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    • 专利摘要:
    The present invention relates to dihydro-benzo [b] [1,4] diazepin-2-one derivatives of formula (I) The present invention also relates to a medicament containing the compound, a method for its preparation and its use for the manufacture of a medicament for the treatment or prevention of acute and / or chronic neurological disorders. Formula I Wherein R 1 , R 2 , R 3 , X and Y are as defined in the specification.
    公开号:KR20030087076A
    申请号:KR10-2003-7013300
    申请日:2002-04-02
    公开日:2003-11-12
    发明作者:아담게오；괴치에르빈；뮈텔뱅상；비흐만유에르겐；볼터링토마스요하네스
    申请人:에프. 호프만-라 로슈 아게；
    IPC主号:
    专利说明:

    DIHYDRO-BENZO [b] [1,4] DIAZEPIN-2-ONE DERIVATIVES AS MGLUR2 ANTAGONISTS II}
    [14] The transmission of stimuli in the central nervous system (CNS) is caused by interactions with neuroreceptors of neurotransmitters transmitted by neurons.
    [15] L-glutamic acid, the most commonly seen 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-controlled ion channels. Metabotropic glutamate receptors (mGluRs) form a second major group and further belong to the class of G-protein-coupled receptors.
    [16] Currently, eight different members of the mGluR are known and some of them even have subtypes. Based on structural parameters, ie different influences on the synthesis of secondary metabolites and different affinity for low molecular weight chemical compounds, these eight receptors can be divided into three subgroups: mGluR1 and mGluR5 are assigned to Group I MGluR2 and mGluR3 belong to group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
    [17] Ligands of metabotropic glutamate receptors belonging to Group II can be used for the treatment or prevention of acute and / or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive impairment and memory loss.
    [18] Other treatable indications in this regard are limited brain function due to bypass surgery or transplantation, poor blood supply to the brain, choroidal damage, head injury, hypoxia due to pregnancy, heart failure and hypoglycemia. Additional treatable signs cause chronic and acute pain, Huntington's chorea, atrophic lateral sclerosis (ALS), dementia due to AIDS, eye damage, retinopathy, Parkinson's disease due to idiopathic Parkinson's disease or drugs, and glutamate-deficient function Conditions such as muscle spasms, races, migraines, incontinence, nicotine addiction, opioid addiction, anxiety, vomiting, dyskinesia and depression.
    [19] It is an object of the present invention to provide a compound of formula (I) and a pharmaceutically acceptable salt thereof and said compound as a pharmaceutically active substance, a process for the preparation thereof, a medicament based on the compound according to the invention and a process for the preparation thereof, and according to the invention The use of the compounds in the control or prevention of diseases of the aforementioned kind and in the preparation of the corresponding medicaments.
    [20] The compounds of formula (I) can also be used in the form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. Prodrugs add to the value of the compounds of the present invention liberty in absorption, pharmacokinetics in distribution and transport to the brain.
    [21] All tautomeric forms of the compounds of the invention are also included herein.
    [1] The present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts thereof:
    [2]
    [3] Where
    [4] X is a single bond or ethyndiyl group;
    [5] When X is a single bond, R 1 is cyano, halogen, lower alkyl, C 3 -C 6 -cycloalkyl, lower alkoxy, fluoro-lower alkoxy, fluoro-lower alkyl, or fluoro, chloro, cyano ,-(CH 2 ) 1-4 -hydroxy, fluoro-lower alkyl, lower alkyl,-(CH 2 ) n -lower alkoxy,-(CH 2 ) n -C (O) OR ",-(CH 2 ) 1-4 -NR'R ", hydroxy-lower alkoxy and-(CH 2 ) n -CONR'R", pyrrole-1-yl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: Phenyl unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, fluoro-lower alkoxy and cyano;
    [6] When X is an ethyndiyl group, R 1 is 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, C 3 -C 6 -cycloalkyl, lower alkoxy and fluoro-lower alkoxy Substituted or unsubstituted phenyl;
    [7] R 2 is —NR′R ″, fluoro-lower alkoxy or 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the ring is optionally defined as R ″ Substituted with;
    [8] R 'is hydrogen, lower alkyl, C 3 -C 6 -cycloalkyl, fluoro-lower alkyl or 2-lower alkoxy lower alkyl;
    [9] R ″ is hydrogen, lower alkyl, C 3 -C 6 -cycloalkyl, fluoro-lower alkyl, 2-lower alkoxy lower alkyl,-(CH 2 ) 2-4 -di-lower alkylamino,-(CH 2 ) 2-4 -morpholinyl,-(CH 2 ) 2-4 -pyrrolidinyl,-(CH 2 ) 2-4 -piperidinyl or 3-hydroxy-lower alkyl;
    [10] Y is -CH = or = N-;
    [11] R 3 is halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, cyano,-(CH 2 ) n -C (O) -OR ",-(CH 2 ) n -C (O) -NR'R "Or an optionally substituted 5-membered aromatic heterocycle [which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano,-(CH 2 ) n -NR'R",-(CH 2 ) n- C (O) -OR ",-(CH 2 ) n -C (O) -NR'R",-(CH 2 ) n -SO 2 -NR'R ",-(CH 2 ) n -C (NH 2 ) = NR ", hydroxy, lower alkoxy, lower alkylthio or lower alkyl, wherein lower alkyl is optionally substituted with fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy. ;
    [12] n is 0, 1, 2, 3 or 4.
    [13] It has surprisingly been found that compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula (I) have valuable therapeutic properties.
    [22] Preference is given to compounds in formula (I) wherein X is a single bond. Preferred exemplary compounds are those in which R 1 is trifluoromethyl and in particular R 3 is cyano, for example the following compounds:
    [23] 4- (4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl)- Pyridine-2-carbonitrile,
    [24] 4- [8- (cyclopropylmethyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Pyridine-2-carbonitrile,
    [25] 4- [8- (cyclopropylmethyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl]- Pyridine-2-carbonitrile,
    [26] 4- [4-oxo-8- (2,2,2-trifluoro-ethoxy) -7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-2-yl] -pyridine-2-carbonitrile, and
    [27] 4- [8- (isopropyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] Pyridine-2-carbonitrile.
    [28] Further preferred are X is a single bond, R 1 is trifluoromethyl and R 3 is an optionally substituted 5-membered aromatic heterocycle, which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, -(CH 2 ) n -NR'R ",-(CH 2 ) n -C (O) -OR",-(CH 2 ) n -C (O) -NR'R ",-(CH 2 ) n —SO 2 —NR′R ″, — (CH 2 ) n —C (NH 2 ) ═NR ″, hydroxy, lower alkoxy, lower alkylthio or lower alkyl, wherein the lower alkyl is fluoro, Compound optionally substituted with hydroxy, lower alkoxy, cyano or carbamoyloxy, examples of such compounds are:
    [29] 7-dimethylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one,
    [30] 7-dimethylamino-4- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    [31] 7-dimethylamino-4- (3-imidazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [32] 4- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    [33] 7- (isobutyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    [34] 7- (isopropyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    [35] 7- (isobutyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl)- 8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [36] 7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoro Rhomethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [37] 7- (methyl-propyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    [38] 7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one,
    [39] 4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one ,
    [40] 7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    [41] 7-dimethylamino-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    [42] 4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b ] [1,4] diazepin-2-ones, and
    [43] 4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one.
    [44] Also preferred are compounds wherein X is a single bond and R 1 is chloro, for example the following compounds:
    [45] 8-chloro-7-isobutylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on,
    [46] 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [47] 8-chloro-7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [48] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [49] 8-chloro-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-ones,
    [50] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isopropyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [51] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isobutyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [52] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-piperidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [53] 8-chloro-7- (isopropyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -Phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [54] 8-chloro-4- (3- {5-[(isobutyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isopropyl-methyl -Amino) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [55] 8-chloro-7-isopropylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on,
    [56] 8-chloro-7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    [57] 8-chloro-4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [58] 8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    [59] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    [60] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    [61] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    [62] 8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    [63] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    [64] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one, and
    [65] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one.
    [66] Further preferred are compounds wherein X is a single bond and R 1 is cyano. Examples of such compounds are as follows:
    [67] 8-diethylamino-2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-7-carbonitrile, and
    [68] 2- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -4-oxo-8-piperidin-1-yl-4,5-dihydro-3H-benzo [b] [1 , 4] diazepine-7-carbonitrile.
    [69] Further in the formula (I) R 3 is an optionally substituted 5-membered aromatic heterocycle, which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano,-(CH 2 ) n -NR'R ",- (CH 2 ) n -C (O) -OR ",-(CH 2 ) n -C (O) -NR'R",-(CH 2 ) n -SO 2 -NR'R ",-(CH 2 ) n -C (NH 2 ) = NR ", hydroxy, lower alkoxy, lower alkylthio or lower alkyl, said lower alkyl being fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy Preference is given to optionally substituted compounds.
    [70] R 3 in Formula I is thiazolyl, oxazolyl, isoxazolyl, imidazolyl, 2H-pyrazolyl, [1,2,3] triazolyl, [1,2,4] triazolyl, [1,3, Particularly preferred are compounds which are optionally substituted 5-membered aromatic heterocycles selected from the group consisting of 4] thiadiazolyl and [1,3,4] oxadiazolyl. Examples of such compounds are as follows:
    [71] 7-dimethylamino-8-phenylethynyl-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one,
    [72] 8- (2-Fluoro-phenyl) -4- (3- [1,2,3] triazol-1-yl-phenyl) -7- (2,2,2-trifluoro-ethoxy)- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    [73] 7- (ethyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    [74] 7-dimethylamino-8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine-2 -On,
    [75] 7- (isobutyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one,
    [76] 7- (isobutyl-methyl-amino) -8-methyl-4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one, and
    [77] 4- (3- {5-[(cyclopropylmethyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isobutyl-methyl-amino) -8 -Methyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one.
    [78] Also preferred are compounds wherein R 2 is -N (CH 3 ) 2 or pyrrolidine. Also preferred are compounds wherein R 3 is isopropyl-amino, isopropyl-methyl-amino, isobutyl-amino or isobutyl-methyl-amino.
    [79] Preferred compounds of the formula (I) in the scope of the invention are also compounds in which R 3 is cyano or optionally substituted 5-membered aromatic heterocycle, which may be substituted with -CH 2 OH or -CH 2 N (CH 3 ) 2 . to be.
    [80] The term "lower alkyl" as used herein denotes straight-chain or branched saturated hydrocarbon residues having 1 to 7, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, I-propyl and the like.
    [81] The term "lower alkoxy" denotes a lower alkyl residue of the meaning defined above bonded via an oxygen atom. Examples of "lower alkoxy" residues include methoxy, ethoxy, isopropoxy and the like.
    [82] The term "halogen" includes fluorine, chlorine, bromine and iodine.
    [83] The term "fluoro-lower alkyl" refers to lower alkyl residues in which one or more hydrogen atoms can be replaced with fluoro.
    [84] The term "fluoro-lower alkoxy" denotes a lower alkoxy residue of the meaning as defined above in which one or more hydrogen atoms may be substituted with fluoro.
    [85] The term "C 3 -C 6 -cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
    [86] The term "lower alkylthio" denotes a lower alkyl residue, for example methylsulfanyl, as defined above bound via a sulfur atom.
    [87] The expression "5-membered aromatic heterocycle" includes furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole and tetrazole. Preferred heterocycles are 1,2,3-triazole, 1,2,4-triazole, isoxazole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole or already It is dozol.
    [88] "Optionally substituted" means that it may or may not be substituted with one or more, preferably one or two, substituents independently selected from the specified group.
    [89] The term "pharmaceutically acceptable addition salt" refers to any salt derived from an inorganic or organic acid or base.
    [90] Compounds of formula (I) and their pharmaceutically acceptable salts can be prepared according to the following methods,
    [91] a) reacting a compound of formula (II) with a compound of formula (IV) or (IVa) to produce a compound of formula (III), followed by deprotection and cyclization of the amino group to give a compound of formula (I)
    [92] If necessary, converting the obtained compound to a pharmaceutically acceptable acid addition salt:
    [93]
    [94]
    [95]
    [96] Wherein R is alkyl, preferably ethyl or butyl
    [97]
    [98] Formula I
    [99]
    [100] [Wherein, R 1 , R 2 , R 3 , X and Y are as described above]
    [101]
    [102] According to Scheme A, compounds in which X, Y, R 1 , R 2 and R 3 in the above formula (I) can be prepared from an acylation-deprotection-ringing process from the compound of formula II:
    [103] For example, the compound of formula (II) is reacted with dioxynon (IV) (where Y and R 3 are as described above) at elevated temperature, preferably from 80 ° C. to 160 ° C., in an inert solvent such as toluene or xylene To obtain a compound.
    [104] Alternatively, the compound of formula III is a β-ketoester (Formula IVa) wherein Y and R 3 are as described above, for example, using the same conditions as described in the reaction of compound of formula II with dioxynon. It can be prepared by reacting with).
    [105] Thereafter, the BOC protecting group in the compound of formula III is decomposed and the deprotected compound is cyclized to give the desired compound of formula I. Any other suitable amino protecting group such as Fmoc or benzyloxycarbonyl (Z) may alternatively be used instead of the BOC group.
    [106] The deprotection-ringing step can be carried out by treating the compound of formula III with Bronsted acid such as, for example, trifluoroacetic acid in an inert solvent such as dichloromethane (DCM). The reaction is preferably carried out at a temperature of 0 ° C to 50 ° C. Anisole or 1,3-dimethoxybenzene can also be advantageously used in the reaction mixture as carboion scavenger.
