Benzodiazepine derivatives

专利摘要:
The present invention relates to compounds of formula (I) Formula I In the above formula X is a single bond or an ethynediyl group, wherein When X is a single bond, R < 1 > is halogen or phenyl optionally substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy or cyano; X is ethynyl-diyl group when, R 1 is halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy the optionally substituted by phenyl; R 3 is an optionally substituted 5-or 6-membered aryl or heteroaryl. The compounds according to the present invention may be used to treat or prevent acute and / or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia.
公开号:KR20020038954A
申请号:KR1020027004838
申请日:2000-09-29
公开日:2002-05-24
发明作者:아담게오；알라닌알렉산더；고에츠쉬어빈；뮤텔빈센트；볼터링토마스요하네스
申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Benzodiazepine Derivatives {BENZODIAZEPINE DERIVATIVES}
[10] Surprisingly, it has been found that the compounds of formula I are metabotropic glutamate receptor antagonists. The compounds of formula I are characterized by having useful therapeutic properties.
[11] In the central nervous system (CNS), the transmission of stimuli is caused by the interaction of the neurotransmitter released by the neuron with the neuroreceptor.
[12] L-Glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays an important role in many physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first major group forms ligand-regulated ion channels. The metabotropic glutamate receptor (mGluR) forms a second major group and also belongs to the G-protein-coupled receptor family.
[13] Currently, eight different mGluRs are known, some of which also have subtypes. Based on structural parameters, different effects on the synthesis of secondary metabolites, and different affinities with low molecular weight chemical compounds, these eight receptors can be subdivided into three sub-groups: mGluR1 and mGluR5, MGluR2 and mGluR3 belong to Group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III.
[14] Ligands of metabotropic glutamate receptors belonging to Group II can be used to treat or prevent acute and / or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia.
[15] Other treatable indications associated therewith include limited brain function by bypass operation or transplantation, poor blood supply to the brain, spinal cord injury, head injury, pregnancy induced hypoxia, cardiac arrest and hypoglycemia. Additional treatable indications include chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia induced by AIDS, eye damage, retinopathy, idiopathic parkinsonism or drug induced parkinsonism as well as glutamate- Such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
[1] The present invention relates to compounds of formula (I): < EMI ID =
[2]
[3] In this formula,
[4] X is a single bond or an ethynediyl group;
[5] R ¹ is phenyl or halogen optionally substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy or cyano when X is a single bond and X is an ethynyl group, Is phenyl optionally substituted by halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy;
[6] R ² is halogen; Hydroxy; Lower alkyl; Halo-lower alkyl; Lower alkoxy; Hydroxymethyl; Hydroxyethoxy; Lower alkoxy- (ethoxy) _n , wherein n is 1 to 4; Lower alkoxymethyl; Cyanomethoxy; Morpholin-4-yl; Thiomorpholin-4-yl; 1-oxothiomorpholin-4-yl; 1,1-dioxothiomorpholin-4-yl; 4-oxo-piperidin-1-yl; 4-alkoxy-piperidin-1-yl; 4-hydroxy-piperidin-1-yl; 4-hydroxyethoxy-piperidin-1-yl; 4-lower alkyl-piperazin-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] des-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 alkylamino; Hydroxycarbamoyl-lower alkoxy; 2,2-Dimethyl-tetrahydro- [1,3] dioxolo [4,5c] -pyrrol-5-yl; Lower alkoxy-carbamoyl-lower alkoxy; 3R-hydroxy-pyrrolidin-1-yl; 3,4-dihydroxy-pyrrolidin-1-yl; 2-oxo-oxazolidin-3-yl; Lower alkyl-carbamoylmethoxy; Or amino carbamoyl-lower alkoxy;
[7] R ³ is halogen; Cyano; Nitro; Azido; Hydroxy; Carboxy; Morpholine-4-carbonyl; Carbamoyl; Thiocarbamoyl; N-hydroxycarbamoyl; Trimethylsilyl-ethynyl;
[8] Lower alkyl; Lower alkoxy; Halo-lower alkyl; 4-lower alkyl-piperazine-1-carbonyl; Lower alkylaminocarbonyl which are substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio or carboxy which is optionally esterified or amidated; or
[9] (Which is optionally esterified or amidated), lower alkyl (which may be substituted by halogen, amino, lower alkylamino, acylamino, hydrocarbyl, amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, Lower alkyl, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkoxyimino, carboxy which optionally esterifies Lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl (which is optionally substituted by lower alkyl), amidino (which is optionally substituted by lower alkyl), or -C (NRR ') = NR " (where R, R' and R " are hydrogen or lower alkyl), with an optionally substituted five membered aromatic heterocycle Optionally a 5 or 6 membered aryl or heteroaryl substituted.
[16] The subject of the present invention is also the compounds of formula I and their pharmaceutically acceptable salts themselves and the above compounds as pharmaceutically active substances, processes for their preparation, medicaments based on the compounds according to the invention and their preparation, The use of the compounds according to the invention for controlling or preventing diseases of the kind and for preparing the corresponding medicaments.
[17] Preferred compounds of formula I are those, wherein R < ³ > is phenyl substituted at the meta position by cyano; halogen; Imidazolyl optionally substituted by lower alkyl or methylsulfanyl; 1,2,3-triazolyl; 1,2,4-triazolyl; Or isoxazolyl optionally substituted by lower alkyl.
[18] Examples of such compounds are:
[19] 3- (8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
[20] Dihydro-3H-benzo [b] [1,4] diazepin-2 < RTI ID = 0.0 & -Yl) -benzonitrile; < / RTI >
[21] 3- (8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
[22] Benzo [b] [1,4] diazepin-7-ylsulfanyl] - (2-oxo-phenyl) Acetic acid methyl ester;
[23] Benzo [b] [1,4] diazepin-7-yl] - (2-oxo-phenyl) Acetamide;
[24] 3- (8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
[25] 3- (8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
[26] Dihydro-benzo [b] [1,4] diazepin-2- (2-methoxy-ethoxy) On;
[27] Dihydro-benzo [b] [1,4] diazo [3,4-d] pyrimidin- 2-one;
[28] [RS] -3- [4-oxo-8- (2-oxo- [1,3] dioxolan-4-ylmethoxy) -7-phenylethynyl-4,5-dihydro-3H-benzo [ ] [1,4] diazepin-2-yl] -benzonitrile;
[29] 7-Hydroxymethyl-4- (3-imidazol-1-yl-phenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one;
[30] Benzo [b] [1,4] diazepin-7-yloxy [l, 4-diazepin- Hour] - acetonitrile;
[31] Benzo [b] [1,4] oxazepin-1-yl) -piperazin-1- Diazepin-2-one;
[32] Phenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazo [ 2-one;
[33] 4- (3-imidazol-1 -yl-phenyl) - (4-fluoro-phenyl) 1,3-Dihydro-benzo [b] [1,4] diazepin-2-one;
[34] Phenyl] -l, 3-dihydro-benzo [b] [1,4] diazepin- 2-one;
[35] Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro-imidazol- , 4] diazepin-2-one;
[36] Synthesis of 8- (2-fluoro-phenyl) -7-hydroxy-4- (3- [ [1, 4] diazepin-2-one;
[37] Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one;
[38] Phenyl] -l, 3-dihydro-benzo [b] thiophene- [1, 4] diazepin-2-one;
[39] Phenyl) -l, 3-dihydro-benzo [l, b] [1,4] diazepin-2-one;
[40] Phenyl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one;
[41] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Benzonitrile;
[42] Dihydro-benzo [b] [1,4] diaza-benzo [b] thiophene- 2-one; And
[43] Synthesis of 8- (4-fluoro-phenylethynyl) -7-hydroxy-4- (3- [1,2,3] triazol- 1 -yl-phenyl) -1,3-dihydro-benzo [b ] [L, 4] diazepin-2-one.
[44] R ³ is thiophenyl optionally substituted by cyano or halogen, preferably thiophen-2-yl; Pyridinyl optionally substituted by cyano or halogen at the 2-position, preferably pyridin-4-yl; Or is thiazolyl optionally substituted by imidazolyl or 4-methylimidazolyl at the 2-position.
[45] Examples of such compounds are:
[46] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro-thiophene Octene-2-carbonitrile;
[47] Dihydro-1H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro- 3-carbonitrile;
[48] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile;
[49] Benzo [b] [1, 4] diazepin-2-yl] -pyridine < EMI ID = -2-carbonitrile;
[50] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile; And
[51] 4-yl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one.
[52] All tautomeric forms of the compounds of the present invention are also encompassed by the present invention.
[53] The term " lower alkyl " as used herein refers to straight or branched chain saturated hydrocarbon moieties having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
[54] The term " lower cycloalkyl " as used herein refers to cyclic saturated hydrocarbon residues of 3 to 5 carbon atoms, preferably 3 carbon atoms, such as cyclopropyl.
[55] The term " lower alkoxy " means a lower alkyl moiety of the above defined meaning attached through an oxygen atom.
[56] The term " halogen " includes fluorine, chlorine, bromine and iodine.
[57] The term " 5 or 6 membered aryl or heteroaryl " includes phenyl, thiophenyl, pyridine, partially hydrated pyridine.
[58] The term " 5-membered aromatic heterocycle " refers to furan, thiazole, imidazole, pyrazole, 1,3-thiazole, 1,3-oxazole, 1,2-oxazole, , 2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,4-thiadiazole, 1,2 , 3-thiadiazole and tetrazole.
[59] The compounds of formula (I) and their pharmaceutically acceptable salts can be prepared according to the following process:
[60]
[61] According to Scheme A above, compounds of formula (I) wherein X, R ¹ , R ² and R ³ are as described above can be prepared by successive acylation-deprotection-cyclization of compounds of formula II.
[62] For example, a compound of formula II is reacted with a dioxinone (IV) (wherein R ³ is as defined above) in an inert solvent such as toluene or xylene at elevated temperature, preferably 80 to 160 ° C, III < / RTI >
[63] Alternatively, the compound of formula III is reacted with a -Keto ester (formula IVa), wherein R ³ is as defined above, using the same conditions as described for the reaction of the compound of formula II with the dioxane .
[64] The desired compound of formula I is then obtained by partitioning the BOC protecting group in the compound of formula III while at the same time cyclising the deprotected compound. In place of the BOC group, any other suitable amino compound such as Fmoc or benzyloxycarbonyl (Z) may alternatively be used.
[65] The deprotection-cyclization step can be carried out by treating the compound of formula III with a Bronsted acid such as trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane (DCM). The reaction is preferably carried out at a temperature between 0 and 50 < 0 > C. It may also be advantageous to use anisole or 1,3-dimethoxybenzene as the carbocation eliminator in the reaction mixture.
[66]
[67] In accordance with the reaction scheme B, R ¹ is, same as the X is described above for the compounds of the case where a single bond, compounds of the same formula III described R ² is described above, by the different routes depending on the nature of R ¹ formula V Of a iodo compound of formula (I) wherein R < ² > is as described above. As shown in Scheme B above, the main step is Suzuki-type and Stille-type coupling reactions in the presence or absence of carbon monoxide. Suitable conditions for each compound of formula II can be found in the experimental part.
[68] The compound of formula V, wherein R ² is as defined above, may be prepared by different routes according to the individual residues R ² .
[69]
[70] As shown in Scheme C above, the compound of formula Va, wherein R < ² > is lower alkyl, halogen or alkoxycarbonyl, may be prepared by the iodination and subsequent protection of synthetic intermediates using compounds of formula XII, ≪ / RTI >
[71] The iodination step can be carried out, for example, by using iodine monochloride in acetic acid in the presence of sodium acetate. The reaction can be carried out, for example, at 20 to 80 占 폚.
[72] Protection of the amino functional group can be accomplished, for example, by reacting the compound of formula XII with di-tert-butyl-carbonate in the presence of a base such as cesium carbonate. The reaction may be carried out in a polar solvent (e.g., acetate or butanone) at 20 to 60 < 0 > C.
[73] As shown in Scheme D, R ² (which is, for example, morpholin-4-yl, thiomorpholino-4-yl, dialkylamino, carboxymethylsulfanyl etc.) is attached via a sulfur atom or a nitrogen atom to a compound of formula Vb And Vc can be prepared from intermediate (XIII) by a nucleophilic substitution reaction with each amine or mercaptan, respectively, in the presence of a suitable base.
[74]
[75] The reaction is preferably carried out in a polar aprotic solvent such as dimethylformamide, N-methyl-pyrrolidone or dimethylsulfoxide. The base may be selected from sterically hindered amines (e.g. Hunig's base), alkoxides (e.g. sodium methoxide and t-butoxide) or hydrides (such as sodium hydride). The reaction may be carried out at from 20 to 110 캜, depending on the individual compounds to be synthesized.
[76] Compounds of formula Vd in which R < ² > is attached via an oxygen atom, such as, for example, lower alkoxy, lower halo-alkoxy, lower cycloalkoxy, lower alkoxy-lower alkoxy etc. may be prepared, have:
[77]
[78] The reaction can be carried out by nucleophilic aromatic substitution reaction with each alcohol in the presence of a suitable base and subsequent protection of the amino functional group. The base may be selected from the group of Bronsted bases (e.g., potassium hydroxide, etc.). The reaction is preferably carried out in a polar aprotic solvent (for example, dimethylformamide, N-methyl-pyrrolidone or dimethylsulfoxide) at 20 to 100 ° C.
[79] Protection of the amino functional group can be accomplished by reacting the compound of formula XV with di-tert-butoxycarbonate in the presence of a base, such as cesium carbonate. The reaction can be carried out in a polar solvent such as acetone or butanone at 20 to 60 < 0 > C.
[80] Another way to achieve this protection step is to first convert the amino group in the compound of formula XV to an isocyanate by reaction with a phosgene or phosgene analogue in the presence of a suitable base and then treat with tert- Lt; RTI ID = 0.0 > Vd. ≪ / RTI >
[81] Another suitable method for achieving such a protection step is by first reacting the amino group in the compound of formula XV with an excess of di-tert-butoxycarbonate in the presence of 4-dimethylaminopyridine (DMAP) Boc compound, followed by treatment with 2 equivalents of dichloromethane to obtain the desired compound of formula Vd.
[82] The reverse step of performing the nucleophilic aromatic substitution on the primary intermediate (XIV), followed by the protection of the amino-functional group, as shown in the reverse step of the above steps, ie, as shown in Synthetic Scheme E, Vc < / RTI > (Synthetic Scheme D).
[83] Another method of preparing a compound of formula Vd is to carry out a de-allylation-alkylation sequential reaction as outlined in Scheme E using an O-allyl compound (XIX). De-allylation is, for example, rhodium (I) - salt: - the salt _{[(PPh 3) 2 RdCl 2} )]) ( for example, Wilkinson's catalyst (Wilkinson's catalyst) [(PPh 3) 3 RhCl)]) or palladium (II) Lt; RTI ID = 0.0 > hydrolysis < / RTI > of the resulting vinyl ether. An example of such a procedure can be found in " J. Org. Chem . 1973 , 38, 3224 ". Alkylation of phenols (XX) with the desired formula Vd is carried out in the presence of a base in the presence of a base in the presence of an electrophilic reagent of formula RX, wherein R is lower alkyl, lower alkenyl, alkyl acetate or benzyl, Which may be a leaving group. The reaction is preferably carried out in a polar aprotic solvent such as a chlorinated solvent (e.g. dichloromethane, chloroform or dichloroethane) or an amide (e.g. dimethylsulfoxide). The base may be a sterically hindered amine such as a cyclic base, an alkoxide such as sodium methoxide and tert-butoxide, a hydride such as sodium hydride, a hydroxide such as potassium hydroxide, Potassium carbonate) or hydrogencarbonate (e.g. potassium hydrogencarbonate). The reaction may be carried out at -20 to 80 캜, depending on the individual compound to be synthesized. In the synthesis of the O-tertiary-butyl compound of formula Vd, the phenol XX can be treated with DMF-di-tertiary in toluene or benzene at 80 ° C, as described in Synthesis 1983,135 .
[84]
[85] According to Scheme F above, compounds of the formula Ve and Vf wherein R < ² > is attached through a carbon atom, such as lower alkoxy-carbonyl-methyl, cyano-methyl and the like, are reacted with a malonic acid ester or a semi- (XIII or XIV) by reaction with an ester followed by removal of one of the alkyl carboxylates via decarboxylation. Suitable reaction conditions depend on the properties of the individual compounds and are described in the examples.
[86] The main intermediates (XIII and XIV) can be prepared as previously described in scheme C.
[87] For the 1 carbon-residue containing compounds of the formulas Vh to Vl, the synthesis starts from the known methyl 3-amino-4-nitrobenzoate. Standard iodination as described in Synthetic Scheme C yields iodide (XXI), which can be subsequently protected with a Boc- group. Reduction of the methyl ester can be carried out, for example, by treatment with lithium borohydride, sodium borohydride or diisobutylaluminum hydride in an aprotic solvent such as THF, ether or toluene. The presence of an alcohol (such as methanol, ethanol or isopropanol) can be beneficial. The reduction is preferably carried out at -20 to 0 占 폚. Following further functionalization, such as the conversion of the resulting benzylic alcohol (Vh) to chloride (Vk), follows standard procedures known to those skilled in the art. Suitable reaction conditions depend on the properties of the individual compounds and are described in the examples.
[88]
[89] This in accordance with the reaction formula G, R ^1, compounds of the same formula II described X is described above for a compound of case ethynyl-diyl group is, R from the ^first and iodo of formula V by the other path is also a compound according to the properties of the R ² Can be manufactured. As shown in Scheme G above, the modification can be carried out, for example,
[90] a) direct attachment of the R < ¹ > -alkindiyl-substituent via a Sonogashira-type coupling followed by reduction of the nitro group, or
[91] b) coupling of the trimethylsilyl-acetylene with the compound of formula V and deprotection with sodium hydroxide in methanol gives the intermediate (XVII), followed by reaction with the appropriate reactants R ¹ -I, R ¹ -Br or R ¹ Can be carried out by two-stage Sonogashira-type coupling which can be modified via a second Sonogashira-type coupling using -OSO ₂ CF ₃ and reduction of the nitro group to the desired compound.
[92] Suitable conditions for each compound can be found in the experimental part.
[93]
[94] According to Scheme H, respectively, formula IV and the non-deoxy and β- keto esters building blocks with the IVa (building block), the corresponding carboxylic acid derivative (R ³ -COR), i.e. methyl or ethyl esters and acid chlorides from the art Can be prepared by methods known to those skilled in the art. The exact conditions for the corresponding compounds can be found in the experimental part.
[95] Wherein R ¹ , R ² and X have the abovementioned meaning and R ³ is a carbamoide of the formula C (O) NR ⁴ R ⁵ wherein R ⁴ and R ⁵ are hydrogen or lower alkyl, Or a N-methyl-piperazine), is shown in Scheme I below.
[96]
[97] The exact conditions for each compound can be found in the experimental part.
[98] The pharmaceutically acceptable salts can be easily prepared in consideration of the properties of the compounds which are converted into the salts according to per se known methods. Examples of the basic compound of the formula (I) include inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p- Are suitable for the formation of pharmaceutically acceptable salts. The compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists and may be used to treat or prevent acute and / or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia . Other treatable signs include bypass surgery, limited brain function by transplantation, poor blood supply to the brain, spinal cord injury, head injury, pregnancy induced hypoxia, cardiac arrest and hypoglycemia. Additional treatable indications include chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia induced by AIDS, eye damage, retinopathy, idiopathic parkinsonism or drug induced parkinsonism as well as glutamate- Such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
[99] The compounds of formula I and their pharmaceutically acceptable salts can be used, for example, as pharmaceuticals in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, such as tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration may be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
[100] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules include, 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 typically required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose and the like. Excipients such as alcohols, polyols, glycerol, vegetable oils and the like can be used for the injectable aqueous solutions of the water-soluble salts of the compounds of formula I, but are usually not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.
[101] The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsions, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.
[102] As described above, medicaments containing one or more compounds of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically inert excipient are also objects of the present invention, and are useful for the treatment of one or more of the compounds of formula I, or a pharmaceutically acceptable salt thereof, It is also an object of the present invention to prepare such a medicament, including, if desired, converting one or more other therapeutically useful substances into a herbal dosage form together with one or more therapeutically inert carriers.
[103] The dosage can vary within wide limits, but will in each specific case meet the individual requirements. In general, the effective amount of oral or parenteral administration is 0.01 to 20 mg / kg body weight per day, and the preferred dosage for all the above-mentioned indications is 0.1 to 10 mg / kg body weight per day. Therefore, the daily dose of an adult of 70 kg body weight is 0.7 to 1400 mg / day, preferably 7 to 700 mg / day.
[104] The invention also relates to the use of compounds of formula I and their pharmaceutically acceptable salts, especially for the preparation of medicaments for the control and prevention of acute and / or chronic neurological disorders of the abovementioned kind.
[105] The compounds of the present invention exhibit activity of 50 μM or less, typically 3 μM or less, ideally 0.5 μM or less, as measured in the assay described below. In the table below, some specific pKi values of preferred compounds are described.
[106] compound Ki mGlu2 ([mu] M) Synthesis of 3- (8-chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin- 0.028 Dihydro-3H-benzo [b] [1,4] diazepin-2 < RTI ID = 0.0 & - yl) -benzonitrile 0.305 Benzo [b] [1,4] diazepin-2-yl) -benzonitrile < EMI ID = 0.120 Benzo [b] [1,4] diazepin-7-ylsulfanyl] - (2-oxo-phenyl) Acetic acid methyl ester 0.051 Benzo [b] [1,4] diazepin-7-yl] - (2-oxo-phenyl) Acetamide 0.037 Synthesis of 3- (8-methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin- 0.046 Synthesis of 3- (8-cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin- 0.016 Dihydro-benzo [b] [1,4] diazepin-2- (2-methoxy-ethoxy) On 0.021 Dihydro-benzo [b] [1,4] diazo [3,4-d] pyrimidin- Zepin-2-one 0.012 [RS] -3- [4-oxo-8- (2-oxo- [1,3] dioxolan-4-ylmethoxy) -7-phenylethynyl-4,5-dihydro-3H-benzo [ ] [1,4] diazepin-2-yl] -benzonitrile 0.035 Dihydro-benzo [b] [1, 4] diazepin-2-one < / RTI > 0.018 Benzo [b] [1,4] diazepin-7-yloxy [l, 4-diazepin- Hour] - acetonitrile 0.009
[107] compound Ki mGlu2 ([mu] M) Benzo [b] [1,4] oxazepin-1-yl) -piperazin-1- Diazepin-2-one 0.009 Phenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazo [ Zepin-2-one 0.032 4- (3-imidazol-1 -yl-phenyl) - (4-fluoro-phenyl) 1,3-Dihydro-benzo [b] [1,4] diazepin-2-one 0.100 Phenyl] -l, 3-dihydro-benzo [b] [1,4] diazepin- 2-on 0.007 Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro-imidazol- , 4] diazepin-2-one 0.138 Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro-thiophene Pentene-2-carbonitrile 0.168 Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile 0.033 Synthesis of 8- (2-fluoro-phenyl) -7-hydroxy-4- (3- [ [1,4] diazepin-2-one 0.028 Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one 0.108 Phenyl] -l, 3-dihydro-benzo [b] thiophene- [1,4] diazepin-2-one 0.021 Phenyl) -l, 3-dihydro-benzo [l, b] [l, 4] diazepin-2-one 0.012 Phenyl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one 0.015 Dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Benzonitrile 0.006 Dihydro-benzo [b] [1,4] diaza-benzo [b] thiophene- Zepin-2-one 0.013 Synthesis of 8- (4-fluoro-phenylethynyl) -7-hydroxy-4- (3- [1,2,3] triazol- 1 -yl-phenyl) -1,3-dihydro-benzo [b ] [L, 4] diazepin-2-one 0.010
[108] mGlu2 Cells [ ³H] -LY354740 bond
[109] Cell infection and cell culture
[110] The cDNA encoding the rat mGlu2 receptor protein in pBluescipt II was obtained from Professor S. Nakanishi (Kyoto, Japan) and served as eukaryotic expression vector pcDNA I-amp from Invitrogen (NV Leek, The Netherlands) Respectively. This vector construct (pcD1mGR2) was co-infected into CHO cells by the modified calcium phosphate method described in the literature "Chen & Okayama (1988)" using the psvNeo plasmid encoding the gene for neomycin resistance. The cells were maintained in Dulbecco's Modified Eagle medium with Dulbecco's modified Eagle medium and 10% dialyzed fetal bovine serum from Gibco BRL (Gibco BRL) (2 mM final concentration) . G-418 (1000 [mu] g / ml final). The clone was reverse transcribed with 5 ㎍ of total RNA and then annealed at 60 째 C for 30 minutes in 1 minute and extended at 72 째 C for 30 seconds and eluted with 60 mM Tris HCl (pH 10), denaturing at 95 째 C for 1 minute, _{, 15mM (NH 4) 2 SO} 4, 2mM MgCl 2, 25 units / ㎖ Taq polymerase identified by PCR using mGlu2 receptor specific primers 5'-atcactgcttgggtttctggcactg-3 'and 5'-agcatcactgtgggtggcataggagc-3' of the dehydratase Respectively.
[111] Membrane fabrication
[112] The cultured cells were harvested, 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 homogenized for 10 seconds at 10000 rpm using a polytron (Kinematica, AG, Ritau, Switzerland) . After centrifugation at 4 캜 for 30 minutes, the pellet was washed once with the same buffer as above and washed 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, RauSane, Switzerland) using bovine serum albumin as standard.
[113] [ ³ H] -LY354740 bond
[114] After thawing, it was suspended in cold 50 mM Tris HCl buffer (pH 7) (binding buffer) containing 2 mM MgCl ₂ and 2 mM CaCl ₂ . The final concentration of membrane in assay was 25 단백질 protein / ml. For 1 hour at room temperature in the presence of various concentrations of the compound to be tested while the culture membrane with ^[3 H] -LY354740, inhibition experiments were carried out. After incubation, the membranes were filtered onto Whatman GF / C glass fiber filters and washed five times with cold binding buffer. Nonspecific binding was measured in the presence of 10 [mu] M DCG IV. After transferring the filter to a plastic vial containing 10 ml of Ultima-gold scintillation fluid (Packard, Zurich, Switzerland), the filter was transferred to a Tri-Carb 2500 TR counter ). ≪ / RTI >
[115] Data Analysis
[116] The inhibition curves were generated using four parameter log equations and Hill coefficients providing IC50 values.
[117] The following example relates to the process for the preparation of (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (synthesis reaction scheme C).
[118] General Procedure A
[119] According to Wilson, J. Gerald and Hunt, Frederick C., Aust. J. Chem. 1983, 36, 2317-25, 4-iodo by iodination of 2-nitroaniline -2-nitroaniline.
[120] To a stirred solution of 2-nitroaniline (1.0 mol) in HOAc (500 mL) containing anhydrous NaOAc (93-103 g, 1.125-1.25 mol) was added iodine monochloride (59-66 mL, 1.1.25 to 1.25 moles) was added over 60 minutes. The reaction mixture was heated in a thin layer chromatography (tlc) until it is confirmed that the starting material is completely converted to a predetermined temperature, and after stirring for a further 30 minutes at 23 ℃, slowly diluted with H ₂ O (1000㎖) , Resulting in the separation of the crystalline product. Stirring was continued for 1 hour, the product was filtered off, washed with HOAc and dried under vacuum at 60 < 0 > C.
[121] Example A1
[122] 5-Chloro-4-iodo-2-nitro-phenylamine
[123] Prepared from 5-chloro-2-nitroaniline by iodination using iodine monochloride in HOAc / NaOAc according to general procedure A (80 <0> C). An orange solid was obtained.
[124] MS (EI) 298 (M &lt; ⁺ & gt ^; ) and 300 [(M + 2) &lt; ⁺ &gt; Melting point: 202 to 203 占 폚 (decomposition).
[125] Example A2
[126] 4-iodo-5-methyl-2-nitro-phenylamine
[127] Prepared from 5-methyl-2-nitroaniline by iodination using iodine monochloride in HOAc / NaOAc according to general procedure A (80 <0> C). A red solid was obtained.
[128] MS (EI) 278 (M ^&lt; ⁺ &gt;); Melting point: 154 캜 (decomposition).
[129] Example A3
[130] 5-Amino-2-iodo-4-nitrobenzoic acid methyl ester
[131] Amino-4-nitrobenzoic acid methyl ester (22.25 g, below [CAS-No. [99512-09-1]) was obtained by iodination using iodine monochloride in HOAc / NaOAc according to general procedure A ). &Lt; / RTI &gt; An orange solid was obtained (29.38 g, 80%).
[132] MS (EI) 322 (M ^&lt; ⁺ &gt;); Melting point 168 캜 (decomposition)
[133] [CAS-No. [99512-09-1]]
[134] 3-Hydroxy-4-nitrobenzoic acid (30 g, 164 mmol) and NH ₄ Cl (21.91 g, 410 mmol) in 25% aq. NH ₃ (180 mL) were heated in a steel autoclave at 160 ° C. for 7 h (Internal pressure: 23 bar). Cooled to 23 [deg.] C and evaporated to dryness. H ₂ O (200 mL) was obtained, the pH was adjusted to 1 with concentrated H ₂ SO ₄ , saturated with NaCl, extracted with EtOAc (6 × 750 mL) and the combined organic layers were dried over MgSO ₄ . The solvent is filtered off under vacuum to leave enough pure 3-amino-4-nitrobenzoic acid (22.26 g, 75%) as an orange solid. This material was suspended in MeOH (500 mL), concentrated H ₂ SO ₄ (3 mL) was added and the mixture was heated to 65 ° C. for 2.5 days. The solvent was removed under vacuum and the solid residue obtained from the EtOAc and saturated NaHCO ₃ - solution and washed with brine, dried over MgSO _4. Removal of the solvent left pure pure 3-amino-4-nitrobenzoic acid methyl ester (22.25 g, 93%) as an orange solid.
[135] General Procedure B
[136] Preparation of (2-nitro-phenyl) -carbamic acid tert-butyl ester from 2-nitroaniline.
[137] Method a
[138] To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0 C was added a solution of 4-iodo-2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL) And heated under reflux for 18 hours. The solvent was removed in vacuo to give a brown solid which was triturated with hot hexanes (200 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure to give pure 4-iodo-2-nitrophenyl isocyanate as a yellow solid. This material was refluxed in a mixture of excess tertiary-BuOH in CH ₂ Cl ₂ for 2.5 hours. Removal of the solvent left an orange solid which was purified by silica gel column chromatography using hexane / EtOAc to give (4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester as a yellow solid Respectively.
[139] Method b
[140] To a mixture of 4-iodo-2-nitroaniline (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 ml) was added Boc ₂ O (37.8 g, , 173 mmol) in THF (5 mL) was added dropwise and the resulting mixture was stirred at 52 &lt; 0 &gt; C for 26 h. The solvent was removed in vacuo and the residue was treated with a mixture of H ₂ O (240 mL) and MeOH (240 mL) and extracted with hexanes (3 × 500 mL). The combined hexane layers were washed with brine (200 mL) and all aqueous layers were re-extracted with hexane (300 mL). All combined hexane layers were dried over MgSO _4, filtered and purified by the solvent removed in vacuo to give an orange solid which, hexane / EtOAc silica gel column chromatography using as a yellow solid (4-iodo- 2-nitro-phenyl) -carbamic acid tert-butyl ester.
[141] Method c
[142] To a solution of 4-iodo-2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23 <0> C was added a solution of Boc ₂ O (246 g, 1128 mmol) in THF The solution was added dropwise within 70 min and stirred continuously at 23 &lt; 0 &gt; C for 75 min. The total mixture was evaporated to dryness and dried in HV to afford a dark brown solid (253.59 g). This material was dissolved in DCM (1100 mL), cooled to 0 &lt; 0 &gt; C and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0 ℃ for 2 hours, ice-cold saturated NaHCO ₃ - Pour the solution was extracted with DCM, washed with brine, dried over MgSO _4. The solvent was removed in vacuo to give a dark brown solid (199.71 g), which was coated on silica gel and purified by silica gel column chromatography using hexane / EtOAc to give (4-iodo-2-nitro- Phenyl) -carbamic acid tert-butyl ester.
[143] Example B1
[144] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[145] Following the general procedure B (method a), from the 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (7.0 g, 23.45 mmol) , 17.6 mmol) followed by treatment with tert-BuOH (100 mL) in CH ₂ Cl ₂ (100 mL) to produce the isocyanate. A yellow solid was obtained (7.1 g, 76%).
[146] MS (EI) 398 (M <^+> ) and 400 [(M + 2) <^+>]; Melting point 82-84 占 폚.
[147] Example B2
[148] (4-Iodo-5-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester
[149] According to general procedure B (method a), from 4-iodo-5-methyl-2-nitro-phenylamine (example A2) (13.51 g, 48.6 mmol) , 36.4 mmol) followed by treatment with tert-BuOH (150 mL) and CH ₂ Cl ₂ (150 mL) to produce the isocyanate. A yellow solid was obtained (14.1 g, 77%).
[150] MS (EI) 378 (M ^&lt; ⁺ &gt;); Melting point 99 to 100 占 폚.
[151] Example B3
[152] 5-tert-Butoxycarbonylamino-2-iodo-4-nitro-benzoic acid methyl ester
[153] Following the general procedure B (method a), from 5-amino-2-iodo-4-nitro-benzoic acid methyl ester (example A3) (5.5 g, 17 mmol) in dioxane ML, 13 mmol) followed by treatment with tert-BuOH (20 mL) and CH ₂ Cl ₂ (70 mL) to give the isocyanate. A yellow solid was obtained (5.2 g, 72%).
[154] MS (ISP) 440 [(M + NH 4) +]; Melting point 126 캜.
[155] Example B4
[156] (5-Allyloxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[157] (Example E1) (9.0 g, 28.2 mmol), according to general procedure B (method a), from diphosgene (2.6 eq) in EtOAc (150 mL) ML, 21.2 mmol) followed by treatment with tert-BuOH (80 mL) and CH ₂ Cl ₂ (80 mL) to produce the isocyanate. A yellow solid was obtained (9.16 g, 77%).
[158] MS (ISP) 421 [(M + H) +] and _{438 [(M + NH 4)} +]; Melting point 93-95 캜.
[159] Example B5
[160] (4-Iodo-5-methoxy-2-nitro-phenyl) -carbamic acid tert-butyl ester
[161] (2.85 g, 9.69 mmol) was reacted with 4-iodo-5-methoxy-2-nitro-phenylamine (0.88 mmol) in EtOAc (52 mL) according to general procedure B ML, 7.27 mmol) followed by treatment with tert-BuOH (25 mL) and CH ₂ Cl ₂ (25 mL) to give the isocyanate. A yellow solid was obtained (3.0 g, 79%).
[162] MS (EI) 394 (M ^&lt; ⁺ &gt;); Melting point 171 캜.
[163] Example B6
[164] [4-Iodo-5- (2-methoxy-ethoxy) -2-nitro-phenyl] -carbamic acid tert-butyl ester
[165] (Example E3) (2.73 g, 8.08 mmol) according to general procedure B (method a), using EtOAc (50 mL) from 4-iodo-5- (2-methoxy-ethoxy) Was treated with tert-BuOH (25 mL) and CH ₂ Cl ₂ (25 mL) to give the isocyanate after using diphosgene (0.8 mL, 6.06 mmol) A yellow solid was obtained (3.0 g, 86%).
[166] MS (ISP) 439 [(M + H) +], 456 [(M + NH 4) +] and ^{461 [(M + Na) +} ]; Melting point 109-111 [deg.] C.
