]-biphenyi-4-yl}-carbamic acid tert-butyl ester

Prepared from [5-amino-2-(l,4-dioxa-8"aza-spiro[4.5]dec-8-yl)-4"-fiuoro-biphenyl-4-yl]-carbamic add tert.-butyl ester (Example L39) (444 mg, 1.0 mmo]} and 6-(3-imidazol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) (321 mg. 1.19 mmol) according to the general procedure 0- Obtained as a brown solid (457 mg).
MS (ISH) 654 [(M-H)-]; mp 110-115 "C (dec).
Example 04Q
{4"-nuoro-5-[3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionylaminol-2-methyl-bipheny!-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-4"-fluoro-2-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L40) (316 mg, 1.0 mmol) and 6-(3-imidazQl-l-yl-phenyi)-2,2-dimethyl-[l,3]dioxin-4-one(ExampleN10} (297 mg, 1.1 mmol) according to the general procedure O. Obtained as an amorphousyeUovf siibstance (361 mg).
MS (ISP) 529 [(M+H)""].
Example 041
l4-tert.-Butoxycarbonylamino-4"-fiuoro-5-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-biphenyI-2-yloxy}-acetic acid tert-butyl ester
Prepared from (5-amino-4-tert.-butoxycarbonylamino-4"-fiuoro-biphenyl-2-yloxy)-acetic acid tert.-butyl ester (Example L41) (1.4 g, 3.24 mmol) and 6-(3-imida2ol-l-yl-phenyl)-2,2-dimethyl-[1.3]dioxin-4-one (Example NlO) (885 mg, 3.27 mmol) according to the general procedure O. Obtained as a light brown solid (759 mg).
MS (ISP) 645 [(M+H)-"]; mp 82-85 X.
Example 042
{2-Chloro-4"-fiuoro-5-[3-(3-imida2ol-l-yl-phenyl)-3-oXo-propionylamino]-biphenyI-4-yl)-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-chloro-4"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L42) (168 mg, 0.5 mmol) and 6"(3-imidazol-l-yl-phenyl)-2,2-dimethyl-[l,3ldioxin-4-one (Example NlO) (252 mg, 0.93 mmol) according to the general procedure O. Obtained as a light yellow solid (156 mg).

MS (ISN) 547 [(M-H)-]. Example 04S
[4"-Fluoro-5-[3-(3-im:dazol-l-yl-phenyI)-3-oxo-propionyIamino]-2-(2-methoxy-ethoxy)-biphenyl-4-yIl-carbamic acid tert.-butyl ester
Prepared from [5-amino-4"-fiuoro-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example L43) (188 mg, 0.5 mmol) and 6-(3-imida2oI-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) (260 mg, 0.96 mmo!) according to the general procedure O. Obtained as an orange solid (218 mg).
MS (ISP) 589 [{M+H)*l; mp 61-63 °C.
Example 044
{2-(2-tert.-BQtoxy-ethoxy)-4"-fluoro-5-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yIl-carbamic acid terL-butyl ester
Prepared from [5-amino-2-(2-tert-biitoxy-ethoxy)-4"-fluoro-biphenyl-4-yl]-caTbamic acid tert-butyl ester (Example L44) (209 mg, 0.5 mmol) and 6-(3-imidazol-I-yl-phenyI)-2,2-dimethyl-[l,3]"iioxin-4-one (Example NlO) {135 mg, 0.5 mraol) according to the general procedure 0. Obtained as a beige solid (194 mg).
MS (ISP) 631 [(M+H)""];mpl01°C.
Example 045
[4"-Fiuoro-5-[3-(3-imidazoI-l-yl-phenyl)-3-oxo-propionylamino]-2-(2-oxo-oxazolidin-3-y\)-biphenyl-4-yl}-caTbamic acid tert.-butyl ester
Prepared from [5-amino-4"-fluoro-2-(2-oxo-oxazolidin-3-yl)-biphenyl-4-yI]-carbamic acid tert-butyl ester (Example L45) (130 mg, 0.34 mmol) and 6-(3-imidazoI-l-yl-phenyl)-2,2-dimethyl-[l,3jdioxin-4-one {Example NlO) (92 mg. 0.34 mmo!) according to the general procedure 0. Obtained as an amorphous yeDovv substance (86 mg).
MS (ISP) 600 [(M+H)^].
Example 046
{4"-Fluoro-5-[3-(3-imidazo!-l-yl-phenyl)-3-oxo-propionylamino]-2-methoxy-2"-methyl-bipheny]-4-yl}-carbamic acid tert.-butyl ester

Prepared from (5-amino-4"-fluoro-2-methoxy-2"-methyl-biphenyl-4-y])-C2rbamic acid tert.-butyl ester (Example lA6) (173 mg, 0.5 mmol) and 6-(3-imida2ol-l-yl-phenyl)-2,2-dimethyl-U.3]dioxin-4-one (Example NlO) (199 mg, 1.47 mmol) according to the general procedure O. Obtained as an orange solid (182 mg).
MS (ISP) 559 [(M+H)*]; mp 99-102 "C.
Example 047
{2-tert.-Butoxy-4"-fiuoro-5-[3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yll-carbamic acid tert-butyl ester
Prepared from (5-amino-2-tert.-butoxy-4"-fiuoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L47) (187 mg, 0.5 mmol) and 6-(3-imidazol-l-yl.phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example HIO) (135 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (237 mg).
MS(ISN)585[(M-H)-].
Example Q4S
(2-tert.-Butoxy-2"-fluoro-5-[3-(3-imidazol-l-yl-phenyI)-3-oxo-propionylamino]-biphenyl-4-yIl-carbamic acid tert.-butyl ester
Prepared from {5-amino-2-tert.-butoxy-2"-fluoro-biphenyI-4-yl}-carbamic acid tert.-butyl ester (Example L4S) (187 mg, 0.5 mmol) and 6-(3-imida2ol-l-yl-phenyl)-2,2-dimethyl-[ l,3]dioxin-4-one (Example NlO) (135 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (234 mg).
MS(ISN)585[(M-H)-].
Example 049
(RS)-{4"-Eluoro-5-[3-(3-imid22ol-l-yl-pheny])-3-oxo-propionylamino]-2-[(R)-3-(tetrahydro-pyran-2-ylox)")-pyrrolidin-l-yl]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (RS)-{5-amino-4"-fluoro-2-[(R)-3-(tetrahydro-pyran-2-ylox>-)-pyrTolidin-l-y!]-biphenyl-4-yll-carbairuc acid tert.-butyl ester (Example L49) (236 mg, 0.5 mmol) and 6-(3-imida2ol-l-yl-pheny])-2>2-dimethyl-[l,3]dioxin-4-one (Example NlO) (200 mg, 0.74 mmol) according to the general procedure O. Obtained as an orange solid (188 mg)-

MS (ISP) 684 [(M+H)*]; mp 99-103 "C. Example O50
{2"-Fluoro-5-[3-(3"iinidazoI-l-yl-phenyl)-3-oxo-propionyIamino]-2-methoxy-biphenyI-4-yl}-carbamic add lert.-buty! ester
Prepared from (5-3mino-2"-f]uoro-2-methoxy-biphenyl-4-yl)-carbamic add tert.-butyl ester (Example L50) (159 mg, 0.5 mmol) and 6-(3-imida2ol-l-y!-phenyI}-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) (135 mg, 0.5 mmol) according to the genera] procedure O. Obtained as an amorphous yeUow substance (199 mg).
MS(ISH)543[(M-H)"].
Example 051
{2-tert.-Butoxy-5-[3-(3-cyano-phenyI)-3-oxo-propionylamino]-4"-fiuoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-4"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L47) (187 mg, 0.5 mmol) and 3-(2,2-dimethyI-6-oxo-6H-[l,3}dio:dn-4-yI)-benzonitrile (Example N4) (126 mg, 0.55 mmol) according to the general procedure O. Obtained as an amorphous light pink substance (196 mg).
MS(ISP)546[(M+H)^].
Example 052
(2-tert.-Butoxy-5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2"-fiuorO"biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-2"-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) and 3-(2,2-d!methyt-6-oxo-6H-[l,3]dioxin-4-yI)-benzonltrile (Example N4) (126 mg, 0.55 mmol) according to the general procedure O. Obtained as an amorphous light pink substance (197 mg).
MS(ISP)546[(M+H)""].
Example 053
{5-l3-(3-Cyano-phenyl)-3-oxo-propionykmino]-2"-fluoro-2-methoxy-b"iphenyl-4-yll-carbamic acid lert.-butyl ester

Prepared from (5-amino-2"-fluoro-2-methoxy-biphenyI-4-yI)-carbamic add tert.-butyl ester (ExampleL50) (112 mg,0.35 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (80 mg, 0.35 mmol) according to the general procedure O. Obtained as a yellow foam (131 mg).
MS(ISN)502[(M-Hr].
Example 054
(2"-Fluoro-2-methoxy-5-{3-[3-(2-methyl-imidazol-l-yl)-phenyl]-3-oxo-propionyIaminol-biphenyl-4-yl)-carbamic acid tert.-butyl ester
Prepared from (5-amino-2"-fluoro-2-metboxy-biphenyI-4-yl}-carbamic acid teit.-butyl ester (Example L50) (249 mg, 0.75 mmol) and 3-[3-(2-methyl-iniidazol-l-yl)-phenyI]-3-oxo-propionic acid tert.-butyl ester (Example M8) (275 mg, 0.92 mmol) according to the general procedure O. Obtained as a yellow solid (312 mg).
MS (ISP) 559 [(M+H)""]; mp 83-86 °C.
Example 055
{5-[3-(5-Cyano-thiophen-2-yl)-3-oxo-propionylamino]-2"-fluoro-2-methoxy-biphenyI-4-ylj-carbamic acid tert.-butyl ester
Prepared from (5-amino-2"-fluorO-2-methoxy-biphenyI-4-yl)-carbamic add tert.-butyl ester (Example L50) (166 mg, 0.5 mmol) 3-(5-cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butyl ester (Example M17) (138 mg, 0.55 mmol) according to the general procedure O. Obtained as a light yellow sohd (244 mg).
MS (ISP) 510 [(M+H)^]; mp 200 °C (dec).
Example 056
i2"-Fluoro-2-methoxy-5-l3-oxo-3-(3-[l,2,4)triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2"-fluo ro-2-methoxy-biphenyl-4-yl)-carbamic add tert.-butyl ester (Example L50) (166 mg, 0.5 mmol) and 3-oxo-3-(3-[l,2,4]triazol-4-yl-phenyl)-propionic add ethyl ester (Example Ml) (260 mg, 1.0 mmol) according to the general procedure O. Obtained as a yellow gum (70 mg).