    [107]
    [108] According to Scheme B, the compound wherein R 1 in Formula II is X is a single bond and R 2 is optionally substituted phenyl as described above for the compound as described above is an iodo-compound of Formula V wherein R 2 may be prepared by different routes depending on the nature of R 1 ). As shown in Scheme B, the key step is the Suzuki type coupling reaction to prepare the compound of formula VIa.
    [109] Compounds as R 1, R 2 and X described above in Formula II can be prepared by reducing the nitro group in the compound of Formula VIa to an amino group, according to Scheme B. Reduction can be carried out, for example, using hydrogen gas in the presence of a suitable catalyst such as Raney-nickel or palladium on carbon. Another possible reduction method is the use of tin (II) chloride (SnCl 2 .2H 2 O) in ethanol at a temperature between 70 ° C. and 80 ° C. ( Tetrahedron Lett. 1984 , 25, 839). ), Or alternatively in a polar aprotic solvent such as DMF, DMA or NMP and the like, optionally in the presence of a base such as pyridine or triethylamine and the like. Another suitable method is to use zinc powder at a temperature of 20 ° C. to 80 ° C. in the presence of ammonium chloride in a protic solvent such as water or ethanol. The exact conditions for each compound of formula (II) can be found in the experimental section.
    [110] Compounds in which R 2 in formula (V) are as described above can be prepared by different routes depending on the individual residue R 2 :
    [111]
    [112] As shown in Scheme C, Compound B1 can be prepared by obtaining iodide from the commercially available 5-chloro-2--nitroaniline to obtain synthetic intermediate A1, which in turn protects it to yield compound B1.
    [113] The iodide step can be carried out, for example, using iodine monochloride in acetic acid in the presence of sodium acetate. The reaction can be carried out, for example, at a temperature of 20 ° C to 80 ° C.
    [114] The protection of amino functional groups is applied to a number of commercially available starting materials or compounds synthesized by those skilled in the art to provide corresponding 2-nitroanilines of formula VII, wherein X is a single bond and R 1 is as described above. Can be prepared. This transformation leads to the key intermediate of formula VIb, and the exact conditions for each compound used in the present invention can be found in the experimental section.
    [115] One possibility for the protection of amino functionalities is to react the compound of formula VII with di-tert.-butyl-carbonate, for example in the presence of a base such as cesium carbonate. The reaction may be carried out at a temperature of 20 ° C. to 60 ° C. in a polar solvent such as acetone or butanone.
    [116] Alternatively, the protection of amino groups may be achieved by preparing the intermediate isocyanates by treating the compound of formula VII with diphosgene, preferably in an aprotic solvent such as ethyl acetate or 1,4-dioxane at 0 ° C. to 100 ° C. The isocyanate was then tert. By treatment with butanol to obtain the desired compound of formula VIb.
    [117] Another suitable method of achieving this protection step is treating the compound of formula VII with di-tert.-butyl-carbonate in an aprotic solvent such as tetrahydrofuran in the presence of DMAP, followed by dichloromethane, chloroform or 1,2 -By selectively removing a single BOC-group by treatment with Bronsted acid, such as TFA, at a temperature between 0 ° C. and 20 ° C., in an aprotic solvent such as dichloroethane, to obtain the desired compound of formula VIb. Intermediate formation of a -BOC compound.
    [118] According to Scheme D, compounds of formula VII wherein R 1 is optionally substituted pyrrole-1-yl, X is a single bond and R is chloride are described in J. Heterocycl. Chem. 1988 , 25 , 1003, known 5-chloro-2-nitro-1,4-phenylenediamine [CAS-No. 26196-45-2 can be prepared by selective condensation of 4-amino-groups with the appropriate substituted 2,5-dimethoxytetrahydrofuran of formula VIII.
    [119]
    [120] The reaction is preferably carried out at a temperature of 40 ° C. to 100 ° C. in an acidic medium such as acetic acid or propionic acid and the like. The exact conditions for each compound can be found in the experimental section.
    [121] Corresponding substituted 2,5-dimethoxytetrahydrofuran having the formula VIII, wherein R a , R b and R c are as described above in the general claim for pyrrole-1-yl compounds, is commercially available or , Synthesized from suitable substituted furans, as shown in Scheme E. Corresponding substituents may be optionally protected with suitable protecting groups known to those skilled in the art, or alternatively may be introduced after pyrrole ring synthesis. The two-step sequence consists of reacting the furan with bromine at low temperature, such as -35 ° C. in MeOH, followed by treatment with a base such as triethylamine or the like or potassium carbonate or sodium hydrogen carbonate or the like. The resulting 2,5-dimethoxydihydrofuran having the formula VIII, wherein R a , R b and R c are as described above, is subjected to catalytic hydrogenation, preferably in MeOH, for example palladium on carbon or It may be reduced using a catalyst such as Raney-Nickel and the like to produce the desired 2,5-dimethoxytetrahydrofuran of Formula VIII. One example of this sequence can be found in Tetrahedron 1971 , 27 , 1973-1996.
    [122]
    [123] The exact conditions for the individual compounds to be synthesized can be found in the experimental section.
    [124] As shown in Scheme F, the compound in which R 2 in formula (VIc) is as described above and attached via a nitrogen atom is the presence of a suitable base from the intermediate compound of formula (VIb), the individual synthesis of which can be found in the experimental section. Under the nucleophilic substitution reaction with the individual amines.
    [125]
    [126] The reaction is preferably carried out in a polar aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like. The base may be selected from sterically hindered amines such as triethylamine or alkoxides such as Hunig base, sodium methoxide and tert.-butoxide, or hydrides such as sodium hydride. The reaction can be carried out at a temperature of 20 ° C. to 110 ° C. depending on the individual compound to be synthesized.
    [127]
    [128] According to Scheme G, the compounds of formula II, wherein R 1 is as described for compounds wherein X is an ethyndiyl group, depend on the properties of R 1 and R 2 and differ in the way that iodo-compound (V) Can be prepared by As shown in Scheme G, the transformation can be performed, for example, as follows.
    [129] a) by attaching R 1 -alkynylyl-substituent directly to the compound of formula V via Sonogashira type coupling to form a compound of formula VId, followed by reduction of the nitro group, or
    [130] b) first coupling trimethylsilyl-acetylene to give a compound of formula V, desilylated with sodium hydroxide in methanol to give intermediate X, which is then reacted with the appropriate reactants R 1 -I, R 1 -Br or By a two- stage sonogashira coupling in which R 1 -OSO 2 CF 3 is converted to the compound of formula VId via a second sonogashira coupling and the nitro group is reduced to yield the desired compound of formula II.
    [131] The exact conditions for each compound can be found in the experimental section.
    [132]
    [133] According to Scheme H, the dioxynon and β-keto ester building blocks having the formulas IV and IVa are prepared by the methods known to those skilled in the art, corresponding to the corresponding carboxylic acid derivatives R 3 -COR, ie free acids, methyl or ethyl esters and It can be prepared from acid chloride. The exact conditions for the corresponding compound can be found in the experimental section.
    [134] Pharmaceutically acceptable salts can be readily prepared according to methods known per se, taking into account the nature of the compound to be converted to the salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc. It is suitable for the formation of pharmaceutically acceptable salts.
    [135] The compounds of formula (I) and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and / or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory loss. have. Other treatable signs are limited brain function due to bypass surgery or transplantation, poor blood supply to the brain, chordal injury, head injury, hypoxia due to pregnancy, heart attack and hypoglycemia. Additional treatable signs include acute and chronic pain, Huntington's chorea, ALS, dementia due to AIDS, eye injury, retinopathy, idiopathic Parkinson's disease or Parkinson's disease due to drugs, and conditions that cause glutamate-deficient function, such as muscle spasms It is, game, migraine, incontinence, nicotine addiction, opium addiction, anxiety, vomiting, dyskinesia and depression.
    [136] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration can, however, be effected rectally, for example in the form of suppositories, or ex vivo, for example in the form of injection solutions.
    [137] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like, but depending on the nature of the active substance no carriers are usually required for soft gelatin capsules. Suitable carriers for solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like may be used for aqueous injection solutions of the water-soluble salts of the compounds of formula (I), but usually are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols and the like.
    [138] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for controlling osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical formulation may also contain another therapeutically valuable substance.
    [139] As mentioned above, a medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient is also an object of the present invention and also comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and It is an object of the present invention to prepare such a medicament comprising, if desired, bringing one or more other therapeutically valuable substances together with one or more therapeutically inert carriers to form an herbal dosage form.
    [140] Dosages can vary within a wide range and are, of course, tailored to the individual needs in each particular case. In general, an effective dosage for oral or extragranular administration is 0.01-20 mg / kg / day, with a dosage of 0.1-10 mg / kg / day being preferred for all indications described. The daily dosage for adults of 70 kg body weight is therefore 0.7 to 1400 mg / day, preferably 7 to 700 mg / day.
    [141] The invention also relates to the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof for the manufacture of a medicament, in particular a medicament for the control or prevention of acute and / or chronic neurological disorders of the aforementioned kind.
    [142] Compounds of the invention are group II mGlu receptor antagonists. The compound shows an activity of 10 μM or less, typically 1 μM or less, ideally 0.3 μM or less, as determined by the following assay.
    [143] The table below shows some specific Ki values of the preferred compounds.
    [144] compound K i mGlu2 (μM) 3- (8-Dimethylamino-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -benzonitrile 0.030 8- (2,3-difluoro-phenyl) -7-dimethylamino-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [ b] [1,4] diazepin-2-one 0.070 8-chloro-7-[(2-methoxy-ethyl) -methyl-amino] -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-ones 0.025 8-chloro-7-dimethylamino-4- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on 0.023 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on 0.030 8- (2-Fluoro-phenyl) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -7- (2,2,2-trifluoro-ethoxy) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one 0.03 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on 0.039 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one 0.030 8-chloro-7- (diethyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones 0.044 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-pyrrolidin-1-yl-1,3-dihydro -Benzo [b] [1,4] diazepin-2-one 0.019
    [145] compound K i mGlu2 (μM) 8-chloro-7- (cyclopropyl-methyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one 0.16 8-chloro-7-dimethylamino-4- (3-pyrazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one 0.11 7-dimethylamino-4- [3- (3-morpholin-4-ylmethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones 0.125 7-dimethylamino-4- [3- (2-methylsulfanyl-imidazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one 0.019 4- [8- (cyclopropylmethyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Pyridine-2-carbonitrile 0.005 4- [3- (5-cyclopropylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7-dimethylamino-8-trifluoromethyl-1, 3-dihydro- Benzo [b] [1,4] diazepin-2-ones 0.049 4- [4-oxo-8- (2,2,2-trifluoro-ethoxy) -7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-2-yl] -pyridine-2-carbonitrile 0.004 3- [7-Methyl-8- (methyl-propyl-amino) -4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl] -benzonitrile 0.025 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one 0.02 8-diethylamino-2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-7-carbonitrile 0.009
    [146] compound K i mGlu2 (μM) 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1,4] diazepin-2-one 0.015 8-chloro-4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one 0.089 7- (methyl-propyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones 0.027 7- (isobutyl-methyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one 0.012 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one 0.003 8-chloro-7-dimethylamino-4- [3- (2-ethylamino-thiazol-4-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on 0.48 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones 0.017 7-dimethylamino-4- [3- (2-methyl-5-propyl-oxazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one 0.046 4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one 0.008
    [147] On mGlu2 transfected CHO cell membrane [ 3H] -LY354740 Combination
    [148] Transfection and Cell Culture
    [149] pBluescript II s cDNA encoding the mouse mGlu2 receptor protein. Obtained from Professor S. Nakanishi (Kyoto, Japan) and subcloned from Invitrogen (NV Leek, The Netherlands) to eukaryotic expression vector pcDNA I-amp. This vector construct (pcDlmGR2) was co-transfected with psvNeo plasmid encoding the gene for neomycin resistance, resulting in CHO cells by the modified calcium phosphate method described by Chen & Okayama (1988). Cells were maintained in Dulbecco's Modified Eagle medium with reduced L-glutamine (final concentration 2 mM) and 10% dialyzed fetal calf serum from Gibco BRL (Switzerland Basel). Selected in the presence of G-418 (1000 ug / ml final). Reverse transcription of 5 μg total RNA, followed by annealing at 60 ° C. for 1 minute, stretching at 72 ° C. for 30 seconds, and denaturing at 95 ° C. for 1 minute with 60 mM Tris HCl (pH 10), 15 mM Clones were identified by PCR using (NH 4 ) 2 SO 4 , 2 mM MgCl 2 , mGlu2 receptor specific primers 5′-atcactgcttgggtttctggcactg-3 ′ and 5′-agcatcactgtgggtggcataggagc-3 ′ in 25 units / ml Taq polymerase. .
    [150] Membrane manufacturing
    [151] Cells cultured as above 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 with polytron (Kinematica, AG, Litau, Switzerland) for 10 seconds at 10,000 rpm. After centrifugation at 4 ° C. for 30 minutes, the pellet was washed once with the same buffer and once with cold 20 mM HEPES-NaOH buffer containing 0.1 mM EDTA (pH 7.4). Protein content was determined using the Pierce method (Socochim, Switzerland) using bovine serum albumin as standard.
    [152] [ 3H] -LY354740 Combination
    [153] After thawing, the membrane was resuspended 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 the assay was 25 μg protein / ml. Inhibition experiments were performed with membranes incubated with 10 nM [ 3 H] LY354740 at room temperature for 1 hour at various concentrations of the compounds of the present invention to be tested. After incubation, the membrane was filtered on Whatmann GF / C glass fiber filters and washed five times with cold binding buffer. Non specific binding was measured in the presence of 10 μM DCG IV. Transfer the filter into a plastic vial containing 10 ml of Ultima-gold scintillation fluid (Packard), Zurich and then in a Tri-Carb 2500 TR counter (Zurich, Switzerland) Radioactivity was measured by liquid flash.