[167] Example B7
[168] Ethoxy] -ethoxy) -2-nitro-phenyl] -carbamic acid tert-butoxycarbonylamino-3- - butyl ester
[169] According to the general procedure B (method a), 4-iodo-5- (2- [2- [2- (2- methoxy-ethoxy) -ethoxy] -ethoxy) -2- BuOH (25 mL) and CH ₂ Cl ₂ (10 mL) were added from nitro-phenylamine (Example E4) (8.0 g, 17 mmol) after use of diphosgene (1.54 mL, 13 mmol) in EtOAc (25 ml) to prepare an isocyanate. A yellow oil was obtained (8.6 g, 89%).
[170] MS (ISP) 588 [(M + NH 4) +].
[171] Example B8
[172] (RS) - [5- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -2-nitro-4-phenylethynyl] -phenyl] -carbamic acid tert-butyl ester
[173] According to general procedure B (method b), (RS) - [5- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) - It was prepared from phenylamine (example K14) (2.678g, 5.7 _{mmol), Cs 2 CO 3 (2.23g} , 6.8 mmol) and Boc ₂ O (1.52g, 7.0 mmol) 2-nitro-4-phenylethynyl . A yellow foam was obtained (2.0 g, 75%).
[174] MS (ISP) 469 [(M + H) +] and _{486 [(M + NH 4)} +]; Melting point 32 캜.
[175] Example B9 [Ve (R = CN; R " = Boc)]
[176] (5-Cyanomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[177] According to general procedure B (method a), (5-amino-2-iodo-4-nitro-phenyl) -acetonitrile (example Vf (R = CN; R "= H)) (5.15 g, 17 mmol ) Was treated with tert-BuOH (25 mL) and CH ₂ Cl ₂ (25 mL) to give the isocyanate after working up with 2.05 mL (17 mmol) of diphosgene in EtOAc (150 mL) (4.0 g, 58%).
[178] MS (ISN) 402 [(MH) ^- ]; Melting point 124 to 126 캜.
[179] Example B10
[180] 2-Nitro-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[181] (Example E6) (13.9 g, 36.6 mmol) and Boc (2-nitro-phenoxy) -4-iodo-2-nitro-phenylamine according to general procedure B (method c) ₂ O (16.35 g, 75 mmol) by treatment with 2 equivalents of TFA in CH ₂ Cl ₂ to give the di-Boc- compound. An orange solid was obtained (14.96 g, 85%).
[182] MS (ISP) 481 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 113 to 116 占 폚.
[183] Example B11
[184] [4-Iodo-5- (4-methoxy-benzyloxy) -2-nitro-phenyl] -carbamic acid tert-butyl ester
[185] (Example E7) (2.88 g, 7.20 mmol) and Boc ₂ O (1.20 mmol) were coupled according to general procedure B (method c) 3.30 g, 15.12 mmol) was treated with 2 equivalents of TFA in CH ₂ Cl ₂ to produce the di-Boc- compound. A waxy yellow solid was obtained (1.74 g).
[186] MS (ISN) 499 [(MH) ^- ].
[187] The following procedure relates to the preparation of (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester having a nitrogen substituent at the 5-position (Scheme D).
[188] General procedure C
[189] 5-N-substituted- (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester.
[190] Method a: Prepared from (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[191] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) was reacted with the desired amine, optionally in the presence of With toluene DMSO and / or DIPEA at a temperature from 23 [deg.] C to 100-130 &lt; 0 &gt; C. The reaction was cooled to 23 [deg.] C, poured into ice water, the precipitate was filtered off, washed with water and dried under vacuum. If the product did not precipitate, the mixture was extracted with EtOAc, washed with water and brine, dried over Na ₂ SO _4. Filtration off of the solvent under vacuum left a crude product which was purified by silica gel column chromatography using hexane / EtOAc to afford the pure title compound.
[192] Method b: Prepared from 5-chloro-4-iodo-2-nitro-phenylamine.
[193] 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (1.49 g, 5.0 mmol), the desired amine (6-25 mmol) and t- A mixture of the appropriate base (e.g. NaHCO ₃ , K ₂ CO ₃ , Et ₃ N or DIPEA) (10-15 mmol) was stirred at 60-130 ° C in DMSO, DMF or toluene (20-50 mL). The reaction was cooled to 23 [deg.] C, poured into ice water, neutralized with 1N HCl, the precipitate was filtered off, washed with water and dried under vacuum. If the product did not precipitate, the mixture was extracted with EtOAc, washed with water and brine, dried over Na ₂ SO _4. Filtration off of the solvent under vacuum left a crude product which was purified by silica gel column chromatography using hexane / EtOAc to afford the pure title compound. The protection of the amino group was achieved by general procedure B.
[194] Example C1
[195] [4-iodo-5- (4-methyl-piperazin-1-yl) -2-nitro-phenyl] -carbamic acid tert-butyl ester
[196] According to general procedure C (method a), (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester (prepared from example B1 ) (2.39 g, 6.0 mmol) and 1-methylpiperazine (1.60 mL, 15 mmol). A yellow solid was obtained (2.2 g).
[197] MS (ISP) 463 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 134 to 136 占 폚.
[198] Example C2
[199] (4-Iodo-2-nitro-5-thiomorpholin-4-yl-phenyl) -carbamic acid tert-butyl ester
[200] (5-Chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester in toluene (3.8 ml) and DIPEA (1.5 ml) at 115 [deg.] C for 48 h according to general procedure C Butyl ester (Example B1) (2.0 g, 5.0 mmol) and thiomorpholine (2.6 mL). A yellow solid was obtained (1.1 g).
[201] MS (ISP) 466 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 132 to 134 占 폚.
[202] Example C3
[203] (4-iodo-5-morpholin-4-yl-2-nitro-phenyl) -carbamic acid tert-butyl ester
[204] Following the general procedure C (method a), (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester (Example B1) (2.0 g, 5.0 mmol ) And morpholine (10 ml). A yellow solid was obtained (0.805 g).
[205] MS (ISP) 450 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 43 to 44 캜.
[206] Example C4
[207] 4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &
[208] (5-Chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) in toluene (4 mL) under reflux for 6 hours, following general procedure C (method a) (3.0 g, 7.53 mmol), 1,4-dioxa-8-aza-spiro (4,5) decane (4.82 ml, 37.63 mmol) and DIPEA (2.58 ml, 15.0 mmol). An orange solid was obtained (4.0 g).
[209] MS (ISP) 506 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 132 to 134 占 폚.
[210] Example C5
[211] [4-methoxy-piperidin-l-yl] -2-nitro-phenyl] -carbamic acid tert-butyl ester
[212] According to the general procedure C (method b), 5-chloro-4-iodo-2-nitro-phenylamine (Example A1) (6.91 g, 23.15 mmol), 4- As it was prepared from piperidine (4.0g, 34.73 mmol) and NaHCO ₃ (5.83㎖, 69.45 mmol). The resulting brown solid (7.95 g) was converted to the title compound according to general procedure B (method c). A yellow solid was obtained (6.55 g).
[213] MS (ISP) 478 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 133-135 占 폚.
[214] Example C6
[215] [5 - [(2-hydroxy-ethyl) -methyl-amino] -4-iodo-2-nitro- phenyl] -carbamic acid tert-butyl ester
[216] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (1.99 g, g, 5.0 mmol) and 2-methylaminoethanol (2.00 mL, 25.0 mmol). Yellow gum was obtained (1.88 g).
[217] MS (ISP) 438 [(M + H) &lt; ⁺ & gt ^; ].
[218] Example C7
[219] 4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[220] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (1.99 g, g, 5 mmol) and 4-hydroxypiperidine (2.53 g, 25 mmol). A yellow solid was obtained (1.88 g).
[221] MS (EI) 463 (M ^&lt; ⁺ &gt;); Melting point 58 to 60 캜.
[222] Example C8
[223] Yl] -4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester &lt; EMI ID =
[224] (5-Chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (2.2 g) in DMSO (2.3 ml) g, 5.5 mmol), 4- (2-hydroxyethoxy) piperidine [CAS-No. [40256-14-2] was prepared from (800㎎, 5.5 mmol) and Et ₃ N (2.3㎖, 16.5 mmol). A yellow solid was obtained (1.65 g).
[225] MS (EI) 507 (M ^&lt; ⁺ &gt;); Melting point 64 to 65 占 폚.
[226] Example C9
[227] 4-dihydroxy-pyrrolidin-l-yl) -4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester
[228] Butyl ester (Example B1) (8.73 g, 21.9 mmol) was reacted with DMSO (5-chloro-4-iodo-2-nitro-phenyl) Was reacted with 3-pyrroline (2.0 mL, 26.3 mmol, 70% purity, containing 30% pyrrolidine), Et ₃ N (9.12 mL, 65.7 mmol) in EtOH (14 mL) and EtOH Butyl ester with 7: 3 of [5- (2,5-dihydro-pyrrol-l-yl) -4-iodo-2-nitro- Nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester. A yellow solid was obtained (8.57 g). A portion of this material (4.31 g) was treated with NMO (1.28 g, 11.0 mmol), 2.5% OsO ₄ (1 mL, 0.1 mmol), and acetone (250 mL) in H 2 O and tert- Was dihydroxylated by reaction with K ₂ OsO ₄ (40 mg, 0.1 mmol) in ₂ O (100 mL). The title compound was obtained as an amorphous yellow substance (2.50 g).
[229] MS (ISP) 466 [(M + H) &lt; ⁺ & gt ^; ].
[230] Example C10
[231] 2-Nitro-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[232] (5-Chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (3.99 mmol) in DMSO g, 10 mmol) and ethanolamine (3.01 mL, 50 mmol). A yellow solid was obtained (4.53 g).
[233] MS (ISP) 424 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 130 to 148 占 폚.
[234] Example C11
[235] (5-Amino-phenyl) -carbamic acid tert-butyl ester
[236] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1), (R) -3 It was prepared from pyrrolidine hydrochloride and Et ₃ N-hydroxy. A yellow solid was obtained (3.153 g).
[237] MS (ISP) 450 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 158 캜 (decomposition).
[238] The following procedure relates to the preparation of (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester having a sulfur substituent at the 5-position (Scheme D).
[239] General Procedure D
[240] (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester - butyl ester.
[241] (5.4M in MeOH, 0.41 mL, 2.2 mmol) was added to a solution of thiol (2.2 mmol) in DMF until tlc confirmed that the chloride had completely disappeared, then (5-chloro-4-iodo -2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (797 mg, 2.0 mmol) was added and stirring was continued at 23 &lt; 0 &gt; C. It was washed with a solution, washed with brine, dried over MgSO ₄ - is poured into a ice-cold 5% citric acid, extracted with EtOAc and saturated NaHCO _3. Removal of the solvent left an orange oil which was purified by silica gel column chromatography using hexane / EtOAc to give the pure title compound.
[242] Example D1
[243] 2-Nitro-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[244] According to general procedure D, (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (399 mg, 1.0 mmol), 2 (312 mg, 2.2 mmol) and 5.4 M NaOMe solution in MeOH (0.8 mL, 8.8 mmol) in dimethylaminoethanol. A yellow solid was obtained (306 mg).
[245] MS (ISP) 468 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 144 캜.
[246] Example D2
[247] (5-tert-butoxycarbonylamino-2-iodo-4-nitro-phenylsulfanyl) -acetic acid methyl ester
[248] According to general procedure D, (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) (797 mg, 2.0 mmol), methyl 2.2 mg, 2.2 mmol) and 5.4 M NaOMe solution in MeOH (0.41 mL, 2.2 mmol). A yellow solid was obtained (847 mg).
[249] MS (EI) 468 (M ^&lt; ⁺ &gt;); Melting point 110 to 112 占 폚.
[250] The following procedure relates to the preparation of (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester with an oxygen substituent at the 5-position (Scheme E).
[251] General Procedure E
[252] Preparation of 5-O-substituted 4-iodo-2-nitro-phenylamine from 5-chloro-4-iodo-2-nitro-phenylamine.
[253] Alcohol (125-500 mmol) was added to a suspension of KOH (85%, 3.62- 7.96 g, 55-121 mmol) in DMSO (50 mL) and the mixture was stirred at 23 [deg.] C until all KOH was dissolved. A small amount of 5-chloro-4-iodo-2-nitro-phenylamine (Example A1) (15.0 g, 50 mmol) was added and the resulting dark red clear solution was added dropwise until tlc showed complete disappearance of the chloride Stir at 23-60 &lt; 0 &gt; C. Poured into ice-cold 1N HCl or ice-cold saturated NH ₄ Cl- solution, extracted with EtOAc or CHCl ₃ , washed with 1N HCl or saturated NH ₄ Cl- solution, brine and dried over MgSO ₄ . Removal of the solvent left a dark red solid which was purified by silica gel column chromatography to give the pure title compound.
[254] Example E1
[255] 5-allyloxy-4-iodo-2-nitro-phenylamine
[256] According to general procedure E, 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (15.0 g, 50 mmol), allyl alcohol (50 ml) and KOH (7.96 g, 121 mmol). An orange solid was obtained (9.38 g).
[257] MS (EI) 320 (M ^&lt; ⁺ &gt;); Melting point 74 캜.
[258] Example E2
[259] 4-iodo-5-methoxy-2-nitro-phenylamine
[260] According to general procedure E, 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (2.98 g, 10 mmol), methanol (10 ml) and KOH (1.45 g, , 22 mmol). An orange solid was obtained (2.9 g).
[261] MS (ISP) 295 [(M + H) +] and _{312 [(M + NH 4)} +]; Melting point 189 캜.
[262] Example E3
[263] 4-Iodo-5- (2-methoxy-ethoxy) -2-nitro-phenylamine
[264] According to general procedure E, 5-chloro-4-iodo-2-nitro-phenylamine (Example A1) (2.98 g, 10 mmol), methoxyethanol (7.9 ml, 100 mmol) in DMSO (8 ml) And KOH (1.45 g, 22 mmol). An orange solid was obtained (2.8 g).
[265] MS (ISN) 337 [(MH) ^- ]; Melting point 121 to 122 占 폚.
[266] Example E4
[267] Ethyl 4-iodo-5- (2- [2- [2- (2- methoxy-ethoxy) -ethoxy] -ethoxy] -ethoxy} -2-nitro-phenylamine
[268] (Example A1) (9.48 g, 32 mmol), tetraethyleneglycol monomethyl ether (prepared according to general procedure E) in 60 ml of DMSO (25 ml) at 60 & 19 g, 91 mmol) and KOH (2.31 g, 35 mmol). A red oil was obtained (8.4 g).
[269] MS (ISP) 471 [(M + H) &lt; ⁺ & gt ^; ].
[270] Example E5
[271] (RS) -5- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -4-iodo-2-nitro-phenylamine
[272] According to general procedure E, 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (4.48 g, 15 mmol), D, L- -Isopropylidene-glycerol (10 mL, 81 mmol) and KOH (1.01 g, 18 mmol). A yellow solid was obtained (4.9 g).
[273] MS (ISN) 393 [(MH) ^- ]; Melting point 151 캜.
[274] Example E6
[275] 5- (2-sec-Butoxy-ethoxy) -4-iodo-2-nitro-phenylamine
[276] According to general procedure E, 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (14.9 g, 50 mmol), 2-tert-butoxybenzoic acid in DMSO (25 mL) Was prepared from ethanol (29.5 g, 250 mmol) and KOH (3.99 g, 60 mmol). A yellow solid was obtained (14.3 g).
[277] MS (ISP) 471 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 144-146 占 폚.
[278] Example E7
[279] 4-iodo-5- (4-methoxy-benzyloxy) -2-nitro-phenylamine
[280] According to general procedure E, the title compound was prepared from 5-chloro-4-iodo-2-nitro-phenylamine (example A1) (5.97 g, 20 mmol), 4-methoxybenzyl alcohol ( 4.98 mL, 40 mmol) and KOH (1.58 g, 24 mmol). A tan solid was obtained (2.94 g).
[281] MS (ISN) 399 [(MH) ^- ]; Melting point 183 ° C.
[282] The following example illustrates the preparation of (5- tert-butoxycarbonylamino-2-iodo-4-nitro-phenyl) -acetic acid methyl ester and (5-cyanomethyl- -Carbamic acid tert-butyl ester (synthesis reaction formula F).
[283] Example XVI (R = CO ₂Me; R '= Me; R " = Boc)
[284] 2- (5-tert-Butoxycarbonylamino-2-iodo-4-nitro-phenyl) -malonic acid dimethyl ester
[285] 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) (Example B1) (1.00 g, 2.51 mmol) was added and the resulting dark red clear solution was stirred at 100 &lt; 0 &gt; C until tlc was found to be complete disappearance of the chloride. It was poured into the ice-cold 5% citric acid (100㎖), extracted with EtOAc (2 × 100㎖), washed with brine, dried over MgSO _4. Removal of the solvent left a yellow oil, which was purified by silica gel column chromatography using hexane / EtOAc (4: 1) to give the pure title compound as a yellow gum (1.13 g, 91%).
[286] MS (ISP) 512 [(M + NH 4) +] and ^{517 [(M + Na) +} ].
[287] Example XVII (R = CN; R '= Et; R " = H)
[288] (RS) - (5-Amino-2-iodo-4-nitro-phenyl) -cyano-acetic acid ethyl ester
[289] 2-Nitro-phenylamine (Example A1) (14.9 g, 50 mmol) in DMSO (60 mL) at 100 &lt; 0 &gt; C for 2 hours as described in Example XVI, ethyl Was prepared from cyanoacetate (14.7 mL, 100 mmol) and KOBut (11.2 g, 100 mmol). A dark brown gum was obtained.
[290] MS (EI) 375 (M) ^&lt; ⁺ & gt ^; .
[291] Example Ve (R = CO ₂Me; R " = Boc)
[292] (5-tert-butoxycarbonylamino-2-iodo-4-nitro-phenyl) -acetic acid methyl ester
[293] (Example XVI (R = CO ₂ Me; R '= &lt; RTI ID = 0.0 &gt; Me, R "= Boc) (3.34 g, 6.76 mmol), LiCl (573 mg, 13.52 mmol) and H ₂ O (0.122 mL, 6.76 mmol) was stirred for 7 h at 100 ° C. Pour into ice water , Extracted twice with EtOAc, washed with brine and dried over MgSO _4. Removal of the solvent left a yellow oil which was purified by silica gel column chromatography using hexane / EtOAc (9: 1) to give Obtained the pure title compound as a yellow solid (1.37 g, 47%).
[294] MS (EI) 436 (M) ^&lt; ⁺ &^gt;; Melting point 93 ° C.
[295] Example Xf (R = CN; R " = H)
[296] (5-Amino-2-iodo-4-nitro-phenyl) -acetonitrile
[297] Embodiments as described in Ve, (RS) in DMSO (370㎖) and H ₂ O (4.4㎖) in 120 ℃ for 2.5 hours - (5-amino-2-iodo-4-nitro-phenyl) - (20.62 g, 55 mmol) and LiCl (9.33 g, 220 mmol) in the same manner as in Example XVII (Example XVII (R = CN; R '= Et; &Lt; / RTI &gt;
[298] MS (EI) 303 (M) ^&lt; ⁺ &^gt;; Melting point 145-183 占 폚.
[299] The following examples illustrate the preparation of (5-hydroxymethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester and the corresponding THP- Dimethyl-aminomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Synthetic reaction formula F).
[300] Example Vh
[301] (5-hydroxymethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[302] LiBH ₄ (0.32 g, 14.78 mmol) was added to a solution of 5-3-butoxycarbonylamino-2-iodo-4-nitro-benzoic acid methyl ester (example B3) (3.12 g, , 7.39 mmol) and MeOH (0.6 mL, 14.78 mmol). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes. It was washed with a solution, washed with brine, dried over MgSO ₄ - was poured into a 5% citric acid, extracted twice with EtOAc and saturated NaHCO _3. Removal of the solvent left a yellow oil, which was purified by silica gel column chromatography using cyclohexane / EtOAc (4: 1) to give the pure title compound as a yellow solid (2.64 g, 91%).
[303] MS (ISP) 412 [(M + NH 4) +]; Melting point 250 ℃ or higher.
[304] Example Vi
[305] (RS) - [4-iodo-2-nitro-5- (tetrahydro-pyran-2- yloxymethyl) -phenyl] -carbamic acid tert- butyl ester
[306] Butyl ester (example Vh) (394 mg, 1.0 mmol) and 3, 6-dimethoxybenzoic acid in DCM (5 mL) at 0 [ To a mixture of 4-dihydro-2H-pyran (0.11 mL, 1.2 mmol) was added p-TsOH.H ₂ O (ca 5 mg) and the reaction was stirred at 0 ° C for 1 h. Diluted with EtOAc, washed with saturated NaHCO ₃ - solution and brine, and dried over MgSO ₄ . Removal of the solvent in vacuo left a yellow oil which was purified by silica gel column chromatography using hexane / EtOAc (9: 1) to give the pure title compound as a yellow gum (470 mg, 98%).
[307] MS (ISN) 477 [(MH) ^- ].
[308] Example Vl
[309] (5-dimethylaminomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[310] 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 & Methanesulfonyl chloride (1.5 eq.) Was added and the reaction was stirred at 23 &lt; 0 &gt; C for 24 h. Me ₂ NH (10 eq) in EtOH was added and stirring was continued for 24 h. Diluted with EtOAc, washed with saturated NaHCO ₃ - solution and brine, and dried over MgSO ₄ . Removal of the solvent in vacuo left a yellow oil which was purified by silica gel column chromatography using cyclohexane / EtOAc (3: 1) to give the pure title compound as a yellow oil (421 mg).
[311] MS (ISP) 422 [(M + H) &lt; ⁺ & gt ^; ].
[312] The following example illustrates the preparation of (2-amino-4- (1-alkenyl) -phenyl) -carbamic acid tert-butyl ester in a regioisomerically pure fashion, ] -Carbamic acid tert-butyl ester and (2-amino-4-aroyl-phenyl) -carbamic acid tert-butyl ester (Synthetic Scheme B).
[313] General Procedure F
[314] (4-Aryl-2-nitro-phenyl) -carbamate by Suzuki coupling of (4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester with aryl boronic acid Lt; RTI ID = 0.0 &gt; tert-butyl &lt; / RTI &gt;
[315] butyl ester (3.0 mmol), arylboronic acid (4.5 mmol) and PdCl ₂ (3.0 mmol) were added until the iodide was found to be fully converted in tlc, (PPh ₃ ) ₂ (2 mol%) was added to a solution of 1M NaHCO ₃ - (7.5 ml) in 1,4-dioxane (25 ml) and 2M NaHCO ₃ - solution (or alternatively DME with ㎖), LiCl (6.0 mmol) and _{(Ph 3 P) 4 Pd (} 3 mol%); Or with Et ₃ N (9.0 mmol), Pd (OAc) ₂ (3 mol%), PPh ₃ (6 mol%) in DMF (10 mL), if possible at 100 ° C. The mixture was transferred into a separatory funnel, H ₂ O (25 mL) was added and the product was extracted with ether or EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50㎖), dried over Na ₂ SO _4. Removal of the solvent left a brown residue which was purified by silica gel column chromatography using cyclohexane / ether or cyclohexane / EtOAc to give the title compound.
[316] Example F1
[317] (2-Chloro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[318] Butyl ester (example B1) (1.20 g, 3.00 mmol) and phenylboronic acid (0.62 g, 3.00 mmol) were coupled according to general procedure F to a solution of (5-chloro-4-iodo-2-nitro- 3.30 mmol). A yellow oil was obtained (843 mg).
[319] MS (EI) 348 (M &lt; ^{+ &} gt ^; ) and 350 [(M + 2) ^&lt; ⁺ &gt;
[320] Example F2
[321] (2-methyl-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[322] Butyl ester (example B2) (1.135 g, 3 mmol) and phenylboronic acid (630 mg, 0.35 mmol) were coupled according to general procedure F, using (4-iodo-5-methyl- 3.3 mmol). A yellow oil was obtained (971 mg).
[323] MS (EI) 328 (M &lt; ^{+ &} gt ^; ).
[324] Example F3
[325] (RS) - [4'-Fluoro-5-nitro-2- [4- (tetrahydro-pyran-2-yloxy) -piperidin- Butyl &lt; / RTI &gt; tert-butyl ester
[326] According to general procedure F, (RS) - [4'-fluoro-2-nitro-5- [4- (tetrahydro-pyran-2- yloxy) -piperidin- Carbamic acid tert-butyl ester [RO-69-4319 / 000 in 3,4-dihydro-2H-pyran and cat. By treatment with _{TsOH · H 2 O [5- (} 4- hydroxy-piperidin-1-yl) -4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester (Example C7) (1.09 g, 2.0 mmol) and 4-fluorophenylboronic acid. An orange solid was obtained (894 mg).
[327] MS (ISP) 516 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 144-146 占 폚.
[328] Example F4
[329] (RS) - [4'-Fluoro-5-nitro-2- [4- [2- (tetrahydro- pyran- 2- yloxy) -ethoxy] -piperidin- l-yl] -4-yl] -carbamic acid tert-butyl ester
[330] According to general procedure F, (RS) - (4-iodo-2-nitro-5- [4- [2- (tetrahydro-pyran- 2- yloxy) -ethoxy] -piperidin- Yl] -phenyl] -carbamic acid tert-butyl ester [RO-69-4355 / 000, by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H ₂ O in DCM at 0 < -Butyl ester (example C8) following the procedure used in the preparation of example C8), in analogy to example 1C, from l- [4- (2-hydroxy-ethoxy) -piperidin- l- ] (950 mg, 1.87 mmol) and 4-fluorophenylboronic acid (314 mg, 2.25 mmol). A viscous orange oil was obtained (930 mg).
[331] MS (ISP) 560 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 144-146 占 폚.
[332] Example F5
[333] (RS) - [4'-fluoro-5-nitro-2- (tetrahydro-pyran-2-yloxymethyl) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[334] Butyl ester (example Vi) was prepared from (RS) - [4-iodo-2-nitro-5- (tetrahydro-pyran- 2- yloxymethyl) -phenyl] -carbamic acid tert- And 4-fluorophenylboronic acid. An orange oil was obtained (1.24 g).
[335] Example F6
[336] (2-cyanomethoxy-4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[337] Butyl ester (Example S2) (838 mg, 2.0 mmol) and 4-fluorophenyl (2-nitro-phenyl) Boronic acid (392 mg, 2.8 mmol). An orange solid was obtained (333 mg).
[338] MS (ISP) 405 [(M + NH 4) +]; Melting point: 148 占 폚.
[339] Example F7
[340] (2-dimethylaminomethyl-4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[341] Prepared from (5-dimethylaminomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example VI) and 4-fluorophenylboronic acid according to general procedure F. A yellow solid was obtained (1.01 g).
[342] Example F8
[343] [2- (2,2-Dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyrrol-5-yl) -4'-fluoro- ] -Carbamic acid tert-butyl ester
[344] According to general procedure F, the title compound was obtained from [5- (cis-2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5- c] pyrrol- -Phenyl] -carbamic acid tert-butyl ester [RO-69-4741 / 000, 2,2-dimethoxypropane in DMF at 23 &lt; 0 &gt; By treatment with TsOH · H ₂ O [5- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester (Example C9)] (845 mg, 1.67 mmol) and 4-fluorophenylboronic acid (327 mg, 2.34 mmol). A yellow solid was obtained (643 mg).
[345] MS (ISP) 474 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 119 占 폚.
[346] Example F9
[347] (4'-Fluoro-2-methoxy-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[348] Butyl ester (example B5) (3.68 g, 9.34 mmol) and 4-fluorophenylboronic acid (example B5) in accordance with the general procedure F and starting from (4-iodo-5-methoxy- Acid (3.61 g, 25.8 mmol). A yellow solid was obtained (2.69 g).
[349] MS (ISN) 361 [(MH) ^- ]; Melting point 250 캜.
[350] Example F10
[351] 4-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester was prepared in analogy to the procedure described for the synthesis of [2- (1,4-dioxa-8-aza- ester
[352] According to general procedure F, the title compound was obtained from [5- (1,4-dioxa-8-aza-spiro [4.5] dec- (Example C4) (4.0 g, 7.02 mmol) and 4-fluorophenylboronic acid (1.33 g, 9.5 mmol). A yellow solid was obtained (2.43 g).
[353] Melting point: 213 캜 (decomposition).
[354] Example F11
[355] (4'-Fluoro-2-methyl-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[356] Butyl ester (example B2) (756 mg, 2.0 mmol) and 4-fluorophenylboronic acid (example B) in accordance with the general procedure F and starting from (4-iodo-5-methyl- (420 mg, 3.0 mmol). Amorphous yellow material was obtained (611 mg).
[357] MS (ISN) 345 [(MH) ^- ].
[358] Example F12
[359] (4-tert-butoxycarbonylamino-4'-fluoro-5-nitro-biphenyl-4-yloxy) -acetic acid tert-butyl ester
[360] (Example S1) (2.14 g, 4.33 mmol) and (tert-butoxycarbonylamino-2-iodo-4-nitro- phenoxy) -acetic acid tert- butyl ester 4-Fluorophenylboronic acid (728 mg, 5.2 mmol). An orange solid was obtained (1.80 g).
[361] MS (ISN) 461 [(MH) ^- ]; 92-93 [deg.] C.
[362] Example F13
[363] (2-Chloro-4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[364] Prepared from (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B1) and 4-fluorophenylboronic acid according to general procedure F. A yellow solid was obtained (625 mg).
[365] MS (EI) 366 (M &lt; ^{+ &} gt ^; ).
[366] Example F14
[367] (4'-Fluoro-2- (2-methoxy-ethoxy) -5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[368] Butyl ester (example B6) and 4-fluorophenylboronic acid (example B6) were coupled according to general procedure F, using [4-iodo-5- (2-methoxy- Acid. A yellow solid was obtained (1.833 g).
[369] MS (EI) 406 (M &lt; ^{+ &} gt ^; ).
[370] Example F15
[371] [2- (2-tert-butoxy-ethoxy) -4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[372] Butyl ester (example B10) and 4-fluoro (2-nitro-phenyl) -carbamic acid tert-butyl ester Phenylboronic acid. A yellow solid was obtained (735 mg).
[373] MS (ISP) 449 [(M + H) &lt; ⁺ & gt ^; ].
[374] Example F16
[375] [4'-Fluoro-5-nitro-2- (2-oxo-oxazolidin-3- yl) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[376] According to general procedure F, the title compound was synthesized from [4-Iodo-2-nitro-5- (2-oxo-oxazolidin-3-yl) -phenyl] -carbamic acid tert- butyl ester [RO-69-6758 / (2-hydroxy-ethylamino) -4-iodo-2-nitro-phenyl) -piperidine was prepared by treatment with 1,1'-carbonyldiimidazole in dioxane, ] -Carbamic acid tert-butyl ester (example C10) (503 mg, 1.12 mmol) and 4-fluorophenylboronic acid (235 mg, 1.68 mmol). A yellow solid was obtained (310 mg).
[377] MS (ISN) 416 [(MH) ^- ]; Melting point: 201 占 폚.
[378] Example F17
[379] (4'-Fluoro-2-methoxy-2'-methyl-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[380] According to general procedure F, from (4-iodo-5-methoxy-2-nitro-phenyl) -carbamic acid tert- butyl ester (example B5) and 4-fluoro-2- . A yellow solid was obtained (699 mg).
[381] MS (EI) 376 (M &lt; ^{+ &} gt ^; ).
[382] Example F18
[383] (2,3-Butoxy-4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[384] Butyl ester (example S4) (1.4 g, 3.21 mmol) and 4-fluoro (2-nitro-phenyl) (0.67 g, 4.42 mmol) according to general procedure II. Amorphous yellow material was obtained (1.2 g).
[385] MS (EI) 404 (M &lt; ^{+ &} gt ^; ).
[386] Example F19
[387] (2,3-Butoxy-2'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[388] Butyl ester (example S4) (1.4 g, 3.21 mmol) and 2-fluoro (2-nitro-phenyl) (0.67 g, 4.83 mmol) according to general procedure II. Amorphous yellow material was obtained (960 mg).
[389] MS (EI) 404 (M &lt; ^{+ &} gt ^; ).
[390] Example F20
[391] (RS) - [4'-fluoro-5-nitro-2 - [(R) -3- (tetrahydro-pyran- 2- yloxy) -pyrrolidin- Yl] -carbamic acid tert-butyl ester
[392] According to general procedure F, (RS) - (4-iodo-2-nitro-5 - [(R) -3- (tetrahydro-pyran-2- yloxy) -pyrrolidin- Phenyl] -carbamic acid tert-butyl ester [RO-69-6376 / 000, by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H ₂ O in DCM at 0 < Butyl ester (prepared from example C11) and 4-fluoro-benzoic acid methyl ester (example C5) in place of 4-chloro- Phenylboronic acid. A yellow solid was obtained (1.053 g).
[393] MS (ISP) 502 [(M + H) &lt; ⁺ & gt ^; ].
[394] Example F21
[395] (2'-Fluoro-2-methoxy-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[396] Butyl ester (example B5) (1.00 g, 2.54 mmol) and 2-fluorophenylboronic acid (example B5) in accordance with the general procedure F and starting from (4-iodo-5-methoxy- Acid (0.60 g, 4.32 mmol). Amorphous yellow material was obtained (687 mg).
[397] MS (EI) 362 (M &lt; ^{+ &} gt ^; ).
[398] Example F22
[399] 2-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester ester
[400] According to general procedure F, the title compound was obtained from [5- (1,4-dioxa-8-aza-spiro [4.5] dec- Ester (Example C4) (1.89 g, 3.47 mmol) and 2-fluorophenylboronic acid (0.63 g, 4.49 mmol). A yellow solid was obtained (1.46 g).
[401] MS (ISP) 474 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 164 캜.
[402] Example F23
[403] (2 ', 5'-difluoro-2-methoxy-5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[404] Butyl ester (Example B5) (3.94 g, 10 mmol) and 2,5-difluoro-4-methoxy-2- (2.21 g, 14 mmol). Amorphous yellow material was obtained (1.05 g).
[405] MS (ISN) 379 [(MH) ^- ].
[406] Example F24
[407] (2'-Fluoro-2- (2-methoxy-ethoxy) -5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[408] According to general procedure F, the title compound was synthesized from [4-iodo-5- (2-methoxy-ethoxy) -2-nitro-phenyl] -carbamic acid tert- butyl ester (example B6) and 2- Acid. A yellow solid was obtained (3.63 g).
[409] MS (ISN) 405 [(MH) ^- ].
[410] Example F25
[411] (RS) - [2'-fluoro-5-nitro-2- (tetrahydro-pyran-2- yloxymethyl) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[412] Butyl ester (example Vi) was prepared from (RS) - [4-iodo-2-nitro-5- (tetrahydro-pyran- 2- yloxymethyl) -phenyl] -carbamic acid tert- And 2-fluorophenylboronic acid. A yellow liquid was obtained (2.606 g).
[413] MS (ISN) 445 [(MH) ^- ].
[414] Example F26
[415] [2'-Fluoro-2- (4-methoxy-benzyloxy) -5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[416] Butyl ester (example B11) (1.69 g, 3.38 mmol) in accordance with the general procedure F, in analogy to Example &lt; RTI ID = And 2-fluorophenylboronic acid (0.61 g, 4.39 mmol). A yellow foam was obtained (940 mg).
[417] MS (ISP) 469 [(M + H) &lt; ⁺ & gt ^; ].
[418] Example F27
[419] (2,3-Butoxy-2 ', 5'-difluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[420] (Example S4) (3.00 g, 6.88 mmol) and 2, 5-dimethyl-2-nitro-phenyl) -carbamic acid tert- butyl ester - difluorophenylboronic acid (2.23 g, 14.1 mmol). Amorphous yellow material was obtained (2.30 g).
[421] MS (ISN) 421 [(MH) ^- ].
[422] General Procedure G
[423] (2-nitro-phenyl) -carbamic acid tert-butyl ester and bis (pinacolato) diboron and subsequent reaction with an aryl halide to give (4-aryl- - nitro-phenyl) -carbamic acid tert-butyl ester.
[424] (see Tetr . Lett. 1997 , 38, 3841-3844) until a complete conversion of iodide in tlc was confirmed . (4-Iodo-2 (2.0 mmol), bis (pinacolato) diboron (2.2 mmol), KOAc (6.0 mmol) and PdCl ₂ (PPh ₃ ) ₂ (3 mol% The mixture was stirred at 100 &lt; 0 &gt; C. After addition of the aryl halide (4.0 mmol), PdCl ₂ (PPh ₃ ) ₂ (3 mol%) and 2M Na ₂ CO ₃ - solution (7.5 ml), the mixture was confirmed to be completely converted to the intermediate voronic ester in tlc Lt; RTI ID = 0.0 &gt; 100 C &lt; / RTI &gt; The mixture was transferred into a separatory funnel, H ₂ O (30 mL) was added and the product was extracted with ether or EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100㎖), dried over Na ₂ SO _4. Removal of the solvent left a brown residue which was purified by silica gel column chromatography using cyclohexane / ether or cyclohexane / EtOAc to give the title compound.
[425] General procedure H
[426] (4-aryl-2-nitro-phenyl) -carbamoyl chloride with carbonylative Suzuki coupling of (4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester with aryl boronic acid Lt; RTI ID = 0.0 &gt; tert-butyl &lt; / RTI &gt;
[427] (Tetr . Lett. 1993 , 34, 7595-7598) in anisole (6 mL) until complete conversion of the iodide was confirmed in thin layer chromatography (4-iodo-2-nitro (1.0 mmol), arylboronic acid (1.1 mmol), K ₂ CO ₃ (3.0 mmol) and PdCl ₂ (PPh ₃ ) ₂ (3 mol% Lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; The mixture was transferred into a separatory funnel, H ₂ O (30 mL) was added and the product was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50㎖), dried over Na ₂ SO _4. Removal of the solvent left a yellow residue which was purified by silica gel column chromatography using hexane / EtOAc to give the title compound.
[428] General Procedure I
[429] (2-nitro-4-tributylstannanyl-phenyl) -carbamic acid tert-butyl ester with an aryl halide or vinyltriflate, or (4-iodo-2-nitro- (4-aryl-2-nitro-phenyl) -carbamic acid tert-butyl ester by stille-coupling of carbamic acid tert-butyl ester and trialkylaryl staran.
[430] (2-Nitro-4-tributylstannanyl-phenyl) -carbamic acid tert-butyl ester (525 mg, 1.0 mmol, 0.25 mmol) in DME (3 mL) was added until stannane was completely consumed in tlc. Document hexahydro-butyl di-star in toluene (20㎖) at 60 ℃ for 5 days according to "Bull. Chem. Soc. Jpn . 1983, 56, 3855-3856" I (7.5㎖, 15 mmol) and Pd (PPh ₃₎ 2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B) (10 mmol) by reaction with ₄ (116 mg, 0.1 mmol) A mixture of halide or vinyl triflate (0.95 to 6.0 mmol), anhydrous LiCl (126 mg, 3.0 mmol) and Pd (PPh ₃ ) ₄ (5 mol%) was stirred at 100 ° C under argon atmosphere. The reaction was cooled to 23 ℃ and 45 minutes with stirring and a saturated aqueous solution KF- (5㎖) while, and then filtered through celite, washed with ether, the filtrate was dried over MgSO _4. Removal of the solvent in vacuo left a brown oil which was purified by silica gel column chromatography using hexane / EtOAc to give the title compound.
[431] The following example relates to a process for the preparation of (2-amino-4-arylethynyl-phenyl) -carbamic acid tert-butyl ester by positional isomeric purification (synthesis scheme G).
[432] General procedure K
[433] (4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester and Sonogashira-coupling of acetylenic compounds; Also, Sonogashira-coupling of (4-ethynyl-2-nitro-phenyl) -carbamic acid tert-butyl ester with aryl halide; And 4-aryl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one with 8-iodo-4- 2-nitro-phenyl) -carbamic acid tert-butyl ester.
[434] Halide (from 3.0 to 4.5 mmol), acetylenic compound (3.0 to 4.5 mmol) in THF (12㎖), Et ₃ N (13.5 _{mmol), PdCl 2 (PPh 3)} 2 (5 mol%) and PPh ₃ (2.5 mol %) [Very insoluble DMF (not more than 12 ml) may be added]. Stir at 20 ° C for 20 minutes while purging with argon. CuI (1.2 mol%) was added and the reaction was continued at 60 캜 under an argon atmosphere until the trace component was completely converted in tlc (see J. Org. Chem . 1998 , 63, 8551) Lt; / RTI &gt; The mixture was transferred into a separatory 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 saturated NaHCO ₃ - solution (50 mL) and brine (50 mL), then dried over MgSO ₄ . Removal of the solvent left a yellow residue, which was purified by silica gel column chromatography using hexane / EtOAc and / or triturated with hexane or aqueous EtOH to give the title compound.