MS(ISP)546I(M+Hr]. Example 057
{5-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylammo]-2"-fiuoro-2-methoxy-biphenyI-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2"-fluoro-2-methoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester {Example L50) and 3-(2-cyano-pyridin-4-yI)-3-oxo-propionic acid tert.-butyl ester (Example MIO) according to the general procedure O. Obtained as a light yellow solid (189 mg).
MS(ISP)522[(M+NH4r].
Example 058
(2-tert.-Butoxy-4"-fluoro-5-{3-[3-(2-methyl-iinidazol-l-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester
Prepared from (5-amino-2-tert.-butoxy-4"-fluoro-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example L47) (140 mg, 0.37 mmol) and 3-[3-(2-methyI-imidazol-l-yI)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example M8) (111 mg, 0.37 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (139 mg).
MS (ISP) 601 [(M+H)""].
Example 059
{5-[3-(5-Cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2"-fluoro-2-methoxy-biphenyI-4-yll-carbamic acid tert.-butyl ester
Prepared from (5-amino-2"-fluoro-2-methoxy-bipheny!-4-yl)-carbamic acid tert.-butyl ester (Example L50) (166 mg, 0.5 mmol) and 3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (Example MIS) (141 mg, 0.6 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (165 mg).
MS(ISP)522[(M+H)""].
Example O60
{2-tert.-Butoxy-5-[3-(2-cyano-pyTidin-4-yl)-3-oxo-propiony!amino]-4"-Suoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester

Prepared from C5-amino-2-tert.-butoxy-4"-fiuoro-biphenyl-4-yI)-carbamic add tert.-butyl ester (Example L47) (140 mg, 0.37 mmol) and 3-(2-cyano-pyridin-4-yI)-3-oXO-propionic acid tert.-butyl ester (Example MIO) (91 mg, 0.37 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (164 mg).
MS (ISP) 547 [(M+H)-"].
Example 061
{2-tert.-Butoxy-2"-fiuoro-5-[3-DXo-3-(3-[ 1,2,3] triazo]-l-yl-phenyl)-propionylamino]-bipheny!-4-yIl-carbamic acid tert.-buty! ester
Prepared from (5-amino-2-tert.-butoxy-2"-£luoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) and 3-oxo-3-(3-[l,2,3]tria2ol-l-yI-phenyl)-propionic acid ethyl ester (Example M2) (180 mg, 0.69 mmol) according to the general procedure O. Obtained as a light yellow solid (257 mg).
MS (ISP) 56S [(M+H)""]-, mp 47-50 =C.
Example 062
[5-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2-(i,4-dioxa-8-aza-spJro[4.5]dec^8-yl)-2"-fluoro-biphenyl-4-yl)-caibamic acidteit.-butyl ester
Prepared from [5-amino-2-(l,4-dioxa"S-a2a-spiro[4.5]dec-8-yl)-2"-fluoro-biplienyl-4-yl]-carbamic acid tert.-butyl ester (Example L51) (222 mg, 0.5 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid tert.-butyl ester (Example M3) (182 mg, 0.8 mmol) according to the genera! procedure O. Obtained as an amorphous yellow substance (258 mg).
MS(1SP)615[(M-HH)-"].
Example 063
{2-(l,4-Dioxa-8-a2a-spiro[4.5]dec-8-yl)-2"-fluoro-5-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from [5-amino-2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2"-Quoro-biphenyl-4-yl]-carbamic acid lert.-butyl ester (Example L51) (222 mg, 0.5 mmol) and 6-(3-imidazol-l-yl-phenyl)-2,2-dimethyl-[l,3]dioxin-4-one (Example NlO) (135 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (294 mg).

MSaSP)656[(M+H)^]. Example 064
(2-tert.-Butoxy-2"-fluoro-5-[3-[3-(2-methyl-iraidazol-l-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic add terL-butyl ester
Prepared from (5-ammo-2-tert.-butoxy-2"-ftuoro-biphenyl-4-yl)-carbamic add tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) and 2,2-dime&yl-6-[3-(2-methyl-imidazol-l-yl)-phenyI]-[l,3]dioxin-4-one (Example N15) (142 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (234 mg).
MSaSP)60lUM+H)^].
Example 065
{2-terL-Butoxy-5-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylaminol-2"-£luoro-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-2"-fiuoro-bipheny!-4-yI)-carbamic add tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) and 4-(2,2-dimethyl-6-oxo-6H-[l,3ldioxin-4-yl)-pyridine-2-carbonitrile (Example Nl6) (115 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (216 mg).
MS(ISP)547[(M+H)""l.
Example 066
(2-tert.-Butoxy-2"-fluoro-5-j3-[3-(2-methylsulfanyl-imidazol-l-yl)-phenyl]-3-oxo-propionylamino)-biphenyl-4-yI)-carbamic add terL-butyl ester
Prepared from (5-amino-2-tert.-butoxy-2"-fluoro-biphenyI-4-yI)-carbamic add tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) and 3-l3-(2-methyisuIfanyl-imidazo!-l-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example M13) (211 mg, 0.63 mmol) according to the general procedure O. Obtained as a light yellow solid (260 mg).
MS (ISN) 631 [(M-H)"]; mp 59-62 "C.
Example 067
{5-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2",5"-difiuoro-2-methDxy-biphenyl-4-yl}-carbamic add tert.-butyl ester

Prepared from (5-amino-2",5"-difluoro-2-methoxy-biphenyl-4-yI)-carbainic add tert.-butyl ester (Example L52) (175 mg,0.5mmo!)and3-(2,2-diInethyl-6-oxo-6H-[l,3]dioxin-4-yl)-ben20nitrile (Example N4) (115 mg. 0.5 mmol) according to the genera] procedure O. Obtained as an amorphous yellow substance (136 mg).
MS(ISP)522[(M+Hr].
Example 068
{2",5"-Difluoro-2-methoxy-5-[3-oxo-3-(3-[l,2,3]triazol-l-yl-phenyi)-propionylamino]-bipheny]-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2",5"-di£luoro-2-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyi ester (Example L52) (175 mg, 0.5 mmol) and 3-oxo-3-(3-[l,2,3]tria2oI-l-yl-phenyl)-propio^ic acid ethyl ester (Example M2) (130 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous light yellow substance (185 mg).
MS(ISN)562 [(M-H)"].
Example 069
{2-tert.-Butoxy-5-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2"-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-2"-fiuoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L4S) (187 mg, 0.5 mmol) and 6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[l,3]dioxin-4-one (Example N3) (130 mg, 0.55 mmol) according to the general procedure O. Obtained as a yellow oil (278 mg).
MS (ISN) 550 l(M-H)-].
Example 07Q
[2-tert.-Butoxy-5-l3-(5-cyano-thiophen-2-yl)-3-oxO"propionylamino]-2"-fiuoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-2"-fluoro-biphenyl-4-yl)-carbamic add tert.-butyl ester (Example L48) (187 mg, 0.5 mmol) 3-(5-cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butyl ester (Example M17) (138 mg, 0.55 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (268 mg).

MS(ISN)550[(M-H)-]. Example 071
[2-tert.-Butoxy-4"-fluoro-5-[3-oxo-3-(3-[l,2,3]triazol-l-y!-pheny])-propionylamino]-bipheny]-4-yl}-carbamic acid tert.-butyl ester
Prepared from (5-amino-2-tert.-butoxy-4"-fluoro-biphenyI-4-yl)-carbaniic add tert.-butyl ester (Example L47) (1S7 mg, 0.5 minol).and 3-oxo-3-(3-[l,2,3]triazol-l-yl-phenyl}-propionic acid ethyl ester (Example M2) (156 mg, 0.6 mmol) according to the general procedure O. Obtained as a yellow gum {198 mg).
MS (ISP) 588 [(M+H)""].
Example 072
f5-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2"-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from {5-amino-2"-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4-ylJ-carbamic acid tert.-butyl ester (Example L53) and 3-(2,2-dimethyI-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) according to the general procedure O. Obtained as a yellow solid (188 mg).
MS(1SP)548[(M+H)^1.
Example 073
(RS)-[5-[3-(3-Cyano-phenyI)-3-oxo-propionylamino]-2"-fluoro-2-(tetrahydro-pyran-2-yloxymethyI)-biphenyl-4-yl]-carbamic acid tert.-butyl ester
Prepared from (RS)-[5-amino-2"-fluoro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-carbamic acid tert-butyl ester (Example L54) and 3-(2,2-dimethyl-6-oxo-SH-[l,3]dioxin-4-yl)-benzonitrile (Example N4) according to the general procedure O. Obtained as a yellow solid (155 mg).
MS (ISP) 548 [(M+NH4)^].
Example 074
(2"-Fluoro-2-(4-methoxy-benzyloxy)-5-{3-(3-(3-methyl-isoxa2ol-5-y])-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carb3mic acid tert.-butyl ester

Prepared [5-amino-2"-fIuoro-2-(4-methoxy-benzyloxy)-biphenyI-4-yl]-carbainicacid tert.-butyl ester (Example L55) (438 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxa2o]-5-yl)-phenyll-3-oxo-propionic acid tert.-butyl ester (Example Ml4) (30! mg, 1.0 mmol) according to the general procedure O. Obtained as an amorphous light yellow substance (561 mg).
MSilSP)666[(M+}iy].
Example 075
{2-tert.-Butoxy-5-[3-(3-cyano-phenyl)-3-Dxo-propionyIamino]-2",5"-difluoro-biphenyl-4-yl}-carbannic acid teit.-butyl ester
Prepared from (5-amino-2-tert.-butOKy-2",5"-difluoro-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example L56) (196 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (115 mg, 0.5 mmol) according to the general procedure O. Obtained as an amorphous beige substance (155 mg).
MS(ISP)564[(M+H)""].
Example 076
{5-tert.-Butoxy-4-(4-fluoro-pheny!ethynyl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-phenylt-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-tert.-butoxy-4-(4-fluoro-phenylethynyl)-phenyI]-carbamic acid tert.-butyl ester (Example L57) (160 mg, 0.4 mmol) and 3-(3-imidazol-l-yl-phenyl)-3-oxo-propionic acid tert.-butyl ester (Example M4) (115 mg, 0.4 mmol) according to the general procedure O. Obtained as an amorphous yellow substance (140 mg).
MS (ISP) 611 [(M+H)^].
Example 077
{5-tert.-Butoxy-4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[l,2,3]triazol-l-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester
Prepared from [2-amino-5-tert.-butoxy-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example L57) (160 mg, 0-4 mmol) and 3-oxo-3-(3-[l,2,3]tria2ol-l-yl-phenyl)-propionic acid ethyl ester (Example M2) (104 mg, 0.4 mmol) according to the general procedure O. Obtained as a yellow gum (150 mg).