    [154] Data analysis
    [155] Inhibition curves were fitted with four parameter logistic equations to obtain Ki and Hill coefficients.
    [156] General Procedure A
    [157] Preparation of 4-iodo-2-nitroaniline by iodide 2-nitroaniline (according to Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983, 36, 2317-25)
    [158] 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), iodine monochloride (59-66 mL) in HOAc (300 mL) , 1.125-1.25 mol) was added over 60 minutes. The reaction mixture is heated to a given temperature and stirred for an additional 30 minutes at 23 ° C. until thin layer chromatography (tlc) indicates complete conversion of the starting material, then slowly diluted with H 2 O (1000 mL) to give crystalline It caused separation of the product. Stirring was continued for 1 hour and the product was filtered off, washed free of HOAc and dried at 60 ° C. in vacuo.
    [159] Example A1
    [160] 5-chloro-4-iodo-2-nitro-phenylamine
    [161] The title compound was prepared by iodide from 5-chloro-2-nitroaniline with iodine monochloride in HOAc / NaOAc according to General Procedure A (80 ° C.). Obtained as an orange solid.
    [162] MS (EI) 298 (M + ) and 300 [(M + 2) + ]; mp 202-203 ° C (dec.).
    [163] General procedure B
    [164] Preparation of (2-nitro-phenyl) -carbamic acid tert.-butyl ester from 2-nitroaniline
    [165] Method a (from 2-nitroaniline) : A solution of 2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL) at 0 ° C. in a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL). Added and the mixture was heated to reflux for 18 h. The solvent was removed in vacuo leaving a brown solid which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to give pure 2-nitrophenylisocyanate as a yellow solid. This material was refluxed for 2.5 h in a mixture of excess tert.-BuOH in CH 2 Cl 2 . The solvent was removed and the remaining orange solid was purified by silica gel column chromatography with hexanes / EtOAc to give (2-nitro-phenyl) -carbamic acid tert.-butyl ester as a yellow solid.
    [166] Method b (from 2-nitroaniline) : Boc in 2-butanone (170 mL) in a mixture of 2-nitroaniline (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 mL). A solution of 2 O (37.8 g, 173 mmol) was added dropwise and the resulting mixture was stirred at 50 ° C. to 80 ° C. until tlc indicated complete conversion. 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 hexane (3 × 500 mL). The combined hexane layer was washed with brine (200 mL) and all aqueous layers were reextracted with hexane (300 mL). All combined hexane layers were dried over MgSO 4 , filtered and the solvent removed in vacuo to give an orange solid which was purified by column chromatography with hexanes / EtOAc to give (2-nitro-phenyl) -carbamic acid tert. -Butyl ester was obtained as a yellow solid.
    [167] Method c (from 2-nitroaniline) : A solution of 2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) in Boc 2 in THF (500 mL) within 70 minutes at 23 ° C. A solution of O (246 g, 1128 mmol) was added dropwise and stirring continued at 23 ° C. for 75 minutes. The entire mixture was evaporated to dryness and dried under high vacuum to give a dark brown solid. This material was dissolved in DCM (1100 mL), cooled to 0 ° C. and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 2 h, poured into ice cold saturated NaHCO 3 -solution, extracted with DCM, washed with brine and dried over MgSO 4 . The solvent was removed in vacuo to give a dark brown solid which was coated on silica gel and purified by silica gel column chromatography with hexanes / EtOAc to afford (2-nitro-phenyl) -carbamic acid tert.-butyl ester as a yellow solid. Obtained.
    [168] Method d (from 2-nitroacetanilide) : A solution of 2-nitroacetanilide (100 mmol) and DMAP (122 mg, 1 mmol) in THF (100 mL) in THF (100 mL) within 15 minutes at 23 ° C. A solution of Boc 2 O (22.92 g, 105 mmol) was added dropwise and stirring continued at 23 ° C. until tlc indicated complete conversion. The entire mixture was evaporated to dryness and dried under high vacuum to yield a yellow to dark brown solid. This material was dissolved in THF (200 mL) and 25% NH 4 OH (77 mL, 500 mmol) was added dropwise. The mixture was stirred at 23 ° C. until tlc indicated complete conversion, poured into 1N HCl-solution, extracted with EtOAc, and the organic layer was washed with saturated NaHCO 3 -solution and brine and dried over MgSO 4 . The solvent was removed in vacuo to give a yellow to dark brown solid, which was generally pure enough for further conversion or coated on silica gel if necessary and purified by silica gel column chromatography with hexanes / EtOAc ( 2-nitro-phenyl) -carbamic acid tert.-butyl ester was obtained as a yellow solid.
    [169] Example B1
    [170] (5-Chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [171] The title compound was purified from 5-chloro-4-iodo-2-nitro-phenylamine (Example A1) (7.0 g, 23.45 mmol) via isocyanate with EtOAc (30 mL) according to General Procedure B (Method a). Prepared by treatment with diphosgene (2.12 mL, 17.6 mmol) followed by tert.-BuOH (100 mL) in CH 2 Cl 2 (100 mL). Obtained as a yellow solid (7.1 g, 76%).
    [172] MS (EI) 398 (M + ) and 400 [(M + 2) + ]; mp 82-84 ° C.
    [173] Example B2
    [174] (4,5-Dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [175] The title compound was di-Boc-compound from 4,5-dichloro-2-nitroaniline (15 g, 72.5 mmol) and Boc 2 O (32.4 g, 148.5 mmol) commercially available according to General Procedure B (Method c). Via, followed by 2 eq. In CH 2 Cl 2 . Prepared by treatment with TFA. Obtained as a brown solid (21.63 g, 97%).
    [176] MS (ISN) 305 [(M − H) − ]; mp 68-73 ° C.
    [177] Example B3
    [178] (5-Fluoro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [179] The title compound was subjected to 23 ° C. from 5-fluoro-2-nitro-4-trifluoromethyl-phenylamine [commercially available 4-amino-2-fluorobenzotrifluoride according to General Procedure B (method c). Acetylation with Ac 2 O in toluene at, Nitriding with 100% nitric acid at 10-23 ° C. And deacetylation with 2N NaOH in THF at 50 ° C.] (5.21 g, 23.2 mmol) and Boc 2 O (10.63 g, 48.7 mmol) via di-Boc-compound followed by CH 2 Cl 2 2 eq of. Prepared by treatment with TFA. Obtained as a light yellow solid (6.33 g, 84%).
    [180] MS (ISN) 323 [(M − H) − ]; mp 104 ° C.
    [181] Example B4
    [182] [4-iodo-2-nitro-5- (2,2,2-trifluoro-ethoxy) -phenyl] -carbamic acid tert.-butyl ester
    [183] The title compound was purified by 4-iodo-2-nitro-5- (2,2,2-trifluoro-ethoxy) -phenylamine [DMSO (60 mL) according to General Procedure B (Method c). -4-iodo-2-nitro-phenylamine (Example A1) (8.95 g, 30 mmol), 2,2,2-trifluoroethanol (30 mL) and KOH (4.36 g, 66 mmol) were added to 23 Prepared by stirring at 35 ° C. for 35 days] (10.41 g, 29 mmol) and Boc 2 O (12.87 g, 59 mmol) through di-Boc-compound followed by 2 eq in CH 2 Cl 2 . Prepared by treatment with TFA. Obtained as a yellow solid (13.34 g, 100%).
    [184] MS (ISN) 461 [(M − H) − ].
    [185] Example B5
    [186] (5-Chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [187] The title compound was subjected to commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine according to General Procedure B (Method c) [CAS-No. 35375-74-7] (22.61 g, 94 mmol) and Boc 2 O (42.06 g, 193 mmol) through di-Boc-compound followed by 2 eq in CH 2 Cl 2 . Prepared by treatment with TFA. Obtained as a yellow solid (31.82 g, 99%).
    [188] MS (ISN) 339.1 [(MH ) -] and 341 [(M + 2-H ) -]; mp 113-115 ° C.
    [189] Example B6
    [190] (5-Chloro-4-fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [191] The title compound was converted to 3'-chloro-4'-fluoro-6'-nitroacetanilide, commercially available according to General Procedure B (Method d) [CAS-No. 81962-58-5] (59 g, 254 mmol), and Boc 2 O (58.13 g, 266 mmol) via di-Boc-compound followed by NH 4 OH (25%, 77.5 mL, 507 mmol) It was prepared by. Obtained as a yellow solid (73.53 g, 100%).
    [192] MS (ISN) 289 [(MH ) -] and 291 [(M + 2-H ) -]; mp 73-74 ° C.
    [193] Example B7
    [194] [2-Nitro-5- (2,2,2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [195] The title compound was purified via 4-iodo-2-nitro-5- (2,2,2-trifluoro-ethoxy) -phenylamine [5-chloro-4-io in DMSO according to General Procedure B (method c). Prepared by stirring 2--2-nitro-phenylamine (Example A1), 2,2,2-trifluoroethanol and KOH at 23 ° C. for 32.5 days] and from Boc 2 O via di-Boc compound, Then 2 eq in CH 2 Cl 2 . Prepared by treatment with TFA. Obtained as a yellow solid (18.955 g).
    [196] MS (ISN) 403 [(M − H) − ].
    [197] Example B8
    [198] (5-Chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [199] The title compound was di-Boc from 5-chloro-4-methyl-2-nitroaniline (10.0 g, 53.6 mmol) and Boc 2 O (23.9 g, 109 mmol) commercially available according to General Procedure B (Method c). Via compound, then 2 eq. In CH 2 Cl 2 . Prepared by treatment with TFA. Column chromatography (toluene / ethyl acetate 19: 1) afforded a yellow solid (14.6 g, 95%).
    [200] MS (ISN) 285.1 [(M − H) − ].
    [201] Example B9
    [202] (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [203] The title compound was purified by 4-cyano-5-fluoro-2-nitroaniline (24.9 g, 137 mmol) according to General Procedure B (Method c) [Ohmori et al. J. Med. Chem. 1994, 37, 467-475] and Boc 2 O (61.5 g, 282 mmol) via di-Boc compound, followed by 2 eq. In CH 2 Cl 2 . Prepared by treatment with TFA. Column chromatography (hexane / ethyl acetate 4: 1) afforded a light yellow solid (14.5 g, 39%).
    [204] MS (ISN) 280.1 [(M − H) − ].
    [205] General procedure C
    [206] Preparation of 5-N-substituted- (2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [207] (5-chloro or -fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester with the desired amine and optionally DMSO, DMF, DMA, NMP or THF and / or DIPEA or Et 3 N Stir at tC-130C until tlc indicates complete disappearance of chloride or fluoride. The reaction was cooled to 23 ° C. and poured into ice water, the precipitate was filtered off, washed with water and dried in vacuo. If the product was not a precipitate, the mixture was extracted with EtOAc, washed with water and brine and dried over Na 2 SO 4 . Filtration and removal of the solvent in vacuo gave the crude product which was purified by silica gel column chromatography with hexanes / EtOAc if necessary to afford pure title compound.
    [208] Example C1
    [209] (4-Chloro-5-dimethylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [210] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) in DMSO (35 mL) and dimethylamine (5.6 N in EtOH). , 8.7 mL, 48.8 mmol) was prepared according to General Procedure C at 23 ° C. Obtained as a yellow solid (2.81 g).
    [211] MS (ISP) 316 [(M + H) + ] and 318 [(M + 2 + H) + ]; mp 136-138 ° C.
    [212] Example C2
    [213] (5-Dimethylamino-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [214] The title compound was purified from (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example Bl) (399 mg, 1 mmol) and dimethylamine (EtOH) in THF (3 mL). In 5.6 N, 0.36 mL, 2 mmol) was prepared in a sealed tube for 18 hours at 65 ° C. according to General Procedure C. Obtained as a yellow solid (386 mg).
    [215] MS (EI) 407 (M < + >); mp 120-122 ° C.
    [216] Example C3
    [217] {4-Chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2-nitro-phenyl} -carbamic acid tert.-butyl ester
    [218] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.07 g, 10 mmol) in DMSO (20 mL), N- (2-methoxy Prepared according to General Procedure C at 23 ° C. from ethyl) methylamine (2.43 mL, 23 mmol) and Et 3 N (4.2 mL, 30 mmol). Obtained as a brown oil (3.57 g).
    [219] MS (ISP) 360 [(M + H) + ] and 362 [(M + 2 + H) + ].
    [220] Example C4
    [221] (5-Dimethylamino-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [222] The title compound was purified from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example B3) (1.62 g, 5.0 mmol) and dimethyl in DMSO (10 mL). Prepared according to General Procedure C at 23 ° C. from an amine (5.6 N in EtOH, 4.47 mL, 25.0 mmol). Obtained as a yellow solid (1.48 g).
    [223] MS (ISN) 348 [(M − H) − ]; mp 110 ° C.
    [224] Example C5
    [225] [4-Chloro-5- (ethyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [226] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-ethyl-methylamine in DMSO (35 mL). 2.89 g, 48.8 mmol) was prepared according to General Procedure C at room temperature. Obtained as a light brown solid (3.21 g).
    [227] MS (ISP) 330.3 [(M + H) + ]; mp 94 ° C.
    [228] Example C6
    [229] [4-Chloro-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [230] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-methyl-propyl-amine in DMSO (30 mL). (2.50 g, 34.2 mmol) was prepared according to General Procedure C at room temperature. Obtained as a light brown solid (3.58 g).
    [231] MS (ISP) 344.3 [(M + H) + ]; mp 68 ° C.
    [232] Example C7
    [233] [4-Chloro-5- (diethyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [234] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and diethyl-amine (3.57 g) in DMSO (35 mL). , 48.8 mmol), according to General Procedure C at 60 ° C. Obtained as a yellow solid (2.63 g).