[435] Example K1
[436] (5-chloro-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[437] Butyl ester (Example B1) (1.2 g, 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 &lt; RTI ID = 0.0 & Mmol). A yellow solid was obtained (944 mg).
[438] MS (ISN) 371 [(MH) ^- ] and 373 [(M-H + 2) ^- ]; Melting point 166-167 占 폚.
[439] Example K2
[440] (5-methyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[441] Butyl ester (example B2) (1.13 g, 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 &lt; RTI ID = 0.0 &gt; Mmol). A green-yellow solid was obtained (794 mg).
[442] MS (EI) 352 (M ^&lt; ⁺ &gt;); Melting point 161 to 164 占 폚.
[443] Example K3
[444] 2-Nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[445] According to general procedure K, the title compound was obtained from [4-iodo-5- (4-methyl-piperazin- 1 -yl) -2-nitro- phenyl] -carbamic acid tert- butyl ester (example C1) 3.0 mmol) and phenylacetylene (0.5 mL, 4.5 mmol). A green-yellow solid was obtained (1.1 g).
[446] MS (ISP) 437 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 170 캜.
[447] Example K4
[448] (5-morpholin-4-yl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[449] Butyl ester (example C3) (890 mg, 2.0 mmol) and phenylacetylene (2 ml) were added to a solution of (4-iodo-5-morpholin- (0.33 ml, 3.0 mmol). An orange solid was obtained (580 mg).
[450] MS (ISP) 424 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 190-191 占 폚.
[451] Example K5
[452] (2-nitro-4-phenylethynyl-5-thiomorpholin-4-yl-phenyl) -carbamic acid tert- butyl ester
[453] Butyl ester (example C2) (1.0 g, 2.15 mmol) and phenyl (4-bromo-phenyl) -carbamic acid tert- butyl ester Acetylene (0.36 mL, 3.22 mmol). An orange solid was obtained (620 mg).
[454] MS (ISP) 440 [(M + H) <^+> ] and 462 [(M + Na) <^+>]; Melting point: 201 캜 (decomposition).
[455] Example K6
[456] 2-Nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[457] Was prepared by the following two steps:
[458] In acetone (25㎖) and H ₂ O (1㎖) (4- iodo-2-nitro-5-tee Omo morpholin-4-yl-phenyl) -carbamic acid tert-butyl ester (Example C2) ( 465 mg, 1 mmol), 0.3 M ammonium molybdate solution (0.3 mL) and 33% H ₂ O ₂ (2.3 mL) at 0 ° C and the mixture was stirred at 23 ° C for 1 hour. According to general procedure K, the title compound was prepared from [5- (1,1-dioxo-thiomorpholin-4-yl) -4-iodo-2-nitro- Ester (497 mg, 1.0 mmol), which was reacted with phenylacetylene (0.17 mL, 1.5 mmol). A yellow solid was obtained (245 mg).
[459] MS (ISP) 472 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 217-221 属 C.
[460] Example K7
[461] 4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[462] According to general procedure K, the title compound was synthesized from [5- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -4-iodo-2-nitro- (Example C4) (3.80 g, 7.53 mmol) and phenylacetylene (1.24 g, 11.3 mmol). An orange solid was obtained (1.8 g).
[463] MS (ISN) 478 [(MH) ^- ]; Melting point 179-180 占 폚.
[464] Example K8
[465] 2-Nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[466] According to general procedure K, 721 mg (1.54 mmol) of [5- (2-dimethylamino-ethylsulfanyl) -4-iodo-2-nitro- phenyl] -carbamic acid tert- butyl ester ) And phenylacetylene (0.25 mL, 2.31 mmol). Amorphous yellow material was obtained (595 mg).
[467] MS (ISP) 442 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 179-180 占 폚.
[468] Example K9
[469] [5-tert-Butoxycarbonylamino-4-nitro-2-phenylethynyl-phenylsulfanyl) -acetic acid methyl ester
[470] (Example D2) (780 mg, 1.67 mmol) and phenylacetylene (2-methoxy-phenyl) -acetic acid methyl ester (0.27 ml, 2.5 mmol). An orange solid was obtained (700 mg).
[471] MS (ISP) 460 [(M + NH 4) +]; Melting point 125 to 127 占 폚.
[472] Example K10
[473] 2-Nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[474] Butyl ester (example B6) (876 mg, 2 mmol) was reacted according to general procedure K, using [4-iodo-5- (2-methoxy-ethoxy) And phenylacetylene (0.33 mL, 3 mmol). A yellow solid was obtained (569 mg).
[475] MS (ISP) 413 [(M + H) +] and _{430 [(M + NH 4)} +]; Melting point 118 to 119 占 폚.
[476] Example K11
[477] (5-methoxy-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[478] Butyl ester (example B5) (1.18 g, 3.00 mmol) and phenylacetylene (0.58 mL, 3.00 mmol) were coupled according to general procedure K to a mixture of (4-iodo-5-methoxy- 4.5 mmol). A yellow solid was obtained (1.1 g).
[479] MS (EI) 368 (M ^&lt; ⁺ &gt;); Melting point 129 캜.
[480] Example K12
[481] Ethoxy] -ethoxy) -2-nitro-4-phenylethynyl-phenyl] -carbamic acid 3 &lt; RTI ID = 0.0 &gt; Tert-butyl ester
[482] According to general procedure K, [4-iodo-5- (2- [2- [2- (2-methoxy-ethoxy) -ethoxy] -ethoxy] ] -Carbamic acid tert-butyl ester (Example B7) (5.7 g, 10.0 mmol) and phenylacetylene (1.65 mL, 15 mmol). A yellow oil was obtained (5.2 g).
[483] MS (ISN) 543 [(MH) ^&lt;&quot;&gt;].
[484] Example K13
[485] (5-tert-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenoxy) -acetic acid tert-butyl ester
[486] According to general procedure K, (tert-butoxycarbonylamino-2-iodo-4-nitro-phenoxy) -acetic acid tert-butyl ester (example S1) (1.46 g, 2.99 mmol) and Was prepared from phenylacetylene (0.49 mL, 4.49 mmol). A yellow solid was obtained (1.4 g).
[487] MS (ISP) 486 [(M + NH 4) +]; Melting point 130 캜.
[488] Example K14
[489] (RS) -5- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -2-nitro-4-phenylethynyl-phenylamine
[490] According to general procedure K, (RS) -5- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -4-iodo-2-nitro-phenylamine (example E5) 4.5 g, 11.4 mmol) and phenylacetylene (1.88 mL, 17.1 mmol). An orange solid was obtained (5.4 g).
[491] MS (ISN) 367 [(MH) ^- ]; Melting point 147-149 占 폚.
[492] Example K15
[493] (5-tert-butoxycarbonylamino-4-nitro-2-phenylethynyl-benzoic acid methyl ester
[494] (Example B3) (1.22 g, 2.89 mmol) and phenylacetylene (0.48 ml, 4.34 mmol) in accordance with the general procedure K, using 5-tert-butoxycarbonylamino-2-iodo-4-nitro- ). A yellow solid was obtained (793 mg).
[495] MS (ISP) 397 [(M + H) +] and _{414 [(M + NH 4)} +]; Melting point: 173 ° C.
[496] Example K16
[497] (5-tert-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenyl) -acetic acid methyl ester
[498] (Example Ve (R = CO ₂ Me; R " = Boc)) according to general procedure K, using (5- tert-butoxycarbonylamino-2-iodo-4-nitro- (1.32 g, 3.03 mmol) and phenylacetylene (0.5 mL, 4.55 mmol). A yellow solid was obtained (1.1 g).
[499] MS (ISP) 411 [(M + H) +], 428 [(M + NH 4) +] and ^{433 [(M + Na) +} ]; Melting point 134 캜.
[500] Example K17
[501] (5-Cyanomethyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[502] According to general procedure K, the title compound was prepared from (5-cyanomethyl-4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester (Example Ve (R = CN; R "= Boc) , 9.85 mmol) and phenylacetylene (3.24 ml, 29.56 mmol). An olive solid was obtained (1.6 g).
[503] MS (ISP) 395 [(M + NH 4) +]; Melting point 166 ° C.
[504] Example K18
[505] (RS) - [5- (2,3-dihydroxy-propoxy) -2-nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[506] According to general procedure K, (RS) - [5- (2,3-dihydroxy-propoxy) -4-iodo-2-nitro- phenyl] -carbamic acid tert- 5451/000 (3.23 g, 7.11 mmol); NMO (1.28 g, 11.0 mmol) in acetone (250 mL) and H ₂ O (100 mL), 2.5% OsO ₄ (1 mL, 0.1 mmol) in tert-BuOH and K ₂ OsO ₄ (Example B4) (4.20 g, 10.0 mmol) by reaction with (5-allyloxy-4-iodo-2-nitro-phenyl) -carbamic acid tert- butyl ester (40 mg, 0.1 mmol) , And phenylacetylene (1.17 mL, 10.67 mmol). A yellow solid was obtained (2.74 g).
[507] MS (ISP) 429 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 157 캜 (decomposition).
[508] Example K19
[509] (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[510] Butyl ester (Example Vh) (2.61 g, 6.62 mmol) and phenylacetylene (1.10 mL) in accordance with the general procedure K, , 9.93 mmol). A yellow solid was obtained (1.76 g).
[511] MS (ISP) 386 [(M + NH 4) +]; Melting point: 177 캜 (decomposition).
[512] Example K20
[513] 4-Phenylethynyl-phenyl) -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[514] According to general procedure K, the title compound was synthesized from [4-iodo-5- (4-methoxy-piperidin- 1 -yl) -2-nitro-phenvD-carbamic acid tert- butyl ester (example C5) 2.1 g, 2.1 mmol) and phenylacetylene (0.35 mL, 3.15 mmol). A yellow solid was obtained (799 mg).
[515] Melting point 147-150 占 폚.
[516] Example K21
[517] (5-cyanomethoxy-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[518] Butyl ester (example S2) (605 mg, 1.44 mmol) and phenylacetylene (0.24 ml, 1.44 mmol) were coupled according to general procedure K to a mixture of (5-cyanomethoxy-4-iodo-2-nitro- , 2.16 mmol). A yellow solid was obtained (508 mg).
[519] MS (EI) 393 (M ^&lt; ⁺ &gt;); Melting point 170 캜.
[520] Example K22
[521] The title compound was prepared from [4- (4-fluoro-phenylethynyl) -5-hydroxymethyl-2-nitro-phenyl] -carbamic acid tert- butyl ester
[522] Butyl ester (Example Vh) (2.00 g, 5.07 mmol) and 4-fluorophenyl (4-fluoro-phenyl) Acetylene (0.91 g, 7.61 mmol). A yellow solid was obtained (1.55 g).
[523] MS (ISN) 385 [(MH) ^- ]; Melting point 198 ° C.
[524] Example K23
[525] (4-fluoro-phenylethynyl) -5- [methyl- [2- (tetrahydro-pyran-2- yloxy) -Carbamic acid tert-butyl ester
[526] According to general procedure K, (RS) - (4-iodo-5- [methyl- [2- (tetrahydro-pyran-2- yloxy) -ethyl] Tert-butyl ester [RO-68-3820 / 000; Dihydro-2H-pyran and &lt; RTI ID = 0.0 &gt; cat. By treatment with _{TsOH · H 2 O [5 -} [(2- hydroxy-ethyl) -methyl-amino] -4-iodo-2-nitro-phenyl] -carbamic acid tert-butyl ester (Example C6) (2.09 g, 4.01 mmol) and 4-fluorophenylacetylene (0.72 g, 6.02 mmol) according to general procedure II. A tan solid was obtained (1.84 g).
[527] MS (ISP) 514 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 134 캜.
[528] Example K24
[529] (RS) - [2-Nitro-4-phenylethynyl-5- [2- (tetrahydro-pyran-2- yloxy) -ethoxy] -phenyl] -carbamic acid tert- butyl ester
[530] According to general procedure K, (RS) - [4-iodo-2-nitro-5- [2- (tetrahydro-pyran-2- yloxy) -ethoxy] -phenyl] -carbamic acid tert- butyl Ester (Example S3) (743 mg, 1.46 mmol) and phenylacetylene (0.24 mL, 2.19 mmol). A tan viscous oil was obtained (429 mg).
[531] MS (EI) 393 (M &lt; ^{+ &} gt ^; ).
[532] Example K25
[533] Butyl ester (example B10) (1.44 g, yield &lt; RTI ID = 0.0 &gt; 3.0 mmol) and 4-fluorophenylacetylene (541 mg, 4.5 mmol). A yellow solid was obtained (777 mg).
[534] MS (EI) 472 (M ^&lt; ⁺ &gt;); Melting point 96-98 캜.
[535] Example K26
[536] The title compound was prepared from [5- tert-butoxy-4- (4-fluoro-phenylethynyl) -2-nitro-phenyl] -carbamic acid tert- butyl ester
[537] Butyl ester (example B4) (1.40 g, 3.21 mmol) and 4-fluoro (tert-butoxycarbonylamino) Was prepared from phenylacetylene (0.66 g, 5.46 mmol). A brown solid was obtained (520 mg).
[538] MS (EI) 428 (M ^&lt; ⁺ &gt;); Melting point: 201 占 폚.
[539] General Procedure L
[540] (2-amino-phenyl) -carbamic acid tert-butyl ester by reduction of (2-nitro-phenyl) -carbamic acid tert-butyl ester; Reduction of 3-aryl-N- (2-nitro-phenyl) -3-oxo-propionamide and simultaneous cyclisation of 4-aryl-1,3-dihydro-benzo [ ] Diazepin-2-one
[541] Method a: Catalytic hydrogenation
[542] (1.0 mmol) of the nitro compound (1.0 mmol) in MeOH or EtOH and THF (1: 1 approximately 20 ml) and 10% palladium on carbon (20 mg) or Raney-Ni (20 mg) The mixture was vigorously stirred at 23 &lt; 0 &gt; C under a hydrogen atmosphere. The catalyst was filtered off, washed thoroughly with MeOH or EtOH and THF (1: 1), and the solvent removed under vacuum leaving a crude product, which was sufficiently purified for further modification.
[543] Method b: SnCl ₂2H ₂Reduction using O
[544] A mixture of the nitro compound (1.0 mmol) and SnCl ₂ .2H ₂ O (1.0 mmol) was stirred in EtOH (30 mL) at 70-80 ° C or alternatively under an argon atmosphere until complete conversion in tlc was verified Was stirred at 23 &lt; 0 &gt; C in pyridine (3 ml) and DMF (12 ml). The reaction mixture was adjusted to pH 8 by the addition of saturated NaHCO ₃ - solution, extracted with EtOH, and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . Removal of the solvent leaves a yellow solid, which can be purified by silica gel column chromatography, if necessary.
[545] Method c: Zn and NH ₄Reduction using Cl
[546] (3.0 mmol) was added to a mixture of the nitro compound (1.0 mmol) in EtOH / THF / sat. NaHCO ₃ - solution (1: 1: 1, 30 mL) until complete conversion in tlc was confirmed, The mixture was stirred at 70 &lt; 0 &gt; C under argon atmosphere. Followed by aqueous post-treatment as described in method b.
[547] Method d: Reduction using Fe and HOAc
[548] To the mixture of the nitro compound (1.0 mmol) in THF / H ₂ O (4: 1, 10-50 ml) was added Fe powder (6.0 mmol) until complete conversion in tlc, 0.0 &gt; 70 C. &lt; / RTI &gt; Followed by aqueous post-treatment as described in method b.
[549] Example L1
[550] (2-Amino-4-iodo-5-thiomorpholin-4-yl-phenyl) -carbamic acid tert- butyl ester
[551] According to general procedure L (method b), by reduction with (2.54 g, 11.3 mmol) SnCl ₂ .2H ₂ O (4-iodo-2-nitro- ) -Carbamic acid tert-butyl ester (example C2) (1.05 g, 2.25 mmol). A yellow solid was obtained (993 mg).
[552] MS (ISP) 436 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 125 to 127 占 폚.
[553] Example L2
[554] (2-Amino-4-iodo-5-morpholin-4-yl-phenyl) -carbamic acid tert-butyl ester
[555] According to general procedure L (method b), (4-iodo-5-morpholin-4-yl-2-nitro-phenyl) -thiophene was obtained by reduction using SnCl ₂ .2H ₂ O (1.9 g, 8.27 mmol) -Carbamic acid tert-butyl ester (example C3) (753 g, 1.65 mmol). A yellow solid was obtained (696 mg).
[556] MS (ISP) 420 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 139-143 占 폚.
[557] Example L3
[558] (2-Amino-5-chloro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[559] According to the general procedure L (method b), (5-chloro-2-nitro-4-phenylethynyl-phenyl) -carbamic acid 3 was obtained by reduction with SnCl ₂ .2H ₂ O (2.245 g, 10 mmol) Butyl ester (example K1) (742 mg, 2.0 mmol). An orange solid was obtained (483 mg).
[560] MS (ISP) 343 [(M + H) <^+> ] and 345 [(M + 2 + H) <^+> ].
[561] Example L4
[562] (2-Amino-5-methyl-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[563] According to the general procedure L (method b), (5-methyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid 3 was obtained by reduction with SnCl ₂ .2H ₂ O (2.37 g, 10.3 mmol) Butyl ester (example K2) (741 mg, 2.1 mmol). A light brown solid was obtained (419 mg).
[564] MS (ISP) 323 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 172-173 占 폚.
[565] Example L5
[566] 4-Phenylethynyl-phenyl] -carbamic acid tert-butyl ester (Example &lt; RTI ID = 0.0 &
[567] According to general procedure L (method _{b), SnCl 2 · 2H 2} O by reduction using a (2.8g, 12.4 mmol) 5- (4-methylpiperazin-l-yl) ethynyl-4-phenyl- Phenyl] -carbamic acid tert-butyl ester (Example K3) (1.08 g, 2.48 mmol). An orange solid was obtained (1.0 g).
[568] MS (ISP) 407 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 81 to 85 캜.
[569] Example L6
[570] (5-Amino-2-chloro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[571] Following the general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O (2.53 g, 11.2 mmol), (2-chloro-2- nitro-biphenyl- -Butyl ester (Example F1) (783 mg, 2.24 mmol). A yellow solid was obtained (684 mg).
[572] MS (EI) 318 (M ^{& lt} ; ⁺ &gt;) and 320 [(M + 2) &lt; ⁺ &gt;]; Melting point 109-111 [deg.] C.
[573] Example L7
[574] (5-Amino-2-methyl-biphenyl-4-yl) -carbamic acid tert-butyl ester
[575] According to general procedure L (method a), (2-methyl-5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester (example F2) 2.21 mmol, 2.21 mmol). A white solid was obtained (796 mg).
[576] MS (EI) 298 (M ^&lt; ⁺ &gt;); Melting point 122 캜.
[577] Example L8
[578] [2-Amino-5- (2-dimethylamino-ethylsulfanyl) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[579] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O (1.41 g, 6.25 mmol), [5- (2- dimethylamino- ethylsulfanyl) Ethynyl-phenyl] -carbamic acid tert-butyl ester (Example K8) (551 mg, 1.25 mmol) according to general procedure II. An orange foam was obtained (510 mg).
[580] MS (ISP) 412 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 115-117 占 폚.
[581] Example L9
[582] (4-amino-5-tert-butoxycarbonylamino-2-phenylethynyl-phenylsulfanyl] -acetic acid methyl ester
[583] According to general procedure L (method b), by reduction with (SnCl ₂ .2H ₂ O (1.62 g, 7.16 mmol)), (5- tert-butoxycarbonylamino-4-nitro- -Phenylsulfanyl) -acetic acid methyl ester (Example K9) (634 mg, 1.43 mmol). An orange foam was obtained (590 mg).
[584] MS (ISP) 413 [(M + H) <^+> ], 435 [(M + Na) <^+> ] and 451 [(M + K) <^+> ].
[585] Example L10
[586] (4-amino-5-tert-butoxycarbonylamino-2-phenylethynyl-phenyl) -acetic acid methyl ester
[587] According to general procedure L (method b), by reduction with (3.00 g, 13.28 mmol) SnCl ₂ .2H ₂ O (5- tert-butoxycarbonylamino-4-nitro- -Phenyl) -acetic acid methyl ester (example K16) (1.09 g, 2.66 mmol). A light yellow foam was obtained (900 mg).
[588] MS (ISP) 381 [(M + H) <^+> ] and 403 [(M + Na) <^+>]; Melting point 130 캜.
[589] Example L11
[590] [2-Amino-5- (2-methoxy-ethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[591] The - (2-methoxyethoxy) -2-nitro-4-phenyl general procedure L (method b), [5- by reduction using an _{SnCl 2 · 2H 2 O (3.88g} , 17.2 mmol) according to the Phenyl] -carbamic acid tert-butyl ester (Example K10) (1.417 g, 3.44 mmol) according to general procedure II. A cloudy white solid was obtained (1.04 g).
[592] MS (EI) 382 (M ^&lt; ⁺ &gt;); Melting point 105 to 107 占 폚.
[593] Example L12
[594] (2-Amino-5-morpholin-4-yl-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[595] Following general procedure L (method b) in accordance with, SnCl ₂ · 2H ₂ O by reduction using a (1.5g, 6.65 mmol) (5-morpholin-4-yl-2-nitro-4-phenylethynyl-phenyl ) -Carbamic acid tert-butyl ester (Example K4) (563 mg, 1.329 mmol). A reddish brown solid was obtained (488 mg).
[596] MS (ISP) 394 (M ^&lt; ⁺ &gt;); Melting point 174-176 占 폚.
[597] Example L13
[598] (2-Amino-5-methoxy-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[599] General procedure according to the L (method _{b), SnCl 2 · 2H 2} O (3.06g, 13.57 mmol) by reduction using (5-ethynyl-methoxy-2-nitro-4-phenyl-phenyl) -carbamic acid Tert-butyl ester (Example K11) (1.00 g, 2.71 mmol). A yellow solid was obtained (870 mg).
[600] MS (EI) 338 (M ^&lt; ⁺ &gt;); Melting point 158 캜.
[601] Example L14
[602] 4-Amino-5-tert-butoxycarbonylamino-2-phenylethynyl-benzoic acid methyl ester
[603] According to the general procedure L (method b), by reduction with (SnCl ₂ .2H ₂ O (2.15 g, 9.51 mmol)), (5- tert-butoxycarbonylamino-4-nitro- -Benzoic acid methyl ester (Example K15) (754 mg, 1.90 mmol) according to the general procedure G. Obtain a pink solid (431 mg).
[604] MS (EI) 366 (M ^&lt; ⁺ &gt;); Melting point 164 캜.
[605] Example L15
[606] Ethoxy] -ethoxy} -4-phenylethynyl-phenyl] -carbamic acid 3 &lt; RTI ID = 0.0 &gt; Tert-butyl ester
[607] According to general procedure L (method _{b), SnCl 2 · 2H 2} O (6.2g, 27.54 mmol) [5- (2- [2- [2- (2-methoxy by reduction using a-ethoxy) -Phenyl] -carbamic acid tert-butyl ester (Example K12) (3.0 g, 5.51 mmol) according to general procedure II. A brown oil was obtained (2.9 g).
[608] MS (ISP) 515 [(M + H) &lt; ⁺ & gt ^; ].
[609] Example L16
[610] (4-Amino-5-tert-butoxycarbonylamino-2-phenylethynyl-phenoxy) -acetic acid tert-butyl ester
[611] According to general procedure L (method b), by reduction with (3.18 g, 14.10 mmol) SnCl ₂ .2H ₂ O (5- tert-butoxycarbonylamino-4-nitro- -Phenoxy) -acetic acid tert-butyl ester (example K13) (1.32 g, 2.82 mmol). An amorphous orange material was obtained (1.2 g).
[612] MS (ISP) 439 [(M + H) <^+> ] and 461 [(M + Na) <^+> ].
[613] Example L17
[614] (2-Amino-5-cyanomethyl-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[615] According to general procedure L (method _{b), SnCl 2 · 2H 2} O by reduction using a (1.13g, 5.0 mmol) (5-ethynyl-cyano-2-nitro-4-phenyl-phenyl) -carbamic Butyl ester (example K17) (377 mg, 1.0 mmol) according to general procedure II. An orange solid was obtained (338 mg).
[616] MS (ISP) 348 [(M + H) <^+> ] and 370 [(M + Na) <^+>]; Melting point 143 캜.
[617] Example L18
[618] 4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester and [2- (2-amino-5- (1,4-dioxa-8-aza- (4,4-Diethoxy-piperidin-l-yl) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[619] Following general procedure L (method b) in accordance with, SnCl ₂ · 2H ₂ O by reduction using a (4.0g, 18.0 mmol) [5- (1,4-dioxa-8-aza-spiro [4.5] des- 4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester (Example K7) (1.73 g, 3.6 mmol). Brown solid (418 mg) and dark brown solid (379 mg), respectively.
[620] MS (ISP) 450 [(M + H) &lt; ⁺ & gt ^; ]; Mp 79-82 째 C; MS (ISP) 450 [(M + H) &lt; ⁺ & gt ^; ].
[621] Example L19
[622] 4-phenyl-ethynyl-phenyl) -carbamic acid tert-butyl ester (Example &lt; RTI ID = 0.0 &
[623] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O (564 mg, 2.5 mmol), [5- (1,1-dioxo-thiomorpholin- -Phenyl) -carbamic acid tert-butyl ester (Example K6) (235 mg, 0.5 mmol) according to general procedure II. Brown solid (418 mg, impure material, used directly in Example 6 without purification and characterization).
[624] Example L20
[625] Phenyl] -carbamic acid tert-butyl ester (Example &lt; RTI ID = 0.0 &gt;
[626] According to general procedure L (method _{b), SnCl 2 · 2H 2} O (4.6g, 20.32 mmol) by reduction (RS) using the - [5- (2,2-dimethyl- [1,3] dioxolan -4-ylmethoxy) -2-nitro-4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester (example B8) (1.90 g, 4.06 mmol). The crude product was again protected by stirring with 2,2-dimethoxypropane (5 ml) and p-TsOH.H ₂ O (1.1 eq.) In DMF (5 ml) at 23 ° C for 4 h. A brown solid was obtained (1.1 g).
[627] MS (ISP) 439 [(M + H) <^+> ], 461 [(M + Na) <^+> ] and 477 [(M + K) <^+> ].
[628] Example L21
[629] 4-Amino-5-tert-butoxycarbonylamino-2-iodo-benzoic acid methyl ester
[630] Following the general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O (8.02 g, 35.55 mmol), 5-3-butoxycarbonylamino-2-iodo-4-nitro- Methyl ester (example B3) (3.00 g, 7.11 mmol). A bright red foam was obtained (1.9 g).
[631] MS (ISP) 393 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 60-78 占 폚.
[632] Example L22
[633] (RS) - [2-Amino-5- (2-oxo- [1,3] dioxolan-4-ylmethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[634] According to general procedure L (method _{b), SnCl 2 · 2H 2} O by reduction (RS) using a (1.02g, 4.5 mmol) [2-nitro-5- (2-oxo- [1, 3] 4-ylmethoxy) -4-phenylethynyl] -carbamic acid tert-butyl ester [RO-68-8108/000, at 0-23 C in the presence of 1,1'- (Example K18) by treatment with (RS) - [5- (2,3-dihydroxy-propoxy) -2-nitro-4-phenylethynyl- phenyl] -carbamic acid tert-butyl ester ] And 4-fluorophenylboronic acid. A yellow-red solid was obtained (370 mg).
[635] MS (ISP) 425 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 140 캜.
[636] Example L23
[637] (2-Amino-5-ethoxymethyl-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[638] Following general procedure L (method b) in accordance with, SnCl ₂ · Grade 5-3 by reduction using the 2H ₂ O-butoxycarbonylamino-4-nitro-2-phenyl-ethynyl-benzyl ester methyl ester [RO- (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester (prepared as described in Example 1, Step 1) by treatment with methyl chloroformate in THF and Et ₃ N at 68-8481/000, Example K19). &Lt; / RTI &gt; An amorphous brown substance was obtained (135 mg).
[639] MS (ISP) 367 [(M + H) &lt; ⁺ & gt ^; ].
[640] Example L24
[641] 2,2-Dimethyl-propionic acid 4-amino-5-tert-butoxycarbonylamino-2-phenylethynyl-benzyl ester
[642] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O, 2,2-dimethyl-propionic acid 5- tert-butoxycarbonylamino-4-nitro- Benzyl ester [RO-68-9779 / 000, pivaloyl chloride in DMAP at 0-23 &lt; 0 &gt; Prepared from (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester (Example K19) by treatment with DMAP. Amorphous yellow material was obtained (182 mg).
[643] MS (ISN) 421 [(MH) ^- ].
[644] Example L25
[645] (RS) - [2-Amino-4-phenylethynyl-5- (tetrahydro-pyran-2- yloxymethyl) -phenyl] -carbamic acid tert- butyl ester
[646] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O, (RS) - (2-nitro-4-phenylethynyl-5- (tetrahydro- ) -Phenyl] -carbamic acid tert-butyl ester [RO-68-2829 / 000 by treatment with 3,4-dihydro-2H-pyran and cat. TsOH.H ₂ O in DCM at 0 < Phenyl-butyric acid tert-butyl ester (example K19)], a yellow solid was obtained (1.78 g).
[647] MS (ISN) 421 [(MH) ^- ]; Melting point 158 캜.
[648] Example L26
[649] Phenyl] -carbamic acid tert-butyl ester (Example &lt; RTI ID = 0.0 &gt;
[650] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O, 5- (4-methoxy-piperidin-l-yl) -2-nitro- ] -Carbamic acid tert-butyl ester (Example K20) (727 mg, 1.61 mmol). A yellow solid was obtained (489 mg).
[651] MS (ISP) 422 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 173-176 占 폚.
[652] Example L27
[653] (2-Amino-5-cyanomethoxy-4-phenylethynyl-phenyl) -carbamic acid tert-butyl ester
[654] According to general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O (5-ethynyl-2-nitro-4-cyanomethoxy-phenyl-phenyl) -carbamic acid tert-butyl ester ( Example K21) (395 mg, 0.91 mmol). Amorphous yellow material was obtained (219 mg).
[655] MS (ISP) 364 [(M + H) &lt; ⁺ & gt ^; ].
[656] Example L28
[657] (RS) - [2-Amino-4- (4-fluoro-phenylethynyl) -5- (tetrahydro-pyran- 2- yloxymethyl) -phenyl] -carbamic acid tert- butyl ester
[658] [4 - according to the general procedure L (method _{b), SnCl 2 · (RS} ) by reduction using the 2H ₂ O (4-fluoro-phenylethynyl) -2-nitro-5- (tetrahydro- Pyran-2-yloxymethyl) -phenyl] -carbamic acid tert-butyl ester [RO-68-3877 / 000 in 3,4-dihydro-2H-pyran and cat. By treatment with TsOH · H ₂ O prepared from butyl ester (Example K22) - [4- (4-Fluoro-phenylethynyl) -5-hydroxymethyl-2-nitro-phenyl] -carbamic acid tert Lt; / RTI &gt; An amorphous light brown substance was obtained (990 mg).
[659] MS (ISP) 441 [(M + H) &lt; ⁺ & gt ^; ].
[660] Example L29
[661] (4-fluoro-phenylethynyl) -5- [methyl- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -Carbamic acid tert-butyl ester
[662] Following general procedure L (method b) to, SnCl ₂ · by reduction using the 2H ₂ O (RS) according to - (4- (4-fluoro-phenylethynyl) -5- [methyl- [2- (tetrahydro (Example K23) (1.79 g, 3.49 mmol) according to general procedure K (method a), starting from 4-amino-2-nitro-phenyl) -carbamic acid tert-butyl ester. An amorphous light brown substance was obtained (1.20 g).
[663] MS (ISP) 484 [(M + H) &lt; ⁺ & gt ^; ].
[664] Example L30
[665] (RS) - [2-Amino-4-phenylethynyl-5- [2- (tetrahydro- pyran-2- yloxy) -ethoxy] -phenyl] -carbamic acid tert-butyl ester
[666] Following general procedure L (method b) to, SnCl ₂ · by reduction using the 2H ₂ O (RS) according to [2-amino-ethynyl-4-phenyl-5- [2- (tetrahydro-pyran-2 Yloxy) -ethoxy] -phenyl] -carbamic acid tert-butyl ester (Example K24) (420 mg, 0.87 mmol). A light brown solid was obtained (346 mg).
[667] MS (ISP) 453 [(M + H) &lt; ⁺ & gt ^; ].
[668] Example L31
[669] (RS) - [5-amino-4'-fluoro-2- [4- (tetrahydro-pyran-2-yloxy) -piperidin- Butyl &lt; / RTI &gt; tert-butyl ester
[670] According to general procedure L (method a), (RS) - [4'-fluoro-5-nitro-2- [4- ) -Piperidin- l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester (Example K3) (845 mg, 1.64 mmol). A bright green solid was obtained (758 mg).
[671] MS (ISP) 486 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 157-161 占 폚.
[672] Example L32
[673] 4- [4-fluoro-phenylethynyl] -phenyl] -carbamic acid tert-butyl ester (2-amino-5-
[674] According to the general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O, [5- (2,3,4-butoxy-ethoxy) -4- (4-fluoro- ) -2-nitro-phenyl] -carbamic acid tert-butyl ester (Example K25) (744 mg, 1.57 mmol). A light yellow solid was obtained (575 mg).
[675] MS (ISP) 443 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 149-150 占 폚.
[676] Example L33
[677] (RS) - (5-Amino-4'-fluoro-2- [4- [2- (tetrahydro- pyran-2- yloxy) -ethoxy] -piperidin- -4-yl] -carbamic acid tert-butyl ester
[678] According to general procedure L (method a), (RS) - [4'-fluoro-5-nitro-2- [4- [2- (tetrahydro- -Butyl ester (example F4) (900 mg, 1.61 mmol) according to general procedure K (method a), starting from l- (tert-butyldimethylsilyloxy) -ethoxy] -piperidin- l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester. A light brown foam was obtained (779 mg).
[679] MS (ISP) 530 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 56-58 占 폚.
[680] Example L34
[681] (RS) - [5-Amino-4'-fluoro-2- (tetrahydro-pyran-2- yloxymethyl) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[682] According to general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O (RS) - [4'-fluoro-5-nitro-2- (tetrahydro-pyran-2-yloxymethyl ) -Biphenyl-4-yl] -carbamic acid tert-butyl ester (Example F5). An orange solid was obtained (1.15 g).
[683] Melting point 139-142 占 폚.
[684] Example L35
[685] (5-Amino-2-cyanomethoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[686] Following general procedure L (method b), SnCl ₂ · 2H ₂ O by reduction using a in accordance with (5-nitro-2-cyanomethoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid Butyl ester (example F6) (310 mg, 0.8 mmol). A light brown solid was obtained (220 mg).
[687] MS (ISP) 356 [(MH) ^- ]; Melting point 118 to 119 占 폚.
[688] Example L36
[689] (5-Amino-2-dimethylaminomethyl-4'-fluoro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[690] Following general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O according to the (2-dimethylaminomethyl-4'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid Butyl ester (example F7). A yellow solid was obtained (908 mg).
[691] Melting point 97 to 125 캜.
[692] Example L37
[693] [5-Amino-2- (2,2-dimethyl-tetrahydro- [1,3] ] -Carbamic acid tert-butyl ester
[694] According to the general procedure L (method a), by catalytic hydrogenation with Pd / C [2- (2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5- c] -Yl) -4'-fluoro-5-nitro-biphenyl-4-yl] -carbamic acid tert-butyl ester (Example F8) (610 mg, 1.29 mmol). A cloudy white foam was obtained (578 mg).
[695] MS (ISP) 444 [(M + H) &lt; ⁺ & gt ^; ].
[696] Example L38
[697] (5-Amino-4'-fluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert-butyl ester
[698] According to general procedure L (method a), by catalytic hydrogenation with Pd / C (4'-fluoro-2-methoxy-5-nitro- biphenyl- Ester (Example F9) (2.64 g, 7.29 mmol). A cloudy white solid was obtained (2.36 g).
[699] MS (ISP) 333 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 155 캜 (decomposition).
[700] Example L39
[701] 4-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[702] According to general procedure L (method a), by catalytic hydrogenation using Pd / C, [2- (1,4-dioxa-8-aza-spiro [4.5] Yl-carbamic acid tert-butyl ester (Example F10) (2.4 g, 5.0 mmol) according to general procedure II. A green solid was obtained (2.37 g).
[703] MS (ISP) 444 [(M + H) &lt; ⁺ & gt ^; ].
[704] Example L40
[705] (5-Amino-4'-fluoro-2-methyl-biphenyl-4-yl) -carbamic acid tert- butyl ester
[706] According to general procedure L (method a), (4'-fluoro-2-methyl-5-nitro-biphenyl-4-yl) -carbamic acid tert- butyl ester (Example F11) (560 mg, 1.62 mmol). A light brown solid was obtained (512 mg).
[707] MS (ISP) 317 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 112 캜.
[708] Example L41
[709] (5-Amino-4-tert-butoxycarbonylamino-4'-fluoro-biphenyl-2-yloxy) -acetic acid tert- butyl ester
[710] According to general procedure L (method a), (4-tert-butoxycarbonylamino-4'-fluoro-5-nitro-biphenyl-2-yloxy) -Acetic acid tert-butyl ester (Example F12) (2.29 g, 4.95 mmol). A dark blue solid was obtained (2.14 g).
[711] MS (ISP) 433 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 30 to 33 占 폚.
[712] Example L42
[713] (5-Amino-2-chloro-4'-fluoro-biphenyl-4-yl) -carbamic acid tert- butyl ester
[714] (-Biphenyl-4-yl-5-nitro-2-chloro-4'-fluoro) - general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O according to the carbamic acid tert- Butyl ester (example F13). A bright red solid was obtained (544 mg).
[715] MS (ISP) 337 [(M + H) &lt; ⁺ & gt ^; ].
[716] Example L43
[717] [5-Amino-4'-fluoro-2- (2-methoxy-ethoxy) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[718] According to general procedure L (method a), [4'-fluoro-2- (2-methoxy-ethoxy) -5-nitro- biphenyl- -Carbamic acid tert-butyl ester (example F14). A light brown solid was obtained (1.652 g).
[719] MS (ISP) 377 [(M + H) &lt; ⁺ & gt ^; ].
[720] Example L44
[721] [5-Amino-2- (2-tert-butoxy-ethoxy) -4'-fluoro-biphenyl-4-yl] -carbamic acid tert- butyl ester
[722] According to the general procedure L (method a), catalytic hydrogenation with Pd / C afforded [2- (2-tert-butoxy-ethoxy) -4'- fluoro-5-nitro- -Yl] -carbamic acid tert-butyl ester (example F15). A purple solid was obtained (547 mg).
[723] MS (ISP) 419 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 133 캜 (decomposition).
[724] Example L45
[725] The title compound was prepared from [5-amino-4'-fluoro-2- (2-oxo-oxazolidin-
[726] According to general procedure L (method a), by catalytic hydrogenation using Pd / C [4'-fluoro-5-nitro-2- (2- oxo-oxazolidin- 4-yl] -carbamic acid tert-butyl ester (Example F16) (280 mg, 0.67 mmol). A yellow solid was obtained (277 mg).
[727] MS (ISP) 388 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 210 캜.
[728] Example L46
[729] [5-Amino-4'-fluoro-2-methoxy-2'-methyl-biphenyl-4-yl] -carbamic acid tert- butyl ester
[730] According to general procedure L (method a), by catalytic hydrogenation using Pd / C, [4'-fluoro-2-methoxy-2'- methyl-5-nitro- biphenyl- / RTI &gt; acid tert-butyl ester (example F17). A brown solid was obtained (588 mg).
[731] MS (ISP) 347 [(M + H) &lt; ⁺ & gt ^; ].
[732] Example L47
[733] (5-Amino-2-tert-butoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[734] According to the general procedure L (method a), by catalytic hydrogenation with Pd / C (2, 3-Butoxy-4'-fluoro-5-nitro- biphenyl- Butyl ester (example F18) (1.15 g, 2.84 mmol). A pink solid was obtained (747 mg).
[735] MS (ISP) 375 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 139 캜.
[736] Example L48
[737] (5-Amino-2-tert-butoxy-2'-fluoro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[738] According to general procedure L (method a), by catalytic hydrogenation with Pd / C (2, 3-Butoxy-2'-fluoro-5-nitro-biphenyl- Butyl ester (example F19) (930 mg, 2.3 mmol) according to general procedure II. A pink solid was obtained (649 mg).
[739] MS (ISP) 375 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 130 캜.
[740] Example L49
[741] (RS) - [5-amino-4'-fluoro-2 - [(R) -3- (tetrahydro-pyran-2- yloxy) -pyrrolidin- Yl] -carbamic acid tert-butyl ester
[742] According to general procedure L (method a), (RS) - [4'-fluoro-5-nitro-2- [(R) -3- (tetrahydro- Yl) -biphenyl-4-yl] -carbamic acid tert-butyl ester (Example F20). A dark green solid was obtained (852 mg).
[743] MS (ISP) 472 [(M + H) &lt; ⁺ & gt ^; ].
[744] Example L50
[745] (5-Amino-2'-fluoro-2-methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester
[746] According to general procedure L (method a), by catalytic hydrogenation with Pd / C, [2'-fluoro-2-methoxy-5-nitro- biphenyl-4-yl] -carbamic acid tert- Ester (Example F21). A light brown solid was obtained (352 mg).
[747] MS (ISP) 333 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 161 캜.
[748] Example L51
[749] 4-yl] -carbamic acid tert-butyl ester was prepared in accordance with the general method of example 1 from 5-amino-2- (1,4-dioxa-8-aza-spiro [4.5] dec- ester
[750] According to the general procedure L (method a), by catalytic hydrogenation using Pd / C [2- (1,4-dioxa-8-aza-spiro [4.5] dec- 4-yl] -carbamic acid tert-butyl ester (Example F22) (1.39 g, 2.94 mmol) according to general procedure II. A light beige solid was obtained (1.01 g).