MS (ISP) 612 UM+HD.
General procedure P:
Preparation of 4,8-diaiyl-I,3-dihydro-benzo[b][l,4]diazepin-2-ones,4-aryI-8-aroyl-l,3-dihydro-benzo[b] [l,4]dia2epin-2-ones or 4-ar)"l-8-a^ylethynyl-I,3-d:hydro-ben2o [b] [ 1,4] diazepin-2-0 nes
A suspension of the {2-[3-aryl-3-oxo-prDpionylamino]-4-aryi-phenyl}-carbamicaddtert-butyl ester or {2-[3-aryl-3-oxo-propiQnylaniinol-4-arylethynyl-phenyl}-carbamic add tert-butyl ester (1.0 mmol) in CHiCli (5 mL) [anisole or 1,3-dimethoxybenzene (5-15 mmol) can be added if necessary] was treated with TFA (0.5-5.0 mL) at 0 °C and stirring was continued at 23 "C until tic indicated complete consumption of the starting material. The solvent was removed in vacuum, the residue treated with little ether, whereupon it crystallized. The solid was stirred with sat. NaHCOj-sol., filtered, washed with H^O and ether or mixtures of ether/hexane and was dried to give the tide compound, which if necessary can be purified by crystallization from THF/CH^Cl;/ether/hexane.
General procedure O:
Preparation of4-[3-(Amino-4-carbonyl)-pheny]]-8-phenyIethynyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-onesbyPd-catalyzed carbonylative amination of4-(3-
iodophenyl)-8-phenylethyiiyl-l,3-dihydTO-ben20[bl[l,4]diazepin-2-one
A solution ofihe 4-(3-iodopheny])-8-pheny]ethyny]-],3-dihydro-benzo[b][l,4)dia2epin-
2-one (1.0 mmol), the secondary amine (5.0 mmol), PPhs (6 moWo) or dppp (3 moI%),
Pd(0Ac)2 (3 mol%) and EtjN (2.0 mmol) in DMP (4 mL) was stirred at 23 "C under CO-
atmosphere until tic indicated complete consumption of the iodide. After dilution with
EtOAc, washing with sat. NaHCOs-sol. and brine, the organic phase was dried over
Na2S04. Removal of the solvent left a brown oil, which was purified by silica gel column
chromatography with hexane/EtOAc to give the title compound.
Genera] procedure R:
Preparation of (5-hydroxy-2-nitro-phenyl)-carbamic acid tert.-butyl esters byRh-catalyzed
deaiiylation of {5-aUyloxy-2-nitro-phenyl)-carbamic acid tert.-butyl esters
A mixture of the (5-allylox>"-2-nitro-phenyl)-carbamic acid terL-butyl ester, (PPh3)3RhCl
(5 mol%) and DABCO (20 moI%) in EtOH was refluxed for 2.5 h according to /. Org.
Chzm. 1973, S8, 3224. Added 5% citric acid, stirred at 23 °C for 15 min, extracted with
EtOAc, washed with brine, dried over MgSO^. Removal of the solvent left an orange solid,
which was purified by silica gel column chromatography with hexane/EtOAc to give the
tide compound.

Example Rl
(5-Hydroxy"4-iodo-2-nitro-phenyl )-carbamic add tert.-butyl ester
Prepared from (5-allyloxy-4-iodo-2-nitro-phenyI)-carbainic add tert.-butyl ester (Example B4), (PPhj)3Rha {5 mol%) and DABCO (20 mol%) in EtOH according to the general procedure R- Obtained as a yellow solid.
MS (ISN) 379 [(M-H)-]; mp 140 "C.
General procedure S:
Preparation of 5-0-substituted-(4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl esters from (5-hydroxy-4-iodo-2-nitro-pheny])-carbamic acid tert.-butyl ester . A mixture of the (5-hydroxy-4-iodo-2-nitro-phenyl)-carbamic add tert.-butyl ester (Example Rl). KHCO3 and the appropriate alkylating reagent were stirred in DMF at 23 to 60 "C until tic indicated complete conversion. Dilution with EtOAc was followed by aqueous workup with 5% citric acid, sat. NaHC03-sol., brine and drying over MgS04. Removal of the solvent left a crude material, which was purified by silica gel column chromatography with hexane/EtOAc to give the title compound.
Example 51
(5-tert.-Butoxycarbonylam!no-2-iodo-4-nitro-phenoxy)-acetic acid tert.-butyl" ester
Prepared from (5-hydroxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl eSter (Example Rl) (1.23 g, 3.24 mmol), KHCOj (0.39 g, 3.89 mmol) and tert.-butyl bromoacetate (0.59 mL, 5.89 mmol) according to the general procedure S. Obtained as a yellow solid(I.5g, 94%).
MS (ISP) 495 [(M+H)^]. 512 [(M+NH,)*] and 517 [(M+Na)*]; mp 103 °C.
Example S2
(5-Cyanomethoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester
Prepared from (5-hydroxy-4-iodo-2-n!tro-phenyl)-carbamic acid tert.-butyl ester (Example Rl) (614 mg, 1.62 mmol), KHCO3 (208 mg. 2.08 mmol) and broraoacetonitrile (0.21 mL, 3.16 mmol) according to the general procedure S. Obuined as a yellow solid (574 mg, 85 %).

MS (ISN) 418 [(M-H)-]; mp 125 °C. Example S3
(RS)-(4-Iodo-2-nitro-5-[2-(tetrahydro-pyian-2-yloxy)-ethoxyl-phenyl}-carbamicacid tert.-butyl ester
Prepared from (5-hydroxy-4-iodo-2-nitro-phenyl)-carbaTnic acid tert.-butyl ester (Example Rl) (760 mg, 2 mmol), KHCOj (260 mg, 4 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.6 mL, 2.6 mmol) according to the genepal procedure S. Obtained as an orange oil (804 mg, 79 %).
MS (EI) 508 (M*).
Example S4
(5-tert.-Butoxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester
N,N-Dimethylformamide di-tert.butylacetal (19.2 mL, 80 mmol) was added dfopwise ■vvithin 15 minto a solution of (5-hydroxy-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example Rl) (7.60 g, 20 mmol) in toluene at 80 "C and stirring wa^ continued at 80 "C for 3 h (c/; Synthesis 1983,135). Obtained as a yellow solid (5.97 g, 68 %).
MS (ISN) 435 [(M-H)"]; mp 94 "C.
Example 1
3-(7-Iodo-4-oxo-8-thiomorpholin-4-yl-4,5-dihydro-3H-benzo[b] [ 1,4] diazepin-2-yl)-benzonitrile
Prepared from 2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-iodo-5-thiotnorpholin-4-yl-phenyl}-carbamic acid tert.-butyl ester (Example 01) (629 mg, 1.04 mmol) by treatment with TEA in CHjCli according to the general procedure P. Obtaineci as an olive soUd (437 mg).
mp 227-228"C (dec).
Example 2
3-(7-Iodo-8-morpholin-4-yI-4-oxo-4,5-dihydro-3H-benzo[b][l,4]dia2epin-2-yl)-benzonitrile

Prepared from {2-l3-(3-cyano-phenyl)-3-oxo-propionyIamino]-4-iodo-5-morpholin-4-yl-phenyl}-carbamic acid tert.-butyl ester (Example 02) (518 mg, 0.877 mmol) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a beige solid (309 mg).
MS (EI) 472 (M^); mp 224 °C (dec).
Example 3
3-(8-Chloro-4-oxo-7-phenyIethynyl-4.5-dihydro-3H-benzo[b][l,4]diazepin-2-yl)-benzonitrile
Prepared from (2-amino-5-chloro-4-pheny!ethyny]-phenyl)-carbamic acid tert.-butyl ester (Example L3) (171 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yI)-benzonitrile (Example N4) (183 mg, 0.6 mmol) according to the general procedure O. Obtained as a light yellow solid (284 mg). This material was deprotected and cyclized by treatment with TFA in CH2C12 according to the general procedure P. Obtained as an orange solid (483 mg).
MS (ISP) 343 [(M+H)^] and 345 [(M+2+Na)""]; mp 248-251 "C (dec).
Example 4
3-(8-Methyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yI)-benzonitrile
Prepared from (2-amino-5-methyl-4-phenylethynyl-phenyl)-carbamic acid tert-butyl ester (Example L4) (161 mg, 0.5 mmol) and 3-(2,2-dimethy]-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile (Example N4) (230 mg, 0.75 mmol, 75% pure) according to the general procedure O. Obtained as a light yellow solid (227 mg). This material was deprotected and cyclized by treatment with TFA in CH2C12 according to the general procedure P. Obtained as a hght yellow solid (83 mg).
MS (ISP) 375 (M""); mp 237-239 °C (dec).
Example 5
3-[8-(4-Methyl-piperazin-l-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzofb] [ 1,4] diazepin-2-yl] -benzonitrile

Prepared from [2-ammo-5-(4-methyl-piperazin-l-yl)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example L5) (203 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yI}-ben2onitriIe (Example N4) (230 mg, 0.75 mmol, 75% pure) according to the general procedure O. Obtained by chromatography as an orange oi! (181 mg). This material was deprotected and cyclized by treatment withTFA in CHiCb according to the general procedure P. Obtained as an orange soHd (82 mg).
MS (ISP) 460.5 [(M+H)*]-, mp 222-224 "C (dec).
Exainple 6
3-[8-(l,l-Dioxo-thiomorpholin-4-yl)-4-oxo-7-phenylethynyI-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from [2-amino-5-(Ul-dioxo- 6-thiomorpholin-4-yl)-4-phenylethynyI-phenyl]-carbamic acid tert.-butyl ester (Example Ll9) (220 mg, 0.5 mmol) and 3-(2,2-dimediyl-6-oxo-6H-[l,3]dioxin-4-yI)-benzonitrile (Example N4) (172 mg, 0.75 mmol) according to the general procedure O. The obtained material was deprotected and cydized by treatment with TFA in CRzCh according to the general procedure P. Obtained as a yellow solid (47 mg).
MS (ISP) 495 [(M+H)""]; mp >250 °C (dec).
Example 7
3-(8-Chloro-4-oxo-7-phenyl-4,5-d!hydro-3H-benzo[b][l,4]diazepin-2-yl)-benzonitrile
Prepared from {2-chloro-5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-biphenyI-4-yli-carbamic acid tert.-butyl ester (Example 03) (720 mg, 1.47 mmol) by treatment with TFA in CHzCi: according to the general procedure P. Obtained as an off-white solid (457 mg).
MS (EI) 371 (M"") and 373 [(M+2)^]; mp 242-244 °C (dec).
Example 8
3-(8-Methyl-4-oxo-7-phenyl-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl)-benzonitrile
Prepared from (5-amino-2-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example L7) (298 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)-benzonitrile -(Example N4) (460 mg, 1.5 mmol) according to the general procedure O. The obtained

material (351 mg) was deprotected and cyclized by treatment with TFA in CH2CI: according to the general procedure P. Obtained as a light yellow solid (206 mg).
MS (EI) 351 (M^); mp 236-239 »C (dec).
Example 9
3-[8-(l,4-Dioxa-S-aza-spiro[4.5]dec-8-yl)-4-oxo-7-pheny]ethynyl-4,5-dihydro-3H-benzo [b] [ 1,4] diazepin-2-yl] -benzonitrile
Prepared from [2-[3-(3-cyano-pheny!}-3-oxo-propionylamino]-5-(l,4-dioxa-8-a2a-spiro[4.5]dec-8-yl)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example 014) (265 mg, 0.43 mmol) by treatment with TFA in CH2CI1 according to the general procedure P. Obtained as a brown solid {121 mg).
MS (ISP) 503 [(M+H)^]; mp 239-243 °C (dec).
Example 10
3-(8-Morpholin-4-yl-4-oxo-7-phenylet}iynyl-4,5-dihydro-3H-ben2o[bl[l,4]diazepin-2-yl)-benzonitrile
Prepared from {2-[3-(3-cyano-pheny]}-3-oxo-propiony]amino] -5-n:orpho]in-4-yI-4-phenylethyny!-phenyl}-carbamic acid terL-butyl ester OlO (370 mg, 0.66 mmol) by treatment with TFA in CHiCli according to the general procedure P. Obtained as a light brown solid (216 mg).
MS (EI) 446 (M*); mp 239-243 °C (dec).
Example 11
3-[8-{2-Dimethylamino-ethylsulfanyl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-ben2o[b][l,4]dia2epin-2-yl]-benzonitrile
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-(2-dimethylamino-ethylsuIfanyI)-4-phenyIethynyl-phenyl]-carbamic acid tert.-buty! ester (example 04) (166 mg, 0.28 mmol) by treatment with TFA and anisole in CH2C12 according to the general procedure P. Obtained as a Ught yellow soHd (103 mg).
MS (ISP) 465 [(M+H)*]; mp 197 "C (dec).