    [235] MS (ISP) 344.3 [(M + H) + ]; mp 95 ° C.
    [236] Example C8
    [237] (4-Chloro-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [238] The title compound was prepared according to General Procedure C at 23 ° C. from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) and pyrrolidine in DMSO. Obtained as a yellow solid (6.65 g).
    [239] MS (ISP) 342 [(M + H) + ] and 344 [(M + 2 + H) + ]; mp 157-158 ° C.
    [240] Example C9
    [241] [4-Chloro-5- (cyclopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester
    [242] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.07 g, 10 mmol) and cyclopropyl-methyl-aminehydrogen in DMSO (30 mL). Prepared from Chloride (3.22 g, 30 mmol) and Et 3 N (6.97 mL, 50 mmol) at 23 ° C. according to General Procedure C. Obtained as a yellow solid (3.25 g).
    [243] MS (ISP) 342.2 [(M + H) + ] and 344 [(M + 2 + H) + ]; mp 104-106 ° C.
    [244] Example C10
    [245] (2-nitro-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [246] The title compound was purified from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example B5) (6.81 g, 20 mmol) and pyrroli in DMSO (70 mL). From Dean (8.27 mL, 100 mmol) at 23 ° C. according to General Procedure C. Obtained as a yellow solid (7.35 g).
    [247] MS (ISN) 374 [(M − H) − ]; mp 138-141 ° C.
    [248] Example C11
    [249] (5-Dimethylamino-4-fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [250] The title compound was purified from (5-chloro-4-fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B6) (4.94 g, 17 mmol) and Me 2 NH in DMSO (35 mL). 40% in H 2 O, 7.9M, 10.9 mL, 86 mmol) was prepared according to General Procedure C at 23 ° C. Obtained as a yellow solid (4.93 g).
    [251] MS (ISP) 303 [(M + H) + ]; mp 144-148 ° C.
    [252] Example C12
    [253] (4-Chloro-2-nitro-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [254] The title compound was prepared according to General Procedure C at 23 ° C. from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) and piperidine in DMSO. Obtained as a yellow solid (1.173 g).
    [255] MS (ISP) 356 [(M + H) + ] and 358 [(M + 2 + H) + ]; mp 132-133 ° C.
    [256] Example C13
    [257] (4-Fluoro-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [258] The title compound was purified from (5-chloro-4-fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B6) (5.81 g, 20 mmol) and pyrrolidine in DMSO (40 mL). 8.27 mL, 100 mmol) was prepared according to General Procedure C at 23 ° C. Obtained as a yellow solid (6.42 g).
    [259] MS (ISP) 326 [(M + H) + ]; mp 188-193 ° C.
    [260] Example C14
    [261] (5-azetidin-1-yl-4-chloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [262] The title compound was dissolved in (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (6.14 g, 20 mmol), azetidine (2.33 mL, 34) in DMSO (40 mL). mmol) and Et 3 N (8.4 mL, 60 mmol) at 23 ° C. according to General Procedure C. Obtained as an orange solid (5.85 g).
    [263] MS (EI) 327 (M + ) and 329 [(M + 2) + ].
    [264] Example C15
    [265] (5-azetidin-1-yl-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [266] The title compound was subjected to General Procedure C at 23 ° C. from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example B5), azetidine and Et 3 N in DMSO. It was prepared according to. Obtained as a yellow solid (6.925 g).
    [267] MS (ISN) 360 [(M − H) − ].
    [268] Example C16
    [269] [5- (Cyclopropylmethyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [270] The title compound was purified by (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example B5) (5.11 g 15 mmol) in DMSO (50 mL), cyclopropylmethyl. Prepared according to General Procedure C at 23 ° C. from -methyl-amine hydrochloride (5.47 g, 45 mmol) and Et 3 N (10.5 mL, 75 mmol). Obtained as a yellow solid (5.73 g).
    [271] MS (ISN) 388 [(M − H) − ]; mp 51 ° C.
    [272] Example C17
    [273] [5- (Cyclopropyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [274] The title compound was purified from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example B5) (3.40 g, 10 mmol) and cyclopropyl in DMSO (50 mL). Prepared according to General Procedure C at 23 ° C. from -methyl-amine hydrochloride (3.22 g, 30 mmol) and Et 3 N (6.97 mL, 50 mmol). Obtained as a yellow solid (3.74 g).
    [275] MS (ISP) 374.2 [(M + H) + ].
    [276] Example C18
    [277] (2-Dimethylamino-2'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester
    [278] The title compound was purified from (2-chloro-2'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example D3) in DMSO (87 mL) (9.568 g, about 26 mmol) and Me 2 NH (60% in H 2 O, 12 mL) at 23 ° C. according to General Procedure C. Obtained as a yellow solid (4.54 g).
    [279] MS (ISP) 376.3 [(M + H) + ].
    [280] Example C19
    [281] (5-Dimethylamino-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [282] The title compound was purified from (5-chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and dimethylamine (11 ml, in DMSO (35 mL). 33% in EtOH, 61.0 mmol) was prepared according to General Procedure C at 50 ° C. Obtained as a yellow solid (3.50 g, 97%).
    [283] MS (ISP) 296.3 [(M + H) + ].
    [284] Example C20
    [285] (4-cyano-5-dimethylamino-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [286] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and dimethylamine (6.3 in DMSO (30 mL). ml, 33% in EtOH, 35.0 mmol) was prepared according to General Procedure C at room temperature. Obtained as a yellow solid (1.87 g, 86%).
    [287] MS (ISP) 307.3 [(M + H) + ].
    [288] Example C21
    [289] [4-Methyl-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [290] The title compound was purified from (5-chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and N-methylpropylamine in DMSO (35 mL). 6.5 ml, 61.0 mmol) was prepared according to General Procedure C at 55 ° C. Obtained as a yellow oil (3.89 g, 98%).
    [291] MS (ISP) 324.4 [(M + H) + ].
    [292] Example C22
    [293] [5- (Ethyl-methyl-amino) -4-methyl-2-nitro-phenyl] -carbamic acid tert-butyl ester
    [294] The title compound was purified from (5-chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and N-ethylmethylamine in DMSO (35 mL). 5.5 ml, 61.0 mmol) was prepared according to General Procedure C at 55 ° C. Obtained as a yellow solid (3.58 g, 95%).
    [295] MS (ISP) 310.3 [(M + H) + ].
    [296] Example C23
    [297] [4-Chloro-5- (isopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [298] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and N-isopropyl-methylamine in DMSO (50 mL). (5.95 g, 81.4 mmol) was prepared according to General Procedure C at 75 ° C. Obtained as a yellow solid (4.07 g, 73%).
    [299] MS (ISP) 344.3 [(M + H) + ].
    [300] Example C24
    [301] [4-Chloro-5- (isobutyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [302] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and N-isobutyl-methylamine in DMSO (50 mL). (7.09 g, 81.4 mmol) was prepared according to General Procedure C at room temperature. Obtained as a brown oil (5.79 g, 99%).
    [303] MS (ISP) 358.2 [(M + H) + ].
    [304] Example C25
    [305] (4-cyano-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester
    [306] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and pyrrolidine in DMSO (30 mL). 2.94 ml, 35.6 mmol) was prepared according to General Procedure C at room temperature. Obtained as a yellow solid (1.97 g, 83%).
    [307] MS (ISP) 331.2 [(M − H) − ].
    [308] Example C26
    [309] [4-cyano-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [310] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-methyl- in DMSO (20 mL). Prepared according to general procedure C from propylamine (3.72 ml, 34.7 mmol) at room temperature. Obtained as a yellow solid (1.75 g, 75%).
    [311] MS (ISP) 333.3 [(M − H) − ].
    [312] Example C27
    [313] (4-cyano-5-diethylamino-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [314] The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N, N- in DMSO (20 mL). Prepared according to general procedure C from diethylamine (3.60 ml, 34.7 mmol) at room temperature. Obtained as a yellow solid (1.78 g, 77%).
    [315] MS (ISP) 333.2 [(M − H) − ].
    [316] Example C28
    [317] [4-cyano-5- (isopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [318] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isopropyl in DMSO (30 mL). Prepared according to General Procedure C from -N-methylamine (3.60 ml, 34.7 mmol) at room temperature. Obtained as a yellow solid (1.84 g, 79%).
    [319] MS (ISP) 333.3 [(M − H) − ].
    [320] Example C29
    [321] [4-cyano-5- (isobutyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert-butyl ester
    [322] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isobutyl in DMSO (20 mL). Prepared according to General Procedure C from -N-methylamine (3.02 g, 34.7 mmol) at room temperature. Obtained as a yellow solid (1.87 g, 77%).
    [323] MS (ISP) 347.4 [(M − H) − ].
    [324] Example C30
    [325] (4-Cyano-2-nitro-5-piperidin-1-yl-phenyl) -carbamic acid tert-butyl ester
    [326] The title compound was purified from (4-cyano-5-fluoro-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and piperidine in DMSO (20 mL). 3.51 ml, 35.6 mmol) was prepared according to General Procedure C at room temperature. Obtained as a yellow solid (1.94 g, 79%).
    [327] MS (ISP) 345.3 [(M − H) − ].
    [328] Example C31
    [329] (4-Chloro-5-isobutylamino-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [330] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and isobutylamine (3.57 g, in DMSO (20 mL), 48.8 mmol) was prepared according to General Procedure C at 55 ° C. Obtained as a brown solid (2.26 g, 67%).
    [331] MS (ISP) 344.2 [(M + H) + ].
    [332] Example C32
    [333] [5- (Methyl-propyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [334] The title compound was purified from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol) in DMSO (30 mL), N-methyl. Prepared according to General Procedure C from propyl-amine (1.89 ml, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) at room temperature. Obtained as a yellow solid (4.04 g, 91%).
    [335] MS (ISP) 378.3 [(M + H) + ].
    [336] Example C33
    [337] [5- (Isobutyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [338] The title compound was purified from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol) in DMSO (30 mL), N-iso. Prepared according to General Procedure C from butyl-methyl-amine (1.54 g, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) at room temperature. Obtained as a yellow solid (4.18 g, 91%).
    [339] MS (ISP) 390.3 [(M − H) − ].
    [340] Example C34
    [341] [5- (Isopropyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [342] The title compound was purified from (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol) in DMSO (30 mL), N-iso. Prepared according to General Procedure C at 50 ° C. from propyl-methyl-amine (3.67 ml, 35.2 mmol) and triethylamine (5.73 ml, 41.1 mmol). Obtained as a yellow solid (3.27 g, 74%).
    [343] MS (ISP) 376.3 [(M − H) − ].
    [344] Example C35
    [345] [5- (Isobutyl-methyl-amino) -4-methyl-2-nitro-phenyl] -carbamic acid tert-butyl ester
    [346] The title compound was purified from (5-chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and N-isobutyl-methyl in DMSO (30 mL). Prepared according to General Procedure C from amine (4.56 g, 52.3 mmol) at 55 ° C. Obtained as a yellow oil (1.84 g, 52%).
    [347] MS (ISP) 336.3 [(M − H) − ].
    [348] Example C36
    [349] (4-Methyl-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester
    [350] The title compound was purified from (5-chloro-4-methyl-2-nitro-phenyl) -carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and pyrrolidine (4.33 ml) in DMSO (30 mL). , 52.3 mmol), at 55 ° C. according to General Procedure C. Obtained as a yellow solid (3.27 g, 97%).
    [351] MS (ISP) 320.3 [(M − H) − ]; mp 145 ° C.
    [352] Example C37
    [353] (4-Chloro-5-isopropylamino-2-nitro-phenyl) -carbamic acid tert-butyl ester
    [354] The title compound was purified from (4,5-dichloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and isopropylamine (7.0 ml, in DMSO (35 mL). 81.4 mmol) was prepared according to General Procedure C at 55 ° C. Obtained as a brown solid (3.95 g, 73%).
    [355] MS (ISP) 330.2 [(M + H) + ].
    [356] Example C38
    [357] (5-Isobutylamino-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester
    [358] The title compound was prepared (5-chloro-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example B5) (5.00 g, 14.7 mmol) in isobutyl- in DMSO (35 mL). Prepared according to General Procedure C from amine (7.36 mL, 73.4 mmol) at room temperature. Obtained as a yellow solid (5.39 g, 97%).
    [359] MS (ISP) 376.3 [(M − H) − ].
    [360] General procedure D
    [361] (4-aryl-2-nitro-phenyl) -carbamic acid tert.- by direct Suzuki-coupling of (4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester with arylboronic acid Preparation of Butyl Ester
    [362] A mixture of (4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (3.0 mmol), arylboronic acid (4.5 mmol) and PdCl 2 (PPh 3 ) 2 (2 mol%) It was refluxed in 1,4-dioxane (25 mL) and 2M Na 2 CO 3 -solution (7.5 mL) until directed to complete conversion of iodide (or else 1M NaHCO 3 -solution in DME (30 mL)). (7.5 mL), LiCl (6.0 mmol) and (Ph 3 P) 4 Pd (3 mol%); It is also possible to use Et 3 N (9.0 mmol), Pd (OAc) 2 (3 mol%), PPh 3 (6 mol%) in DMF (10 mL) at 100 ° C.]. The mixture was transferred to a separatory funnel, H 2 O (25 mL) was added and the product extracted with ether or EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL) and dried over Na 2 SO 4 . The solvent was removed to give a brown residue which was purified by silica gel column chromatography with cyclohexane / ether or cyclohexane / EtOAc to afford the title compound.
    [363] Example D1
    [364] (2-Dimethylamino-2 ', 3'-difluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester
    [365] The title compound was prepared according to the general procedure D from (5-dimethylamino-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C2) and 2,3-difluorophenylboronic acid Prepared. Obtained as a yellow solid (3.096 g).