[751] MS (ISP) 444 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 198 ° C.
[752] Example L52
[753] (5-Amino-2 ', 5'-difluoro-2-methoxy-biphenyl-4-yl] -carbamic acid tert- butyl ester
[754] According to the general procedure L (method a), by catalytic hydrogenation with Pd / C, [2 ', 5'-difluoro-2-methoxy- Tert-butyl ester (Example F23) (1.05 g, 2.76 mmol). A beige solid was obtained (618 mg).
[755] MS (ISP) 349 [(MH) ^- ]; Melting point 144 캜.
[756] Example L53
[757] [5-Amino-2'-fluoro-2- (2-methoxy-ethoxy) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[758] According to general procedure L (method a), [2'-fluoro-2- (2-methoxy-ethoxy) -5-nitro- biphenyl- -Carbamic acid tert-butyl ester (example F24). A purple solid was obtained (2.581 g).
[759] Example L54
[760] (RS) - [5-amino-2'-fluoro-2- (tetrahydro-pyran-2-yloxymethyl) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[761] According to general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O (RS) - [2'-fluoro-5-nitro-2- (tetrahydro-pyran-2-yloxymethyl ) -Biphenyl-4-yl] -carbamic acid tert-butyl ester (Example F25). A yellow liquid was obtained (2.676 g).
[762] MS (ISP) 439 [(M + Na) &lt; ⁺ & gt ^; ].
[763] Example L55
[764] [5-Amino-2'-fluoro-2- (4-methoxy-benzyloxy) -biphenyl-4-yl] -carbamic acid tert- butyl ester
[765] According to general procedure L (method b), by reduction with SnCl ₂ .2H ₂ O [2'-fluoro-2- (4-methoxy-benzyloxy) Yl-carbamic acid tert-butyl ester (Example F25) (0.90 g, 1.92 mmol). A beige solid was obtained (719 mg).
[766] MS (ISP) 439 [(M + H) &lt; ⁺ & gt ^; ].
[767] Example L56
[768] (5-Amino-2-tert-butoxy-2 ', 5'-difluoro-biphenyl-4-yl) -carbamic acid tert-butyl ester
[769] According to general procedure L (method a), (2, 3-butoxy-2 ', 5'-difluoro-5-nitro- biphenyl- -Carbamic acid tert-butyl ester (example F27). Amorphous gray-blue material was obtained (2.37 g).
[770] MS (ISP) 393 [(M + H) &lt; ⁺ & gt ^; ].
[771] Example L57
[772] 4-Fluoro-phenylethynyl) -phenyl] -carbamic acid tert-butyl ester
[773] According to general procedure L (method b), SnCl ₂ · by reduction using the 2H ₂ O [5-3-tert-butoxycarbonyl-4- (4-fluoro-phenylethynyl) -2-nitro-phenyl; -Carbamic acid tert-butyl ester (Example F26) (649 mg, 1.51 mmol) according to general procedure II. A light yellow solid was obtained (410 mg).
[774] MS (ISP) 399 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 183 ° C.
[775] The following example relates to a process for the preparation of ethyl or tert-butyl 3-aryl-3-oxo-propionate (Formula VIIa) provided as a building block in the synthesis of the target compound ).
[776] General procedure M
[777] Method a: Preparation of ethyl or tert-butyl 3-aryl-3-oxo-propionate
[778] Using ethyl ₃ N and MgCl ₂ in CH ₃ CN at 0-23 ° C according to the literature " Synthesis 1993, 290", aryl acid chloride and ethyl or tert-butyl malonate potassium salt [CAS-no. 6148-64-7 and 75486-33-8, ethyl or tert-butyl 3-aryl-3-oxo-propionate. If free alicarboxylic acids are used in this reaction, they are activated by treatment with Et ₃ N in THF / CH ₃ CN prior to reaction with the malonate salt.
[779] Method b: Preparation of tert-butyl 3-aryl-3-oxo-propionate
[780] Alternatively, lithium tertiary-butyl acetate in the presence of lithium tertiary-butoxide, according to Synthesis 1985,45, can be obtained by treating tertiary-butyl acetate with lithium diisopropylamide in THF at -78 & Butyl 3-aryl-3-oxo-propionate from methyl or ethyl aryl esters. If the product contains residual starting material after the processing, in the end, it should be removed by selective saponification using LiOH in a THF / MeOH / H ₂ O at 23 ℃.
[781] Method c: Preparation of 3-aryl-3-oxo-propionic acid
[782] Et ₃ N and Et ₃ N in CH ₃ CN at 0 ° C according to the method of Synth. Commun . 1985, 15, 1039 (method c1) or at -60 to 0 ° C according to the literature " Synthesis 1979, 787" 3-aryl-3-oxo-propionic acid was prepared from aryl acid chloride and bis (trimethylsilyl) malonate using LiBr.
[783] Example M1
[784] Oxo-3- (3- [1,2,4] triazol-4-yl-phenyl) -propionic acid ethyl ester
[785] RO-71-2790 / 000
[786]
[787] According to general procedure M (method a), the activation with ethyl chloroformate / Et ₃ N and the reaction with ethyl malonate potassium salt using Et ₃ N and MgCl ₂ in CH ₃ CN afforded 3- [ 1,2,4] triazol-4-yl-benzoic acid [RO-71-1432 / 000, prepared by reacting 3-aminobenzoic acid with hydrazine hydrate and triethylorthoformate in acetic acid at 120 & . A white solid was obtained (5.74 g).
[788] MS (EI) 259 (M &lt; ^{+ &} gt ^; ).
[789] Example M2
[790] 3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid ethyl ester
[791] According to general procedure M (method a), the activation with ethyl chloroformate / Et ₃ N and the reaction with ethyl malonate potassium salt using Et ₃ N and MgCl ₂ in CH ₃ CN afforded 3- [ 1,2,4] triazol-1-yl-benzoic acid [RO-71-3703 / 000, methyl 3-azidobenzoate in trimethylsilylacetylene [CAS-No. 93066-93-4], followed by saponification of EtOH with aqueous NaOH with reflux]. A light yellow solid was obtained (2.22 g).
[792] MS (EI) 259 (M ^&lt; ⁺ &gt;); Melting point 72-74 占 폚.
[793] Example M3
[794] 3- (3-Cyano-phenyl) -3-oxo-propionic acid tert-butyl ester
[795] According to general procedure M (method b), 3-cyanobenzoate [CAS-No. 13531-48-1]. A light brown oily semi-solid was obtained.
[796] MS (EI) 245 (M &lt; ^{+ &} gt ^; ).
[797] Example M4
[798] 3- (3-Imidazol-1-yl-phenyl) -3-oxo-propionic acid tert-butyl ester
[799] According to general procedure M (method b), 3- (1H-imidazol-1-yl) benzoate [refluxing in concentrated H ₂ SO ₄ / MeOH to give 3- (1H- (Prepared from imidazol-1-yl) benzoic acid ( J. Med. Chem . 1987 , 30, 1342, CAS-No. 108035-47-8). An orange-brown oil was obtained.
[800] MS (ISP) 287 [(M + H) &lt; ⁺ & gt ^; ].
[801] Example M5
[802] 3- (2-Imidazol-1-yl-pyridin-4-yl) -3-oxo-propionic acid tert- butyl ester
[803] General procedure M (method a) according to, CH ₃ CN of Et ₃ N and MgCl ₂ using 2-imidazol-1-yl-isonicotinoyl chloride hydrochloride [tert-butyl 2-chloro-isonicotinoyl Prepared by reaction of imidazole with NaH in DMF at 80 &lt; 0 &gt; C, treatment with formic acid at 50 &lt; 0 &gt; C and reaction with thionyl chloride in toluene at 100 &lt; 0 &gt; C] and tert- butylmalonate potassium salt. A brown solid was obtained (10.8 g).
[804] MS (EI) 287 (M ^&lt; ⁺ &gt;); Melting point 80 캜 (decomposition).
[805] Example M6
[806] 3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester
[807] According to general procedure M (method b), methyl 3- [1,2,4] triazol-1-yl-benzoate [CAS-No. 167626-27-9. An orange liquid was obtained (2.41 g).
[808] MS (EI) 287 (M &lt; ^{+ &} gt ^; ).
[809] Example M7
[810] 3- [3- (4-Methyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[811] According to general procedure M (method b), lithium tert-butyl acetate by treatment with methyl 3- (4-methyl-imidazol-1-yl) benzoate [RO-69-6483 / 000, the literature "J. Med Prepared from 3-isothiocyanato benzoic acid and 2-aminopropionaldehyde dimethylacetal in concentrated H ₂ SO ₄ / MeOH according to the procedure described in J. Med. Chem . 1987 , 30, 1342 to give the corresponding acid. A tan oil was obtained (10.69 g).
[812] MS (EI) 300 (M &lt; ^{+ &} gt ^; ).
[813] Example M8
[814] 3- [3- (2-Methyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[815] According to general procedure M (method b), treatment with lithium tertiary-butyl acetate gave ethyl 3- (2-methyl-imidazol-1-yl) -benzoate [RO- 69-7480 / prepared from benzo search after Eight from 0 ℃ from EtOH ethylacetamide imidate hydrochloride and the reaction was directly treated with amino acetaldehyde diethyl acetal in EtOH at 23 ℃, the addition of concentrated H ₂ SO ₄ was prepared by refluxing; Respectively. A brown oil was obtained (9.66 g).
[816] MS (ISN) 299 [(MH) ^- ].
[817] Example M9
[818] 3- [3- (2,4-Dimethyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester
[819] According to general procedure M (method b), treatment with lithium tertiary-butyl acetate gave ethyl 3- (2,4-dimethyl-imidazol-l-yl) -benzoate [RO- 71-0583/000, ethyl 3 -Aminobenzoate was reacted with ethylacetimidate hydrochloride in EtOH at 0 &lt; 0 &gt; C, treated directly with 2-aminoacetaldehyde dimethylacetal in EtOH at 23 &lt; 0 &gt; C, then concentrated H ₂ SO ₄ and refluxing Lt; / RTI &gt; A tan oil was obtained (6.00 g).
[820] MS (ISN) 313 [(MH) ^- ].
[821] Example M10
[822] 3- (2-Cyano-pyridin-4-yl) -3-oxo-propionic acid tert-butyl ester
[823] According to general procedure M (method b), 2-cyano-isonicotinic acid ethyl ester [CAS-No. 58481-14-4. A light brown solid was obtained (7.70 g).
[824] MS (ISN) 245 [(MH) ^- ].
[825] Example M11
[826] 3- (3- [1,2,4] Triazol-4-yl-phenyl) -propionic acid tert-butyl ester
[827] According to the general procedure M (method b), methyl 3- [1,2,4] triazol-4-yl-benzoate [3-aminobenzoic acid was reacted with lithium hydride Hydrate and triethylorthoformate, followed by addition of concentrated H ₂ SO ₄ with refluxing MeOH]. A light yellow gum was obtained (870 mg).
[828] MS (ISN) 286 [(MH) ^- ].
[829] Example M12
[830] 3- [3- (2-Methoxymethylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[831] According to general procedure M (method b), by treatment with lithium tertiary-butyl acetate, methyl 3- (2-methoxymethylsulfanyl-imidazol-l-yl) benzoate, which is 3- (2- Sulfanyl-imidazol-1-yl) benzoic acid [CAS-No. 108035-46-7] was esterified with concentrated H ₂ SO ₄ in EtOH followed by treatment with CH ₂ Cl ₂ and treated with NaH in THF / DMF. An orange oil was obtained (1.82 g).
[832] MS (EI) 362 (M &lt; ^{+ &} gt ^; ).
[833] Example M13
[834] 3- [3- (2-Methylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[835] According to general procedure M (method b), by treatment with lithium tertiary-butyl acetate, ethyl 3- (2-methoxymethylsulfanyl-imidazol-1-yl) benzoate, which is 3- (2- Sulfanyl-imidazol-1-yl) benzoic acid [CAS-No. 108035-46-7] was esterified with concentrated H ₂ SO ₄ in EtOH followed by treatment with methyl iodide and NaH in THF / DMF. A light brown oil was obtained (4.41 g).
[836] MS (ISP) 333 [(M + H) &lt; ⁺ & gt ^; ].
[837] Example M14
[838] 3- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[839] According to general procedure M (method b), by treatment with lithium tert-butyl acetate, ethyl 3- (3-methyl-isoxazol-5-yl) benzoate [which is described in Tetrahedron 1984 , 40 , 2985-2988 Ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] was prepared from prepared by reaction of pyridine with NCS, acetamido al doksim, Et ₃ N in CHCl ₃ and a catalytic amount eseo 50 ℃]. A yellow solid was obtained (2.54 g).
[840] MS (ISP) 302 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 50 to 56 占 폚.
[841] Example M15
[842] 3-oxo-3- (3-tetrazol-l-yl-phenyl) -propionic acid ethyl ester
[843] According to general procedure M (method a), the activation with ethyl chloroformate / Et ₃ N and the reaction with ethyl malonate potassium salt using Et ₃ N and MgCl ₂ in CH ₃ CN afforded 3-tetra 1-yl-benzoic acid [CAS-No. 204196-80-5. A light yellow solid was obtained (211 mg).
[844] MS (EI) 260 (M &lt; ^{+ &} gt ^; ).
[845] Example M16
[846] 3- (3-Chloro-thiophen-2-yl) -3-oxo-propionic acid ethyl ester
[847] Following general procedure M (method a), ethyl malonate potassium salt was reacted with Et ₃ N and MgCl ₂ in CH ₃ CN to give 3-tetrazole-2-thiophene carbonyl chloride [CAS-No. 86427-02-3. A brown oil was obtained (6.84 g).
[848] MS (EI) 232 (M ⁺ ) and 234 [(M + 2) ^&lt; ⁺ &gt;
[849] Example M17
[850] 3- (5-Cyano-thiophen-2-yl) -3-oxo-propionic acid tert-butyl ester
[851] According to general procedure M (method b), by treatment with lithium tertiary-butyl acetate, ethyl 5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9. A yellow solid was obtained (6.66 g).
[852] MS (EI) 251 (M ^&lt; ⁺ &gt;); Melting point: 78 캜.
[853] Example M18
[854] 3- (5-Cyano-2-fluoro-phenyl) -3-oxo-propionic acid ethyl ester
[855] According to general procedure M (method a), ethyl malonate potassium salt was reacted with Et ₃ N and MgCl ₂ in CH ₃ CN to give 5-cyano-2-fluoro-benzoyl chloride, which was reacted with SOCl ₂ , cat. Treatment with DMF gave the corresponding acid [CAS-No. 146328-87-2]. A light yellow solid was obtained (3.85 g).
[856] MS (EI) 235 (M ^&lt; ⁺ &gt;); Melting point 55 to 60 占 폚.
[857] Example M19
[858] 3- (2-Imidazol-1-yl-thiazol-4-yl) -3-oxo-propionic acid tert- butyl ester
[859] According to general procedure M (method b), by treatment with lithium tertiary-butyl acetate, ethyl 2-imidazol-1-yl-thiazole-4-carboxylate [CAS- 256420-32-3]. An orange oil was obtained (12.0 g).
[860] Example M20
[861] 3- [2- (4-Methyl-imidazol-1-yl) -thiazol-4-yl] -3-oxo-propionic acid tert- butyl ester
[862] According to general procedure M (method b), by treatment with lithium tertiary-butyl acetate, ethyl 2- (4-methyl-imidazol-l-yl) -thiazole- 1) NaH, 2-isothiocyanato-1,1-dimethoxy-propane, DMF, 23 C; 2) aqueous H ₂ SO ₄ , refluxing; 3) EtOH, concentrated H ₂ SO ₄ , 23 ° C; 4) by _{30% H 2 O 2, HOAc} , 23 ℃ ethyl 2-amino-4-thiazole carboxylate [CAS-No. 256420-32-3]. A brown oil was obtained (8.73 g).
[863] MS (EI) 307 (M &lt; ^{+ &} gt ^; ).
[864] Example M21
[865] 3- [3- (l-methyl-lH-imidazol-l-yl) -phenyl] -3-oxo-propionic acid tert- butyl ester
[866] According to general procedure M (method b), by treatment with lithium tert-butyl acetate, ethyl 3- (1-methyl-1H-imidazol-2-yl) -benzoate [CAS- 168422-44-4. A light yellow liquid was obtained (1.26 g).
[867] MS (ISP) 301.3 [(M + H) &lt; ⁺ & gt ^; ].
[868] The following example relates to a process for the preparation of 6-aryl-2,2-dimethyl- [1,3] dioxin-4-one (Formula VII) provided as a building block in the synthesis of the target compound ).
[869] General procedure N
[870] Preparation of 6-aryl-2,2-dimethyl- [1,3] dioxin-4-one
[871] Method a
[872] Aryl-3-oxo-propionic acid and a catalytic amount of concentrated H ₂ SO ₄ or trifluoroacetic acid (TFA) in isopropenyl acetate at 23 ° C according to the literature " Chem. Pharm. Bull. 1983, 31, Aryl-2,2-dimethyl- [1,3] dioxin-4-one. The final product was purified by silica gel column chromatography using hexane / EtOAc.
[873] Method b
[874] Butyl 3-aryl-3-oxo-propionate was prepared from 6-tert-butyl 3-aryl-3-oxo-propionate by treatment with trifluoro acetic anhydride (TFAA) in a mixture of TFA and acetone at 23 [deg.] C according to the literature " Tetrahedron Lett. 1998, 39, -Aryl-2,2-dimethyl- [1,3] dioxin-4-one. The final product was purified by silica gel column chromatography using hexane / EtOAc as necessary.
[875] Example N1
[876] 2,2-dimethyl-6-thiophen-2-yl- [1,3] dioxin-
[877] According to general procedure M (method c), from thiophene-2-carbonyl chloride (5.3 mL, 50 mmol) was added 3 - (- -Oxo-3-thiophen-2-yl-propionic acid. Following the general procedure N (method a), crude material (7.88 g) was converted to the title compound by stirring in isopropenyl acetate and TFA. A yellow solid was obtained (4.09 g).
[878] MS (EI) 210 (M ^&lt; ⁺ &gt;); Melting point 42 캜 (decomposition).
[879] Example N2
[880] 6- (3-chloro-thiophen-2-yl) -2,2-dimethyl- [1,3] dioxin-
[881] General procedure M (method c) in accordance with, by using the Et ₃ N (12.65㎖, 90.7 mmol) and LiBr (3.53g, 47.5 mmol) in CH ₃ CN at 0 ℃ 3- Chloro-2-carbonyl 3- (3-Chloro-thiophen-2-yl) -3-oxo-propionic acid was prepared from the hydrochloride (7.82 g, 43.2 mmol) and bis (trimethylsilyl) malonate (11.6 mL, 45.4 mmol). Following the general procedure N (method a), crude material (5.69 g) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . An orange solid was obtained (2.3 g).
[882] MS (EI) 244 (M ⁺ ) and 246 [(M + 2) <^+>]; Melting point: 88-89 DEG C (decomposition).
[883] Example N3
[884] Synthesis of 6- (3-cyano-thiophen-2-yl) -2,2-dimethyl- [1,3] dioxin-
[885] General procedure M (method c1) in accordance with, by using the Et ₃ N (41㎖, 295.4 mmol) and LiBr (13.5g, 154.7 mmol) in CH ₃ CN at 0 ℃ 3- cyano-thiophene-2-carbonyl 3- (3-cyano-thiophen-2-yl) -3-oxo-propionic acid was prepared from 2-chlorophenylsulfonyl chloride (24.33 g, 140.6 mmol) and bis (trimethylsilyl) malonate (38.0 mL, 147.7 mmol). Following the general procedure N (method a), crude material (24.8 g) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . An orange solid was obtained (5.6 g).
[886] MS (EI) 235 (M ^&lt; ⁺ &gt;); Melting point 116-120 占 폚 (decomposition).
[887] Example N4
[888] 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile
[889] According to general procedure M (method c2), 3-cyanobenzoyl chloride (828 mg, 5 mmol) and bis (trimethylsilyl chloride) were reacted with n-BuLi (1.6 M in hexane, 6.25 ml) 3- (3-cyano-phenyl) -3-oxo-propionic acid was prepared from 3- (3-cyano-silyl) malonate (2.56 ml, 10 mmol). Following general procedure N (method a), crude material (1.04 g) was converted to the title compound by stirring in isopropenyl acetate and TFA. A light yellow solid was obtained (0.8 g).
[890] MS (EI) 229 (M ^&lt; ⁺ &gt;); Melting point: 138 캜 (decomposition).
[891] Example N5
[892] 2,2-dimethyl-6- (3-trifluoromethyl-phenyl) - [1,3] dioxin-
[893] According to general procedure M (method c1) 3-Trifluoromethylbenzoyl chloride (10 mL) was obtained by using Et ₃ N (20 mL, 142 mmol) and LiBr (6.46 g, 74.4 mmol) in CH ₃ CN at 0 ° C. (3-trifluoromethyl-phenyl) -propionic acid was prepared from 3-oxo-3-oxo-propionic acid, 67.6 mmol) and bis (trimethylsilyl) malonate (18.2 mL, 71 mmol). According to general procedure N (method a), crude material (7.0 g in 15.4 g of the obtained material) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . A light yellow solid was obtained (5.3 g).
[894] MS (EI) 272 (M ^&lt; ⁺ &gt;); Melting point 77-78 캜 (decomposition).
[895] Example N6
[896] 6- (3-Chloro-phenyl) -2,2-dimethyl- [1,3] dioxin-
[897] According to general procedure M (method c1), from 0 ℃ CH ₃ CN in Et ₃ N (25㎖, 180 mmol) and LiBr (8.19g, 94.3 mmol) using 3-chlorobenzoyl chloride (11㎖, 85.7 mmol 3- (3-chloro-phenyl) -3-oxo-propionic acid was prepared from 3- (3-methoxyethoxy) propane and bis (trimethylsilyl) malonate (23.0 mL, 90.0 mmol). Following general procedure N (method a), crude material (17.1 g) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . A tan solid was obtained (8.0 g).
[898] MS (EI) 238 (M ^{& lt} ; ⁺ &gt;) and 240 [(M + 2) &lt; ⁺ &gt; Melting point 87 to 88 占 폚 (decomposition).
[899] Example N7
[900] 6- (3-Iodo-phenyl) -2,2-dimethyl- [1,3] dioxin-
[901] According to general procedure M (method c1), from 0 ℃ CH ₃ CN in Et ₃ N (23㎖, 165.5 mmol) and LiBr (7.54g, 86.7 mmol) using 3-iodo-benzoyl chloride (21.0g, 78.8 3- (3-iodo-phenyl) -3-oxo-propionic acid was prepared from bis (trimethylsilyl) malonate (21.0 mL, 82.8 mmol). According to general procedure N (method a), crude material (21.9 g) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . A yellow solid was obtained (9.6 g).
[902] MS (EI) 330 (M ^&lt; ⁺ &gt;); Melting point 79-80 캜 (decomposition).
[903] Example N8
[904] 2,2-dimethyl-6- (3-trifluoromethoxy-phenyl) - [l, 3] dioxin-
[905] According to general procedure M (method c1), from 3-trifluoromethoxybenzoyl chloride and bis (trimethylsilyl) malonate using Et ₃ N and LiBr in CH ₃ CN at 0 & -Trifluoromethoxy-phenyl) -propionic acid was prepared. Following the general procedure N (method a), the crude material was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . An orange solid was obtained (2.27 g).
[906] MS (EI) 288 (M ^&lt; ⁺ &gt;); Melting point 49 to 54 캜 (decomposition).
[907] Example N9
[908] 2,2-dimethyl-6-pyridin-4-yl- [1,3] dioxin-4-
[909] According to the general procedure N (method b), 3-oxo-3-pyridin-4-yl-propionic acid [repared according to Journal of Antibiotics 1978, 31, 1245 & From 4-acetylpyridine, magnesium methyl carbonate and CO ₂ ]. A white solid was obtained (1.3 g).
[910] MS (EI) 205 (M &lt; ^{+ &} gt ^; ).
[911] Example N10
[912] 6- (3-Imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-
[913] General procedure M (method c1) in accordance with, 3- (1H- imidazol-1-yl) using Et ₃ N and LiBr in CH ₃ CN at 0 ℃ benzoyl chloride hydrochloride [which 3- (1H- imidazole (Prepared by treating SOCl ₂ with CAS-No [108035-47-8] in accordance with the procedure described in J. Med. Chem . 1987 , 30, 1342) -Yl) -phenyl) -3-oxo-propionic acid was prepared according to general procedure N (method a). The crude material was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . A solid was obtained (617 mg).
[914] MS (EI) 270 (M &lt; ^{+ &} gt ^; ).
[915] Example N11
[916] 2,2-dimethyl-6- (3-methoxy-phenyl) - [l, 3] dioxin-
[917] According to general procedure M (method c1), from 0 ℃ CH ₃ CN in Et ₃ N (17.7㎖, 127 mmol) and LiBr using (5.77g, 66.4 mmol) 3-methoxybenzoyl chloride (10.3g, 60.4 3- (3-methoxy-phenyl) -3-oxo-propionic acid was prepared from bis (trimethylsilyl) malonate (16.2 mL, 63.4 mmol). Following the general procedure N (method a), crude material (6.38 g) was converted to the title compound by stirring in isopropenyl acetate and concentrated H ₂ SO ₄ . A yellow oil was obtained (640 mg).
[918] MS (ISP) 235 [(M + H) +] and _{252 [(M + NH 4)} +].
[919] Example N12
[920] 2,2-Dimethyl-6- (3-nitro-phenyl) - [1,3] dioxin-
[921] General procedure M (method a), CH ₃ CN in Et ₃ N (4.5㎖, 32.2 mmol) and MgCl ₂ (3.48g, 36.52 mmol) using 3-nitrobenzoyl chloride (2.71g, 14.6 mmol) and according to 3- (3-nitro-phenyl) -3-oxo-propionic acid tert-butyl ester was prepared from tert-butyl malonate potassium salt (6.0 g, 30.0 mmol). According to general procedure N (method b), crude material (3.88 g) was converted to the title compound by stirring with TFAA in TFA / acetone. A yellow solid was obtained (2.76 g).
[922] MS (EI) 249 (M ^&lt; ⁺ &gt;); Melting point 110-117 占 폚.
[923] Example N13
[924] 2,2-Dimethyl-6- (3- [1,2,4] triazol-1-yl-phenyl) - [1,3] dioxin-
[925] General procedure M (method a), CH ₃ CN in Et ₃ N (4.5㎖, 32.2 mmol) and MgCl ₂ (3.48g, 36.52 mmol) using 3-nitrobenzoyl chloride (2.71g, 14.6 mmol) and according to 3- (3-nitro-phenyl) -3-oxo-propionic acid tert-butyl ester was prepared from tert-butyl malonate potassium salt (6.0 g, 30.0 mmol). According to general procedure N (method b), crude material (3.88 g) was converted to the title compound by stirring with TFAA in TFA / acetone. A yellow solid was obtained (539 mg).
[926] MS (EI) 271 (M &lt; ^{+ &} gt ^; ).
[927] Example N14
[928] 6- (2-Imidazol-1-yl-pyridin-4-yl) -2,2-dimethyl- [1,3] dioxin-
[929] Following the general procedure N (method b), from TFA / acetone in a mixture of 3- (2-imidazol-1-yl-pyridin-4-yl) -3-oxo-propionic acid tert- butyl ester (example M5) &Lt; / RTI &gt; A brown solid was obtained (10.8 g).
[930] MS (EI) 271 (M ^&lt; ⁺ &gt;); Melting point: 151 캜 (decomposition).
[931] Example N15
[932] Dimethyl-6- [3- (2-methyl-imidazol-1-yl) -phenyl] - [
[933] Butyl ester (example M8) was reacted with TFA / acetone &lt; RTI ID = 0.0 &gt; (DMSO) &lt; / RTI &Lt; RTI ID = 0.0 &gt; TFAA. &Lt; / RTI &gt; A beige solid was obtained (2.13 g).
[934] MS (EI) 284 (M ^&lt; ⁺ &gt;); Melting point 122 캜.
[935] Example N16
[936] 4- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -pyridine-
[937] Following the general procedure N (method b), by stirring with 3- (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert- butyl ester (example M10) in TFA / acetone with TFAA . A brown solid was obtained (3.30 g).
[938] MS (EI) 230 (M ^&lt; ⁺ &gt;); Melting point 132 캜 (decomposition).
[939] The following example illustrates the preparation of 4,8-diaryl-1,3-dihydrobenzo [b] [1,4] diazepin-2-one and 4-aryl- Dihydrobenzo [b] [1,4] diazepin-2-one and 8-aroyl-4-aryl-1,3-dihydrobenzo [b] [1,4] 2-one (synthetic reaction formula A).
[940] General procedure O
[941] (2-amino-4-aryl-phenyl) -carbamic acid tert-butyl ester with ethyl 3-aryl-3-oxopropionate or 6-aryl- Butyl ester of [2- [3-aryl-3-oxo-propionylamino] -4-aryl-phenyl] -carbamic acid tert-butyl ester by reaction of 4- And also by the reaction of 2-nitro-4-aryl-phenylamine with 6-aryl-2,2-dimethyl- [1,3] dioxin- -Aryl-phenyl) -3-oxopropionamide. &Lt; / RTI &gt;
[942] (2-amino-4-aryl-phenyl) -carbamic acid tert-butyl ester or 2-nitro-4-aryl-phenylamine (1.0 mmol) and excess (1.2 to 1.5 mmol) of ethyl 3-aryl-3-oxo-propionate [This document ". Synthesis 1993, 290" in accordance with the Et ₃ N and MgCl ₂ in CH ₃ CN at 23 ℃ aryl acid chlorides and Ethyl malonate potassium salt] or 6-aryl-2,2-dimethyl- [1,3] dioxin-4-one was refluxed in toluene (8 mL). The solution was cooled to 23 [deg.] C, so that the product was generally crystallized (hexane was added if crystallization was observed to fail). The solid was filtered off and washed with a mixture of ether or ether / hexane and dried under vacuum to give [2- [3-aryl-3-oxo-propionylamino] -4-aryl- phenyl] -carbamic acid tert- butyl Ester or 3-aryl-N- (2-nitro-4-aryl-phenyl) -3-oxopropionamide, which is used directly in the next step or, if necessary, purified by crystallization or silica gel column chromatography Respectively.
[943] Example O1
[944] 5-thiomorpholin-4-yl-phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt;
[945] Butyl ester (example L1) (653 mg, 1.5 mmol) and 3 (tert-butoxycarbonylamino-ethyl) - (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (690 mg, 2.25 mmol). A yellow solid was obtained (629 mg).
[946] MS (ISP) 607 [(M + H) &lt; ⁺ & gt ^; ].
[947] Example O2
[948] 5-morpholin-4-yl-phenyl] -carbamic acid tert-butyl ester (Example &lt; RTI ID = 0.0 &
[949] Butyl ester (example L2) (690 mg, 1.65 mmol) and 3 (tert-butoxycarbonylamino) - (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (example N4) (566 mg, 2.47 mmol). An orange solid was obtained (523 mg).
[950] MS (ISP) 591 [(M + H) <^+> ] and 613 [(M + Na) <^+> ].
[951] Example O3
[952] The title compound was prepared from [2-chloro-5- [3- (3-cyano-phenyl) -3-oxo- propionylamino] -biphenyl-4-yl] -carbamic acid tert- butyl ester
[953] Butyl ester (example L6) (652 mg, 2.05 mmol) and 3- (2,2-dimethyl-lH-pyrazol- (Example N4) (564 mg, 2.46 mmol) according to general procedure II. A cloudy white solid was obtained (725 mg).
[954] MS (ISN) 488 [(MH) ^&lt;&quot;&gt;].
[955] Example O4
[956] Phenyl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] -5- (2-dimethylamino-ethylsulfanyl) - butyl ester
[957] Butyl ester (example L8) (206 mg, 0.5 &lt; RTI ID = 0.0 &gt; Yl) -benzonitrile (example N4) (138 mg, 0.6 mmol) according to the general procedure L (method a). A yellow solid was obtained (210 mg).
[958] MS (ISP) 583 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 88 캜.
[959] Example O5
[960] 2-Phenylethynyl-phenylsulfanyl] -acetic acid methyl ester (prepared as described in Example 1)
[961] (Example L9) (534 mg, 1.3 mmol) and 3- (4-amino-5-tert-butoxycarbonyl-2-phenylethynyl-phenylsulfanyl) -acetic acid methyl ester (Example N4) (358 mg, 1.56 mmol) according to general procedure II (2). A yellow foam was obtained (457 mg).
[962] MS (ISP) 584 [(M + H) +], 601 [(M + NH 4) +] and ^{605 [(M + Na) +} ]; Melting point 69-73 캜.
[963] Example O6
[964] Phenyl] -acetic &lt; / RTI &gt; acid methyl ester (5-tert-butoxycarbonylamino-4- [3- (3- cyano- phenyl) -3-oxo-propionylamino]
[965] (Example L10) (721 mg, 2.0 mmol) and 3- (2-methoxy-phenyl) -acetic acid methyl ester (2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (550 mg, 2.4 mmol). A light yellow solid was obtained (886 mg).
[966] MS (ISP) 552 [(M + H) +] and _{569 [(M + NH 4)} +]; Melting point 138 占 폚.
[967] Example O7
[968] Phenyl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] -5- (2-methoxy-ethoxy) Butyl ester
[969] Butyl ester (example L11) (415 mg, 1.09 mmol) was reacted with 2-amino-5- (2-methoxy-ethoxy) ) And 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (373 mg, 1.63 mmol). A light yellow solid was obtained (137 mg).
[970] MS (ISP) 554 [(M + H) +], 571 [(M + NH 4) +] and ^{576 [(M + Na) +} ]; Melting point 175-176 占 폚.
[971] Example O8
[972] Phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt; (2-methoxy- &lt; / RTI &
[973] Butyl ester (example L12) (338 mg, 1.0 mmol) and 3- (2-amino-5-methoxy-4-phenylethynyl- (Example N4) (252 mg, 1.1 mmol) according to general procedure II. A yellow solid was obtained (388 mg).
[974] MS (ISP) 510 [(M + H) +], 527 [(M + NH 4) +] and ^{532 [(M + Na) +} ]; Melting point 169 캜.
[975] Example O9
[976] 3- (3-Cyano-phenyl) -3-oxo-propionylamino] -2-phenylethynyl-benzoic acid methyl ester
[977] According to general procedure O, 4-amino-5-tert-butoxycarbonyl-2-phenylethynyl-benzoic acid methyl ester (Example L14) (396 mg, 1.08 mmol) and 3- (2,2- -6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (273 mg, 1.19 mmol). A cloudy white solid was obtained (540 mg).
[978] MS (ISP) 538 [(M + H) +], 555 [(M + NH 4) +] and ^{560 [(M + Na) +} ]; Melting point 158 캜 (decomposition).
[979] Example O10
[980] 5-morpholin-4-yl-4-phenyl-ethynyl-phenyl] -carbamic acid tert-butyl ester
[981] (Example L12) (483 mg, 1.23 mmol) and 3 &lt; RTI ID = 0.0 &gt; (Example N4) (422 mg, 1.84 mmol) according to the procedure described in Example 1. Yellow solid was obtained (375 mg).
[982] MS (ISP) 565 [(M + H) <^+> ] and 587 [(M + Na) <^+> ].
[983] Example O11
[984] 2- [2- [2- (2-methoxy-ethoxy) -ethoxy] - &lt; / RTI &gt; Ethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[985] According to general procedure O, the title compound was prepared from [2-amino-5- (2- [2- [2- (2-methoxy-ethoxy) -ethoxy] -ethoxy] Phenyl] -carbamic acid tert-butyl ester (Example L15) (514 mg, 1.0 mmol) and 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin- -Benzonitrile (example N4) (344 mg, 1.5 mmol). A light yellow solid was obtained (353 mg).
[986] MS (ISP) 686 [(M + H) +] and _{703 [(M + NH 4)} +]; Melting point 135-136 占 폚.
[987] Example O12
[988] Phenoxy] -acetic acid tert-butyl ester was prepared in analogy to the procedure described for the synthesis of [5- tert-butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino] ester
[989] (Example L16) (877 mg, 2.0 mmol) was coupled to (4-amino-5-tert-butoxycarbonylamino-2-phenylethynyl- phenoxy) (Example N4) (504 mg, 2.2 mmol) according to general procedure II (2). A yellow solid was obtained (723 mg).
[990] MS (ISP) 610 [(M + H) +], 627 [(M + NH 4) +] and ^{632 [(M + Na) +} ]; Melting point 95 캜.
[991] Example O13
[992] Phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt; (3-cyano-
[993] (Example L17) (298 mg, 0.86 mmol) and 3- (2-amino-5-cyanomethyl-4-phenylethynyl-phenyl) -carbamic acid tert- butyl ester (Example N4) (218 mg, 0.95 mmol) according to the general method of example 1. Yielding a yellow solid (299 mg ).
[994] MS (ISP) 519 [(M + H) +], 536 [(M + NH 4) +] and ^{541 [(M + Na) +} ]; Melting point 98 캜.
[995] Example O14
[996] 8-aza-spiro [4.5] dec-8-yl) -4-oxo-propionylamino] -5- (1,4-dioxa-8- -Phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[997] According to general procedure O, the title compound was prepared from [2-amino-5- (1,4-dioxa-8-aza-spiro [4.5] dec- (Example N4) (393 mg, 0.87 mmol) and 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin- (301 mg, 1.31 mmol). An amorphous orange material was obtained (268 mg).
[998] MS (ISP) 621 [(M + H) &lt; ⁺ & gt ^; ].
[999] Example O15
[1000] 4-phenylethynyl-phenyl] -carbamic acid tert-butoxycarbonylamino-3- (2-methoxy-ethoxy) Butyl ester
[1001] According to general procedure O, the title compound was prepared from [2-amino-5- (2-methoxy-ethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert- butyl ester (example L11) (840 mg, 2.2 mmol ) And 6- (3-iodo-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N7) (780 mg, 2.36 mmol). A white solid was obtained (1.3 g).
[1002] MS (ISP) 655 [(M + H) +], 672 [(M + NH 4) +], 677 [(M + Na) +] and ^{693 [(M + K) +} ]; Melting point: 172 占 폚.
[1003] Example O16
[1004] [2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -5- (2,2- dimethyl- [1.3] dioxolan- -Phenyl] -carbamic acid tert-butyl ester
[1005] According to general procedure O, the title compound was prepared from [2-amino-5- (2,2-dimethyl- [1.3] dioxolan-4-ylmethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester Example L7) (345 mg, 1.0 mmol) and 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin- 1.5 mmol). A yellow solid was obtained (275 mg).
[1006] MS (ISP) 610 [(M + H) +], 627 [(M + NH 4) +] and ^{632 [(M + Na) +} ]; Melting point 132 to 134 占 폚.
[1007] Example O17
[1008] 3- tert-Butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2-iodo-benzoic acid methyl ester
[1009] (Example L21) (395 mg, 1.0 mmol) and 3- (2,2-dimethyl-2-methyl-2-iodo-benzoic acid methyl ester -6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (254 mg, 1.1 mmol). A pale-colored solid was obtained (435 mg).
[1010] MS (ISP) 564 [(M + H) +], 581 [(M + NH 4) +] and ^{586 [(M + Na) +} ]; Melting point 162-166 占 폚.
[1011] Example O18
[1012] Methoxy-ethoxy) -4-phenylethynyl] -phenyl] - (2-methoxy-ethoxy) Carbamic acid tert-butyl ester
[1013] Following the general procedure O, the title compound was prepared from (2-amino-5- (2-methoxy-ethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert- butyl ester ) And 6- (3-imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10) (135 mg, 0.5 mmol). A light brown waxy solid was obtained (206 mg).
[1014] MS (ISN) 593 [(MH) ^- ]; Melting point 122-129 占 폚.
[1015] Example O19
[1016] [RS] - [2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -Phenylethynyl-phenyl] -carbamic acid tert-butyl ester
[1017] 4-ylmethoxy) -4-phenylethynyl] -phenyl] -carbamic acid tert-butyl ester as a light yellow solid, MS (ISP) 6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (206 mg, 0.9 mmol). A light yellow solid was obtained (433 mg).
[1018] MS (ISP) 594 [(MH) &lt; ⁺ & gt ^; ]; Melting point 181 ° C.
[1019] Example O20
[1020] Phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt; (2-ethoxy-
[1021] (Example L23) (130 mg, 0.35 mmol) and 3- (2-amino-5-ethoxymethyl-4-phenylethynyl-phenyl) -carbamic acid tert- butyl ester (Example N4) (80 mg, 0.35 mmol) according to the general method of example 1, step 2. Obtained amorphous yellow material (148 mg, 0.35 mmol) Mg).
[1022] MS (ISP) 538 [(MH) ^&lt; ⁺ & gt ^; ].
[1023] Example O21
[1024] 3-oxo-propionylamino] -2-phenyl-ethynyl-benzyl ester (prepared by reacting 2,2-dimethyl-propionic acid 5-tert-butoxycarbonylamino-4- [3-
[1025] (Example L24) (155 mg, 0.37 mmol) and 3, 2-dimethyl-propionic acid 4-amino-5-tert-butoxycarbonylamino-2-phenylethynyl- benzyl ester - (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (example N4) (94 mg, 0.41 mmol). An amorphous bright orange material was obtained (184 mg).
[1026] MS (ISP) 611 [(M + NH 4) +].
[1027] Example O22
[1028] (R) - [2- [3- (3-Imidazol-1 -yl-phenyl) -3-oxo-propionylamino] -4- phenylethynyl-5- (tetrahydro- Methyl) -phenyl] -carbamic acid tert-butyl ester
[1029] According to general procedure O, (RS) - [2-amino-4-phenylethynyl-5- (tetrahydro-pyran-2-yloxymethyl) -phenyl] -carbamic acid tert- ) And 6- (3-imidazol-1-yl-phenyl) - (2,2-dimethyl- [1,3] dioxin-4-one (example N10). Amorphous yellow material was obtained (267 mg).
[1030] MS (ISP) 635 [(M + H) &lt; ⁺ & gt ^; ].
[1031] Example O23
[1032] Phenyl] -3-oxo-propionylamino] -5- (4-methoxy-piperidin- -Phenyl] -carbamic acid tert-butyl ester
[1033] Phenyl] -carbamic acid tert-butyl ester (Example L26) ((2-Amino-5- (4-methoxy-piperidin- Phenyl) - (2,2-dimethyl- [1,3] dioxin-4-one (example N10) (151 mg, 0.56 mmol) Mmol). Amorphous yellow material was obtained (253 mg).
[1034] MS (ISP) 634 [(M + H) &lt; ⁺ & gt ^; ].
[1035] Example O24
[1036] Phenyl] - (4-methoxy-piperidin-l-yl) -4-phenyl- Carbamic acid tert-butyl ester
[1037] Phenyl] -carbamic acid tert-butyl ester (Example L26) ((2-Amino-5- (4-methoxy-piperidin- (Example N4) (125 mg, 0.53 mmol) was reacted with 3- (2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile . A yellow foam was obtained (274 mg).
[1038] MS (ISN) 591 [(MH) ^- ]; Melting point 97-100 占 폚.
[1039] Example O25
[1040] Phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt; (5-cyanomethoxy-2- [3-
[1041] (Example L27) and 6- (3-imidazol-1-yl) -carbamic acid tert-butyl ester -Phenyl) - (2,2-dimethyl- [1,3] dioxin-4-one (example N10). Amorphous yellow material was obtained (169 mg).
[1042] MS (ISP) 576 [(M + H) &lt; ⁺ & gt ^; ].
[1043] Example O26