Example 12
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3- Prepared from j5-tert.-butoxycarbonyiamino-4-[3-(3-cyano-phenyl)-3-oxo" propionylamino]-2-phenylethynyl-phenylsulfaiiyl}-acetic add methyl ester (Example 05}(421 mg, 0.72 mmol) by treatment with TEA and anisole in CHjCiz according to the general procedure P. Obtained as a light yellow soUd (309 mg).
MS (ISP) 465 [(M+H)*]; mp 201 "C (dec).
Example 13
[4-(3-Cyano-pheny!)-2-oxo-8-phenylethynyI-2,3-dihydro-lH-benzo[b][l,4]daazepin-7-ylsulfanyl]-acetic acid
A solution of [4-(3-cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b] [1.4)dja2epin-7-yIsulfanyl]-acetic acid methyl ester (Example 12) (265 mg, 0.57 mmol) and LiOH-H:0 (26 mg. 0.63 mmol) in THF (5 mL). MeOH (1 mL) apd H2O (1 iiiL) was stirred at 23 "C for 24 h. Obtained as a light yellow solid (257 mg).
MS USP) 452 KM-i-H)^V. mp 202 "C Idee).
Example 14
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b][l,4]diazepin-7-ylj-acetic acid methyl ester
Prepared from {5-tert.-bQtoj:ycarbonylamino-4-[3-(3-cyano-phenyl)-3-oxo" propionylamino]-2-phenylethynyl-phenyl)-acetic acid methyl ester (Example 06) (846 mg, 1.53 mmol) by treatment with TEA in CH2CI2 according to the general procedure P. Obtained as a light yellow sohd (557 mg).
MS (EI) 433 (M*); mp 236 X (dec).
Example 15
[4-(3-Cyano-phenyl}-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[bl[l,4)diazepin-7-ylj-acetic acid

A solution of LiOHHjO (54 mg, 1.28 mmol) in H2O {2 mL) and MeOH {2 mL) was added to [4-(3-cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-ben2o[b][l,4]diazepin-7-yl] -acetic acid methyl ester (Example 14) (505 mg, 1.17 mmol) in THF (10 mL) .and the reaction mixture was stirred at 23 "C for 48 h. Obtained as a light yellow solid (62 mg).
MS (ISP) 452 [(M+H)*]; mp 248 "C (dec).
Example 16
4-(3-Cyano-phenyl)-8-iodo-2-oxo-2,3-dihydro-lH-ben2o[b][l,4]diazepine-7-carboxyIic acid methyl ester
Prepared from 5-tert.-butoxycarbonylamino-4-[3-(3-cy3no-phenyl)-3-oxo-propionylamino]-2-iodo-benzoic add methyl ester (Example 017) (430 mg, 0.763mmol) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a salmon colored solid (199 mg).
MS (H) 445 (M""); mp 247-248 *C (dec).
Example 17
2-[4-(3-Cyano-phenyl)-2-oxo-S-phenylethynyl-2.3-dihydro-lH-benzo[b][l,4]diazepin-7-yl]-acetamide
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b][l,4]dia2epin-7-yl]-acetic acid (Example 15) (48 mg, 0.114 mmol) was treated with BocjO (37 mg), NH4HCO3 (13 mg) and pyridine (6 nL) in DMF (0.6 mL) at 23 °C for 24 h [cf. Tetrahedron Letters 1995,36,7115]. Obtained as a light yellow solid (14 mg).
MS (ISN) 417 [(M-H)-]; mp 250 »C (dec).
Example 18
3-[8-(2-Methoxy-ethoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenylj-carbamic acid lert.-butyl ester (Example 07) (135 mg, 0.251 mmol) by treatment with TFA in CHjCli according to the general procedure P. Obtained as a light green solid (82 mg).

MS (EI) 435 (M"*"); mp 174-176 °C
Example 19
4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-ben2o[bl[l,4]di3zepme-7-carboxylic add methyl ester
Prepared from 5-tert.-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2-phenyIethynyl-benZoic add methyl ester (Example 09) (511 mg, 0.95 mmol) by treatment with TFA in CH2CI: according to the general procedure P, Obtained as an off-white solid (321 mg).
MS (EI) 419 (M^); mp >250 °C.
Example 20
3-(8-Methoxy-4-oxo-7-phenylethyiiyl-4,5-dihydro-3H-ben2o[b][l,4]dia2epin"2-yl)-benzonitrile
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-methoxy-4-phenylethynyl-phenyl}-carbamic add tert.-butyl ester (Example 08) (359 mg, 0-7 mmol) by treatment with TFA in CH^Ch according to the general procedure P. Obtained as a yeUovi-b^ovm, solid (S? m?,).
MS (EI) 391 (M*); mp >250 °C.
Example 21
3-[8-(2-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-4-oxo-7-phenylethynyI-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from [2-[3-(3-cyano-phenyI)-3-oxo-propionylamino]-5-(2-(2-[2-(2"methoxy-ethoxy)-ethDXy]-ethoxy}-ethoxy)-4-phenylethynyl-phenyl]-carbamic add tert.-butyl ester (Example Oil) (300 mg, 0.437 mmol) by treatment with TFA m CH2CI2 according to the general procedure P. Obtained as a light yellow solid (211 mg).
MS (EI) 435 (M*); mp 140-141 °C (dec).
Example 22
(4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b][l,4]diazepin-7-yloxyj-acetic acid

Prepared from {5-tert.-butoxycarbonylaniino-4-[3-(3-cyano-phenyl)-3-oxo-propionyiamino]-2-phenylethynyl-phenoxy]-acetic acid tert.-butyl ester (Example 012) (698 mg, 1.14 mmol) by treatment with TFA in CH2CI2 and anisole according to the general procedure P. Obtained as a yellow solid (265 mg).
MS (ISN) 434 [(M-H)-]; mp 257 "C (dec).
Example 23
3-(8-Cyanomethy]-4-oxo-7-phenylethynyl-4,5-dihydro-3H-ben2o[b][l,4]dia2epin-2-yl)-benzonitrile
Prepared from {5-cyanomethyl-2-[3-(3-cyanD-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example 013) (266 mg, 0.51 mmol) by treatment with TEA in CH2CI2 and anisole according to the general procedure P. Obtained as a yeUow solid (145 mg).
MS (EI) 400 {U^y, mp 262 "C (dec). ■
Example 24
3-[8-(2,3-Dihydroxy-propoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4jdiazepin-2-yl]-benzanitrile
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-(2,2-dimethyl-[ 1,3] dioxolan-4-ylmethoxy)-4-phenylethynyl-phenyl] -carbamic acid tert.-butyl ester (Example 016) (265 mg, 0.435 mmol) by treatment with TFA in CH2CI2 and anisole according to the general procedure P. Obtained as a yellow solid (62 mg).
MS (ISP) 452 [(M+H)""] and 474 [(M+Na)""]; mp 230-234 X (dec).
Example 25
4-(3-lodo-phenyl}-7-(2-methoxy-ethoxy)-8-phenylethynyl-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from [2-[3-(3-iodo-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]-carbamic acid tert.-butyl ester (Example 015) (1.24 g, 1-89 mmol) by treatment with TFA in CH2CI2 and anisole according to the general procedure P. Obtained as a yellow solid (517 mg).

MS (EI) 536 (M""); mp 192 "C (dec). Example 26
2-[4-(3-Cyano-phenyl)-2-oxo-8-phenylethyny!-2,3-dihydro-lH-benzo[b][l,4]dia2epin-7-yloxy ] -acetamide
EDC (42 mg, 0.22 mmol) was added to [4-(3-cyano-phenyI)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-ben2o[b][l,4]dia2epin-7-yioxy]-aceticacid (Example 22) (50 mg, 0.11 mmol), NH4CI (18 mg, 0.33 mmol) and NMM (56 mg, 0.55 mmol) in DMF (l.l mL) at 0 °C and the reaction mixture was stirred at 23 °C for 2 h. Obtained as a yellow solid (5 mg).
MS (ISN) 417 [(M-H)-]; mp 250 °C (dec).
Example 27
4-(3-Imidazo!-l-yl-phenyl)-7-(2-methoxy-ethoxy)-8-phenylethynyl-l,3-dihydro-ben2o[b][l,4]diazepin-2-one
Prepared from [[[2-[3-(3-ImidazoI-l-yl-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]-carbamic acid teit.-butyl ester (Example 018) (200 mg, 0.336 mmol) by treatment with TFA in CH2CI2 and anisole according to the general procedure P. Obtained as a yellow solid (28 m^.
MS (EI) 476 (M""); mp 187-189 "C.
Example 28
[RSl-3-[4-Oxo-8-(2-oxo-[13]dioxo!an-4-ylmethoxy)-7-phenylethynyl-4,5-diliydro-3H-ben2o[b][l,4]dia2epin-2-yl]-benzonitrile
Prepared from [RS]-[2-[3-(3-cyano-phenyl)-3-oxo-propionylamJno]-5-(2-oxf)-[l,3]dioxolan-4-^methoxy)-4-phenylethynyl-phenyll-carbamic add tert.-butyl ester (Example 019) (400 mg, 0.67 mmol) by treatment with TFA in CHjCb accortiing to the general procedure P. Obtained as a yellow soHd (287 mg).
MS (EI) 477 (M""); mp 222 »C (dec).
Example 29
3-(8-Ethoxymethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl)-benzonitrile

Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionyIarnino]-5-etlioxyinethyI-4-phenylethynyl-phenyll-carbamic acid tert.-butyl ester (Example O20) (140 mg, 0.26 mmol) by treatment with TFA in CHjCb according to the genera! procedure P. Obtained as a yellow solid (93 mg).
MS(H)419(M*);mp229"C.
Example 30
2,2-Dimethyl-propionicacid4-(3-cyano-phenyl)-2-oxo-8-phenyIethynyl-2,3-dihydro-lH-benzofb] [I,4]diazepin-7-ylmethyl ester
Prepared from 2,2-dimethyl-propiamc acid 5-tert.-butoxycarbonyIamino-4-[3-(3-cyano-phenyI)-3-oxo-propionylaimno]-2-phenyIethynyl-benzyl ester (Example 021) (156 mg, 0.26 mmol) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (75 mg).
MS (EI) 475 (MO; mp 218 "C.
Example 31
3-(8-Hydroxymethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yi)-benzomtrile
Prepared from 2,2-dimethyl-propionic acid 4-(3-cyano-phenyl)-2-oxo-S-phenylethynyl-2,3-dihydro-lH-benzo[b] [l,4]diazepin-7-ylmethyl ester (Example 30) (30 mg, 0.063 mmol) and LiOH.HzO (8 mg, 0.289 mmo!) in THF (2 mL), MeOH (0.4 mL) and H2O (0.4 mL) at 23 "C for 3 days. Obtained as a yellow solid (17 mg).
MS (EI) 391 (M*)-, mp >255 "C.
Example 32
7-Hydroxymethyl-4-(3-imidazol-l-yl-phenyl)-8-phenylethynyI-l,3-dihydro-benzo[b] [ 1,4] diazepin-2-one
Prepared from (RS)-[2-[3-(3-imidazol-l-y!-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-carbamic acid tert.-butyl ester (Example 022) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (77 mg).