    [366] MS (ISN) 392 [(M − H) − ].
    [367] Example D2
    [368] [2'-Fluoro-5-nitro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [369] The title compound was purified by [4-iodo-2-nitro-5- (2,2,2-trifluoro-ethoxy) -phenyl] -carbamic acid tert.-butyl ester (Example B4) and 2-fluoro Prepared according to general procedure D from phenylboronic acid. Obtained as a yellow solid (1.39 g).
    [370] MS (ISP) 491 [(M + H) + ]; mp 73-75 ° C.
    [371] Example D3
    [372] (2-Chloro-2'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester
    [373] The title compound was purified from (5-chloro-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example B1) (30 g, 75.3 mmol) and 2-fluorophenylboronic acid (13.82 g , 98.8 mmol), according to General Procedure D. Obtained as a yellow gum (1.39 g).
    [374] MS (ISN) 365.0 [(M − H) − ].
    [375] General procedure E
    [376] (4-aryl- by coupling Suzuki-coupling of (4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester with bis (pinacolato) diboron and subsequent reaction with aryl halides Preparation of 2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [377] (4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester (2.0 mmol), bis (pinacolato) diboron (2.2 mmol), KOAc in 1,4-dioxane (25 mL) (6.0 mmol) and a mixture of PdCl 2 (PPh 3 ) 2 (3 mol%) were stirred at 100 ° C. until tlc indicated complete conversion of iodide ( Tetr. Lett. 1997 , 38, 3841). -3844]. After the addition of 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 added when tlc indicated complete conversion of the intermediate boronic acid ester. Stir at 100 ° C. until. The mixture was transferred to a separatory funnel, H 2 O (30 mL) was added and the product extracted with ether or EtOAc (3 × 50 mL). The combined organic layer was washed with brine (100 mL) and dried over Na 2 SO 4 . Solvent was removed to give a brown residue, which was purified by silica gel column chromatography with cyclohexane / ether or cyclohexane / EtOAc to afford the title compound.
    [378] General procedure F
    [379] Preparation of 5-chloro-2-nitro-4-pyrrole-1-yl-phenylamine by condensation of 5-chloro-2-nitro-1,4-phenylenediamine with 2,5-dimethoxytetrahydrofuran (See J. Heterocycl. Chem. 1988 , 25, 1003-1005)
    [380] A mixture of 5-chloro-2-nitro-1,4-phenylenediamine (4.69 g, 25 mmol) and 2,5-dimethoxytetrahydrofuran (26-32.5 mmol) in HOAc (150 mL) was prepared by tlc phenyl. Stir at 60-120 ° C. until directed to complete conversion of lendiamine. After cooling to 23 ° C., the mixture was poured into brine (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layer was washed with brine (300 mL) and dried over MgSO 4 . Solvent was removed to give a brown residue, which was purified by silica gel column chromatography with cyclohexane / EtOAc to afford the title compound.
    [381] General procedure G
    [382] Preparation of 2,5-dimethoxydihydrofuran by bromination of furan in MeOH (see Tetrahedron 1971 , 27, 1973-1996)
    [383] To a solution of furan (177.5 mmol) in a mixture of anhydrous ether (54 mL) and pure MeOH (79 mL) maintained at −35 ° C., bromine (10.0 mL, 195 mmol) in MeOH (105 mL) was added gradually with stirring It was. The reaction mixture was stirred for 30 minutes, saturated with gaseous NH 3 to pH 8 and warmed to 23 ° C. Poured into ice water, extracted with ether (3 × 400 mL), washed with brine and dried over Na 2 SO 4 . The solvent was evaporated to give a yellow liquid which was purified by vacuum distillation to give the title compound.
    [384] General procedure H
    [385] (4-alkynyl-2-nitro-phenyl) -carbamic acid tert by sonogashira-coupling of (4-iodo-2-nitro-phenyl) -carbamic acid tert.-butyl ester using an acetylene compound. Preparation of butyl ester;
    [386] Sonogashira-coupling of (4-ethynyl-2-nitro-phenyl) -carbamic acid tert.-butyl ester also with aryl halides:
    [387] Halide (3.0-4.5 mmol), acetylene compound (3.0-4.5 mmol), Et 3 N (13.5 mmol), PdCl 2 (PPh 3 ) 2 (5 mol%) and PPh 3 (2.5 mol) in THF (12 mL) %) (Which can be added DMF (up to 12 mL) if very insoluble) is stirred at 23 ° C. for 20 minutes while purging with argon. CuI (1.2 mol%) was added and stirring continued at 60 ° C. under an argon atmosphere until tlc indicated complete conversion of minor components (see J. Org. Chem. 1998, 63, 8551). The mixture was transferred to a separatory funnel, 5% citric acid (50 mL) was added and the product extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with saturated NaHCO 3 -solution (50 mL) and brine (50 mL) and then dried over MgSO 4 . Removal of the solvent gave a yellow residue which was purified by silica gel column chromatography with hexanes / EtOAc and / or triturated with hexanes or aqueous EtOH to afford the title compound.
    [388] Example H1
    [389] (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert.-butyl ester
    [390] The title compound was purified from (5-dimethylamino-4-iodo-2-nitro-phenyl) -carbamic acid tert.-butylester (Example C2) (386 mg, 0.97 mmol) and phenylacetylene (149 mg, 1.46 mmol). From General Procedure H from Obtained as an orange solid (370 mg).
    [391] MS (EI) 381 (M + ); mp 141-149 ° C.
    [392] General procedure J
    [393] Preparation of (2-amino-phenyl) -carbamic acid tert.-butyl ester by reduction of (2-nitro-phenyl) -carbamic acid tert.-butyl ester
    [394] Method a: catalytic hydrogenation
    [395] A mixture of Nitro compound (1.0 mmol) in MeOH or EtOH and THF (1: 1 about 20 mL) [or EtOAc for aromatic chloride only] and 10% palladium on carbon (20 mg), Raney-Ni (20 mg) or Platinum 5% carbon was stirred vigorously at 23 ° C. under hydrogen atmosphere until tlc indicated complete conversion. The catalyst was filtered off and washed thoroughly with MeOH or EtOH and THF (1: 1) [or EtOAc] and the solvent removed in vacuo to afford the title compound, which is generally pure enough for further modification but high temperature if necessary It could crystallize from the nucleic acid.
    [396] Method b: SnCl 22H 2Reduction with O
    [397] A mixture of nitro compound (1.0 mmol) and SnCl 2 .2H 2 O (5.0 mmol) may be stirred in EtOH (30 mL) at 70-80 ° C., or alternatively tlc may indicate complete conversion under an argon atmosphere at 23 ° C. Stir in pyridine (3 mL) and DMF (12 mL) until this time (see Tetr. Lett . 1984, 25, 839). The reaction mixture was brought to pH 8 by addition of saturated NaHCO 3 -sol and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent is removed to give a yellow solid, which can be purified-if necessary-by silica gel column chromatography.
    [398] Method c: Zn and NH 4Reduction with Cl
    [399] Zinc dust (3.0 mmol) was added to a mixture of nitro compounds (1.0 mmol) in EtOH / THF / saturated NH 4 Cl-sol (1: 1: 1, 30 mL), and the mixture was tlc at 70 ° C. under argon atmosphere. Stir until complete conversion is indicated. Aqueous workup was carried out as described in method b.
    [400] Example J1
    [401] (2-Amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester
    [402] The title compound was prepared from SnCl from (4-chloro-5-dimethylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C1) (2.76 g, 8.74 mmol) according to General Procedure J (Method b). Prepared by reduction with 2 · 2H 2 O. Obtained as an orange solid (2.3 g).
    [403] MS (ISP) 286 [(M + H) + ] and 288 [(M + 2 + H) + ]; mp 96-101 ° C.
    [404] Example J2
    [405] (2-Amino-5-dimethylamino-4-phenylethynyl-phenyl) -carbamic acid tert.-butyl ester
    [406] The title compound was prepared from SnCl 2 .2H 2 O from (5-dimethylamino-2-nitro-4-phenylethynyl-phenyl) -carbamic acid tert.-butyl ester (Example H1) according to General Procedure J (method b). Prepared by reducing to. Obtained as a brown solid (1.927 g).
    [407] MS (ISP) 352 [(M + H) + ].
    [408] Example J3
    [409] (5-Amino-2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester
    [410] The title compound was prepared according to general procedure J (method b) (2-dimethylamino-2 ', 3'-difluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example Prepared by reducing with SnCl 2 .2H 2 O from D1). Obtained as an orange solid (2.206 g).
    [411] MS (ISP) 364 [(M + H) + ].
    [412] Example J4
    [413] {2-Amino-4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -carbamic acid tert.-butyl ester
    [414] The title compound was purified (3.46 g, 9.62 mmol) according to General Procedure J (Method b), {4-Chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2-nitro-phenyl} -carbamic acid Prepared by reduction with tert.-butyl ester (Example C3) to SnCl 2 .2H 2 O. Obtained as a yellow solid (2.25 g).
    [415] MS (ISP) 330 [(M + H) + ] and 332 [(M + 2 + H) + ]; mp 112 ° C.
    [416] Example J5
    [417] [5-Amino-2'-fluoro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [418] The title compound was prepared according to general procedure J (method a) [2'-fluoro-5-nitro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid Prepared by hydrogenation from tert.-butyl ester (Example D2) at 10% Pd / C. Obtained as a gray solid (1.17 g).
    [419] MS (ISP) 401 [(M + H) + ].
    [420] Example J6
    [421] (2-Amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [422] The title compound was purified from 10% Pd / C from (5-dimethylamino-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example C4) according to General Procedure J (method a). Prepared by hydrogenation. Obtained as an amorphous yellowish material (1.34 g).
    [423] MS (ISP) 320 [(M + H) + ].
    [424] Example J7
    [425] [2-Amino-4-chloro-5- (ethyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [426] The title compound was purified according to general procedure J (method b) [4-chloro-5- (ethyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C5) (3.0 g, 9.09 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (2.64 g).
    [427] MS (ISP) 300.3 [(M + H) + ]; mp 81 ° C.
    [428] Example J8
    [429] [2-Amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [430] The title compound was prepared according to general procedure J (method b) [4-chloro-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C6) (3.15 g, 9.16 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (2.58 g).
    [431] MS (ISP) 314.3 [(M + H) + ]; mp 92 ° C.
    [432] Example J9
    [433] [2-Amino-4-chloro-5- (diethyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [434] The title compound was prepared according to general procedure J (method b) [4-chloro-5- (diethyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C7) (2.25 g, 6.54 mmol) to SnCl 2 .2H 2 O. Obtained as an orange solid (1.55 g).
    [435] MS (ISP) 314.3 [(M + H) + ]; mp 110 ° C.
    [436] Example J10
    [437] (2-Amino-4-chloro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [438] The title compound was prepared from SnCl 2 from (4-chloro-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C8) according to General Procedure J (method b). Prepared by reduction with 2H 2 O. Obtained as a red solid (4.80 g).
    [439] MS (ISP) 312 [(M + H) + ] and 314 [(M + 2 + H) + ]; mp 136-138 ° C.
    [440] Example J11
    [441] [2-Amino-4-chloro-5- (cyclopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [442] The title compound was purified according to General Procedure J (Method b) [4-Chloro-5- (cyclopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C9) (3.2 g , 9.36 mmol) to SnCl 2 .2H 2 O. Obtained as a brown solid (2.00 g).
    [443] MS (ISP) 312 [(M + H) + ] and 314 [(M + 2 + H) + ].
    [444] Example J12
    [445] (2-Amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [446] The title compound was prepared according to general procedure J (method a) (2-nitro-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example C10) ( 7.35 g, 19.75 mmol), followed by hydrogenation with 10% Pd / C. Obtained as a light orange solid (6.75 g).
    [447] MS (ISP) 346 [(M + H) + ]; mp 101-103 ° C.
    [448] Example J13
    [449] (2-Amino-5-dimethylamino-4-fluoro-phenyl) -carbamic acid tert.-butyl ester
    [450] The title compound was obtained from (5-dimethylamino-4-fluoro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C11) (4.88 g, 16 mmol) according to General Procedure J (Method a). Prepared by hydrogenation at 10% Pd / C. Obtained as a green solid (4.55 g).
    [451] MS (ISP) 270 [(M + H) + ]; mp 120-123 ° C.
    [452] Example J14
    [453] (2-Amino-4-chloro-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [454] The title compound was prepared from SnCl 2 from (4-chloro-2-nitro-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C12) according to General Procedure J (method b). Prepared by reduction with 2H 2 O. Obtained as a light brown solid (747 mg).
    [455] MS (ISP) 326 [(M + H) + ] and 328 [(M + 2 + H) + ]; mp 149-151 ° C.
    [456] Example J15
    [457] (2-Amino-4-fluoro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [458] The title compound was purified according to general procedure J (method a) (4-fluoro-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C13) (6.37 g , 20 mmol) to give 10% Pd / C. Obtained as a gray solid (5.92 g).
    [459] MS (ISP) 296 [(M + H) + ]; mp 75-76 ° C.
    [460] Example J16
    [461] (2-Amino-5-azetidin-1-yl-4-chloro-phenyl) -carbamic acid tert.-butyl ester
    [462] The title compound was purified from 5% Pt / from (5-azetidin-1-yl-4-chloro-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C14) according to General Procedure J (method a). Prepared by hydrogenation with C. Obtained as a white solid (3.664 g).
    [463] MS (ISP) 298 [(M + H) + ] and 300 [(M + 2 + H) + ]; mp 176-179 ° C.
    [464] Example J17
    [465] (2-Amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [466] The title compound was purified from (5-azetidin-1-yl-2-nitro-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example C15) according to General Procedure J (method a). Prepared by hydrogenation in% Pt / C. Obtained as a white solid (5.173 g).