[1044] Phenyl] -carbamic acid tert-butyl ester &lt; RTI ID = 0.0 &gt; (5-cyanomethoxy-2- [3-
[1045] (Example L27) (80 mg, 0.22 mmol) and 3- (2-amino-5-cyanomethoxy-4-phenylethynyl-phenyl) -carbamic acid tert- butyl ester (2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) benzonitrile (Example N4) (55 mg, 0.24 mmol). Amorphous yellow material was obtained (96 mg).
[1046] MS (ISP) 533 [(MH) ^- ].
[1047] Example O27
[1048] (4-fluoro-phenylethynyl) -2- [3- (3-imidazol- 1 -yl-phenyl) -3-oxo-propionylamino] -5- (tetrahydro -Pyran-2-yloxymethyl) -phenyl] -carbamic acid tert-butyl ester
[1049] Following general procedure O, the title compound was obtained from (RS) - [2-amino-4- (4-fluoro-phenylethynyl) -5- (tetrahydro- pyran- 2- yloxymethyl) -phenyl] -Butyl ester (example L28) and 6- (3-imidazol-l-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10). Amorphous yellow material was obtained (990 mg).
[1050] MS (ISN) 651 [(MH) ^- ].
[1051] Example O28
[1052] (4-fluoro-phenylethynyl) -2- [3- (3-imidazol-1 -yl-phenyl) -3-oxo-propionylamino] [2- (Tetrahydro-pyran-2-yloxy) -ethyl] -amino} -phenyl) -carbamic acid tert- butyl ester
[1053] According to general procedure O, (RS) - [2-amino-4- (4-fluoro-phenylethynyl) -5- [methyl- [2- (tetrahydro- (2-amino-phenyl) -carbamic acid tert-butyl ester (Example L29) (242 mg, 0.5 mmol) and 6- (3-imidazol- , 3] dioxin-4-one (example N10) (135 mg, 0.5 mmol). Amorphous yellow material was obtained (198 mg).
[1054] MS (ISN) 694 [(MH) ^- ].
[1055] Example O29
[1056] Phenyl] -3-oxo-propionylamino] -4-phenyl-3-oxo-2- Ethynyl-phenyl] -carbamic acid tert-butyl ester
[1057] According to general procedure O, the title compound was synthesized from [2-amino-5- (4,4-diethoxy-piperidin- 1 -yl) -4-phenylethynyl- ) (321 mg, 0.67 mmol) and 6- (3-imidazol-l-yl-phenyl) -2,2- dimethyl- [1,3] dioxin- 0.89 mmol). An orange foam was obtained (295 mg).
[1058] MS (ISP) 692 [(M + H) &lt; ⁺ & gt ^; ].
[1059] Example O30
[1060] (RS) - [2- [3- (3-Imidazol-1 -yl-phenyl) -3-oxo-propionylamino] -4- phenylethynyl-5- [2- (tetrahydro- - yloxy) -ethoxy] -phenyl] -carbamic acid tert-butyl ester
[1061] According to general procedure O, the title compound was obtained from (RS) - [2-amino-4-phenylethynyl-5- [2- (tetrahydro- pyran- 2- yloxy) -ethoxy] -phenyl] (Example L30) (346 mg, 0.76 mmol) and 6- (3-imidazol-l-yl-phenyl) -2,2- dimethyl- [l, 3] dioxin- N10) (300 mg, 1.11 mmol). A yellow foam was obtained (196 mg).
[1062] MS (ISP) 665 [(M + H) &lt; ⁺ & gt ^; ].
[1063] Example O31
[1064] (RS) - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -2- [4- -Yloxy) -piperidin- l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1065] Following general procedure O, the title compound was obtained from (RS) - [2-amino-4- (4-fluoro-phenylethynyl-5- (tetrahydro- pyran- 2- yloxymethyl) -phenyl] Butyl ester (example L28) and 6- (3-imidazol-l-yl-phenyl) -2,2-dimethyl- [1,3] dioxin- A solid was obtained (282 mg).
[1066] MS (ISP) 698 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 129 to 132 占 폚.
[1067] Example O32
[1068] 2- [3- (3-Imidazol-1 -yl-phenyl) -3-oxo-thiophene- -Propionylamino] -phenyl] -carbamic acid tert-butyl ester
[1069] According to general procedure O, the title compound was synthesized from [2-amino- [5- (2,3-butoxy-ethoxy) -4- (4- fluoro- phenylethynyl) -phenyl] -carbamic acid tert- butyl ester (Example L02) (560 mg, 1.27 mmol) and 6- (3-imidazol-l-yl-phenyl) -2,2- dimethyl- [1,3] dioxin- (413 mg, 1.53 mmol). A yellow solid was obtained (507 mg).
[1070] MS (ISP) 655 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 62 to 65 占 폚.
[1071] Example O33
[1072] (RS) - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -2- [4- -Yloxy) -ethoxy] -piperidin-l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1073] According to general procedure O, (RS) - (5-amino-4'-fluoro-2- [4- (2- (tetrahydro-pyran-2-yloxy) -ethoxy] -piperidin- Yl) -carbamic acid tert-butyl ester (Example L33) and 6- (3-imidazol-l-yl-phenyl) -2,2-dimethyl- [1,3 ] Dioxin-4-one (example N10). A yellow solid was obtained (473 mg).
[1074] MS (ISP) 742 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 57-58 占 폚.
[1075] Example O34
[1076] (RS) - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -2- (tetrahydro- Methyl) -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1077] According to general procedure O, the title compound was obtained from (RS) - [5-amino-4'-fluoro-2- (tetrahydro-pyran- 2- yloxymethyl] Ester (example L34) and 6- (3-Imidazol-l-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10). A light yellow solid was obtained (330 mg).
[1078] Example O35
[1079] Phenyl] -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert- Tert-butyl ester
[1080] (Example L35) (190 mg, 0.53 mmol) according to general procedure O following the procedure used for the synthesis of (5-amino-2-cyanomethoxy-4'- 2-dimethyl- [l, 3] dioxin-4-one (example N10) (164 mg, 0.61 mmol) according to general procedure II. Yellow gum was obtained (90 mg).
[1081] MS (ISP) 570 [(M + H) &lt; ⁺ & gt ^; ].
[1082] Example O36
[1083] 4- [3- (3-Imidazol-1-yl-phenyl) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid Tert-butyl ester
[1084] Following the general procedure O, the title compound was obtained from (5- amino-2-dimethylaminomethyl-4'-fluoro-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L36) L-yl-phenyl) -2,2-dimethyl- [l, 3] dioxin-4-one (example N10). A light yellow solid was obtained (329 mg).
[1085] Example O37
[1086] [4, 5-c] pyrrol-5-yl) -4'-fluoro-5- [3- (3-imidazole Yl-phenyl) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1087] According to general procedure O, the title compound was obtained from [5-amino-2- (2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5- c] pyrrol- Yl) -carbamic acid tert-butyl ester (Example L37) (465 mg, 1.05 mmol) and 6- (3-imidazol- 1,3] dioxin-4-one (example N10) (314 mg, 1.16 mmol). Amorphous yellow material was obtained (540 mg).
[1088] MS (ISN) 654 [(MH) ^&lt;&quot;&gt;].
[1089] Example O38
[1090] Biphenyl-4-yl] -carbamic acid 3 &lt; RTI ID = 0.0 &gt; 3-oxo-propionylamino] -2-methoxy-biphenyl- Tert-butyl ester
[1091] According to general procedure O, (5-amino-4'-fluoro-2-methoxy-biphenyl-4-yl] -carbamic acid tert- butyl ester (example L38) (332 mg, 1.0 mmol) Prepared from 6- (3-imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10) (270 mg, 1.0 mmol) The material was obtained (328 mg).
[1092] MS (ISN) 543 [(MH) ^&lt;&quot;&gt;].
[1093] Example O39
[1094] 4-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -pyridin- ) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1095] According to general procedure O, the title compound was synthesized from [5-amino-2- (1,4-dioxa-8-aza- spiro [4,5] dec-8-yl) -4'- ] -Carbamic acid tert-butyl ester (Example L39) (444 mg, 1.0 mmol) and 6- (3-imidazol- One (example N10) (321 mg, 1.19 mmol). A brown solid was obtained (457 mg).
[1096] MS (ISN) 654 [(MH) ^- ]; Melting point 110 to 115 캜.
[1097] Example O40
[1098] Biphenyl-4-yl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] -2-methyl-biphenyl- - butyl ester
[1099] Butyl ester (example L40) (316 mg, 1.0 mmol) and 6 (tert-butoxycarbonylamino) -4-fluoro-2-methyl- (Example N10) (297 mg, 1.1 mmol) according to the general method of example 1, step 2. The title compound was prepared as an amorphous yellow material (361 mg).
[1100] MS (ISP) 529 [(M + H) &lt; ⁺ & gt ^; ].
[1101] Example O41
[1102] 4- [3- (3-imidazol-1 -yl-phenyl) -3-oxo-propionylamino] -biphenyl- Yloxy] -acetic acid tert-butyl ester
[1103] According to general procedure O, tert-butyl ester (example L41) (1.4-tert-Butoxycarbonylamino-4'-fluoro-biphenyl- 3.25 mmol, 3.24 mmol) and 6- (3-imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin- (759 mg). &Lt; / RTI &gt;
[1104] MS (ISP) 645 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 82-85 캜.
[1105] Example O42
[1106] 4-yl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] - biphenyl- - butyl ester
[1107] Butyl ester (example L42) (168 mg, 0.5 mmol) and 6 (5-amino-2-chloro-4'- (Example N10) (252 mg, 0.93 mmol) according to the general procedure L (a) as a light yellow solid, MS (ISP) (156 mg).
[1108] MS (ISN) 547 [(MH) ^&lt;&quot;&gt;].
[1109] Example O43
[1110] (4-fluoro-5- [3- (3-imidazol-l-yl-phenyl) -3-oxo-propionylamino] -2- (2-methoxy-ethoxy) -Yl] -carbamic acid tert-butyl ester
[1111] 4-yl] -carbamic acid tert-butyl ester (Example L43) ((2-Methoxy-ethoxy) (Example N10) (260 mg, 0.96 mmol, 0.5 mmol) and 6- (3-imidazol-1-yl-phenyl) -2,2- dimethyl- [1,3] dioxin- ). An orange solid was obtained (218 mg).
[1112] MS (ISP) 589 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 61 to 63 캜.
[1113] Example O44
[1114] Phenyl] -3-oxo-propionylamino] -bis (4-fluoro-phenyl) Phenyl-4-yl] -carbamic acid tert-butyl ester
[1115] According to general procedure O, the title compound was prepared from [5-amino-2- (2,3-butoxy-ethoxy) -4'- fluoro- L44) (209 mg, 0.5 mmol) and 6- (3-imidazol-l-yl-phenyl) -2,2- dimethyl- [1,3] dioxin- , 0.5 mmol). A beige solid was obtained (194 mg).
[1116] MS (ISP) 631 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 101 캜.
[1117] Example O45
[1118] 2- (2-oxo-oxazolidin-3-yl) - (4-fluoro-5- [3- Biphenyl-4-yl] -carbamic acid tert-butyl ester
[1119] Following general procedure O, the title compound was prepared from [5-amino-4'-fluoro-2- (2-oxo-oxazolidin-3-yl) -biphenyl-4-yl] -carbamic acid tert- (Example N10) (92 mg, 0.34 mmol) and 6- (3-imidazol-l-yl-phenyl) -2,2- dimethyl- [1,3] dioxin- Mg, 0.34 mmol) according to general procedure II. Amorphous yellow material was obtained (86 mg).
[1120] MS (ISP) 600 [(M + H) &lt; ⁺ & gt ^; ].
[1121] Example O46
[1122] [4'-fluoro-5- [3- (3-imidazol-l-yl-phenyl) -3-oxo-propionylamino] -2- methoxy- ] -Carbamic acid tert-butyl ester
[1123] According to general procedure O, (5-amino-4'-fluoro-2-methoxy-2'-methyl-biphenyl-4-yl] -carbamic acid tert- butyl ester (example L46) , 0.5 mmol) and 6- (3-imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10) (199 mg, 1.47 mmol) Orange solid (182 mg).
[1124] MS (ISP) 559 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 99-102 占 폚.
[1125] Example O47
[1126] Phenyl] -4-oxo-propionylamino] - biphenyl-4-yl] - Carbamic acid tert-butyl ester
[1127] According to general procedure O, (5-amino-2-tert-butoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L47) Phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10) (135 mg, 0.5 mmol) according to general procedure II . Amorphous yellow material was obtained (237 mg).
[1128] MS (ISN) 585 [(MH) ^&lt;&quot;&gt;].
[1129] Example O48
[1130] Phenyl] -4-oxo-propionylamino] -biphenyl-4-yl] - (2-fluoro- Carbamic acid tert-butyl ester
[1131] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; Phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (example N10) (135 mg, 0.5 mmol) according to general procedure II . Amorphous yellow material was obtained (234 mg).
[1132] MS (ISN) 585 [(MH) ^&lt;&quot;&gt;].
[1133] Example O49
[1134] (RS) - [4'-fluoro-5- [3- (3-imidazol- 1 -yl-phenyl) -3-oxo-propionylamino] -Pyran-2-yloxy) -pyrrolidin- l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1135] According to general procedure O, (RS) - (5-amino-4'-fluoro-2 - [(R) -3- (tetrahydro-pyran- 2- yloxy) -pyrrolidin- Yl) -carbamic acid tert-butyl ester (Example L49) (236 mg, 0.5 mmol) and 6- (3-imidazol- - [l, 3] dioxin-4-one (example N10) (200 mg, 0.74 mmol). An orange solid was obtained (188 mg).
[1136] MS (ISP) 684 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 99 to 103 캜.
[1137] Example O50
[1138] Biphenyl-4-yl] -carbamic acid 3 &lt; RTI ID = 0.0 &gt; 3-oxo-propionylamino] -2-methoxy-biphenyl- Tert-butyl ester
[1139] Butyl ester (example L50) (159 mg, 0.5 mmol) and (5-amino-2'-fluoro-2-methoxy- Phenyl) -2,2-dimethyl- [l, 3] dioxin-4-one (example N10) (135 mg, 0.5 mmol) according to general procedure II. Amorphous yellow material was obtained (199 mg).
[1140] MS (ISN) 543 [(MH) ^&lt;&quot;&gt;].
[1141] Example O51
[1142] 4-fluoro-biphenyl-4-yl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] -4'-fluoro-biphenyl- - butyl ester
[1143] According to general procedure O, (5-amino-2-tert-butoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L47) Yl) -benzonitrile (Example N4) (126 mg, 0.55 mmol) according to general procedure II. An amorphous bright pink material was obtained (196 mg).
[1144] MS (ISP) 546 [(M + H) &lt; ⁺ & gt ^; ].
[1145] Example O52
[1146] 2-fluoro-biphenyl-4-yl] -carbamic acid tert-butoxycarbonylamino-3-oxo-propionylamino] -2'-fluoro-biphenyl- - butyl ester
[1147] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; Yl) -benzonitrile (Example N4) (126 mg, 0.55 mmol) according to general procedure II. An amorphous bright pink substance was obtained (197 mg).
[1148] MS (ISP) 546 [(M + H) &lt; ⁺ & gt ^; ].
[1149] Example O53
[1150] The title compound was prepared from [5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2'-fluoro-2-methoxy- biphenyl-
[1151] Butyl ester (Example L50) (112 mg, 0.35 mmol) and (5-amino-2'-fluoro-2-methoxy-biphenyl- Oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (80 mg, 0.35 mmol). A yellow foam was obtained (131 mg).
[1152] MS (ISN) 502 [(MH) ^- ].
[1153] Example O54
[1154] (2'-fluoro-2-methoxy-5- [3- [3- (2-methyl- imidazol- 1 -yl) -phenyl] -3-oxo-propionylamino] Yl) -carbamic acid tert-butyl ester
[1155] (Example L50) (249 mg, 0.75 mmol) and (5-amino-2'-fluoro-2-methoxy-biphenyl- Prepared from 3- [3- (2-methyl-imidazol-l-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (example N8) (275 mg, 0.92 mmol). A yellow solid was obtained (312 mg).
[1156] MS (ISP) 559 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 83 to 86 占 폚.
[1157] Example O55
[1158] 2-fluoro-2-methoxy-biphenyl-4-yl] -carbamic acid ethyl ester was prepared in analogy to the procedure described for the synthesis of [5- [3- (5-cyano-thiophen- Tert-butyl ester
[1159] Butyl ester (example L50) (166 mg, 0.5 mmol) and (5-amino-2'- fluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- Prepared from 3- (5-cyano-thiophen-2-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (example N17) (138 mg, 0.55 mmol). A light yellow solid was obtained (244 mg).
[1160] MS (ISP) 510 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 200 캜 (decomposition).
[1161] Example O56
[1162] [2'-fluoro-2-methoxy-5- [3-oxo-3- -Yl] -carbamic acid tert-butyl ester
[1163] Butyl ester (example L50) (166 mg, 0.5 mmol) and (5-amino-2'- fluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- Prepared from 3-oxo-3- (3- [1,2,4] triazol-4-yl-phenyl) -propionic acid ethyl ester (Example M1) (260 mg, 1.0 mmol). Yellow gum was obtained (70 mg).
[1164] MS (ISP) 546 [(M + H) &lt; ⁺ & gt ^; ].
[1165] Example O57
[1166] 2-methoxy-biphenyl-4-yl] -carbamic acid 3 &lt; RTI ID = 0.0 &gt; Tert-butyl ester
[1167] According to general procedure O, the title compound was obtained from (5-amino-2'-fluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L50) and 3- -Pyridin-4-yl) -3-oxo-propionic acid tert-butyl ester (example N10). A light yellow solid was obtained (189 mg).
[1168] MS (ISP) 522 [(M + NH 4) +].
[1169] Example O58
[1170] (2-methyl-imidazol-1-yl) -phenyl] -3-oxo-propionylamino] -biphenyl -4-yl] -carbamic acid tert-butyl ester
[1171] Butyl ester (example L47) (140 mg, 0.37 &lt; RTI ID = 0.0 &gt; Butyl ester (example N8) (111 mg, 0.37 mmol) according to the general procedure G (method a), starting from l- (2-methyl-imidazol- Amorphous yellow material was obtained (139 mg).
[1172] MS (ISP) 601 [(M + H) &lt; ⁺ & gt ^; ].
[1173] Example O59
[1174] 2-fluoro-2-methoxy-biphenyl-4-yl] -carbamic acid tert- Tert-butyl ester
[1175] Butyl ester (example L50) (166 mg, 0.5 mmol) and (5-amino-2'- fluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- Prepared from 3- (5-cyano-2-fluoro-phenyl) -3-oxo-propionic acid tert-butyl ester (Example N18) (141 mg, 0.6 mmol). An amorphous yellow solid was obtained (165 mg).
[1176] MS (ISP) 522 [(M + H) &lt; ⁺ & gt ^; ].
[1177] Example O60
[1178] 4-fluoro-biphenyl-4-yl] - (3-oxo-propionylamino) Carbamic acid tert-butyl ester
[1179] Butyl ester (example L47) (140 mg, 0.37 &lt; RTI ID = 0.0 &gt; Propionic acid tert-butyl ester (example M10) (91 mg, 0.37 mmol) according to general procedure II (2). Amorphous yellow material was obtained (164 mg).
[1180] MS (ISP) 547 [(M + H) &lt; ⁺ & gt ^; ].
[1181] Example O61
[1182] 3- [3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -bis (tert-butoxycarbonylamino) Phenyl-4-yl] -carbamic acid tert-butyl ester
[1183] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; -Propionic acid ethyl ester (example M2) (180 mg, 0.69 mmol) according to general procedure K (method b). A light yellow solid was obtained (257 mg).
[1184] MS (ISP) 588 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 47-50 캜.
[1185] Example O62
[1186] A solution of [5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] - [2- (1,4- dioxa-8-aza- spiro [4,5] ) -2'-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester
[1187] According to general procedure O, the title compound was synthesized from [5-amino-2- (1,4-dioxa-8-aza- spiro [4,5] dec-8-yl) -2'- ] -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) Mg, 0.8 mmol) according to general procedure II. Amorphous yellow material was obtained (258 mg).
[1188] MS (ISP) 615 [(M + H) &lt; ⁺ & gt ^; ].
[1189] Example O63
[1190] 8-aza-spiro [4,5] dec-8-yl) -2'-fluoro-5- [3- (3-imidazol- ) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester
[1191] According to general procedure O, the title compound was synthesized from [5-amino-2- (1,4-dioxa-8-aza- spiro [4,5] dec-8-yl) -2'- ] -Carbamic acid tert-butyl ester (Example L51) (222 mg, 0.5 mmol) and 6- (3-imidazol- One (example N10) (135 mg, 0.5 mmol). Amorphous yellow material was obtained (294 mg).
[1192] MS (ISP) 656 [(M + H) &lt; ⁺ & gt ^; ].
[1193] Example O64
[1194] (2-methyl-imidazol-1-yl) -phenyl] -3-oxo-propionylamino] -biphenyl -4-yl] -carbamic acid tert-butyl ester
[1195] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; Yl) -phenyl] - [1,3] dioxin-4-one (example N15) (142 mg, 0.5 mmol). Amorphous yellow material was obtained (234 mg).
[1196] MS (ISP) 601 [(M + H) &lt; ⁺ & gt ^; ].
[1197] Example O65
[1198] 2-fluoro-biphenyl-4-yl] - (3-oxo-propionylamino) Carbamic acid tert-butyl ester
[1199] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; (Example M16) (115 mg, 0.5 mmol) was reacted from 4- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) . Amorphous yellow material was obtained (216 mg).
[1200] MS (ISP) 547 [(M + H) &lt; ⁺ & gt ^; ].
[1201] Example O66
[1202] (2-methylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionylamino] - Biphenyl-4-yl] -carbamic acid tert-butyl ester
[1203] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; Butyl ester (example M13) (211 mg, 0.63 mmol) in dichloromethane (3 ml_) and 3- [3- (2- methylsulfanyl- imidazol- l-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester Respectively. A light yellow solid was obtained (260 mg).
[1204] MS (ISN) 631 [(MH) ^- ]; Melting point 59 to 62 占 폚.
[1205] Example O67
[1206] 2-Methoxy-biphenyl-4-yl] -carbamic acid 3 '-( 3-cyano-phenyl) -3-oxo-propionylamino] Tert-butyl ester
[1207] According to general procedure O, (5-amino-2 ', 5'-difluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L52) 0.5 mmol) and 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (example N4) (115 mg, 0.5 mmol). An amorphous yellow material was obtained (136 mg).
[1208] MS (ISP) 522 [(M + H) &lt; ⁺ & gt ^; ].
[1209] Example O68
[1210] 3-oxo-3- (3- [1,2,4] triazol-l-yl-phenyl) - propionylamino] - Biphenyl-4-yl] -carbamic acid tert-butyl ester
[1211] According to general procedure O, (5-amino-2 ', 5'-difluoro-2-methoxy-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L52) 0.5 mmol) and 3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid ethyl ester (Example M2) (130 mg, 0.5 mmol). Amorphous light yellow material was obtained (185 mg).
[1212] MS (ISN) 562 [(MH) ^&lt;&quot;&gt;].
[1213] Example O69
[1214] Yl] -3-oxo-propionylamino] -2'-fluoro-biphenyl-4-yl] -Carbamic acid tert-butyl ester
[1215] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; 2-yl) -2,2-dimethyl- [1,3] dioxin-4-one (example N3) (130 mg, 0.55 mmol) Respectively. A yellow oil was obtained (278 mg).
[1216] MS (ISN) 550 [(MH) ^&lt;&quot;&gt;].
[1217] Example O70
[1218] Yl] -3-oxo-propionylamino] -2'-fluoro-biphenyl-4-yl] -Carbamic acid tert-butyl ester
[1219] Butyl ester (example L48) (187 mg, 0.5 &lt; RTI ID = 0.0 &gt; Propionic acid tert-butyl ester (example M17) (138 mg, 0.55 mmol) according to general procedure II. Amorphous yellow material was obtained (268 mg).
[1220] MS (ISN) 550 [(MH) ^&lt;&quot;&gt;].
[1221] Example O71
[1222] 3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -bis Phenyl-4-yl] -carbamic acid tert-butyl ester
[1223] According to general procedure O, (5-amino-2-tert-butoxy-4'-fluoro-biphenyl-4-yl) -carbamic acid tert- butyl ester (example L47) -Propionic acid ethyl ester (Example M2) (156 mg, 0.6 mmol) according to the general method of example 1, step 2c) and 3-oxo-3- (3- [l, 2,4] triazol-l-yl-phenyl) Yellow gum was obtained (198 mg).
[1224] MS (ISN) 588 [(M + H) &lt; ⁺ & gt ^; ].
[1225] Example O72
[1226] 2- [2-methoxy-ethoxy) -biphenyl-4-yl] - (2-methoxy- Carbamic acid tert-butyl ester
[1227] According to general procedure O, (5-amino-2'-fluoro-2- (2-methoxy-ethoxy) -biphenyl-4-yl] -carbamic acid tert- butyl ester (example L53) 6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (example N4) as a yellow solid (188 mg).
[1228] MS (ISP) 548 [(M + H) &lt; ⁺ & gt ^; ].
[1229] Example O73
[1230] (RS) - [5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2'-fluoro-2- (tetrahydro- Phenyl-4-yl] -carbamic acid tert-butyl ester
[1231] According to general procedure O, the title compound was obtained from (RS) - (5-amino-2'-fluoro-2- (tetrahydro-pyran- 2- yloxymethyl) (Example L4) and 3- (2,2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (example N4) to give a yellow solid (155 mg).
[1232] MS (ISP) 548 [(M + NH 4) +].
[1233] Example O74
[1234] (2-fluoro-2- (4-methoxy-benzyloxy) -5- [3- [3- ] -Biphenyl-4-yl) -carbamic acid tert-butyl ester
[1235] According to general procedure O, the title compound was synthesized from [5-amino-2'-fluoro-2- (4-methoxy-benzyloxy) Butyl ester (example M14) (301 mg, 1.0 mmol) in anhydrous dichloromethane (10 mL) at 0 &lt; 0 &Lt; / RTI &gt; Amorphous light yellow material was obtained (561 mg).
[1236] MS (ISP) 666 [(M + H) &lt; ⁺ & gt ^; ].
[1237] Example O75
[1238] 2 ', 5'-difluoro-biphenyl-4-yl] - (3-cyano-phenyl) Carbamic acid tert-butyl ester
[1239] According to general procedure O, the title compound was obtained from (5-amino-2-tert-butoxy-2 ', 5'-difluoro-biphenyl- (Example N4) (115 mg, 0.5 mmol) was reacted with 3- (2-dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile . Amorphous beige material was obtained (155 mg).
[1240] MS (ISP) 564 [(M + H) &lt; ⁺ & gt ^; ].
[1241] Example O76
[1242] Phenyl] -3-oxo-propionylamino] -phenyl) - &lt; / RTI & ] -Carbamic acid tert-butyl ester
[1243] According to general procedure O, the title compound was prepared from [2-amino-5-tert-butoxy-4- (4- fluoro-phenylethynyl) -phenyl] -carbamic acid tert- butyl ester (example L57) , 0.4 mmol) and 3- (3-imidazol-1-yl-phenyl) -3-oxo-propionic acid tert-butyl ester (Example M4) (115 mg, 0.4 mmol). Amorphous yellow material was obtained (140 mg).
[1244] MS (ISP) 611 [(M + H) &lt; ⁺ & gt ^; ].
[1245] Example O77
[1246] 3- [3- [3- [1,2,3] triazol-1-yl-phenyl) -5- -Propionylamino] -phenyl] -carbamic acid tert-butyl ester
[1247] According to general procedure O, the title compound was prepared from [2-amino-5-tert-butoxy-4- (4- fluoro-phenylethynyl) -phenyl] -carbamic acid tert- butyl ester (example L57) , 0.4 mmol) and 3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid ethyl ester (Example M2) (104 mg, 0.4 mmol). Yellow gum was obtained (150 mg).
[1248] MS (ISP) 612 [(M + H) &lt; ⁺ & gt ^; ].
[1249] General procedure P
[1250] Dihydro-benzo [b] [1,4] diazepin-2-one, 4-aryl-8-aroyl- [1,4] diazepin-2-one or 4-aryl-8-arylethynyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one.
[1251] CH ₂ Cl ₂ (5㎖) of [2- [3-aryl-3-oxo-propionylamino] -4-aryl-phenyl] -carbamic acid tert-butyl ester or [2- [3-aryl -3 (1.0 mmol) [anisole or 1, 3-dimethoxybenzene (5-15 mmol)) was prepared in analogy to the procedure described for the preparation of Can be added if necessary) was treated with TFA (0.5-5.0 ml) at 0 ° C and stirred continuously at 23 ° C until tlc was found to be completely consumed starting material. The solvent was removed in vacuo, the residue was treated with some ether and crystallized during this time. The solid was stirred with saturated NaHCO ₃ - solution, filtered and washed with H ₂ O and a mixture of ether or ether / hexane and dried to give the title compound, which was dissolved in THF / CH ₂ Cl ₂ / ether / hexane And then crystallized.
[1252] General Procedure Q
[1253] The Pd-catalyzed carbonylating amination of 4- (3-iodophenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazepin- phenyl] -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one &Lt; / RTI &gt;
[1254] To a stirred solution of 4- (3-iodophenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one (1.0 mmol), the secondary amine (5.0 mmol), PPh ₃ (6 mol%) or dppp (3 mol%), Pd (OAc) ₂ (3 mol%) and Et ₃ N (2.0 mmol) in dichloromethane was stirred at 23 &lt; 0 &gt; C under CO-atmosphere. Diluted with EtOAc, washed with saturated NaHCO ₃ - solution and brine, and the organic phase was dried over Na ₂ SO ₄ . Removal of the solvent left a brown oil which was purified by silica gel column chromatography using hexane / EtOAc to give the title compound.
[1255] General procedure R
[1256] (5-hydroxy-2-nitro-phenyl) -carbamic acid tert-butyl ester by the Rh-catalyzed deallylation of (5-allyloxy-2-nitro- Lt; / RTI &gt;
[1257] (5-allyloxy-2-nitro-phenyl) -carbamic acid tert-butyl ester, (PPh ₃ ) ₃ RhCl (5 mol%) in EtOH according to the method described in J. Org. Chem . 1973 , 38, ) Or DABCO (20 mol%) was refluxed for 2.5 hours. Was added to 5% citric acid, it stirred at 23 ℃ for 15 minutes, extracted with EtOAc, washed with brine, dried over MgSO _4. Removal of the solvent left an orange solid which was purified by silica gel column chromatography using hexane / EtOAc to give the title compound.
[1258] Example Rl
[1259] (5-hydroxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[1260] According to the general procedures R, EtOH solution of (5-allyloxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B4), (PPh _{3) 3} RhCl (5 mol%) Or DABCO (20 mol%). A yellow solid was obtained.
[1261] MS (ISN) 379 [(MH) ^- ]; Melting point 140 캜.
[1262] General procedure S
[1263] (5-hydroxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester gave 5-O- - butyl ester.
[1264] until the complete conversion is confirmed from tlc, (5- hydroxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example R1), KHCO ₃ and mixtures of the appropriate alkylating reagent Was stirred in DMF at 23 &lt; 0 &gt; C. After dilution with EtOAc, 5% citric acid, saturated NaHCO ₃ - solution and with brine and then water was treated, dried over MgSO _4. Removal of the solvent left a crude material which was purified by silica gel column chromatography using hexane / EtOAc to give the title compound.
[1265] Example S1
[1266] (5-tert-butoxycarbonylamino-2-iodo-2-nitro-phenoxy) -acetic acid tert-butyl ester
[1267] According to general procedure S, (5- hydroxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example _{R1), KHCO 3 (0.39g,} 3.89 mmol) or tert- Prepared from butyl bromoacetate (0.59 mL, 3.89 mmol). A yellow solid was obtained (1.5 g, 95%).
[1268] MS (ISP) 495 [(M + H) +], 512 [(M + NH 4) +] and ^{517 [(M + Na) +} ]; Melting point 103 캜.
[1269] Example S2
[1270] (5-cyanomethoxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[1271] Butyl ester (example R1) (614 mg, 1.62 mmol), KHCO ₃ (208 mg, 1.62 mmol), and (2-hydroxy- 2.08 mmol) or bromoacetonitrile (0.21 mL, 3.16 mmol). A yellow solid was obtained (574 mg, 85%).
[1272] MS (ISN) 418 [(MH) ^- ]; Melting point 125 캜.
[1273] Example S3
[1274] (RS) - [4-iodo-2-nitro-5- [2- (tetrahydro-pyran-2- yloxy) -ethoxy] -phenyl] -carbamic acid tert- butyl ester
[1275] According to general procedure S, (5- hydroxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example R1) (760㎎, 2 mmol), KHCO ₃ (260㎎, 4 mmol) or 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.6 mL, 2.6 mmol). An orange oil was obtained (804 mg, 79%).
[1276] MS (EI) 508 (M &lt; ^{+ &} gt ^; ).
[1277] Example S4
[1278] (5-tert-butoxy-4-iodo-2-nitro-phenyl) -carbamic acid tert-butyl ester
[1279] N, N-Dimethylformamide di-tert-butyl acetal (19.2 ml, 80 mmol) was added to a solution of (5-hydroxy-4-iodo-2-nitro- phenyl) Butyl ester (Example R1) (7.60 g, 20 mmol) in tetrahydrofuran (20 mL) and stirred continuously at 80 ° C for 3 hours (see Synthesis 1983 , 135). A yellow solid was obtained (5.97 g, 68%).
[1280] MS (ISN) 435 [(MH) ^- ]; Melting point 94 캜.
[1281] Example 1
[1282] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile
[1283] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded 2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -4-iodo-5-thiomorpholine- -Yl-phenyl) -carbamic acid tert-butyl ester (example O1) (629 mg, 1.04 mmol) according to general procedure II. An olive solid was obtained (437 mg).
[1284] Melting point 227 to 228 캜.
[1285] Example 2
[1286] Preparation of 3- (7-iodo-8-morpholin-4-yl-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1287] Treatment with TFA in CH ₂ Cl ₂ according to general procedure P gave [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -4-iodo-5- 4-yl-phenyl] -carbamic acid tert-butyl ester (Example O2) (518 mg, 0.877 mmol). A beige solid was obtained (309 mg).
[1288] MS (EI) 472 (M ^&lt; ⁺ &gt;); Melting point 224 캜.
[1289] Example 3
[1290] Synthesis of 3- (8-chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1291] Butyl ester (example L3) (171 mg, 0.5 mmol) and 3- (2,2,2-trifluoroethyl) -piperidine- (Example N4) (183 mg, 0.6 mmol) according to general procedure II. According to general procedure P, the material was cyclized by deprotection and treatment with TFA in CH ₂ Cl ₂ . An orange solid was obtained (483 mg).
[1292] MS (ISP) 343 [(M + H) <^+> ] and 345 [(M + 2 + Na) <^+>]; Melting point: 248 to 251 캜 (decomposition).
[1293] Example 4
[1294] Synthesis of 3- (8-methyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1295] (Example L4) (161 mg, 0.5 mmol) and 3- (2,2,2-trifluoroethyl) -carbamic acid tert-butyl ester (Example N4) (230 mg, 0.75 mmol, 75% purity) according to the general procedure G (method a). According to general procedure P, the material was cyclized by deprotection and treatment with TFA in CH ₂ Cl ₂ . A light yellow solid was obtained (83 mg).
[1296] MS (ISP) 375 (M ^&lt; ⁺ &gt;); Melting point 237 to 239 캜 (decomposition).
[1297] Example 5
[1298] Dihydro-3H-benzo [b] [1,4] diazepin-2-one [ - yl] -benzonitrile
[1299] Phenyl) -carbamic acid tert-butyl ester (Example L5) (203 mg, 0.20 mmol) was reacted with 2-amino-5- (Example N4) (230 mg, 0.75 mmol, 75%) was obtained as white crystals from 4- (2,2-dimethoxy-6-oxo-6H- [1,3] dioxin- Purity). According to general procedure P, the material was cyclized by deprotection and treatment with TFA in CH ₂ Cl ₂ . An orange solid was obtained (82 mg).
[1300] MS (ISP) 460.5 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 222-224 占 폚 (decomposition).
[1301] Example 6
[1302] Dihydro-3H-benzo [b] [1, 4] dioxol- Diazepin-2-yl] -benzonitrile
[1303] According to general procedure O, the title compound was prepared from [2-amino-5- (1,1-dioxo-6-thiomorpholin-4-yl) -4-phenylethynyl-phenyl) -carbamic acid tert- Example L4) (172 mg, 0.5 mmol) and (3- (2,2-dimethoxy-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile , 0.75 mmol). According to general procedure P, the material was cyclized by deprotection and treatment with TFA in CH ₂ Cl ₂ . A yellow solid was obtained (47 mg).
[1304] MS (ISP) 495 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 250 ° C or higher (decomposition).
[1305] Example 7
[1306] Synthesis of 3- (8-chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1307] 3-oxo-propionylamino] -biphenyl-4-yl] -ethanone was prepared by treatment with TFA in CH ₂ Cl ₂ according to general procedure P to give [2-chloro-5- [3- -Carbamic acid tert-butyl ester (example O3) (720 mg, 1.47 mmol). A cloudy white solid was obtained (457 mg).
[1308] MS (EI) 371 (M ^{& lt} ; ⁺ &gt;) and 373 [(M + 2) &lt; ⁺ &gt;]; Melting point: 242 to 244 캜 (decomposition).
[1309] Example 8
[1310] Synthesis of 3- (8-methyl-4-oxo-7-phenyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1311] Butyl ester (Example L7) (298 mg, 1.0 mmol) and 3- (2,2-dimethyl-biphenyl-4-yl) Dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example N4) (460 mg, 1.5 mmol). According to general procedure P, the resultant material (351 mg) was cyclized by deprotection and treatment with TFA in CH ₂ Cl ₂ . A light yellow solid was obtained (206 mg).
[1312] MS (EI) 351 (M ^&lt; ⁺ &gt;); Melting point: 236 to 239 캜 (decomposition).
[1313] Example 9
[1314] 4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] thiophen-2- ] [1,4] diazepin-2-yl] -benzonitrile
[1315] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [2- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -5- (1,4-oxazol -8 -Phenyl] -carbamic acid tert-butyl ester (example O14) (265 mg, 0.43 mmol) according to the general procedure G (method a). A brown solid was obtained (121 mg).
[1316] MS (ISP) 503 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 239-243 占 폚 (decomposition).
[1317] Example 10
[1318] Preparation of 3- (8-morpholin-4-yl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1319] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [2- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -5-morpholin-4-yl-4 Phenyl] -carbamic acid tert-butyl ester (example O10) (370 mg, 0.66 mmol) according to general procedure II. A light brown solid was obtained (216 mg).
[1320] MS (EI) 446 (M ^&lt; ⁺ &gt;); Melting point 239-243 占 폚 (decomposition).
[1321] Example 11
[1322] Preparation of 3- [8- (2-Dimethylamino-ethylsulfanyl) -4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin- ] -Benzonitrile
[1323] According to general procedure P, CH ₂ Cl ₂ in TFA and not by solo [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5- (2-dimethylamino-ethyl Phenyl) -carbamic acid tert-butyl ester (example O4) (166 mg, 0.28 mmol) according to general procedure II. A light yellow solid was obtained (103 mg).
[1324] MS (ISP) 465 [(M + H) &lt; ⁺ & gt ^; ); Melting point 197 캜 (decomposition).
[1325] Example 12
[1326] Benzo [b] [1,4] diazepin-7-ylsulfanyl] - (2-oxo-phenyl) Acetic acid methyl ester
[1327] According to general procedure P, treatment with TFA and anisole in CH ₂ Cl ₂ afforded [5- tert -butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino ] -2-phenylethynyl-phenylsulfanyl] -acetic acid methyl ester (example O5) (421 mg, 0.72 mmol). A light yellow solid was obtained (309 mg).
[1328] MS (ISP) 465 [(M + H) &lt; ⁺ & gt ^; ); Melting point: 201 캜 (decomposition).
[1329] Example 13
[1330] Benzo [b] [1,4] diazepin-7-ylsulfanyl] - (2-oxo-phenyl) Acetic acid
[1331] THF (5㎖), MeOH (1㎖ ) and H ₂ O of [4- (3-cyano-phenyl) -2-oxo-8-2,3-dihydro -1H- benzo phenylethynyl [b ] [1,4] diazepin-7-ylsulfanyl] -acetic acid methyl ester (example 12) (265 mg, 0.57 mmol) and LiOH.H ₂ O (26 mg, 0.63 mmol) 0.0 &gt; 23 C. &lt; / RTI &gt; A light yellow solid was obtained (257 mg).
[1332] MS (ISP) 452 [(M + H) &lt; ⁺ & gt ^; ); Melting point: 202 째 C (decomposition).
[1333] Example 14
[1334] Benzo [b] [1,4] diazepin-7-yl] -acetic acid methyl ester was obtained as colorless crystals from methyl [4- (3-cyano- phenyl) -2-oxo-8-phenylethynyl-2,3-dihydro- ester
[1335] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [5-3-tert-butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino] - 2-phenylethynyl-phenyl] -acetic acid methyl ester (example O6) (846 mg, 1.53 mmol) according to general procedure II. A light yellow solid was obtained (557 mg).
[1336] MS (EI) 433 (M ^&lt; ⁺ &gt;); Melting point 236 캜 (decomposition).
[1337] Example 15
[1338] Benzo [b] [1, 4] diazepin-7-yl] -acetic acid &lt; EMI ID =