MS (EI) 432 (M"^); mp 227 "C. Example 33
4-(3-Imidazol-l-yl-phenyl)-7-(4-niethoxy-piperidm-l-yl)-8-phenyIethynyM,3-dihydro-benzo [b] [ 1,4] diazepm-2-one
Prepared from [2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propiony]ammo]-5-(4-methoxy-piperidin-l-yl)-4-phenylethynyl-ph.enyl]-carbamic acid tert.-butyl ester (Example 023) by treatment with TEA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (159 mg).
MS (ISP) 516 [(M+H)""]; mp 222 "C.
Example 34
3-[8-(4-Methoxy-piperidin-l-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b] [ 1,4] diazepin-2-yl] -benzonitrile
Prepared from [2-[3-(3-cyano-phen>^)-3-oxo-propionylamino]-5-(4-methoxy-piperidin-1 -yI)-4-phenylethynyI-phenyl] -carbamic acid tert.-butyl ester (Example 024) by treatment with TEA in CH2CI: according to the general procedure P. Obtained as a yellow solid (128
MS (ISP) 475 [(M+H)""]; mp 250-251 °C.
Example 35
[4-(3-Imidazol-l-yl-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzofb] [ 1,4] diazepin-7-yloxy] -acetonitrile
Prepared from {5-cyanomethoxy-2-[3-{3-imida2ol-l-yl-phenyl)-3-oxo-propionylanuno]-4-phenylethynyl-phenyI}-carbamic acid ten.-butyl ester (Example 025) by treatment with TEA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (43 mg).
MS (EI) 457 (M""); mp 214 "C.
Example 36
3-(8-Cyanomethoxy-4-oxo-7-phenyIethynyl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl)-benzonitrile

Prepared from {5-cyanomethox)"-2-[3-(3-cyano-phenyI)-3-oxo-propionylamino]-4-phenylethynyl-phenyll-carbamic add tert.-butyl ester (Example 026) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid.{71 mg).
MS(EI)416(M*);mp2i2""C.
Example 37
8-(4-FIuoro-phenylethynyl)-7-hydioxymethyl-4-(3-imida2ol-l-yl-phenyl)-l,?-dihydro-benzo [b] [ 1,4] dia2epin-2-one
Prepared from (RS)-[4-(4-fluoro-phenylethynyl)-2-[3-C3-imida2oM-yl-phenyl)-3-oxo-propionylamino]-5-(tetrahydro-pyTan-2-yloxymethyl)-phenyl]-carbamic acid tert.-butyl ester (Example 027) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (462 mg).
MS (EI) 450 (M""); mp 234 °C (dec).
Example 38
8-(4-Fluoro-phen>dethynyl)-7-[(2-hydroxy-ethyl)-methyl-amino]-4-(3-imidazoi-l-yI-phenyl)-l,3"dihydro-benzo[b][l,4]diazepin-2-one
Prepared from (RS)-(4-(4-fluoro-phenylethynyl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethylj-amino}-pbenyl)-carbamic acid tert.-butyl ester (Example 028) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (73 mg).
MS (EI) 493 (M*); mp 217 =C (dec).
Example 39
4-(3-Imidazol-l-yl-phenyl)-7-(4-oxo-piperidin-l-yl)-8-phenylethynyl-l,3-dihydro-benzo[b] [ 14]diazepin-2-one
Prepared from {5-(4,4-diethoxy-piperidin-l-yl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example 029) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (180 mg).
MS (EI) 499 (M^); mp 231 "C (dec).

Example 40
N-tert.-Butyl-2-[4-(3-cyano-phenyI)-2"OXo-8-phenyIethynyl-2,3-dihydro-lH-benzo[b][l,4]diazepin-7-yloxy]-acetamide
Prepared from [4-{3-cyano-pheny!)-2-oxo-8-phenyiethynyl-2,3-dihydro-lH-benzo[b] [l,4]dia2epin-7-yIoxy]-acetic acid (Example 22) (87 mg, 0.2 mmol) by treatment with oxalyl chloride (26 uL, 0.3 mmol) in DMF (0.6 mL) at 0 °C for 1 h, then with tert.-butylamine (106 uL, 1.0 mmol) at 0 °C for further 30 min. Obtained as a yellow solid (21 mg).
MS (EI) 490 (M""); mp >250 "C.
Example 41
2-[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-ben2o[b][l,4]dia2epin-7-yloxy] -N-methoxy-acelamide
Prepared from [4-(3-cyano-phenyl)-2-oxo-8-phenyIethyn)d-2,3-dihydro-lH-benzo[b][l,4]diazepin-7-yloxy]-acetic acid (Example 22) (44 mg, 0.1 mmol) by treatment with EDC (38 mg, 0.2 mmol), MeONH2.HCl (9 mg, 0.11 mmol), NMM (0.021 mL, 0.3 mmol) and HOBt (15 mg, 0.11 mmol) in DMF (1 mL) at 0 to 23 "C for 20 h. Obtained as a ydlow solid (36 mg).
MS (ISP) 465 [(M+H)^]; mp >250 "C.
Example 42
7-(2-Hydroxy-ethoxy)-4-(3-imidazol-l-yl-phenyl)-8-phenylethynyl-l,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
Prepared from (RS)-|2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phen>d}-carbamicacid terL-butyl ester (Example 029) by treatment with TEA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (48 mg).
MS (EI) 462 (M^); mp 224-227 °C.

Example 43
8-(4-Fluoro-phenyl)-7-(4-hydroxy-piperidm-l-yi)-4-(3-imida2o!-l-yl-phenyl)-l,3-dihydro-benzo[b] [ 1,4] diazepin-2-one
Prepared from {RS)-{4"-fluoro-5-[3-(3-imidazol-l-yl-phenyI)-3-oxo-propionylamino]-2-[4-{tetxahydro-pyran-2-yloxy)-piperidin-l-yl]-biphenyI-4-yl}-carbaniicaddtert.-butyl ester (Example 031) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow soHd (109 mg).
MS (ISP) 496 [(M+H)"*"]; mp 238-240 "C.
Example 44
8-(4-Fluoro-phenylethynyl)-7-(2-hydroxy-ethoxy)-4-(3-imida2oI-l-yI-phenyl)-l,3-dihydro-benzo[b] [ l,4ldiazepin-2-one
Prepared from {5-(2-tert.-butOKy-ethoxy)-4-(4-fiuoro-phenylethyiiyl)-2-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionyIamino]-phenyl|-carbamic acid terL-butyl ester (Example 032) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (83 mg).
MS (El) 480 (M""); mp 220-222 "C.
Example 45
8-(4-Fluoro-phenyl)-7-E4-(2-hydroxy-ethoxy)-piperidin-l-yl]-4-(3-imidazol-l-yl-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from (RS)-(4"-fluoro-5-(3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylaminol-2-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-piperidin-l-yl}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example 033) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (97 mg).
MS (ISP) 540 [(M+H)""]; mp 225-227 °C.
Example 46
8-(4-Fluoro-phenyl)-7-hydroxymethyl-4-(3-imida2ol-l-yl-phenyl)-l,3-dihydro-benzofb] [ l,4]diazepin-2-one

Prepared from (RS)-l4"-fluoro-5-[3-{3-iinidazol-l-yl-phenyl)-3-oxo-propionyIamino]-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-y]]-carbaniic acid tert.-butyl ester (Example 034) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a hght yellow solid {162 mg).
MS {ED 426 [(M)*]; rap 180-195 ^C.
Example 47
[8-(4-Fluoro-phenyl)-4-(3-imidazoI-l-yl-phenyl}-2-oxo-2,3-dihydro-lH-benzo[b][l,4]dia2epin-7-yloxy]-acetonitrile
Prepared from {2-cy3nomethoxy-4"-fluoro-5- [3-(3-imidazol- 1-yI-phenyl)-3-oxo-propionylamino]-biphenyI-4-yl}-carbamic acid tert.-butyl ester (Example 035) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (11 mg).
MS(EI)451{M*);mpl64°C.
Example 48
7-Dimethylaminomethyl-8-{4-fluoro-phenyl)-4-(3-imida2ol-l-yl-phenyl)-l,3-dihydro-benzolb] [l,4]diazepin-2-one
Prepared from {2-dimethyIaminomethyI-4"-fluoro-5-[3-C3-imidazol-l-yl-phenyI)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example 036) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a brown solid (180 mg).
MS (ISP) 454 (M+H)*; mp 115-140 "^C (dec).
Example 49
7-(2,2-DimethyI-tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-5-yl)-8-{4-£luoro-phenyl)-4-(3-imidazol-l-yl-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from {2-(2,2-dimethyI-tetrahydro-[I,3]dioxolo[4,5-c]pyTrol-5-yl)-4"-£luoro-5-l3-{3-tmidazoi-l-yl-phenyi)-3-oxo-propionylamino]-bipheny"i-4-yl}-carbamic acid tert.-butyl ester (Example 037) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid {358 mg).

MS tEI) 537 (M*); mp 240 ^C (dec).
Example 50
7-{cis-3,4-Dihydroxy-pyrrolidin-l-yi)-8-(4-fluoro-phenyl)-4-(3-imidazol-l-yl-phenyl)-lj3-dihydro-benzo[bl[l,4ldia2epin-2-Qne
Prepared from 7-(2,2-dimethyl-tetrahydro-[l,3]dioxoIo[4,5-c]pyTrol-5-yI)-8-(4-fluoro-phenyl)-4-(3-imidazol-l-yl-phenyI)-l,3-dihydro-benzo[b]Il,4]dia2epm-2-one (Example 49) (304 mg, 0.57 mmol) by treatment 13% HCI (15 mL) in THF (50 mL) at 23 "C for 16 h. Obtained as a yellow solid (209 mg).
MS (ISP) 498 [(M+H)*]; mp 244 °C.
Example 51
8-(4-Fluoro-phenyl)-4-(3-imidazo!-l-yl-phenyI)-7-methoxy-l,3-dihydro-ben2o[b][1.4]diazepin-2-one
Prepared from {4"-fiuoro-5-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino]-2-methoxy-biphenyI-4-yI}-carbamic acid tert.-butyl ester (Example 038) by treatment with TEA in CH2CI2 according to the general procedure P. Ofatamed as a yellow solid (182 mg).
MS (EI) 426 (M^); mp 221 "C (dec).
Example 52
8-(4-Fluoro-phenyl)-4-(3-imidazol-l-yl-phenyl)-7-(4-oxo-piperidin-l-yl)-l,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
Prepared from {2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4"-fluoro-5-[3-(3-imida2ol-l-yI-phenyl)-3-oxo-prDpionylamino]-biphenyl-4-yll-carbamic acid tert.-butyl ester (Example 039) by treatment with TFA in CHjCla according to the general procedure P- Obtained as an orange-brown solid (150 mg).
MS (ISP) 494 [(M+H)""]; mp 204 "C.
Example 53
8-(4-Fluoro-phenyI)-4-(3-imidazoI-l-^-phenyl)-7-methyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-one