    [467] MS (ISP) 332 [(M + H) + ]; mp 166-167 ° C.
    [468] Example J18
    [469] [2-Amino-5- (cyclopropylmethyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [470] The title compound was prepared according to general procedure J (method b) [5- (cyclopropylmethyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C16 ) (5.66 g, 14.5 mmol) by reduction with SnCl 2 .2H 2 O. Obtained as a yellow solid (4.7 g).
    [471] MS (ISP) 360 [(M + H) + ]; mp 56 ° C.
    [472] Example J19
    [473] [2-Amino-5- (cyclopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [474] The title compound was prepared according to general procedure J (method b) [5- (cyclopropyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C17) Prepared by reducing (3.74 g, 9.96 mmol) with SnCl 2 .2H 2 O. Obtained as an orange semisolid (2.00 g).
    [475] MS (ISP) 346.4 [(M + H) + ].
    [476] Example J20
    [477] (5-Amino-2-dimethylamino-2'-fluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester
    [478] The title compound was prepared according to general procedure J (method a) (2-dimethylamino-2'-fluoro-5-nitro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example C18) (4.54). g, 12.1 mmol) and then hydrogenated at 10% Pd / C. Obtained as a light brown solid (3.324 g).
    [479] MS (ISP) 346.4 [(M + H) + ].
    [480] Example J21
    [481] [2-Amino-5- (2, 2, 2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [482] The title compound was prepared according to general procedure J (method a) [2-nitro-5- (2,2,2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl Prepared by hydrogenation from ester (Example B7) at 5% Pt / C. Obtained as a yellow solid (17.374 g).
    [483] MS (ISP) 375 [(M + H) + ].
    [484] Example J22
    [485] (2-Amino-5-dimethylamino-4-methyl-phenyl) -carbamic acid tert.-butyl ester
    [486] The title compound was purified from (5-dimethylamino-4-methyl-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C19) (3.22 g, 10.9 mmol) according to General Procedure J (method a). Prepared by hydrogenation with% Pd / C. Obtained as a gray solid (2.05 g, 58%).
    [487] MS (ISP) 266.3 [(M + H) + ]; mp 78 ° C.
    [488] Example J23
    [489] (2-Amino-4-cyano-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester
    [490] The title compound was purified from (4-cyano-5-dimethylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C20) (3.9 g, 12.7 mmol) according to General Procedure J (Method b). Prepared by reduction with SnCl 2 .2H 2 O. Obtained as a light brown solid (2.05 g, 58%).
    [491] MS (ISP) 277.2 [(M + H) + ]; mp 120 ° C.
    [492] Example J24
    [493] [2-Amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [494] The title compound was prepared according to general procedure J (method a) [4-methyl-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C21) (3.59 g, 11.1 mmol), followed by hydrogenation with 10% Pd / C. Obtained as a purple solid (3.23 g, 99%).
    [495] MS (ISP) 294.4 [(M + H) + ].
    [496] Example J25
    [497] [2-Amino-5- (ethyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert.-butyl ester
    [498] The title compound was prepared according to general procedure J (method a) [5- (ethyl-methyl-amino) -4-methyl-2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C22) (3.28 g, 10.6 mmol) from 10% Pd / C. Obtained as a purple solid (2.94 g, 99%).
    [499] MS (ISP) 280.3 [(M + H) + ].
    [500] Example J26
    [501] [2-Amino-4-chloro-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [502] The title compound was purified according to General Procedure J (Method b) [4-Chloro-5- (isopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C23) (4.07 g). , 11.8 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (3.08 g, 83%).
    [503] MS (ISP) 314.3 [(M + H) + ]; mp 116 ° C.
    [504] Example J27
    [505] [2-Amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [506] The title compound was purified according to general procedure J (method b) [4-chloro-5- (isobutyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C24) (5.55 g , 15.5 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (3.98 g, 78%).
    [507] MS (ISP) 328.3 [(M + H) + ].
    [508] Example J28
    [509] (2-Amino-4-cyano-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [510] The title compound was purified according to general procedure J (method b) (4-cyano-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C25) (1.82 g). , 5.48 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (1.27 g, 77%).
    [511] MS (ISP) 303.2 [(M + H) + ].
    [512] Example J29
    [513] [2-Amino-4-cyano-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [514] The title compound was purified using [4-cyano-5- (methyl-propyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C26) (1.64 g) according to General Procedure J (method b). , 4.90 mmol) to SnCl 2 .2H 2 O. Obtained as a dark red oil (1.24 g, 83%).
    [515] MS (ISP) 305.3 [(M + H) + ].
    [516] Example J30
    [517] (2-Amino-4-cyano-5-diethylamino-phenyl) -carbamic acid tert.-butyl ester
    [518] The title compound was prepared according to general procedure J (method b) (4-cyano-5-diethylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C27) (1.66 g, 4.96 mmol) Prepared by reduction with SnCl 2 .2H 2 O. Obtained as a greyish white solid (1.38 g, 91%).
    [519] MS (ISP) 305.3 [(M + H) + ]; mp 151 ° C.
    [520] Example J31
    [521] [2-Amino-4-cyano-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [522] The title compound was prepared according to general procedure J (method b) [4-cyano-5- (isopropyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C28) (1.73 g, 5.17 mmol) to SnCl 2 .2H 2 O. Obtained as a greyish white solid (1.56 g, 99%).
    [523] MS (ISP) 305.3 [(M + H) + ]; mp 77 ° C.
    [524] Example J32
    [525] [2-Amino-4-cyano-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester
    [526] The title compound was prepared according to general procedure J (method b) [4-cyano-5- (isobutyl-methyl-amino) -2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C29) (1.76). g, 5.05 mmol) to SnCl 2 .2H 2 O. Obtained as a light brown solid (1.55 g, 96%).
    [527] MS (ISP) 319.5 [(M + H) + ]; mp 88 ° C.
    [528] Example J33
    [529] (2-Amino-4-cyano-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [530] The title compound was purified according to general procedure J (method b) (4-cyano-2-nitro-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C30) (2.08 g , 5.71 mmol) to SnCl 2 .2H 2 O. Obtained as a greyish white solid (1.67 g, 99%).
    [531] MS (ISP) 317.2 [(M + H) + ]; mp 86 ° C.
    [532] Example J34
    [533] (2-Amino-4-chloro-5-isobutylamino-phenyl) -carbamic acid tert.-butyl ester
    [534] The title compound was prepared from (4-chloro-5-isobutylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C31) (1.93 g, 5.61 mmol) according to General Procedure J (Method b). Prepared by reduction with SnCl 2 .2H 2 O. Obtained as a brown solid (1.30 g, 74%).
    [535] MS (ISP) 314.3 [(M + H) + ].
    [536] Example J35
    [537] [2-Amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [538] The title compound was prepared according to general procedure J (method a) [5- (methyl-propyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C32) ( 3.78 g, 10.0 mmol), followed by hydrogenation with 10% Pd / C. Obtained as a red oil (3.40 g, 98%).
    [539] MS (ISP) 248.4 [(M + H) + ].
    [540] Example J36
    [541] [2-Amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [542] The title compound was prepared according to general procedure J (method a) [5- (isobutyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C33) Prepared by hydrogenation from (3.88 g, 9.91 mmol) to 10% Pd / C. Obtained as an orange oil (2.70 g, 75%).
    [543] MS (ISP) 362.3 [(M + H) + ].
    [544] Example J37
    [545] [2-Amino-5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [546] The title compound was prepared according to general procedure J (method a) [5- (isopropyl-methyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C34) Prepared by hydrogenation from (2.98 g, 7.90 mmol) to 10% Pd / C. Obtained as an orange oil (2.42 g, 88%).
    [547] MS (ISP) 348.5 [(M + H) + ].
    [548] Example J38
    [549] [2-Amino-5- (isobutyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert.-butyl ester
    [550] The title compound was purified according to General Procedure J (Method a) [5- (isobutyl-methyl-amino) -4-methyl-2-nitro-phenyl] -carbamic acid tert.-butyl ester (Example C35) (1.48 g) , 4.39 mmol) in 10% Pd / C. Obtained as a white solid (1.08 g, 80%).
    [551] MS (ISP) 308.3 [(M + H) + ]; mp 71 ° C.
    [552] Example J39
    [553] (2-Amino-4-methyl-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester
    [554] The title compound was prepared according to general procedure J (method a) (4-methyl-2-nitro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example C36) (3.27 g, 10.2 mmol) prepared by hydrogenation with 10% Pd / C. Obtained as a light brown solid (2.48 g, 83%).
    [555] MS (ISP) 292.3 [(M + H) + ]; mp 115 ° C.
    [556] Example J40
    [557] (2-Amino-4-chloro-5-isopropylamino-phenyl) -carbamic acid tert.-butyl ester
    [558] The title compound was prepared from (4-chloro-5-isopropylamino-2-nitro-phenyl) -carbamic acid tert.-butyl ester (Example C37) (3.75 g, 11.3 mmol) according to General Procedure J (Method b). Prepared by reduction with SnCl 2 .2H 2 O. Obtained as a brown solid (2.90 g, 86%).
    [559] MS (ISP) 303.3 [(M + H) + ].
    [560] Example J41
    [561] [2-Amino-5- (isobutyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [562] The title compound was prepared according to general procedure J (method a) [5- (isobutyl-amino) -2-nitro-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example C38) (5.28). g, 13.99 mmol) for 10% Pd / C. Obtained as a pale yellow solid (3.69 g, 76%).
    [563] MS (ISP) 348.5 [(M + H) + ]; mp 141 ° C.
    [564] The following examples relate to the preparation of ethyl or tert.-butyl 3-aryl-3-oxo-propionate (Formula IVa), which acts as a building block in the synthesis of the target compound (Scheme H).
    [565] General procedure K
    [566] Method a) Preparation of ethyl or tert.-butyl 3-aryl-3-oxo-propionate
    [567] Ethyl or tert.-butyl 3-aryl-3-oxo-propionate is prepared according to aryl acid chloride and ethyl or tert.-butyl malonate potassium salt according to Synthesis 1993, 290 [CAS-no. 6148-64-7 and 75486-33-8] using Et 3 N and MgCl 2 in CH 3 CN at a temperature from 0 ° C. to 23 ° C. If free aryl carboxylic acid was used in this reaction, it was activated by treatment with ethyl chloroformate and Et 3 N in THF / CH 3 CN at 0 ° C. before reacting with the malonate salt.
    [568] Method b) Preparation of tert.-Butyl 3-aryl-3-oxo-propionate
    [569] Alternatively, tert.-butyl 3-aryl-3-oxo-propionate was prepared in the presence of lithium tert.-butyl acetate from methyl or ethyl aryl esters according to Synthesis 1985, 45 [ tert.-butyl acetate was prepared by treatment with lithium diisopropylamide in THF at −78 ° C.]. If the product contained residual starting material after workup, it had to be removed by saponification with LiOH in THF / MeOH / H 2 O at 23 ° C.
    [570] Method c) Preparation of 3-aryl-3-oxo-propionic acid
    [571] 3-aryl-3-oxo-propionic acid was synthesized from aryl acid chloride and bis (trimethylsilyl) malonate . Commun . 1985, 15, 1039 (method c1) using Et 3 N and LiBr in CH 3 CN at 0 ° C., or from −60 ° C. to 0 ° C. according to Synthesis 1979, 787 (method c2). Prepared using n-BuLi in ether at temperature.
    [572] Example K1
    [573] 3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid ethyl ester
    [574] The title compound was subjected to reflux of methyl 3-azidobenzoate in trimethylsilyl-acetylene from 3- [1,2,3] triazol-1-yl-benzoic acid according to General Procedure K (method a) [CAS -No. 93066-93-4], saponified with aqueous NaOH in reflux EtOH, activated with ethyl chloroformate / Et 3 N, and reacted with ethyl malonate potassium salt with Et 3 N and MgCl 2 in CH 3 CN . Obtained as a light yellow solid (2.22 g).
    [575] MS (EI) 259 (M + ); mp 72-74 ° C.
    [576] Example K2
    [577] 3- (3-cyano-phenyl) -3-oxo-propionic acid tert.-butyl ester
    [578] The title compound was prepared according to general procedure K (method b) methyl 3-cyanobenzoate [CAS-No. 13531-48-1] was prepared by treatment with lithium tert.-butyl acetate. Obtained as a light brown oily semisolid.
    [579] MS (EI) 245 (M + ).
    [580] Example K3
    [581] 3- (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester
    [582] The title compound was prepared according to general procedure K (method b) 2-cyano-isonicotinic acid ethyl ester [CAS-No. 58481-14-4] by treatment with lithium tert.-butyl acetate. Obtained as a light brown solid (7.70 g).
    [583] MS (ISN) 245 [(M − H) − ].
    [584] Example K4
    [585] 3- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [586] The title compound is ethyl 3- (3-methyl-isoxazol-5-yl) -benzoate [ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5, prepared by reacting at 50 ° C. with a mixture of NCS, acetaldoxin, Et 3 N and a catalytic amount of pyridine in CHCl 3 according to the document “ Tetrahedron 1984, 40, 2985-2988”. According to K (method b) it was prepared using lithium tert.-butyl acetate. Obtained as a yellow solid (2.54 g).
    [587] MS (ISP) 302 [(M + H) + ]; mp 50-56 ° C.