[1339] A solution of LiOH.H ₂ O (54 mg, 1.28 mmol) in H ₂ O (2 mL) and MeOH (2 mL) was added to a solution of [4- (3-cyano- Benzyl [b] [1,4] diazepin-7-yl] -acetic acid methyl ester (Example 14) (505 mg, 1.17 mmol) And the reaction mixture was stirred at 23 &lt; 0 &gt; C for 48 hours. A light yellow solid was obtained (62 mg).
[1340] MS (ISP) 452 [(M + H) &lt; ⁺ & gt ^; ); Melting point: 248 캜 (decomposition).
[1341] Example 16
[1342] Preparation of [4- (3-cyano-phenyl) -8-iodo-2-oxo-2,3-dihydro-1H- benzo [b] [1,4] diazepine-
[1343] According to general procedure P, CH ₂ Cl ₂ in a 5-3 class by treatment with TFA-butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2 - iodo-benzoic acid methyl ester (example O17) (430 mg, 0.763 mmol). A salmoncolored solid was obtained (199 mg).
[1344] MS (EI) 445 (M ^&lt; ⁺ &gt;); Melting point: 247 to 248 캜 (decomposition).
[1345] Example 17
[1346] Benzo [b] [1,4] diazepin-7-yl] - (2-oxo-phenyl) Acetamide
[1347] Benzo [b] [1,4] diazepin-7-yl] -acetic acid (prepared as described for the preparation of 4- Example O15) (48 mg, 0.114 mmol) was treated with Boc ₂ O (37 mg), NH ₄ HCO ₃ (13 mg) and pyridine (6 μL) in DMF (0.6 mL) See Tetrahedron Letters 1995 , 36, 7115). A light yellow solid was obtained (14 mg).
[1348] MS (ISn) 417 [(MH) ^- ]; Melting point 250 캜 (decomposition).
[1349] Example 18
[1350] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] benzo [b] thiophene- - benzonitrile
[1351] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -5- (2-methoxy-ethoxy) Phenyl] -carbamic acid tert-butyl ester (example O7) (135 mg, 0.251 mmol) according to general procedure II. A bright green solid was obtained (82 mg).
[1352] MS (EI) 435 (M ^&lt; ⁺ &gt;); Melting point 174-176 占 폚.
[1353] Example 19
[1354] Benzo [b] [1, 4] diazepine-7-carboxylic acid methyl ester
[1355] According to general procedure P, CH ₂ Cl ₂ in a 5-3 class by treatment with TFA-butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2 -Phenylethynyl-benzoic acid methyl ester (example O9) (511 mg, 0.95 mmol). A cloudy white solid was obtained (321 mg).
[1356] MS (EI) 419 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1357] Example 20
[1358] Synthesis of 3- (8-methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1359] Treatment with TFA in CH ₂ Cl ₂ according to general procedure P gave [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5- Phenyl] -carbamic acid tert-butyl ester (Example O8) (359 mg, 0.7 mmol) according to general procedure II. A tan solid was obtained (87 mg).
[1360] MS (EI) 391 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1361] Example 21
[1362] Ethoxy] -ethoxy) -4-oxo-7-phenylethynyl-4,5-dihydro- Dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile
[1363] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [2- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -5- (2- [2- [2- (Example O11) (300 mg, 0.437 mmol) in dichloromethane (10 mL) was treated with &lt; RTI ID = 0.0 &Lt; / RTI &gt; A tan solid was obtained (211 mg).
[1364] MS (EI) 435 (M ^&lt; ⁺ &gt;); Melting point 140-141 占 폚 (decomposition).
[1365] Example 22
[1366] Benzo [b] [1,4] diazepin-7-yloxy] - acetic acid
[1367] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ and anisole, [5- tert -butoxycarbonylamino-4- [3- (3-cyano-phenyl) -3-oxo-propionyl Amino] -2-phenylethynyl-phenoxy] -acetic acid tert-butyl ester (example O12) (698 mg, 1.14 mmol). A yellow solid was obtained (265 mg).
[1368] MS (ISN) 434 [(MH) ^- ]; Melting point: 257 캜 (decomposition).
[1369] Example 23
[1370] Synthesis of 3- (8-cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1371] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ and anisole, [5-cyanomethyl- [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -Phenylethynyl-phenyl] -carbamic acid tert-butyl ester (example O13) (266 mg, 0.51 mmol) according to general procedure II. A yellow solid was obtained (145 mg).
[1372] MS (EI) 400 (M ^&lt; ⁺ &gt;); Melting point: 262 캜 (decomposition).
[1373] Example 24
[1374] Dihydro-3H-benzo [b] [1,4] diazepin-2-one [ - yl] -benzonitrile
[1375] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ and anisole [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5- (2,2-dimethyl Phenyl] -carbamic acid tert-butyl ester (example O16) (265 mg, 0.435 mmol) according to general procedure II. A yellow solid was obtained (62 mg).
[1376] MS (ISP) 452 [(M + H) <^+> ] and 474 [(M + Na) <^+>]; Melting point 230 to 234 캜 (decomposition).
[1377] Example 25
[1378] Dihydro-benzo [b] [1,4] diazepin-2- (2-methoxy-ethoxy) On
[1379] According to general procedure P, CH ₂ Cl _2, and not by processing in a brush with TFA [2- [3- (3- iodo-phenyl) -3-oxo-propionylamino] -5- (2-methoxy- Phenyl) -carbamic acid tert-butyl ester (example O15) (1.24 mg, 1.89 mmol) according to general procedure II. A yellow solid was obtained (517 mg).
[1380] MS (EI) 536 (M ^&lt; ⁺ &gt;); Melting point: 192 째 C (decomposition).
[1381] Example 26
[1382] Benzo [b] [1,4] diazepin-7-yloxy] -2-oxo-8-phenylethynyl] -2,3-dihydro- - acetamide
[1383] EDC (42 mg, 0.22 mmol) was added to a solution of [5- (3-cyano-phenyl) -2-oxo-8-phenylethynyl-2,3-dihydro- [b] [1,4] diazepin-7-yloxy] -acetic acid (example 22) (50㎎, 0.11 _{mmol), NH 4 Cl (18㎎,} 0.33 mmol) and NMM (56㎎, 0.55 mmol) And the reaction mixture was stirred for 2 h at 23 &lt; 0 &gt; C. A yellow solid was obtained (5 mg).
[1384] MS (ISN) 4174 [(MH) ^- ]; Melting point 250 캜 (decomposition).
[1385] Example 27
[1386] Dihydro-benzo [b] [1,4] diazo [3,4-d] pyrimidin- Zepin-2-one
[1387] According to general procedure P, CH ₂ Cl _2, and not by processing in a brush with TFA [[[2- [3- ( 3- imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5 (Example O18) (200 mg, 0.336 mmol) according to general procedure K (method a). A yellow solid was obtained (28 mg).
[1388] MS (EI) 476 (M ^&lt; ⁺ &gt;); Melting point 187-189 ° C.
[1389] Example 28
[1390] (RS) -3- [4-oxo-8- (2-oxo- [1,3] dioxolan-4-ylmethoxy) -7-phenylethynyl-4,5-dihydro-3H-benzo [ ] [1,4] diazepin-2-yl] -benzonitrile
[1391] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [RS] - [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5- [1,3] dioxolan-4-ylmethoxy) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester (example O19) (400 mg, 0.67 mmol). A yellow solid was obtained (287 mg).
[1392] MS (EI) 477 (M ^&lt; ⁺ &gt;); Melting point: 222 째 C (decomposition).
[1393] Example 29
[1394] Synthesis of 3- (8-ethoxymethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1395] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5-ethoxymethyl- -Phenyl] -carbamic acid tert-butyl ester (example O20) (140 mg, 0.26 mmol) according to general procedure II. A yellow solid was obtained (93 mg).
[1396] MS (EI) 419 (M ^&lt; ⁺ &gt;); Melting point 229 캜.
[1397] Example 30
[1398] Benzo [b] [1,4] diazepin-7-one [0156] To a solution of 2,2-dimethyl-propionic acid 4- (3-cyano- Yl methyl ester
[1399] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave 2,2-dimethyl-propionic acid 5- tert-butoxycarbonylamino-4- [3- (3-cyano-phenyl) -Propionylamino] -2-phenylethynyl-benzyl ester (example O21) (156 mg, 0.26 mmol) according to general procedure II. A light yellow solid was obtained (75 mg).
[1400] MS (EI) 475 (M ^&lt; ⁺ &gt;); Melting point 218 캜.
[1401] Example 31
[1402] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -benzonitrile
[1403] THF for 3 days at 23 ℃ (2㎖), 2,2- dimethyl in MeOH (0.4㎖) and H ₂ O (0.4㎖) - propionic acid [4- (3-cyano-phenyl) -2-oxo -8 Benzo [b] [1,4] diazepin-7-ylmethyl ester (example 30) (30 mg, 0.063 mmol) and LiOH.H ₂ O 8 mg, 0.289 mmol). A yellow solid was obtained (17 mg).
[1404] MS (EI) 391 (M ^&lt; ⁺ &gt;); Melting point: 255 ℃ or higher.
[1405] Example 32
[1406] Dihydro-benzo [b] [1, 4] diazepin-2-one &lt; / RTI &gt;
[1407] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded (RS) - [2- [3- (3-Imidazol-1-yl-phenyl) -3-oxo-propionylamino] (Tetrahydro-pyran-2-yloxymethyl) -phenyl] -carbamic acid tert-butyl ester (example O22). A yellow solid was obtained (77 mg).
[1408] MS (EI) 432 (M ^&lt; ⁺ &gt;); Melting point 227 캜.
[1409] Example 33
[1410] Benzo [b] [1, &lt; RTI ID = 0.0 &gt; (4-methoxypiperidin- 1,4] diazepin-2-one
[1411] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5- -Phenyl] -carbamic acid tert-butyl ester (example O23) in accordance with the general method of example 1, supra. A yellow solid was obtained (159 mg).
[1412] MS (ISP) 516 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 222 占 폚.
[1413] Example 34
[1414] Synthesis of 3- [8- (4-methoxy-piperidin-1-yl) -4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] -2-yl] -benzonitrile
[1415] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5- (4-methoxy-piperidine -L-yl) -4-phenylethynyl-phenyl] -carbamic acid tert-butyl ester (example O24). A yellow solid was obtained (128 mg).
[1416] MS (ISP) 475 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 250 to 251 캜.
[1417] Example 35
[1418] Benzo [b] [1,4] diazepin-7-yloxy [l, 4-diazepin- Hour] - acetonitrile
[1419] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [5-cyanomethoxy-2- [3- (3-cyano-1-yl-phenyl) -3-oxo-propionylamino] -Phenyl-ethynyl-phenyl] -carbamic acid tert-butyl ester (example O25). A yellow solid was obtained (43 mg).
[1420] MS (ISP) 457 (M ^&lt; ⁺ &gt;); Melting point 214 캜.
[1421] Example 36
[1422] Synthesis of 3- (8-cyanomethoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-
[1423] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [5-cyanomethoxy-2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -Phenyl] -carbamic acid tert-butyl ester (example O26). A yellow solid was obtained (71 mg).
[1424] MS (EI) 416 (M ^&lt; ⁺ &gt;); Melting point 212 캜.
[1425] Example 37
[1426] Benzo [b] [1,4] oxazepin-1-yl) -piperazin-1- Diazepin-2-one
[1427] By treatment in accordance with the general procedure P, with TFA in _{CH 2 Cl 2 (RS) -} [4- ( 4-fluoro-phenylethynyl) -2- [3- (3-imidazol-1-yl-phenyl) -Propylamino] -5- (tetrahydro-pyran-2-yloxymethyl) -phenyl] -carbamic acid tert-butyl ester (example O27). A yellow solid was obtained (462 mg).
[1428] MS (EI) 450 (M ^&lt; ⁺ &gt;); Melting point 234 캜 (decomposition).
[1429] Example 38
[1430] Amino] -4- (3-imidazol-1-yl-phenyl) -1, 3-di Dihydro-benzo [b] [1,4] diazepin-2-one
[1431] By treatment in accordance with the general procedure P, with TFA in _{CH 2 Cl 2 (RS) -} (4- ( 4-fluoro-phenylethynyl) -2- [3- (3-imidazol-1-yl-phenyl) Butyl ester (example O28) was obtained from &lt; RTI ID = 0.0 &gt; 2- &lt; / RTI & ). A yellow solid was obtained (73 mg).
[1432] MS (EI) 493 (M ^&lt; ⁺ &gt;); Melting point: 217 캜 (decomposition).
[1433] Example 39
[1434] Preparation of 4- (3-imidazol-l-yl-phenyl) -7- (4-oxo-piperidin- l-yl) -8- phenylethynyl-l, 3- dihydro-benzo [ , 4] diazepin-2-one
[1435] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [5- (4,4-diethoxy-1-yl) -2- [3- (3-imidazol- -Phenyl] -carbamic acid tert-butyl ester (example O29) in accordance with the general method of example 29, supra. A yellow solid was obtained (180 mg).
[1436] MS (EI) 499 (M ^&lt; ⁺ &gt;); Melting point 231 캜 (decomposition).
[1437] Example 40
[1438] N-tert-Butyl-2- [4- (3-cyano-phenyl) -2-oxo-8-phenylethynyl-2,3-dihydro-1H- benzo [ 7-yloxy] -acetamide &lt; / RTI &gt;
[1439] Was treated with oxalyl chloride (26 [mu] L, 0.3 mmol) in DMF (0.6 mL) at 0 [deg.] C for 1 hour and then treated with tert-butylamine (106 [mu] L, 1.0 mmol) at 0 [ Benzo [b] [1,4] diazepin-7-yloxy] - acetic acid (Example 22) (87 mg, 0.2 mmol) according to general procedure II. A yellow solid was obtained (21 mg).
[1440] MS (EI) 490 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1441] Example 41
[1442] Benzo [b] [1,4] diazepin-7-yloxy] -2-oxo-8-phenylethynyl] -2,3-dihydro- -N-methoxy-acetamide &lt; / RTI &gt;
[1443] (38 mg, 0.2 mmol), MeONH ₂ .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 0-23 & Benzo [b] [1,4] diazepine-7-carboxylic acid ethyl ester was prepared from [4- (3-cyano-phenyl) Yloxy] -acetic acid (example 22) (44 mg, 0.1 mmol). A yellow solid was obtained (36 mg).
[1444] MS (EI) 465 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1445] Example 42
[1446] Phenyl] -8-phenylethynyl-1,3-dihydro-benzo [b] [l, 4] benzodiazepin- Diazepin-2-one
[1447] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded (RS) - [2- [3- (3-Imidazol-1-yl-phenyl) -3-oxo-propionylamino] Ethoxy] -phenyl] -carbamic acid tert-butyl ester (example O29) in accordance with the general method of example 29, supra. A yellow solid was obtained (48 mg).
[1448] MS (EI) 462 (M ^&lt; ⁺ &gt;); Melting point 224-222 占 폚.
[1449] Example 43
[1450] (4-fluoro-phenyl) -7- (4-oxo-piperidin-l-yl) -4- b] [l, 4] diazepin-2-one
[1451] According to general procedure P, (RS) by treatment with TFA in CH ₂ Cl ₂ in - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionyl Amino] -2- [4- (tetrahydro-pyran-2-yloxy) -piperidin-l-yl] carbamic acid tert-butyl ester (example O31). A light yellow solid was obtained (109 mg).
[1452] MS (ISP) 496 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 238-240 占 폚.
[1453] Example 44
[1454] 4- (3-imidazol-1-yl-phenyl) -1,3-dihydro-benzo [b ] [L, 4] diazepin-2-one
[1455] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [5- (2-3-t-butoxy-ethoxy) -4- (4-fluoro-phenylethynyl) -2- [3- ( Yl-phenyl) -3-oxo-propionylamino] -phenyl] -carbamic acid tert-butyl ester (Example O32). A light yellow solid was obtained (83 mg).
[1456] MS (ISP) 496 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 238-240 占 폚.
[1457] Example 45
[1458] 4- (3-imidazol-1 -ylphenyl) - l- (4-fluoro-phenyl) , 3-dihydro-benzo [b] [1,4] diazepin-2-one
[1459] According to general procedure P, (RS) by treatment with TFA in CH ₂ Cl ₂ in - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionyl -Amino] -2- [4- (2- (tetrahydro-pyran-2-yloxy) -ethoxy] -piperidin- l-yl] -biphenyl-4-yl) -carbamic acid tert- butyl Ester (Example O33). A light yellow solid was obtained (97 mg).
[1460] MS (ISP) 540 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 225-222 占 폚.
[1461] Example 46
[1462] Fluoro-phenyl) -7-hydroxymethyl-4- (3-imidazol-1-ylphenyl) -1,3- dihydro- benzo [b] [1,4] diazepine- 2-on
[1463] According to general procedure P, (RS) by treatment with TFA in CH ₂ Cl ₂ in - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionyl 4-yl] carbamic acid tert-butyl ester (example O34) in analogous manner as described in example O34. A light yellow solid was obtained (162 mg).
[1464] MS (EI) 426 (M ^&lt; ⁺ &gt;); Melting point 180-195 占 폚.
[1465] Example 47
[1466] Benzo [b] [1,4] diazo [2,3-d] pyrimidin-4- 7-yloxy] -acetonitrile &lt; / RTI &gt;
[1467] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2- cyanomethoxy-4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo- Propionylamino] -biphenyl-4-yl] carbamic acid tert-butyl ester (Example O35). A yellow solid was obtained (11 mg).
[1468] MS (EI) 451 (M ^&lt; ⁺ &gt;); Melting point 164 캜.
[1469] Example 48
[1470] Dihydro-benzo [b] [1,4] diazepine &lt; / RTI &gt; -2-one
[1471] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2- dimethylaminomethyl-4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo- Propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O36). A brown solid was obtained (180 mg).
[1472] MS (ISP) 454 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 115-140 占 폚 (decomposition).
[1473] Example 49
[1474] 4-fluoro-phenyl) -4- (3-imidazo [4,5- c] pyrrol-5-yl) -8- Yl) -phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-
[1475] According to general procedure P, the title compound was prepared from [2- (2,2-Dimethyl-tetrahydro- [1,3] dioxolo [4,5- c] pyrrol-5-yl) -4'- -Biphenyl-4-yl] -carbamic acid tert-butyl ester (example L37). A yellow solid was obtained (358 mg).
[1476] MS (EI) 537 (M ^&lt; ⁺ &gt;); Melting point 240 캜 (decomposition).
[1477] Example 50
[1478] 4- (3-imidazol-1 -yl-phenyl) -1, 3-dihydroxy-pyrrolidin- Dihydro-benzo [b] [1,4] diazepin-2-one
[1479] [2,1-dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyrrole- Benzo [b] [1,4] diazepin-1-yl) -piperazin-1- 2-one (example 49) (304 mg, 0.57 mmol). A yellow solid was obtained (209 mg).
[1480] MS (ISP) 498 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 244 占 폚.
[1481] Example 51
[1482] Benzo [b] [1,4] diazepin-1-yl) -piperazin-1- 2-on
[1483] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -Methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O38). A yellow solid was obtained (182 mg).
[1484] MS (EI) 426 (M ^&lt; ⁺ &gt;); Melting point: 221 째 C (decomposition).
[1485] Example 52
[1486] (4-fluoro-phenyl) -4- (3-imidazol-l-yl-phenyl) [b] [1,4] diazepin-2-one
[1487] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2- (1,4- dioxa-8-aza-spiro [4.5] des-8-yl) -4'-fluoro-5- [ 4-yl] -carbamic acid tert-butyl ester (example O39) in accordance with the general method of example 29, supra. An orange-brown solid was obtained (150 mg).
[1488] MS (ISP) 494 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 204 캜.
[1489] Example 53
[1490] Dihydro-benzo [b] [1,4] diazepin-2-one [0252] To a solution of 8- (4-fluoro- -On
[1491] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -Methyl-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O40). A light yellow solid was obtained (216 mg).
[1492] MS (EI) 410 (M ^&lt; ⁺ &gt;); Melting point 196 ° C.
[1493] Example 54
[1494] Benzo [b] [1,4] diazo [2,3-d] pyrimidin-4- Zipine-7-yloxy] -acetic acid
[1495] Treatment with TFA in CH ₂ Cl ₂ according to general procedure P gave [4-tert-butoxycarbonylamino-4'-fluoro-5- [3- (3-imidazol- -3-oxo-propionylamino] -biphenyl-2-yloxy] -acetic acid tert-butyl ester (example O41). A beige solid was obtained (570 mg).
[1496] MS (ISP) 471 [(M + H) &lt; ⁺ & gt ^; ]; Melting point: 209 캜 (decomposition).
[1497] Example 55
[1498] Benzo [b] [1,4, &lt; / RTI &gt; &lt; RTI ID = 0.0 & ] Diazepin-7-yloxy] -N-hydroxy-acetamide
[1499] (61 mg, 0.22 mmol), OHBT (30 mg, 0.22 mmol), N-methyl morpholine (66 [mu] L, 0.6 mmol) in DMF (2 mL) at 0-23 & And EDC (77 mg, 0.4 mmol) to give [8- (4-fluoro-phenyl) -4- (3-imidazol- -LH- benzo [b] [1,4] diazepin-7-yloxy] -acetic acid (example 54) (94 mg, 0.2 mmol). After extraction and chromatography, the resulting orange solid was stirred with TFA in CH ₂ Cl ₂ according to general procedure P. A light yellow solid was obtained (71 mg).
[1500] MS (ISP) 486 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 147 to 157 占 폚 (decomposition).
[1501] Example 56
[1502] Dihydro-benzo [b] [1,4] diazepin-2-one [0251] -On
[1503] According to general procedure P, CH ₂ Cl ₂ by treatment with TFA in [2- chloro-4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionyl Amino] -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O42). A light yellow solid was obtained (35 mg).
[1504] MS (EI) 430 (M ^&lt; ⁺ &gt;); Melting point 206 to 211 캜.
[1505] Example 57
[1506] Benzo [b] [l- (4-fluoro-phenyl) -4- (3-imidazol- 1,4] diazepin-2-one
[1507] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] - (2-methoxy-ethoxy) -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O43). A yellow solid was obtained (96 mg).
[1508] MS (EI) 470 (M ^&lt; ⁺ &gt;); Melting point 196-197 占 폚.
[1509] Example 58
[1510] Preparation of 8- (4-fluoro-phenyl) -7- (2-hydroxy-ethoxy) -4- (3-imidazol- 1,4] diazepin-2-one
[1511] 4-fluoro-5- [3- (3-imidazol-1-yl) -propionic acid ethyl ester was prepared by treatment with TFA in CH ₂ Cl ₂ according to general procedure P. [ Yl-phenyl) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O44). A bright green solid was obtained (95 mg).
[1512] MS (EI) 456 (M ^&lt; ⁺ &gt;); Melting point 225 캜.
[1513] Example 59
[1514] (2-oxo-oxazolidin-3-yl) -l, 3-dihydro-benzo [ [b] [1,4] diazepin-2-one
[1515] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] - (2-oxo-oxazolidin-3-yl) -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O45). A yellow solid was obtained (35 mg).
[1516] MS (EI) 481 (M ^&lt; ⁺ &gt;); Melting point 230 캜.
[1517] Example 60
[1518] Methyl-phenyl) -4- (3-imidazol-1 -yl-phenyl) -7-methoxy-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
[1519] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -Methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O46). A beige solid was obtained (101 mg).
[1520] MS (EI) 440 (M ^&lt; ⁺ &gt;); Melting point 225 캜.
[1521] Example 61
[1522] Phenyl] -l, 3-dihydro-benzo [b] [1,4] diazepin- 2-on
[1523] According to general procedure P, CH ₂ Cl ₂ by treatment with TFA in [2-3-tert-butoxy-4'-fluoro-5-a [3- (3-imidazol-1-yl-phenyl) -3 Oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O47). A yellow solid was obtained (109 mg).
[1524] MS (EI) 412 (M ^&lt; ⁺ &gt;); Melting point 250 캜.
[1525] Example 62
[1526] Phenyl] -l, 3-dihydro-benzo [b] [1,4] diazepin- 2-on
[1527] According to general procedure P, CH ₂ Cl ₂ by treatment with TFA in [2-3-tert-butoxy-4'-fluoro-5-a [3- (3-imidazol-1-yl-phenyl) -3 Oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O48). A yellow solid was obtained (132 mg).
[1528] MS (EI) 412 (M ^&lt; ⁺ &gt;); Melting point 220 캜.
[1529] Example 63
[1530] Yl) -4- (3-imidazol-1-yl-phenyl) - 1, 3-dihydro-pyrrolo [ Dihydro-benzo [b] [1,4] diazepin-2-one
[1531] According to general procedure P, (RS) by treatment with TFA in CH ₂ Cl ₂ in - [4'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionyl -Amino] -2 - [(R) -3- (tetrahydro-pyran-2-yloxy) -pyrrolidin-l-yl] -biphenyl-4-yl] -carbamic acid tert-butyl ester Example O49). A yellow solid was obtained (74 mg).
[1532] MS (EI) 481 (M ^&lt; ⁺ &gt;); Melting point 155 to 158 캜.
[1533] Example 64
[1534] Benzo [b] [1,4] diazepin-1-yl) -piperazin-1- 2-on
[1535] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [2'-fluoro-5- [3- (3-imidazol-1-yl- phenyl) -3-oxo-propionylamino] -Methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O50). A yellow solid was obtained (68 mg).
[1536] MS (EI) 426 (M ^&lt; ⁺ &gt;); Melting point 216 캜 (decomposition).
[1537] Example 65
[1538] Benzo [b] [1,4] diazepin-2-yl] -benzo [b] thiophene- Nitrile
[1539] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [2,3-Butoxy-5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] Fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O51). A yellow solid was obtained (66 mg).
[1540] MS (EI) 371 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1541] Example 66
[1542] Benzo [b] [1,4] diazepin-2-yl] -benzo [b] thiophene- Nitrile
[1543] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2,3-Butoxy-5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] Fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O52). A yellow solid was obtained (80 mg).
[1544] MS (EI) 371 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1545] Example 67
[1546] Benzo [b] [1,4] diazepin-2-yl] -benzo [b] thiophene- Nitrile
[1547] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2'- Biphenyl-4-yl] -carbamic acid tert-butyl ester (example O53). A light yellow solid was obtained (51 mg).
[1548] MS (EI) 385 (M ^&lt; ⁺ &gt;); Melting point 245-247 占 폚.
[1549] Example 68
[1550] Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro-imidazol- , 4] diazepin-2-one
[1551] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded (2'-fluoro-2-methoxy-5- [3- [3- (2-methyl- imidazol- 3-oxo-propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O54). A yellow solid was obtained (207 mg).
[1552] MS (EI) 440 (M ^&lt; ⁺ &gt;); Melting point 220 to 222 占 폚.
[1553] Example 69
[1554] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro-thiophene Pentene-2-carbonitrile
[1555] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [5- [3- to propionylamino] -2'-fluoro - (5-cyano-thiophen-2-yl) -3-oxo- Biphenyl-4-yl] -carbamic acid tert-butyl ester (example O55). A yellow solid was obtained (103 mg).
[1556] MS (EI) 391 (M ^&lt; ⁺ &gt;); Melting point 250 ℃ or higher.
[1557] Example 70
[1558] Synthesis of 8- (2-fluoro-phenyl) -7-methoxy-4- [3- [1,2,4] triazol- 1,4] diazepin-2-one
[1559] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2'-fluoro-2-methoxy-5- [3-oxo-3- -Yl) -phenyl) -propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O56). A yellow solid was obtained (22 mg).
[1560] MS (EI) 427 (M ^&lt; ⁺ &gt;); Melting point 188 캜 (decomposition).
[1561] Example 71
[1562] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile
[1563] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [5- [3- (2- cyano-4-yl) -3-oxo-propionylamino] -2'-fluoro-2 by -Methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O57). A yellow solid was obtained (68 mg).
[1564] MS (EI) 386 (M ^&lt; ⁺ &gt;); Melting point 240-242 占 폚.
[1565] Example 72
[1566] Phenyl] -l, 3-dihydro-benzo [b] [1, 4-dihydro- ] Diazepin-2-one
[1567] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2-3-tert-butoxy-4'-fluoro-5- [3- (3-2- methyl-imidazol-1-yl) - Phenyl] -3-oxo-propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O58). A yellow solid was obtained (49 mg).
[1568] MS (ISP) 427 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 260 캜.
[1569] Example 73
[1570] Fluoro-3- [7- (2-fluoro-phenyl) -8-methoxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin- - yl] -benzonitrile
[1571] According to general procedure P, by treatment with TFA in _{CH 2 Cl 2 [5- [3-} (2- to-cyano-2-fluoro-phenyl) -3-oxo-propionylamino] -2'-fluoro-a- Biphenyl-4-yl] -carbamic acid tert-butyl ester (example O59). A yellow solid was obtained (52 mg).
[1572] MS (ISP) 404 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 250 ℃ or higher.
[1573] Example 74
[1574] Benzo [b] [1, 4] diazepin-2-yl] -pyridine &lt; EMI ID = -2-carbonitrile
[1575] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2-3-tert-butoxy-5- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -4'-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O60). A yellow solid was obtained (24 mg).
[1576] MS (EI) 372 (M ^&lt; ⁺ &gt;); Melting point 164 캜.
[1577] Example 75
[1578] Preparation of 8- (2-fluoro-phenyl) -7-hydroxy-4- [3- [1,2,3] triazol- 1,4] diazepin-2-one
[1579] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2,3-Butoxy-2'-fluoro-5- [3-oxo-3- L-yl-phenyl) -propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O61). A light yellow solid was obtained (61 mg).
[1580] MS (ISP) 414 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 250 ℃ or higher.
[1581] Example 76
[1582] (2-fluoro-phenyl) -4-oxo-4,5-dihydro-pyrazol- 3H-benzo [b] [1,4] diazepin-2-yl] -benzonitrile
[1583] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [5- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -2- (1,4-dioxa -8 4-yl] -carbamic acid tert-butyl ester (example O62) in the same manner as in step 2 of Example 1. A yellow solid was obtained 132 mg).
[1584] MS (ISP) 497 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 253 ° C.
[1585] Example 77
[1586] Phenyl) -4- (3-imidazol-1 -yl-phenyl) - &lt; / RTI & -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
[1587] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2- (1,4- dioxa-8-aza-spiro [4.5] des-8-yl) -2'-fluoro-5- [ 4-yl] -carbamic acid tert-butyl ester (example O63) was prepared in accordance with the general method of example 1 (supra) from 3- (3-imidazol- 1 -yl-phenyl) -3-oxo-propionylamino] -biphenyl-4-yl] -carbamic acid tert-butyl ester. A yellow solid was obtained (133 mg).
[1588] MS (ISP) 538 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 225 캜.
[1589] Example 78
[1590] (4-oxo-piperidin-l-yl) -l, 3-dihydro-benzo [ [b] [1,4] diazepin-2-one
[1591] (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) is obtained by stirring in 1N HCl (1 ml) and acetone (1 ml) at 23 & Phenyl) -l, 3-dihydro-benzo [b] [l, 4] diazepin-2-one (Example 77). A yellow solid was obtained (39 mg).
[1592] MS (EI) 493 (M ^&lt; ⁺ &gt;); Melting point 230 캜.
[1593] Example 79
[1594] Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one
[1595] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [2,3-Butoxy-2'-fluoro-5- [3- (3-2-methyl- imidazol- Phenyl] -3-oxo-propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O64). A yellow solid was obtained (111 mg).
[1596] MS (ISP) 425 [(MH) ^- ]; Melting point 250 ℃ or higher.
[1597] Example 80
[1598] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile
[1599] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [2-3-tert-butoxy-5- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -2'-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O65). A yellow solid was obtained (47 mg).
[1600] MS (ISN) 371 [(MH) ^- ]; Melting point 250 ℃ or higher.
[1601] Example 81
[1602] Phenyl] -l, 3-dihydro-benzo [b] thiophene- [1,4] diazepin-2-one
[1603] Treatment with TFA in CH ₂ Cl ₂ according to general procedure P provided [2,3-Butoxy-2'-fluoro-5- [3- [3- (2- methylsulfanyl- Yl) -phenyl] -3-oxo-propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O66). A light yellow solid was obtained (148 mg).
[1604] MS (ISN) 457 [(MH) ^- ]; Melting point 250 ℃ or higher.
[1605] Example 82
[1606] Benzo [b] [1,4] diazepin-2-yl (4-fluoro-phenyl) -8-methoxy- ] -Benzonitrile
[1607] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA [5- [3- (3- cyano-phenyl) -3-oxo-propionylamino] -2 ', 5'-di-fluoro-2 -Methoxy-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O67). A yellow solid was obtained (49 mg).
[1608] MS (EI) 403 (M ^&lt; ⁺ &gt;); Melting point 251 캜.
[1609] Example 83
[1610] Phenyl) -l, 3-dihydro-benzo [l, b] [l, 4] diazepin-2-one
[1611] According to general procedure P, by treatment with TFA in CH ₂ Cl ₂ , [2 ', 5'-difluoro-2-methoxy-5- [ Yl-phenyl) -propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O68). A yellow solid was obtained (78 mg).
[1612] MS (EI) 445 (M ^&lt; ⁺ &gt;); Melting point 241 캜.
[1613] Example 84
[1614] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro- 3-carbonitrile
[1615] According to general procedure P, by treatment with TFA in CH ₂ Cl _{2 there} was obtained [2,3-Butoxy-5- [3- (3-cyano-thiophen-2-yl) -3-oxo-propionylamino ] -2'-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O69). An orange solid was obtained (82 mg).
[1616] MS (ISN) 376 (MH) &lt; ^- &gt;]; Melting point: 242 캜.
[1617] Example 85
[1618] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro- 3-carbonitrile
[1619] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2,3-Butoxy-5- [3- (5-cyano-thiophen-2-yl) -3-oxo-propionylamino ] -2'-fluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O70). A yellow solid was obtained (126 mg).
[1620] MS (EI) 377 (M ^&lt; ⁺ &gt;); Melting point.
[1621] Example 86
[1622] Preparation of 8- (4-fluoro-phenyl) -7-hydroxy-4- [3- [1,2,3] triazol- 1,4] diazepin-2-one
[1623] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [2,3-Butoxy-4'-fluoro-5- [3-oxo-3- L-yl-phenyl) -propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O71). A yellow solid was obtained (78 mg).
[1624] MS (ISP) 414 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 250 ℃ or higher.
[1625] Example 87
[1626] Benzo [b] [1, 4] diazepine [0154] To a solution of 3- [7- (2- fluoro- phenyl) -8- -2-yl] -benzonitrile
[1627] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ afforded [5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -2'- Methoxy-ethoxy) -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O72). A light yellow solid was obtained (141 mg).
[1628] MS (EI) 429 (M ^&lt; ⁺ &gt;); Melting point 211 to 213 占 폚.
[1629] Example 88
[1630] Benzo [b] [1,4] diazepin-2-yl] - (2-fluoro-phenyl) Benzonitrile
[1631] According to general procedure P, CH ₂ Cl _2, by treatment in a TFA (RS) - [5- [ 3- (3- cyano-phenyl) -3-oxo-propionylamino] -2'-fluoro-2 by - (tetrahydro-pyran-2-yloxymethyl) -biphenyl-4-yl] -carbamic acid tert-butyl ester (example O73). A light yellow solid was obtained (69 mg).
[1632] MS (EI) 385 (M ^&lt; ⁺ &gt;); Melting point 90 to 91 占 폚.
[1633] Example 89
[1634] Phenyl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one
[1635] By, treatment with TFA in CH ₂ Cl ₂ according to the general procedure P (2'-fluoro-2- (4-methoxy-benzyloxy) -5- [3- [3- (3-methyl-isoxazole- 5-yl) -phenyl] -3-oxo-propionylamino] -biphenyl-4-yl) -carbamic acid tert-butyl ester (example O74). A yellow solid was obtained (278 mg).
[1636] MS (ISP) 428 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 237 캜.
[1637] Example 90
[1638] Dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Benzonitrile
[1639] According to general procedure P, treatment with TFA in CH ₂ Cl ₂ gave [2,3-Butoxy-5- [3- (3-cyano-phenyl) -3-oxo-propionylamino] 5'-difluoro-biphenyl-4-yl] -carbamic acid tert-butyl ester (example O75). A yellow solid was obtained (56 mg).
[1640] MS (ISP) 390 [(M + H) &lt; ⁺ & gt ^; ]; Melting point 250 ℃ or higher.
[1641] Example 91
[1642] Dihydro-benzo [b] [1,4] diaza-benzo [b] thiophene- Zepin-2-one
[1643] According to general procedure P, CH ₂ Cl ₂ by treatment with TFA in [5-3-tert-butoxycarbonyl-4- (4-fluoro-phenylethynyl) -2- [3- [3-imidazol-1-yl Yl-phenyl) -3-oxo-propionylamino] -phenyl] -carbamic acid tert-butyl ester (example O76). A light yellow solid was obtained (55 mg).
[1644] MS (EI) 436 (M ^&lt; ⁺ &gt;); Melting point: 247 캜.
[1645] Example 92
[1646] Synthesis of 8- (4-fluoro-phenylethynyl) -7-hydroxy-4- (3- [1,2,3] triazol- 1 -yl-phenyl) -1,3-dihydro-benzo [b ] [L, 4] diazepin-2-one
[1647] According to general procedure P, by treatment in CH ₂ Cl ₂ with TFA [5-3-tert-butoxycarbonyl-4- (4-fluoro-phenylethynyl) -2- [3-oxo-3- (3- [ L, 2,3] triazol-l-yl-phenyl) -propionylamino] -phenyl] -carbamic acid tert- butyl ester (example O77). A yellow solid was obtained (56 mg).
[1648] MS (EI) 437 (M ^&lt; ⁺ &gt;); Melting point: 243 캜.
[1649] The following example illustrates the preparation of 4-aryl-8-iodo-1,3-dihydro-benzo [b] [1,4] diazepin 2- Can be provided as a starting material.
[1650] Example 93
[1651] Benzo [b] [1,4] diazepin-2-yl) -benzo [b] thiophen-4- Nitrile
[1652] According to general procedure K, 3- (7-iodo-4-oxo-8-thiomorpholin-4-yl-4,5-dihydro-3H-benzo [b] [1,4] 2-yl) -benzonitrile (Example 1) (437 mg, 0.895 mmol) and phenylacetylene (0.15 mL, 1.34 mmol). A curry solid was obtained (334 mg).
[1653] MS (EI) 391 (M ^&lt; ⁺ &gt;); Melting point: 234-235 캜 (decomposition).
[1654] Example 94
[1655] (RS) -3- (4-oxo-8- (1-oxo-thiomorpholin-4-yl) -7-phenylethynyl-4,5-dihydro-3H-benzo [ ] Diazepin-2-yl) -benzonitrile
[1656] Dihydro-3H-benzo [b] [1,4] diazepin-4-yl-4,5-dihydro- 2-yl) -benzonitrile (Example 27) (50 mg, 0.180 mmol) and Davis reagent (116 mg, 0.432 mmol) was stirred for 1 h at 23 <0> C. The product was filtered off and washed with DCM. A light yellow solid was obtained (16 mg).
[1657] MS (ISP) 479 [(M + H) <^+> ] and 501 [(M + Na) <^+>]; Melting point: 250 ° C or higher (decomposition).
[1658] Dihydro-benzo [b] [1,4] diazepin-2-one is reacted with palladium-catalyzed (3-iodophenyl) -8-phenylethynyl- Carbonylation affords the corresponding amide directly as shown in Synthetic Scheme I.
[1659] Example 95
[1660] Benzo [b] [1,4] diazepin-2-yl) -4-oxo-7-phenylethynyl-4,5-dihydro-3H- - benzamide
[1661] According to general procedure Q, 4- (3-iodo-phenyl) -7- (2-methoxy-ethoxy) -8-phenylethynyl-1,3-dihydro-benzo [ ] Diazepin-2-one (example 25) (268 mg, 0.5 mmol) and hexamethyldisilazane (0.52 mL, 2.5 mmol). A yellow solid was obtained (102 mg).
[1662] MS (EI) 453 (M ^&lt; ⁺ &gt;); Melting point: 227 to 230 캜 (decomposition).
[1663] Example I
[1664] Tablets of the following composition are prepared in a conventional manner:
[1665] mg / tablet Active ingredient100 Powdered lactose95 White corn starch35 Polyvinylpyrrolidone8 Na carboxymethyl starch10 Magnesium stearate2 Total amount of tablets250
[1666] Example II
[1667] Tablets of the following composition are prepared in a conventional manner:
[1668] mg / tablet Active ingredient200 Powdered lactose100 White corn starch64 Polyvinylpyrrolidone12 Na carboxymethyl starch20 Magnesium stearate4 Total amount of tablets400
[1669] Example III
[1670] A capsule of the following composition is prepared:
[1671] mg / capsule Active ingredient50 Crystalline lactose60 Microcrystalline cellulose34 talc5 Magnesium stearateOne Capsule filling amount150
[1672] The active ingredient having a suitable particle size, crystalline lactose and microcrystalline cellulose are uniformly mixed with each other, sieved, and then mixed with talc and magnesium stearate. The final mixture is filled into hard gelatin capsules of suitable size.