Prepared from {4"-fluoro-5-[3-(3-iinidazol-l-yi-phenyi)-3-oxo-propion)4ainmo]-2-methyl-biphenyl-4-yI)-carbamic acid tert.-butyl ester (Example O40) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow^olid (216 mg).
MS(EI)410(M*);mpl96""C.
Example 54
[8-(4-FIuoro-phenyl)-4-(3-imida2oi-l-yI-phenyI)-2-oxo-2,3-dihydTO-lH-benzofb] [ 1,4] diazepin-7-yIoxy] -acetic acid
Prepared from {4-tert.-butoxycarbonyIamino-4"-fluoro-5- [3-(3-imidazol- l-yl-phenylJ-3-oxo-propionylamino]-biphenyl-2-yloxy}-acetic acid tert.-butyl ester (Example 041) by treatment with TFA in CH^CU according to the general procedure P. Obtained as a beige solid (570 mg).
MS (ISP) 471 [(M+H)*]; mp 209 °C (dec).
Example 55
2-[8-(4-FIuoro-phenyl)-4-(3-imidazol-l-yl-phenyl)-2-oxo-2,3-dihydro-lH-benzo|b][l,4]diazepin-7-yloxy]-N-hydroxy-acetamide
Prepared from [8-(4-fluoro-phenyl)-4-(3-imida2ol-l-yl-phenyI}-2-oxo-2,3-dihydro-lH-benzo[b][l,4jdia2epin-7-yloxy]-aceticacid (Example 54) (94 mg, 0.2 mmol) by reaction with O-tritylhydroxylamine (61 mg, 0.22 mmol), HOBT {30 mg, 0-22 mmol), N-■ methylmorpholine (66 ^L, 0.6 mmol) and EDC (77 mg, 0.4 mmol) in DMF (2 ml) from 0 to 23 °C for 18 h. After extraction and chromatography the resulting orange solid was stirred with TFA in CHjCb according to the general procedure P. Obtained as 3 light yellow solid (71 mg).
MS (ISP) 486 [(M+H)""];mp 147-157 °C (dec).
Example 56
7-Chloro-8-(4-fluoro-phenyl)-4-(3-imidazol-l-yI-phenyl)-13-dihydro-benzolb] [ 1,4] dia2epin-2-one
Prepared from {2-chloro-4"-fluoro-5-[3-(3-imidazol-l-yl-phenyl)-3-oxo-propionylamino] -biphenyl-4-ylt-carbamic acid tert.-butyl ester (Example 042) by

treatment with TFA in CHjCl: according to the general procedure P. Obtained as a light yellow solid (35 mg).
MS (EI) 430 (M"^); mp 209-211 "C.
Example 57
8-(4-FIuoro-phen>^)-4-{3-imidazol-l-yl-phenyl)-7-(2-methoxy-ethoxy)-l,3-dihydro-, benzo [b] [ 1,4] diazepin-2-one
Prepared from [4"-fluoio-5-[3-(3-iniida2ol-l-yl-phenyl)-3-oxo-propionylamino]-2-C2-inethoxy-ethoxy)-biphenyl-4-yl]-carbamic add tert.-butyl ester {Example 043) by treatment with TFA in CH1CI2 according to the general procedure P. Obtained as a yellow sohd (96 mg).
MS (EI) 470 (M""); mp 196-197 "C.
Example ^8
8-(4-Fluoro-phenyl)-7-(2-hydroxy-ethoxy)-4-(3-imida2ol-l-yl-phenyl)-l,3-dihydro-ben2o[b][l,4]diazepin-2-one
Prepared from {2-(2-tert.-butoxy-ethoxy)-4"-fluDro-5-[3-(3-imida2oI-l-yl-phenyl}-3-oxo-propiony]amino]-biphenyi-4-yl}-carbamic acid tert-butyl ester (Example 044) by treatment with TFA in CH^Cb according to the general procedure P. Obtained as a light green soUd (95 mg).
MS (EI) 456 (M*)-, mp 225 "C.
Example 59
8-(4-Fluoro-phenyl)-4-(3-imidazoI-l-yl-phenyl)-7-(2-oxo-oxazolidin-3-yI)-l,3-tiihydro-benzo [b] [ 1,4] diazepin- 2 -one
Prepared from [4"-fluoro-5"[3-(3-imida2ol-l-yl-phenyl)-3-oxo-propionyIamino]-2-(2-oxo-oxazolidin-3-yl)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example 045) by treatment with TFA in CH2CI2 according to the genera! procedure P. Obtained as a yellow solid 135 mg).
MS (EI) 481 (M""); mp 230 "C

Example 60
8-{4-F!uoro-2-methyl-phenyl)-4-(3-JmidazoI-l-yI-phenyl)-7-mcthoxy-l,3-dihydro-benzo[b] [ 1,4] diazepin-2-one
Prepared from {4"-fluoro-5-[3-(3-imJdazo!-l-yI-phenyI)-3-oxo-propionyiamino]-2-methoxy-2"-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 046) by treatment with TEA in CHjCl; according to the general procedure P. Obtained as a beige solid (101 mg).
MS (EI) 440 (NT); mp 225 °C.
Example 61
8-(4-Fluoro-phenyl)-7-hydroxy-4-(3-iinidazol-l-yl-phenyl)-l,3-dihydro-benzofb] [ 1,4] diazepin-2-one
Prepared from {2-Iert.-butoxy-4"-fiuoro-5-[3-(3-imida2oI-l-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yI}-carbainic acid terL-butyl ester (Example 047) by treatment vrith TFA in CH2Ci2 according to the general procedure P. Obtained as a yellow solid (109 mg).
MS(EI)412(M^);mp250X.
Example 62
8-(2-FIuoro-phenyl)-7-hydroxy-4-(3-imida2ol-l-yl-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from l2-tert.-butoxy-2"-fluoro-5-[3-(3-imidazol-l-yI-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 048) by treatment with TFA in CH2CI2 according to the general procedure P. Obteined as a yellow solid (132 mg).
MS (EI) 412 (M"); mp 220 "C.
Example 63
8-(4-Fl.uoro-phenyl)-7-((R)-3-hydroxy-pyrrolidin-l-yl)-4-(3-imidazol-l-yl-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one

Prepared from{RS)-{4"-fluoro-5-[3-{3-imidazol-l-yl-phenyl)-3-oxo-propionylammo]-2-[{R)-3-(tetrahydro-pyran-2-yIoxy)-pyrrolidin-l-y]]"biphenyI-4-yI}-carbamicacidtert.-butyl ester (Example 049) by treatment ■with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid {74 mg).
MS (EI) 481 (M^); mp 155-158 °C.
Example 64
8-(2-Fluoro-phenyl)-4-(3-imida2ol-l-yl-phenyl)-7-methoxy-l,3-dihydro-ben2o[b] [l,4]diazepin-2-one
Prepared from {2"-fluoro-5-[3-(3-imidazol-l-yI-phenyI}-3-oxo-propionylamino]-2-methoxy-bJphenyl-4-yl}-carbamic add tert.-butyl ester (Example 050} by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (68 mg).
MS (EI) 426 (M""); mp 216 "C (dec).
Example 65
3-[7-(4-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dJhydro-3H-benzoEb][l,4]dia2epin-2-yl]-benzonitrile
Prepared from {2-tert.-butoxy-5- [3-(3-cyano-phenyl)-3-oxo-propionylamino]-4"-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 051) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (66 mg).
MS (EI) 371 (M^); mp >250 "C
Example 66
3-[7-(2-FluorD-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-ben2o[b]U.4ldiazepin-2-yl]-benzonitrile
Prepared from {2-tert.-butoxy-5-[3-(3-cyano-phenyl)-3-oxo-propiony!araino]-2"-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example 052) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (80 mg).
MS (EI) 371 (M""); mp >250 "C.

Example 67
3-[7-(2-Fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from {5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2"-£luoro-2-methoxy-biphenyl-4-yl)-carbamic add tert.-buty! ester (Example 053) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (51 mg).
MS (EI) 385 (M"^); mp 245-247 °C.
Example 68
8-(2-Fluoro-pheny!)-7-methoxy-4-[3-(2-methyl-imida2ol-l-yl)-phenyl]-l,3-dihydro-benzo[b] [ 1,4] diazepin-2-one
Prepared from (2"-fluoro-2-methoxy-5-t3-[3-(2-methyl-iinida2ol-l-yl)-phenyl]-3-oxo-propionylamino}-biphenyI-4-yl)-carbamic acid tert.-butyl ester (Example 054) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (207 mg).
MS (EI) 440 (M*)i mp 220-222 "C.
Example 69
5-[7-(2-Fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-thiophen e-2 - carbonitrile
Prepared from {5-[3-(5-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2"-fiuoro-2-methoxy-biphenyl-4-yil-carbamic acid tert.-butyl ester (Example 053) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (103 mg).
MS (EI) 391 (M^); mp >250 °C.
Example 70
8-(2-Fluoro-phenyl)-7-methoxy-4-(3-[l,2,4]triazol-4-yl-phenyl)-l,3-dihydro-ben2o[bl [ l,4ldiazepin-2-one
Prepared from {2"-fiuoro-2-methoxy-5-[3-oxo-3-(3-[l,2,4]triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 056) by

treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (22 mg).
MS (EI) 427 (M*); mp 188 "C (dec).
Example 71
4-[7-(2-Fluoro-phenyl)-8-metho3cy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yI]-pyTidine-2-carb onitrile
Prepared from {5-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2"-Suoro-2-methoxy-biphenyl-4-yli-carbamic add tert.-butyl ester (Example 057) by treatment with TFA in, CH2CI2 according to the general procedure P. Obtained as a yellow solid (68 mg).
MS CEI) 386 (M*); mp 240-242 °C.
Example 72
8-(4-Fluoro-phenyi)-7-hydroxy-4-[3-{2-methyl-imida2ol-l-yI)-phenyI]-l,3-dihydro-benzo[b][l,4ldiazepin-2-one
Prepared from {2-tert.-butoxy-4"-fluoro-5-13-[3-(2-methyl-imidazol-l-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example 058) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow soHd (49 mg).
MS (ISP) 427 [(M+H)^]; mp 260 °C.
Example 73
4-Fluoro-3-[7-(2-fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from {5-[3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2"-fluoro-2-methoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 059) by treatment with TFA in CH2C12 according to the general procedure P. Obtained as a yellow solid (52 mg).
MS (ISP) 404 [(M+H)*l; mp >250 "C.