    [588] Example K5
    [589] (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert. -Butyl ester
    [590] The title compound was prepared according to general procedure K (method b) (RS) -3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -benzoic acid Methyl ester [which is prepared according to the following sequence: i.) Methyl 3-azidobenzoate [CAS-No. 93066-93-4] (15.55 g, 88 mmol) and (RS) -tert.-butyl-dimethyl- [3- (tetrahydro-pyran-2-yloxy) -prop-1-ynyl] -silane [CAS -No. 135294-85-8] (33.50 g, 132 mmol) was heated to 60 ° C. for 10 days; ii.) The material obtained (48.2 g, about 88 mmol) was stirred in TBAF (300 mL, 1M in THF) for 6 days at 70 ° C. and subsequently refluxed in 1N HCl (400 mL) for 2 h; iii.) The material obtained (16.15 g, 74 mmol) was stirred in MeOH (400 mL) and concentrated H 2 SO 4 (30 mL) at 23 ° C. for 11 days. iv.) A portion of the obtained material (4.60 g, 19.7 mmol) was added with 3,4-dihydro-2H-pyran (2.67 mL, 29.5 mmol) and a catalytic amount of p- in DCM (38 mL) at 23 ° C. for 20 hours. Reaction with TsOH.H 2 O] (6.20 g, 19.5 mmol) was prepared by treatment with lithium tert.-butyl acetate. Obtained as a yellow oil (8.47 g).
    [591] MS (ISP) 402 [(M + H) + ].
    [592] Example K6
    [593] 3- [2- (3-Methyl-isoxazol-5-yl) -pyridin-4-yl] -3-oxo-propionic acid tert.-butyl ester
    [594] The title compound was prepared according to general procedure K (method b) 2- (3-methyl-isoxazol-5-yl) -isonicotinic acid methyl ester [i.) 2-iodo-isonicotinic acid methyl ester [CAS-No. 134579-47-8] with trimethylsilylacetylene according to General Procedure H; ii.) desilylated by reaction with a catalytic amount of K 2 CO 3 in MeOH for 4 hours at 0 ° C .; iii.) prepared by ring addition reaction with a mixture of NCS, acetaldoxin, Et 3 N and a catalytic amount of pyridine in CHCl 3 at 50 ° C. according to the document “ Tetrahedron 1984, 40, 2985-2988” from lithium tert.- Prepared by treatment with butyl acetate. Obtained as a brown solid (5.17 g).
    [595] MS (EI) 302 (M + ); mp 59-67 ° C.
    [596] Example K7
    [597] 3- [3- (2-Methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [598] The title compound was prepared according to general procedure K (method b) 3- (2-methyl-2H-pyrazol-3-yl) -benzoic acid methyl ester [i.) 1- (3-bromo-phenyl) -3-dimethyl Amino-propenone [CAS-No. 163852-04-8] with methylhydrazine in EtOH for 2.5 days at 23 ° C .; ii.) chromatographic separation of the isomers obtained; iii.) The clear isomers were treated with n-BuLi in THF for 1 hour at −78 ° C., then quenched with CO 2 stream and subsequently esterified with MeOH and concentrated H 2 SO 4 at 23 ° C. for 48 hours. Prepared by treating with lithium tert.-butyl acetate. Obtained as a yellow oil (5.96 g).
    [599] MS (EI) 300 (M + ).
    [600] Example K8
    [601] 3- [3- (5-Dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [602] The title compound was prepared according to the general procedure K (method b) from 3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -benzoic acid methyl ester [methyl 3-azidobenzoate Following the synthesis steps i.) To iii.) As described in the preparation of K5, the product obtained is reacted with SOCl 2 in THF for 1 h at 0-23 ° C., followed by dimethylamine (7.9 in H 2 O). M) was added and stirred at 23-70 ° C. for 1 hour] (2.14 g, 8.22 mmol) from lithium tert.-butyl acetate. Obtained as a yellow oil (2.90 g).
    [603] MS (ISP) 345 [(M + H) + ].
    [604] Example K9
    [605] 3- [3- (3-methoxymethyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [606] The title compound was prepared according to general procedure K (method b) methyl 3- (3-methoxymethyl-isoxazol-5-yl) -benzoate [ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] according to a literature "Tetrahedron 1984, 40, 2985-2988" at 50 ℃ CHCl 3 in the NCS, 2- methoxy-acetamide al doksim [CAS-No. 71494-93-4, prepared by reacting with a mixture of Et 3 N and a catalytic amount of pyridine]. Obtained as a light yellow liquid (1.548 g).
    [607] MS (EI) 331 (M + ).
    [608] Example K10
    [609] (RS) -3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl} -propionic acid tert.-butyl ester
    [610] The title compound was prepared according to general procedure K (method b) (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -benzoic acid methyl ester [in the following sequence: Prepared according to: i.) 3-thiocarbamoyl-benzoic acid methyl ester in 1,4-dioxane (180 mL) [CAS-No. 106748-27-0] (7.8 g), 1,3-dichloro-2-propanone (8.4 g) and sodium bicarbonate (8.4 g) were heated to 60 ° C for 24 h. The reaction mixture was cooled to 20 ° C. and added to a stirred solution of sodium methoxide (5.4 g) in methanol (200 mL). Stirring was continued for 0.5 hours. The mixture was poured into ice cold 2N HCl (200 mL) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from dichloromethane / hexanes to give 3- (4-hydroxymethyl-thiazol-2-yl) -benzoic acid methyl ester (7.5 g) as light-brown crystals (115-117 ° C.). ii.) A mixture of the above material (7.5 g), dihydropyran (4.1 mL) and p-toluenesulfonic acid hydrate (0.19 g) in ethyl acetate (50 mL) was stirred at 20 ° C for 1 h. The solution was diluted with ethyl acetate and washed with 5% sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The residual oil was purified by chromatography on silica gel using ethyl acetate / hexanes (1: 2) as eluent to give (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazole. -2-yl] -benzoic acid methyl ester (9.6 g) was obtained as a pale yellow oil.] (3.5 g, 11 mmol) was prepared by treatment with lithium tert.-butyl acetate. Obtained as a pale yellow oil (3.8 g).
    [611] MS (ISP) 418.2 [(M + H) + ].
    [612] Example K11
    [613] (RS) -3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl} -propionic acid tert.-butyl ester
    [614] The title compound was prepared according to general procedure K (method b) (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -benzoic acid methyl ester [in the following sequence: Prepared according to: i.) 3-carbamoyl-benzoic acid methyl ester [CAS-No. 106748-24-7] (17.9 g) and 1,3-dichloro-2-propanone (14.0 g) were heated to 140 ° C. for 1.5 h. The mixture was cooled to 20 ° C. and concentrated sulfuric acid (12 mL) was added carefully. The mixture was stirred for 10 minutes and then poured into ice water. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate / hexanes (1: 1) as eluent to give 3- (4-chloromethyl-oxazol-2-yl) -benzoic acid methyl ester (11.8 g) in pale yellow color. Obtained as an oil. MS (ISP) 252.2 [(M + H) + ]. ii.) A solution of this material (7.6 g) and lithium hydroxy monohydrate (5.0 g) in DMSO (30 mL) was heated to 60 ° C. for 7 h. The cooled reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The aqueous layer was acidified to pH 1 by addition of 6N HCl and the precipitate formed was collected by filtration and crystallized from dichloromethane / hexanes. Light-yellow crystals (5.5 g) are dissolved in DMSO (25 mL) and after addition of N, N, N ', N'-tetramethyl-guanidine (4.4 mL) and methyl iodide (2.2 mL), the mixture is Was stirred at 20 ° C. for 1 h. Ethyl acetate was added and the mixture was washed successively with water, 1N HCl and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to chromatography on silica gel using ethyl acetate / hexanes (1: 1) as eluent, and the purified product was crystallized from diethyl ether / hexanes to give 3- (4-hydroxymethyl-oxazole-2 -Yl) -benzoic acid methyl ester (2.1 g) was obtained as white crystals (mp 118-119 ° C.). iii.) A mixture of the above material (2.1 g), dihydropyran (1.2 mL) and p-toluenesulfonic acid hydrate (0.1 g) in ethyl acetate (15 mL) was stirred at 20 ° C for 1 h. The solution was diluted with ethyl acetate and washed with 5% sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The residual oil was chromatographed on silica gel using as ethyl acetate / hexane (1: 2) eluent to give (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -oxazole-2 -Yl] -benzoic acid methyl ester (3.5 g) as a pale yellow oil] (3.5 g, 11 mmol) was prepared by treatment with lithium tert.-butyl acetate. Obtained as a pale yellow oil (3.8 g).
    [615] MS (ISP) 402.5 [(M + H) + ].
    [616] Example K12
    [617] (RS) -3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -propionic acid tert.-butyl ester
    [618] The title compound was prepared according to general procedure K (method b) (RS) -3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -benzoic acid methyl ester [in the following sequence: Prepared according to: i.) 4- (3-Bromo-phenyl) -2,4-dioxo-butyric acid ethyl ester [CAS-No. 151646-31-0] (7.55 g, 23 mmol) and hydroxylamine hydrochloride (4.74 g, 68 mmol) were refluxed in EtOH for 1 hour; ii.) the obtained ester (5.94 g, 20 mmol) was reduced with LiAlH 4 (761 mg, 20 mmol) in THF for 1 h at −10 ° C .; iii.) The obtained alcohol (4.90 g, 19 mmol) was reacted with 3,4-dihydro-2H-pyran and a catalytic amount of p-TsOH.H 2 O in DCM at 23 ° C. for 20 hours. iv.) The obtained THP-ether (5.24 g, 15 mmol) was treated with n-BuLi for 45 min at −78 ° C. followed by a CO 2 stream. v.) The crude acid obtained was stirred in MeOH (90 mL) and concentrated H 2 SO 4 (6.5 mL) at 50 ° C. for 12 h. vi.) The obtained material (2.01 g, 8.62 mmol) was added with 3,4-dihydro-2H-pyran (1.17 mL, 12.9 mmol) and a catalytic amount of p-TsOH in DCM (17 mL) at 23 ° C. for 5 hours. Reaction with H 2 O] (2.44 g, 7.7 mmol) was prepared by treatment with lithium tert.-butyl acetate. Obtained as a yellow oil (3.06 g).
    [619] MS (ISP) 402 [(M + H) + ].
    [620] Example K13
    [621] (RS) -3- {3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -3-oxo-propionic acid tert.-butyl ester
    [622] The title compound was prepared according to general procedure K (method b) (RS) -3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -benzoic acid methyl ester [ It is prepared according to the following sequence: i.) (3-Bromo-phenyl) -3-oxo-propionic acid ethyl ester in benzene [CAS-No. 21575-91-7], pyrrolidine and TMSOTf were refluxed for 16 hours ("Org. Synth. 53, 59"); ii.) reacting the obtained 3- (3-bromo-phenyl) -3-pyrrolidin-1-yl-acrylic acid ethyl ester with nitroethane, POCl 3 and Et 3 N at 23 ° C .; iii.) the 5- (3-bromo-phenyl) -3-methyl-isoxazole-4-carboxylic acid ethyl ester obtained is reduced with LiAlH 4 in THF for 1 hour at −10 ° C .; iv.) The obtained [5- (3-bromo-phenyl) -3-methyl-isoxazol-4-yl] -methanol was added with 3,4-dihydro-2H-pyran in DCM at 23 ° C. for 20 hours and React with a catalytic amount of p-TsOH.H 2 O; iv.) the obtained THP-ether was treated with n-BuLi at −78 ° C. for 45 minutes and then with a CO 2 stream; v.) the crude acid obtained is stirred in MeOH and concentrated H 2 SO 4 at 50 ° C. for 18 h; vi.) 3,4-Dihydro-2H-pyran and catalytic amount of 3- (4-hydroxymethyl-3-methyl-isoxazol-5-yl) -benzoic acid methyl ester obtained in DCM for 1 hour at 23 ° C. Was reacted with p-TsOH.H 2 O] to produce lithium tert.-butyl acetate. Obtained as a light yellow oil (972 mg).
    [623] MS (EI) 416 [(M + H) + ].
    [624] Example K14
    [625] (RS) -3- {3- [2-Methyl-5- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -phenyl} -3-oxo-propionic acid tert.- Butyl ester
    [626] The title compound was prepared according to general procedure K (method b) (RS) -3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -methyl benzoate Ester [roduced according to the following sequence: i.) 4- (3-Bromo-phenyl) -2,4-dioxo-butyric acid ethyl ester in EtOH (35 mL) [CAS-No. 151646-31-0] (6.135 g, 21 mmol), MeNHNH 2 (1.296 mL, 25 mmol) and HCl (4M in dioxane, 6.25 mL, 25 mol) were refluxed for 1.5 h; ii.) The obtained 5- (3-bromo-phenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (7.02 g, 22.7 mmol) was THF (60 mL) at -10 ° C for 1 hour. To LiAlH 4 (862 mg, 22.7 mmol) in water; iii.) The obtained [5- (3-bromo-phenyl) -1-methyl-1H-pyrazol-3-yl] -methanol (6.34 g, 24 mmol) was added with DCM (50 mL at 23 ° C. for 23 hours. Reacted with 3,4-dihydro-2H-pyran (3.25 mL, 36 mmol) and a catalytic amount of p-TsOH.H 2 O; iv.) (RS)-[5- (3-Bromo-phenyl) -1-methyl-3- (tetrahydro-pyran-2-yloxymethyl) -1H-pyrazole (8.64 g, 25 mmol) obtained ) Is treated with n-BuLi for 45 minutes at -78 ° C. and then with a CO 2 stream; v.) the crude acid obtained is stirred in MeOH (90 mL) and concentrated H 2 SO 4 (6.5 mL) at 50 ° C. for 5 h; vi.) The obtained 3- (5-hydroxymethyl-2-methyl-2H-pyrazol-3-yl) -benzoic acid methyl ester (3.41 g, 13.85 mmol) was DCM (28 mL) at 23 ° C. for 18 hours. From 3,4-dihydro-2H-pyran (1.75 mL, 20.77 mmol) and a catalytic amount of p-TsOH.H 2 O] (3.93 g, 11.9 mmol) prepared by treatment with lithium tert.-butyl acetate It was. Obtained as a yellow oil (4.90 g).