权利要求:
Claims (13)
[1" claim-type="Currently amended] Claims 1. Compounds of the formula &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &
Formula I

In this formula,
X is a single bond or an ethynediyl group;
R ¹ is phenyl or halogen optionally substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy or cyano when X is a single bond and X is an ethynyl group, Is phenyl optionally substituted by halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy;
R ² is halogen; Hydroxy; Lower alkyl; Halo-lower alkyl; Lower alkoxy; Hydroxymethyl; Hydroxyethoxy; Lower alkoxy- (ethoxy) _n , wherein n is 1 to 4; Lower alkoxymethyl; Cyanomethoxy; Morpholin-4-yl; Thiomorpholin-4-yl; 1-oxothiomorpholin-4-yl; 1,1-dioxothiomorpholin-4-yl; 4-oxo-piperidin-1-yl; 4-alkoxy-piperidin-1-yl; 4-hydroxy-piperidin-1-yl; 4-hydroxyethoxy-piperidin-1-yl; 4-lower alkyl-piperazin-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] des-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 alkylamino; Hydroxycarbamoyl-lower alkoxy; 2,2-Dimethyl-tetrahydro- [1,3] dioxolo [4,5c] -pyrrol-5-yl; Lower alkoxy-carbamoyl-lower alkoxy; 3R-hydroxy-pyrrolidin-1-yl; 3,4-dihydroxy-pyrrolidin-1-yl; 2-oxo-oxazolidin-3-yl; Lower alkyl-carbamoylmethoxy; Or amino carbamoyl-lower alkoxy;
R ³ is
halogen; Cyano; Nitro; Azido; Hydroxy; Carboxy; Morpholine-4-carbonyl; Carbamoyl; Thiocarbamoyl; N-hydroxycarbamoyl; Trimethylsilyl-ethynyl;
Lower alkyl; Lower alkoxy; Halo-lower alkyl; 4-lower alkyl-piperazine-1-carbonyl; Lower alkylaminocarbonyl which are substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio or carboxy which is optionally esterified or amidated; or
(Which is optionally esterified or amidated), lower alkyl (which may be substituted by halogen, amino, lower alkylamino, acylamino, hydrocarbyl, amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, Lower alkyl, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkoxyimino, carboxy which optionally esterifies Lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl (which is optionally substituted by lower alkyl), amidino (which is optionally substituted by lower alkyl), or -C (NRR ') = NR " (where R, R' and R " are hydrogen or lower alkyl), with an optionally substituted five membered aromatic heterocycle Optionally a 5 or 6 membered aryl or heteroaryl substituted.
[2" claim-type="Currently amended] The method according to claim 1,
R ³ is phenyl substituted at the meta position by cyano; halogen; Imidazolyl optionally substituted by lower alkyl or methylsulfanyl; 1,2,3-triazolyl; 1,2,4-triazolyl; Or isoxazolyl optionally substituted by lower alkyl.
[3" claim-type="Currently amended] 3. The method of claim 2,
3- (8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
Dihydro-3H-benzo [b] [1,4] diazepin-2 &lt; RTI ID = 0.0 & -Yl) -benzonitrile; &lt; / RTI &gt;
3- (8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
Benzo [b] [1,4] diazepin-7-ylsulfanyl] - (2-oxo-phenyl) Acetic acid methyl ester;
Benzo [b] [1,4] diazepin-7-yl] - (2-oxo-phenyl) Acetamide;
3- (8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
3- (8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile;
Dihydro-benzo [b] [1,4] diazepin-2- (2-methoxy-ethoxy) On;
Dihydro-benzo [b] [1,4] diazo [3,4-d] pyrimidin- 2-one;
[RS] -3- [4-oxo-8- (2-oxo- [1,3] dioxolan-4-ylmethoxy) -7-phenylethynyl-4,5-dihydro-3H-benzo [ ] [1,4] diazepin-2-yl] -benzonitrile;
7-Hydroxymethyl-4- (3-imidazol-1-yl-phenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one;
Benzo [b] [1,4] diazepin-7-yloxy [l, 4-diazepin- Hour] - acetonitrile;
Benzo [b] [1,4] oxazepin-1-yl) -piperazin-1- Diazepin-2-one;
Phenyl) -8-phenylethynyl-1,3-dihydro-benzo [b] [1,4] diazo [ 2-one;
4- (3-imidazol-1 -yl-phenyl) - (4-fluoro-phenyl) 1,3-Dihydro-benzo [b] [1,4] diazepin-2-one;
Phenyl] -l, 3-dihydro-benzo [b] [1,4] diazepin- 2-one;
Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro-imidazol- , 4] diazepin-2-one;
Synthesis of 8- (2-fluoro-phenyl) -7-hydroxy-4- (3- [ [1, 4] diazepin-2-one;
Phenyl] -l, 3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one;
Phenyl] -l, 3-dihydro-benzo [b] thiophene- [1, 4] diazepin-2-one;
Phenyl) -l, 3-dihydro-benzo [l, b] [1,4] diazepin-2-one;
Phenyl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one;
Dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Benzonitrile;
Dihydro-benzo [b] [1,4] diaza-benzo [b] thiophene- 2-one; or
Synthesis of 8- (4-fluoro-phenylethynyl) -7-hydroxy-4- (3- [1,2,3] triazol- 1 -yl-phenyl) -1,3-dihydro-benzo [b ] [L, 4] diazepin-2-one.
[4" claim-type="Currently amended] The method according to claim 1,
R ³ is thiophenyl optionally substituted by cyano or halogen; Pyridinyl optionally substituted at the 2-position by cyano or halogen; Or thiazolyl optionally substituted by imidazolyl or 4-methylimidazolyl at the 2-position.
[5" claim-type="Currently amended] 5. The method of claim 4,
Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro-thiophene Octene-2-carbonitrile;
Dihydro-1H-benzo [b] [1,4] diazepin-2-yl] -tetrahydro- 3-carbonitrile;
Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile;
Benzo [b] [1, 4] diazepin-2-yl] -pyridine &lt; EMI ID = -2-carbonitrile;
Dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -pyridine -2-carbonitrile; And
4-yl] -1,3-dihydro-benzo [b] [1, 2-dihydro- , 4] diazepin-2-one.
[6" claim-type="Currently amended] 7. A medicament comprising at least one compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.
[7" claim-type="Currently amended] The method according to claim 6,
A medicament for treating or preventing acute and / or chronic neurological disorders including psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia.
[8" claim-type="Currently amended] Reacting a compound of formula II with a compound of formula IV or IVa to give a compound of formula III, followed by deprotection and cyclization of the amino group to give a compound of formula I, , &Lt; / RTI &gt; as defined in claim 1,