Example 74
4-[7-(4-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yI]-pyridine-2- carbonitriie
Prepared from {2-tert.-butoxy-5-[3-{2-cyano-pyridin-4-y])-3-oxo-propionylamino]-4"-fluoro-biphenyI-4-yl}-carbamic acid tert.-butyl ester (Example O60) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (24 mg).
MS (EI) 372 (M^); mp 164 "C.
Example 75
8-(2-Fluoro-phenyl)-7-hydroxy-4-(3-[l,2,3ltria2ol-l-yl-phenyl)-l,3-dihydro-benzo[b][l,4]dia2epin-2-one
Prepared from {2-tert.-butQj:y-2"-fLuoro-5-[3-oxo-3-(3-ll,23]triazol-l-yi-phenyI)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example 061) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (61 mg).
MS (ISP) 414 [(M+H)""]; mp >250 ""C.
Example 76
3-[8-(l,4-Dioxa-8-a2a-spiro[4.5]dec-8-yl)-7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-ben2o[b][l,4]dia2epin-2-yl]-benzonitrile
Prepared from [5-[3-(3-cyano-phenyl)-3-oxo-prapionylamino]-2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2"-fluoro-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example 062) by treatment with TFA in CH2Ci2 according to the genera! procedure P. Obtained as a yellow solid (132 mg).
MS (ISP) 497 [(M+H)^}; mp 253 °C.
Exa.mple 77
7-(l,4-Dioxa-8-a2a-spiro[4.5]dec-8-">d)-8-(2-fluoro-phenyl)-4-(3-imida2ol-l-)d-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from {2-(l,4-dioxa-8-aza-spiro[4.5]dec-8->^)-2"-fluoro-5-[3-(3-imidazo]-l-yl-phenyI)-3-oxo-propionylaraino]-biphenyl-4-yI}-carbamic acid tert.-butyl ester (Example

063) by treatment with TFA in CHjCl; according to the general procedure P. Obtained as a yellow solid (133 mg).
MS (ISP) 538 [(M+H)""]; mp 225 "C.
Example 78
8-(2-Fluoro-phenyl)-4-(3-iniida2ol-l-yI-phenyl)-7-(4-oxo-piperidin-l-yl)-l,3-dihydro-ben2o^b^ U ,4^ dia2epin-2-one
Prepared from 7-(l,4-dioKa-8-aza-spiro[4.5]dec-8-yl)-8-(2-fluoro-phenyl)-4-(3-imidazoI-l-yl-phenyl)-l,3-dihydTO-benzo[b] [l,4]diazepin-2-one (Example 77) (54 mg, 0.1 mmol) by stirring in IN HCl (1 mL) and acetone (1 mL) at 23 "C for 44 h. Obtained as a yellow solid (39 mg).
MS (EI) 493 (M"^); mp 230 "C.
Example 79
8-(2-Fluoro-phenyl)-7-hydrOxy-4-[3-(2-methy]-imidazol-l-yl)-phenyl]-l,3-dihydro-benzo[b][l,4]dia2epin-2-one
Prepared from (2-tert.-butoxy-2"-fluoro-5-{3-[3-(2-methyl-imidazol-l-yl)-phenyl]-3-oxo-propionylaraino}-biphenyl-4-yI)-carbamic acid tert-butyl ester (Example 064) by treatment with TFA in CHiCl; according to the general procedure P. Obtained as a yellow solid (111 mg).
MS aS^i^) 425 UM-Hy V, mp >230"C.
Example 80
4-[7-(2-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]dia2epin-2-yIl-pyridine-2-carbonitiile
Prepared from {2-tert.-butoSy-5-[3-(2-cyano-pyTidin-4-yl)-3"OXo-propionylamino]-2"-fluoro-biphenyi-4-yi}-carbamic add terL-butyl ester (Example 065) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (47 mg).
MS (ISN) 371 [(M-H)-); mp >250 *=C.

Example 81
8-(2-Fluoro-phenyI)-7-hydroxy-4-[3-(2-methylsuIfanyI-imidazol-l-yl)-phenj^]-l,3-dihydro-benzo[b][l,4]diazepm-2-one
Prepared from (2-tert.-butoxy-2"-fluoro-5-{3-[3-(2-methylsulfanyl-imidazoi-l-yl)-phenyl]-3-oxo-propionylammo}-biphenyl-4-yl)-carbamic add tert.-butyl ester (Example 066) by treatment with TFA in CH2C12 according to the general procedure P. Obtained as a light yellow solid {148 mg).
MS (ISN) 457 [(M-H)-]; mp >250 °C.
Example 82
3-[7-(2,5-Difluoro-phenyI)-8-methoxy-4-oxo-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl]-ben20nitrile
Prepared &om |5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2",5"-difluoro-2-methoxy-biphenyl-4-yIl-carbamic acid tert.-butyl ester (Example 067) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow soUd (49 mg)-
MS (EI) 403 (M^); mp 251 °C.
Example 83
8-(2,5-Difluoro-phenyl)-7-methoxy-4-(3-[l,2,3]triazol-l-yl-phenyI)-l,3-dihydro-benzo[b][l,4]diazepin-2-one
Prepared from {2",5"-difluoro-2-methoxy-5-[3-oxo-3-(3-[l,2,3]tria2oI-l-yl-phenyl)-propionylamino]-biphenyl-4-yl}-c2rbamic acid tert.-butyl ester (Example 058) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (78 mg).
MS (EI) 445 (M*); mp 241 X.
Example 84
2-l7-(2-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-lH-benzo[bj[l,4]dia2epin-2-yl]-thiophene-3-carbonitrile

Prepared from |2-tert.-butoxy-5-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2"-fluoro-biphenyl-4-yl)-carbamic add lert-butyl ester (Example 069) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as an orange solid (82 mg).
MS (ISN) 376 [(M-H)-]; mp 242 °C.
Example 85
5-[7-(2-Fluoro-phenyI)-8-hydroxy-4-oxo-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yl]-thiophene-2-carbonitrile
Prepared from {2-tert.-butoxy-5-[3-(5-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2"-fiuoro-biphen}d-4-yl}-carbamic acid tert.-butyl ester (Example O70) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (126 mg).
MS (EI) 377 (M"*"); mp.
Example 86
8-(4-FIuoro-phen)d)-7-hydroxy-4-(3-[l,2,3]triazol-l-yl-phenyl)-l,3-dihydro-benzo[b] [ 1,4] diazepin-2-one
Prepared from {2-tert.-butoxy-4"-fluoro-5-[3-oxo-3-(3-[I,2,3]triazol-l-yl-phenyl)-propionylamino]-bipheny]-4-yll-carbamic acid tert.-butyl ester (Example 071) by treatment with TFA in CH2CI2 according to the general procedure P. Obtainedas 2 yellow solid (78 mg).
MS (ISP) 414 [(M+H)*]; mp >250 "C.
Example 87
3-[7-(2-Fluoro-phenyl)-8-(2-methoxy-ethoxy)-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2->dj-benzonitrile
Prepared from [5-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2"-fluoro-2-(2-methoxy-ethoxy)-biphenyI-4-yI] -carbamic acid tert.-butyl ester (Example 072) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a light yellow solid (141 mg).
MS (EI) 429 (M^); mp 211-213 "C.

Example 88
3-[7-{2-Fluoro-phenyl)-8-hydroxymethyl-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-benzonitrile
Prepared from CRS)-[5-[3-{3-cyano-phenyI)-3-oxo-propionylamino]-2"-fluoro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyI-4-yI]-carbamic acid tert.-butyl ester (Example
073) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as
a light yellow solid (69 mg).
MS (EI) 385 (M""); mp 90-91 "C.
Example 89
8-(2-FIuoro-pheny])-7-hydroxy-4-[3-(3-methyl-isoxazol-5-yl)-phenyI]-l,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
Prepared from (2"-fluoro-2-(4-methoxy-benz}doxy)-5-{3-[3-(3-metbyl-isoxazol-5-yI)-phenyl]-3-oxo-propionyiainino}-biphenyI-4-yl)-carbamic acid tert.-butyl ester (Example
074) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as
a yellow solid (278 mg).
MS (ISP) 428 (M+H)*; mp 237 "C.
Example 90
3-[7-(2,5-DiQuoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-ylj-benzonitrile
Prepared from {2-tert.-butoxy-5-[3-(3-cyano-phenyI)-3-oxo-propionylamino]-2",5"-difluoro-biphenyl-4-ylJ-carbamic acid tert-"butyl ester (Example 075) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (56 mg).
MS (ISP) 390 (M+H)^; mp >250 "C.
Example 91
8-(4-FIuoro-phenylethynyl)-7-hydroxy-4-(3-imida2ol-l-yl-phenyl)-l,3-dihydro-ben2o[b] [l,4]diazepin-2-one
Prepared from {5-tert.-butoxy-4-(4-fluoro-phenyIethynyI)-2-[3-(3-imidazoI-l-yl-phenyl)-3-oxo-propionyIamino]-phenyl}-carbamic acid tert.-butyl ester (Example 076) by

treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow soBd (55 mg).
MS(EI)436(M^);mp247""C.
Example 92
8-(4-Fluoro-phenylethynyl)-7-hydroxy-4-C3-[l,2,3]triazol-l-yi-phenyI)-l,3-dihydro-benzo[b] [l,4]diazepin-2-one
Prepared from {5"tert.-butoxy-4-(4-fluoro-phenylethynyI)-2-[3-oxo-3-(3-[l,2,3]tria2oI-l-y]-phenyI)-propiony!amino]-phenyI}-carbamic acidtert.-butyl ester (Example 077) by treatment with TFA in CH2CI2 according to the general procedure P. Obtained as a yellow solid (56 mg).
MS (EI) 437 (M"*"); mp 243 *C.
The following examples exemplify, that the 4-aryl-8-iodo-l,3-dihydro-ben2o[b][l,4]diazepin-2-ones could also serve as starting material for the Sonogashira-coupling as illustrated in synthetic scheme G.
Example 93
3-(4-Oxo-7-phenylethynyl-8-thiomorpholin-4-yl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl)-benzonitrile
Prepared from 3-(7-iodo-4-oxo-8-thiQmorpholin-4-yl-4,5-dihydro-3H-ben2o[b][l,4]diazepin-2-yI)-ben2onitrile (Example 1) (437 mg, 0.895 mmol) and phenylacetylene (0.15 mL, 1.34 mmol) according to the general procedure K. Obtained as a curry solid (334 mg).
MS (EI) 391 (M""); mp 234-235 °C (dec).
Example 94
(RS)-3-[4-Oxo-8-(l-oxo-thiomorpholin-4-yl)-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-benzonitrile
A mixture of 3-(4-oxo-7-phenylethynyl-8-thiomo^phoIi^-4-yl-4,5-dihyd^o-3H-ben2o[b] [l,4]diazepin-2-yl)-benzonitrile (Example 27) (50 mg, 0.180 mmol) and Davis-

reagent (116 mg, 0.432 mmo!) in DCM (4.5 mL) was stirred at 23 "C for 1 h. The product was filtered off and washed with DCM. Obt^ned as a light yellow solid (16 mg).
MS (ISP) 479 [(M+H)1 and 501 [(M+Na)^]; mp >250 "C (dec).
Palladium-catalyzed carbonyiation of the 4-(3-iodophenyl)-8-phenylethynyl-l,3-dihydro-ben2o[b][l,4]dia2epin-2-onein the presence of secondary amines leads directly to the corresponding amides as shown in synthetic scheme I.
Example 95
3-[S-(2-Methoxy-ethoxy)-4-oxo-7-phenyIethynyl-4,5-dihydro-3H-ben2o[b][l,4]dia2epin-2-yl]-benzamide
Prepared from 4-(3-iodo-phenyl)-7-(2-methoxy-ethoxy)-8-phenylethynyM,3-dihydro-benzo[b][l,4ldiazepin-2-one (Example 25) (268 mg, 0.5 mmol) and hexamethyldisilazane (0.52 mL, 2.5 mmol) according to the general procedure Q. Obtained as a yeUow solid (102 mg).
MS (EI) 453 (M""); mp 227-230 "C (dec).
Example I
Tablets of the following composition are produced in a conventional manner;
mg/Tablet
Active ingredient 100
Powdered, lactose 95
White com starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Example II
Tablets of the following composition are produced in a conventional manner

mg/Tablet
Active ingredient 200
Powdered. lactose 100
White corn starch 64
PolyvinyipyrroUdone 12
Na carboxymethylstarch 20
Magnesium stearate _4
Tablet weight 400
Example III
Capsules of the following composition are produced:
mg/Capsule
Active ingredient 50
Crystalline, lactose 60
Microcrystalline cellulose 34
Talc 5
Magnesium stearate 1
Capsule fill weight 150
The active ingredient having a suitable particle size, the crystalline laaose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.



WE CLAIM:
1. Compounds of general formula

wherein
X is a single bond or an ethynediyi group, wherein,
In case X is a single bond,
R^ is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower aikyl, lower alkoxy, halo-lower alkoxy, or cyano;
In case X is an ethynediyi group,
R" is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy,
R^ is halogen; hydroxy, lower alkyl; lower halo-aUcyl; lower alkoxy; hydroxymethyl; hydroxyethoxy; lower alkoxy-(ethoxy)n (n = 1 to 4); lower alkoxymethyl; cyanomethoxy; morphoIine-4-yI; thiomorpholine-4-yI; l-oxothiomorpholine-4-yI; 1,1-dioKothiomorpholine-4-yl;4-oxo-piperidine-l-yl;4-alkoxy-piperidine-L-yli4-hydroxy-piperidine-l-yl; 4-hydroxyethoxy-piperidine-l-yl; 4-lower alkyl-piperazine-l-yl; alkoxycarbonyl; 2-diaIkylamino-ethylsulfanyl-; N,N-bis lower alkylamino lower alkyl; carbamoylmethyl; alkylsulfonyl; lower alkoxycarbonyl-lower alkyl; alkylcarboxy-lower alkyl; carboxy-Iower alkyl; alkoxycarbonylmethylsulfanyl; carboxymethylsulfanyl; 1,4-dioxa-8-aza-spiro|4.5]dec-8-yl; carboxy-Iower alkoxy; cyano-lower alkyl; 2,3-dihydroxy-lower alkoxy; carbanioylmethoxy,2-oxo-[l,3]-dioxoIan-4-yl-lower alkoxy (2-hydroxy-lower alkyl)-lower alkyl amino; hydroxycarbamoyl-lower alkoxy, 2,2-dimethyl-tetrahydro-[l,3ldioxolo[4,5c]-pyrroI-5-yl; lower alkoxy-carbamoyl-lower alkoxy 3R-hydroxy-pyrroUdin-l-yl; 3,4-dihydroxy-pyrrolidin-l-yl; 2-oxo-oxazoIidin-3-yl; lower alkyl-carbamoylmethoxy, or aminocarbamoyl-lower alkoxy

R is a 5 or 6 membered aryl or heteroaryl which are optionally substituted by
halogen; cyano; nitre; azido; hydroxy; carboxy; morpholine-4-carbony]; carbamoyl; thiocarbamoyl; N-hydroxycarbamoyl; trimethylsilyl-ethynyl;
or lower alkyl; lower aJkoxy; halo-lower alkyl; 4-lower alkyl-piperazine-1 -carbonyl; lower alkylcarbamoyl which are optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated;
or an optionally substituted five-membered aromatic heterocycle, which may be optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated, or lower alkyl which is optionally substituted by halogen, amino, lower alkylamino, acylamino, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloaUcylsulfonyl, hydroxyimino, alkoxyimino, carboxy which is optionally esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyi which is optionally substituted by lower alkyl, or amidino which is optionally substituted by lower alkyl, -C(NRR")=NR" (where R, R" and R" are hydrogen or lower alk>d)
and their pharmaceuticaUy acceptable addition salts.
2. Compounds according to claim 1, wherein R^ is phenyl substituted in meta position by cyano; halogen; or imidazolyl which is optionally substituted by lower alky or methylsulfanyl; l,2,3-tria2olyI; l,2,4-tria2olyl; or isoxazolyl which is optionally substituted by lower alkyl.
3. Compounds according to claim 2, being 3-(8-Chloro-4-oxo-7-phenylethynyI-4,5-dihydro-3H-ben2o[b][l,4]diazepJn-2-yl)-benzonitrile; 3-[8-(4-Methyl-piperazin-l-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-
benzo [b] [ 1,4] diazepin-2-ylI -benzonitrile; 3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl)-
benzonitrite;
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo[b][l,4]diazepin-
7-ylsulfanyI]-acetic acid methyl ester;
2-[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-lH-benzo [b] [ 1,4] diazepin-7->i] -acetamide; 3-{8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]dia2epin-2-yl)-
benzonitrile;

3-(8-CyanomethyI-4-oxo-7-phenyIethynyI-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-
yl)-benzonitrile;
4-(3-Iodo-phenyl)-7-(2-methoxy-ethoxy)-8-phenylethyiiyl-l,3-dihydrD-
benzo[b][l,4jdia2epin-2-one;
4-(3-linida2ol-l-yl-phenyl)-7-(2-methoxy-ethoxy)-8-phenylethynyl-l,3-dihydro-
ben2o[b][l,4]dia2epin-2-one;
[RS]-3-[4-Oxo-8-C2-oxo-[l,3]dioxolan-4-ylmelhoxy)-7-phenylethynyl-4,5-dihydro-
3H-benzo[b]{l,4]diazepin-2-yl]-benzomtrile;
7-Hydroxymethyl-4-(3-imidazoM-y]-phenyl)-8-phenylethynyl-l,3-dihydro-
benzo[b][l,4]diazepin-2-one;
[4-(3-Imidazol-l-y!-phenyl)-2-oxo-8-phenyiethynyl-2,3-dihydro-lH-
benzo[b][l,4]diazepin-7-yloxy]-acetonitrUe;
8-(4-Fluoro-phenylethyny!)-7-hydroxyinethyI-4-(3-imidazol-l-yI-phenyI)-l,3-
dihydro-benzo[bl[l,4]diazepin-2-one;
7-(2-Hydroxy-ethoxy)-4-{3-imidazol-l-yI-phenyl)-8-phenylethynyl-1.3-diliy benzo[b][l,4]diazepin-2-one;
8-(4-Fluoro-phenyl)-7-[4-{2-hydroxy-ethoxy)-piperidin-l-yl]-4-{3-iimdazol-l-yl-
pbenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one;
8-C4-FIuoro-phenyI)-7-hydroxy-4-(3-imid3zol-l-yl-phenyl)-l,3-dihydro-
benzo[b][l,4]diazepm-2-one;
8-(2-Fluoro-phenyl)-7-methoxy-4-[3-(2-methyl-imidazol-l-yl)-phenyl]-lf3-dihydro-
benzo[b][l,4]diazepin-2-one;
8-(2-Fluoro-pheny!)-7-hydroxy-4-(3-U,2,3]triazol-l-yI-phenyl)-l,3-dihydro-
benzo[b][l,4]dia2epin-2-one;
8-(2-Fluoro-phenyl)-7-hydroxy-4-[3-(2-methyl-iinida2ol-l-yl)-phenylj-l,3-dihydro-
benzo [b] [ 1,4] diazepin-2-one; 8-(2-Fluoro-phenyl)-7-hydroxy-4-[3-(2-inethylsulfenyl-imidazol-l-yl)-phenyl]-l,3-
dihydro-benzo[b] [ l,4]diazepin-2-one;
8-(2,5-Difluoro-pheny])-7-methoxy-4-(3-[l,2,3]tTia2o!-l-yI-phenyl)-l,3-dihydro-benzo[b][l,4]diazepin-2-one; 8-(2-Fluoro-phenyI)-7-hydroxy-4-[3-(3-methy!-isoxazol-5-yI)-phenyl]-l,3-dihydro-
benzo [b] [ 1,4] dja2epin-2-one; 3-[7-(2,5-Difluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1.4]diazepin-
2-yl] -benzonitrile;
8-(4-Fluoro-phenyIethynyl)-7-hydroxy-4-{3-imida2ol-l-yl-phenyl)-l,3-dihydro-
benzo[b][l,4]diazepin-2-one;and

8-(4-Fluoro-phenyIethyn)d)-7-hydroxy-4-(3-[l,23]tria2oI-l-yl-phen)1)-l,3-d:hydro-benzo[b][l,4]dtazepin-2-one.
4. Compounds according to claim 1, wherein R^ is thiophenyl, optionally substituted by
cyano or halogen; pyridinjd, optionally substituted in 2-position by cyano or halogen,
or thiazolyl, optionally substituted in 2-position with imidazolyl or 4-
meth>dim idazol)d.
5. Compounds according to claim 4, being
5-l7-(2-Fluoro-phenyl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[bl[l,4]diazepin-2-
jd] -thiophcne-2-carbonitrile;
2-[7-(2-Fluoro-phenyl)-8-hydroxy-4-oxo-4,5-dihydro-lH-benzo[b][l,4]diazepin-2-yl]-thiophene-3-carbonitri]e;
4-[7-(2-Fluoro-phen)4)-8-methoxy-4-oxo-4^-dihydro-3H-benzo[b][l,4]dia2epin-2-yl] -pyridine-2-carbonitrile;
4-l7-{4-Fluoro-phen>d)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-pyridine-2-carbonitrile;
4-[7-(2-Fluoro-phcnyl)-8-hydroxy-4-oxo-43-dihydro-3H-benzo[b][l,4]diazepin-2-yl]-pyridine-2-carbonitrile; and
8-{2-Fluoro-phenyl)-4-[2-(4-methyl-imida2ol-l-yl)-thiazol-4-yl]-l,3-dihydro-benzo[b] ll,4]diazepin-2-one.
6. A medicament containing one or more compounds of any one of claims 1 to 5 and
pharmaceutically acceptable exdpients.
■J A process for preparing compounds of formula I as defined in claim 1, vdiich process comprises reacting a compound of formula II

with a compound of formula IV or IVa


which subsequently undergoes deprotection of the amino group and cyclization, to obtain a compound of formula I of daim 1.
8. A compound according to any one of claims 1 to 5, \\^enever prepared by a process as claimed in claim
g Compounds of general formula substantially as herein above described.

Documents:

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in-pct-2002-0519-che abstract.pdf

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in-pct-2002-0519-che claims.pdf

in-pct-2002-0519-che correspondnece-others.pdf

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Patent Number 202434
Indian Patent Application Number IN/PCT/2002/519/CHE
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 03-Oct-2006
Date of Filing 10-Apr-2002
Name of Patentee M/S. F HOFFMANN-LA ROCHE AG
Applicant Address 124 Grenzacherstrasse CH-4070 Basel
Inventors:
# Inventor's Name Inventor's Address
1 ADAM, Geo 8 Untere Staltenstrasse 79650 Schopfheim
2 ALANINE, Alexander 5, rue d'Altkirch F-68400 Riedisheim
3 GOETSCHI, Erwin 23 Landhofweg CH-4153 Reinach
4 MUTEL, Vincent 15, place des Marechaux F-68100 Mulhouse
5 WOLTERING, Thomas, Johannes 13 Riedlistrasse 79576 Weil am Rhein
PCT International Classification Number C07D 243/00
PCT International Application Number PCT/EP2000/009553
PCT International Filing date 2000-09-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 99120520.4 1999-10-15 EUROPEAN UNION