In this formula,
R is ethyl or butyl.
[9" claim-type="Currently amended] A compound according to any one of claims 1 to 5, which is prepared by the process of claim 9 or a similar method.
[10" claim-type="Currently amended] 6. The use of a compound according to any one of claims 1 to 5 for the treatment of acute and / or chronic neurological disorders including psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia.
[11" claim-type="Currently amended] Use of at least one compound according to any one of claims 1 to 5 and / or at least one pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment or prevention of a disease.
[12" claim-type="Currently amended] 14. The method of claim 13,
For the treatment or prevention of acute and / or chronic neurological disorders including psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and amnesia.
[13" claim-type="Currently amended] The invention as hereinbefore described.

类似技术:

---

公开号 | 公开日 | 专利标题

---

JP5918859B2|2016-05-18|Pyrrolocarboxamide for the treatment of chronic inflammatory and autoimmune diseases as a modulator of orphan receptor-gamma | activity associated with the orphan nuclear receptor RAR

---

US9447100B2|2016-09-20|Substituted pyrazolo[1,5-A] pyrimidines as calcium receptor modulating agents

---

US7973071B2|2011-07-05|Substituted gamma lactams as therapeutic agents

---

US6576653B2|2003-06-10|Bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors

---

US6335327B1|2002-01-01|Benzoheterocyclic derivatives

---

KR100838852B1|2008-06-16|Malonamide derivatives blocking the activity of gama-secretase

---

KR101335050B1|2013-11-29|Pyrrolidine derivative or salt thereof

---

US6444687B1|2002-09-03|Substituted imidazole neuropeptide Y Y5 receptor antagonists

---

AU679719B2|1997-07-10|New benzamide derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

---

CN101715442B|2014-03-26|Heterocyclic aspartyl protease inhibitors

---

ES2219762T3|2004-12-01|Bifenil isoxazolil sulfonamides replaced.

---

AU2002240855B2|2006-08-17|Novel benzazepines and related heterocyclic derivatives which are useful as orexin receptor antagonists

---

ES2245029T3|2005-12-16|Imidazol and imidazoline derivatives and use of the same.

---

KR0182798B1|1999-05-01|Pyrazole derivatives, processes for preparation thereof and pharmaceutical composition comprising the same

---

AU2004277981B2|2009-10-01|Benzylether and benzylamino beta-secretase inhibitors for the treatment of Alzheimer&#39;s disease

---

ES2223536T3|2005-03-01|Gamma-carbolins condensed with replaced heterocicles.

---

ES2474166T3|2014-07-08|Novel compounds for the modulation of the activity of the orphan gamma receptor | related to RAR of the orphan nuclear receptor and for the treatment of chronic autoimmune and inflammatory disease

---

DE60310991T2|2007-10-18|Phenyl alanol derivatives as an inhibitors of dipeptidyl peptidase for the treatment or prevention of diabetes

---

JP4592077B2|2010-12-01|1-amido-4-phenyl-4-benzyloxymethyl-piperidine derivatives and related compounds as neurokinin-1 | antagonists for the treatment of vomiting, depression, anxiety and cough

---

US5902813A|1999-05-11|Benzimidazole compounds, pharmaceutical compositions containing the compounds and their use

---

EP1740581B1|2012-08-22|2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer&#39;s disease

---

KR100884872B1|2009-02-23|Substituted dibenzo-azepine and benzo-diazepine derivatives useful as gamma-secretase inhibitors

---

ES2318556T3|2009-05-01|Derivatives of sulfonil bencimidazol.

---

ES2307925T3|2008-12-01|Antagonists of the taquiquinina receptors.

---

AU2006251138B2|2012-08-09|Tricyclic spiro derivatives as CRTH2 modulators

同族专利:

---

公开号 | 公开日

---

HK1051038A1|2005-07-22|

---

ZA200202544B|2003-09-23|

---

CA2386974A1|2001-04-26|

---

CN1379765A|2002-11-13|

---

IL148816A|2006-10-31|

---

DK1224174T3|2004-01-26|

---

DE60005386T2|2004-06-24|

---

PT1224174E|2004-01-30|

---

NZ517999A|2004-07-30|

---

JP2003512359A|2003-04-02|

---

JO2262B1|2004-10-07|

---

DE60005386D1|2003-10-23|

---

RU2259360C2|2005-08-27|

---

EP1224174A2|2002-07-24|

---

TR200201023T2|2002-09-23|

---

BR0014859A|2002-07-16|

---

WO2001029011A3|2001-11-08|

---

AU7910200A|2001-04-30|

---

MY125540A|2006-08-30|

---

HU0203142A3|2003-03-28|

---

JP3857138B2|2006-12-13|

---

EP1224174B1|2003-09-17|

---

GC0000263A|2006-11-01|

---

MA26831A1|2004-12-20|

---

EG24079A|2008-05-11|

---

WO2001029011A2|2001-04-26|

---

AU774451B2|2004-06-24|

---

NO20021690L|2002-04-10|

---

PE20010681A1|2001-06-28|

---

US6407094B1|2002-06-18|

---

NO20021690D0|2002-04-10|

---

PL357418A1|2004-07-26|

---

SI1224174T1|2003-12-31|

---

AR026029A1|2002-12-26|

---

CA2386974C|2009-10-13|

---

KR100480320B1|2005-04-07|

---

ES2204704T3|2004-05-01|

---

CO5261604A1|2003-03-31|

---

CN1195522C|2005-04-06|

---

AT250039T|2003-10-15|

---

NO327817B1|2009-09-28|

---

IL148816D0|2002-09-12|

---

CZ20021653A3|2002-08-14|

---

HRP20020259A2|2004-04-30|

---

YU26202A|2004-12-31|

---

HU0203142A2|2003-02-28|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1999-10-15|Priority to EP99120520.4

---

1999-10-15|Priority to EP99120520

---

2000-09-29|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 아게

---

2002-05-24|Publication of KR20020038954A

---

2005-04-07|Application granted

---

2005-04-07|Publication of KR100480320B1

优先权:

---

申请号 | 申请日 | 专利标题

---

EP99120520.4|1999-10-15|

---

EP99120520|1999-10-15|