    [627] MS (ISP) 415 [(M + H) + ].
    [628] Example K15
    [629] (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester
    [630] The title compound was prepared according to general procedure K (method b) (RS) -3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -benzoic acid methyl ester [(Z)- 3- (hydroxyimino-methyl) -benzoic acid methyl ester [CAS-No. 91186-80-0] was treated with NCS in pyridine, CHCl 3 of a catalytic amount of from, (RS) - of tetrahydro-2- (2-propynyl oxy) was added in CHCl -2H- pyran, and 23 ℃ 3 Prepared by the slow addition of Et 3 N], followed by treatment with lithium tert.-butyl acetate. Obtained as a yellow oil (3.00 g).
    [631] MS (ISN) 400.5 [(M − H) − ].
    [632] Example K16
    [633] 3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionic acid tert.-butyl ester
    [634] The title compound was prepared according to general procedure K (method b) 3-pyrazol-1-yl-benzoic acid methyl ester [CAS-No. 168618-35-7 from lithium tert.-butyl acetate. Obtained as a yellow oil (5.00 g).
    [635] MS (EI) 286 (M + ).
    [636] Example K17
    [637] (RS) -3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propionic acid tert.-butyl ester
    [638] The title compound was prepared according to general procedure K (method b) (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -benzoic acid methyl ester [in the following sequence: Prepared according to: i.) 3-hydrazino-benzoic acid methyl ester hydrochloride in isopropanol (115 mL) [CAS-No. 167626-26-8] (15.14 g, 75 mmol), 2-cyano-3-ethoxy-acrylic acid benzyl ester [CAS-No. 32016-27-6] (17.36 g, 75 mmol) and a mixture of Et 3 N (10.5 mL, 75 mmol) were refluxed for 1.5 h; ii.) Obtained 5-amino-1- (3-methoxycarbonyl-phenyl) -1H-pyrazole-4-carboxylic acid benzyl ester (26.0 g, 74 mmol) in isotropic THF (200 mL) for 22 hours. Reflux with pentyl nitrite (30 mL, 225 mmol; 10 mL); iii.) The obtained 1- (3-methoxycarbonyl-phenyl) -1H-pyrazole-4-carboxylic acid benzyl ester (18.98 g, 56 mmol) was added with Pd / C (10% Pd /) for 16 hours at 23 ° C. Hydrogenated in EtOAc (350 mL) and THF (250 mL) in the presence of C, 600 mg, 1 mol%); iv.) Obtained 1- (3-methoxycarbonyl-phenyl) -1H-pyrazole-4-carboxylic acid (13.70 g, 55.6 mmol) in BH 3 in THF (364 mL) at 5 to 23 ° C. for 16 h. Reduced to SMe 2 (28.46 mL, 278.2 mmol); v.) The obtained 3- (4-hydroxymethyl-pyrazol-1-yl) -benzoic acid methyl ester (10.66 g, 45.9 mmol) in 3,4-di in DCM (91 mL) at 23 ° C. for 22 hours. Reacted with lithium tert.-butyl acetate from hydro-2H-pyran (6.24 mL, 68.9 mmol) and a catalytic amount of p-TsOH.H 2 O] (14.18 g, 44.8 mmol). Obtained as a yellow oil (15.87 g).
    [639] MS (ISN) 399 [(M − H) − ].
    [640] Example K18
    [641] (RS) -3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester
    [642] The title compound was prepared according to general procedure K (method b) (RS) -3- [4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -benzoic acid methyl ester [ Prepared according to: i.) (Z) -3- (hydroxyimino-methyl) -benzoic acid methyl ester [CAS-No. 91186-80-0] was treated with NCS in CHCl 3 , catalytic amount of pyridine and then (E) -3-pyrrolidin-1-yl-acrylic acid tert.-butyl ester [CAS-No. 340257-76-3] and slowly add Et 3 N in CHCl 3 at 23 ° C .; ii.) the 3- (3-methoxycarbonyl-phenyl) -isoxazole-4-carboxylic acid tert.-butyl ester obtained is stirred in formic acid at 50 ° C. for 18 hours; iii.) reducing the obtained 3- (3-methoxycarbonyl-phenyl) -isoxazole-4-carboxylic acid with BH 3 .SMe 2 in THF for 16 hours at 5 to 23 ° C .; iv.) The obtained 3- (4-hydroxymethyl-isoxazol-3-yl) -benzoic acid methyl ester at 23 ° C. for 1 hour in 3,4-dihydro-2H-pyran and catalytic amount of p-TsOH Reacted with H 2 O] to prepare with lithium tert.-butyl acetate. Obtained as a yellow oil (1.817 g).
    [643] MS (ISN) 400 [(M − H) − ].
    [644] Example K19
    [645] (RS) -3- {3- [2-Methyl-4- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -phenyl} -3-oxo-propionic acid tert.- Butyl ester
    [646] The title compound was prepared according to general procedure K (method b) (RS) -3- [2-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -methyl benzoate Esters [which are prepared according to the following sequence: i.) 3-bromobenzoyl chloride and 3-isopropylamino-acrylic acid methyl ester [CAS-No. 89895-40-9 are reacted in toluene and Et 3 N according to the document “ Synthesis 1982, 318”; ii.) reacting the obtained 2- (3-bromo-benzoyl) -3-isopropylamino-acrylic acid methyl ester at 23 ° C. with methylhydrazine in ether according to the document “ Synthesis 1982, 318”; iii.) reducing 5- (3-bromo-phenyl) -1-methyl-1H-pyrazole-4-carboxylic acid methyl ester obtained with LiAlH 4 in THF for 1 hour at −10 ° C .; iv.) The obtained [5- (3-Bromo-phenyl) -1-methyl-1H-pyrazol-4-yl] -methanol at 3 ° C. for 20 hours at 3,4-dihydro-2H- in DCM. Reacted with pyran and a catalytic amount of p-TsOH.H 2 O; v.) Obtained (RS) -5- (3-bromo-phenyl) -1-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -1H-pyrazole at −78 ° C. for 45 minutes. Treated with n-BuLi, and treated with a CO 2 stream; vi.) the crude acid obtained is stirred in MeOH and concentrated H 2 SO 4 at 50 ° C. for 18 h; vii.) Reaction of the obtained 3- (4-methoxymethyl-2-methyl-2H-pyrazol-3-yl) -benzoic acid methyl ester with 1M BBr 3 -sol in DCM for 1 hour at -78 to 23 ° C. To; viii.) the crude bromide obtained is reacted with KOAc in DMF at 60 ° C. for 30 minutes; ix.) the crude acetate obtained is reacted with NaOMe-sol in MeOH for 20 min at 23 ° C .; x.) The obtained 3- (4-hydroxymethyl-2-methyl-2H-pyrazol-3-yl) -benzoic acid methyl ester at 23 ° C. for 1 hour in 3,4-dihydro-2H-pyran in DCM And reacted with a catalytic amount of p-TsOH.H 2 O]. Obtained as a yellow solid (11.106 g).
    [647] MS (ISN) 413 [(M − H) − ].
    [648] Example K20
    [649] (RS) -3-oxo-3- (3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazol-3-yl} -phenyl) -propionic acid tert. -Butyl ester
    [650] The title compound was prepared according to general procedure K (method b) (RS) -3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazol-3-yl} -benzoic acid Methyl ester [i.) 1- (3-Bromo-phenyl) -3-dimethylamino-propenone [CAS-No. 163852-04-8] is reacted with 2-hydroxy-ethylhydrazine in EtOH at 23 ° C. for 2.5 days; ii.) The resulting mixture of pyrazole (12.36 g, 35.19 mmol) was added with 3,4-dihydro-2H-pyran (4.79 mL, 52.8 mmol) and catalytic amount of p in DCM (70 mL) for 20 hours at 23 ° C Reacted with -TsOH.H 2 O; iii.) chromatographic separation of the isomers obtained; iv.) the clear isomer (7.35 g, 73.7 mmol) was treated with n-BuLi (13.08 mL, 20.9 mmol) in THF (42 mL) for 45 min at −78 ° C. and treated with a CO 2 stream; v.) reacted (RS) -3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazol-3-yl} -benzoic acid (4.56 g, 14.1 mmol), reacted with KHCO 3 (2.89 g, 28.8 mmol) and MeI (0.99 mL, 15.9 mmol) in DMF (29 mL) at 23 ° C. for 2 h] (2.96 g, 8.96 mmol) from lithium tert.- Prepared by treatment with butyl acetate. Obtained as a yellow oil (3.00 g).
    [651] MS (ISP) 415 [(M + H) + ].
    [652] Example K21
    [653] (RS) -3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,2,3] triazol-1-yl} -phenyl ) -Propionic acid tert.-butyl ester
    [654] The title compound was prepared according to general procedure K (method b) (RS) -3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,2,3] triazole-1 -Yl} -benzoic acid methyl ester [which is prepared according to the following sequence: i.) Methyl 3-azidobenzoate [CAS-No. 93066-93-4] and (RS) -tert.-Butyl-dimethyl- [4- (tetrahydro-pyran-2-yloxy) -but-1-ynyl] -silane [CAS-No. 198411-20-0] is heated to 60 ° C. for 10 days; ii.) the material obtained is stirred in TBAF (1M in THF) for 6 days at 70 ° C. and subsequently refluxed in 1N HCl for 2 hours; iii.) 3- [5- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -benzoic acid obtained in MeOH and concentrated H 2 SO 4 at 23 ° C. for 11 days. Stirring; iv.) The obtained 3- [5- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -benzoic acid methyl ester at 23 ° C. for 20 hours in 3,4-DCM Reacted with dihydro-2H-pyran and a catalytic amount of p-TsOH.H 2 O] to lithium tert.-butyl acetate. Obtained as a yellow oil (6.748 g).
    [655] MS (ISP) 416 [(M + H) + ].
    [656] Example K22
    [657] (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenol} -propionic acid ethyl ester
    [658] The title compound was subjected to general procedure K for 2 days at 0-23 ° C. (method a) (RS) -3- [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl]- Benzoic acid [roduced by the following sequence: i.) 3-hydrazino-benzoic acid [CAS-No. 38235-71-1], 4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester [CAS-No. 67751-14-8] at reflux for 15.5 hours; ii.) the obtained 2- (3-carboxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester was stirred in DMF-di-tert.-butyl acetal in toluene at 45C for 45 hours; iii.) saponified 2- (3-tert.-butoxycarbonyl-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester with 3N NaOH in THF for 16 h at 0-23 ° C .; iv. ) The obtained 2- (3-tert.-butoxy-carbonyl-phenyl) -2H-pyrazole-3-carboxylic acid is reduced to BH 3 .SMe 2 in THF for 18 hours at 5 to 23 ° C .; v.) 3- (5-hydroxymethyl-pyrazol-1-yl) -benzoic acid tert.-butyl ester (3.188 g, 11.62 mmol) obtained was stirred in formic acid (22 mL) at 50 ° C. for 5 h. ; vi.) the crude acid obtained is stirred in MeOH (50 mL) and SOCl 2 (1.54 mL, 21.25 mmol) at 23 ° C. for 6.5 h; vii.) The obtained 3- (5-hydroxymethyl-pyrazol-1-yl) -benzoic acid methyl ester (2.84 g, 12.2 mmol) was added 3,4-di in DCM (25 mL) at 23 ° C. for 3 days. Reacted with hydro-2H-pyran (1.66 mL, 18.3 mmol) and a catalytic amount of p-TsOH.H 2 O; viii.) The obtained (RS) -3- [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -benzoic acid methyl ester (2.926 g, 9.25 mmol) was added at 23 ° C. Saponified with 6N NaOH (5 mL) in THF (20 mL)] (1.90 g, 6.3 mmol) from ClCO 2 Et in THF (9 mL) / CH 3 CN (7 mL) at 0 ° C. for 2 h. 0.63 mL, 6.6 mmol) and Et 3 N (1 mL, 7.0 mmol), followed by mono-ethyl malonate potassium salt (2.15 g, 12.6 mmol), MgCl 2 (1.5 g, 15.8 mmol) and Et 3 N Prepared by reaction with (2.9 mL, 20.8 mmol). Obtained as a light yellow oil (1.124 g).
    [659] MS (ISP) 373.4 [(M + H) + ].
    [660] Example K23
    [661] 3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert.-butyl ester
    [662] The title compound was prepared according to general procedure K (method a) 3- [1,2,3] triazol-1-yl-benzoic acid, which is methyl 3-azidobenzoate in trimethylsilyl-acetylene [CAS-No. 93066-93-4] and then refluxed, reflux prepared by saponification with aqueous NaOH in EtOH] activation with ethyl chloroformate / Et 3 N from (10.0g, 52.86 mmol) and, CH 3 CN of Et 3 N and Prepared by reaction with mono tert.-butyl malonate potassium salt with MgCl 2 . Obtained as an orange oil (11.55 g).
    [663] MS (ISP) 288 [(M + H) + ].
    [664] Example K24
    [665] (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,4] triazol-1-yl] -phenyl} -propionic acid tert. -Butyl ester
    [666] The title compound was prepared according to general procedure K (method b) (RS) -3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,4] triazol-1-yl] -benzoic acid Methyl ester [which is prepared according to the following sequence: i.) Methyl 3- (1H-1,2,4-triazol-1-yl) -benzoate [CAS-No. 167626-27-9] (39.4 g, 194 mmol) was heated in 36% formaldehyde-water (250 mL) at 150 ° C. for 41 h in an autoclave; Crystallization from water and ethyl acetate / hexanes (1: 1) to give a light brown solid (24.3 g, 54%) (mp 164 ° C.); ii.) The obtained material (24.3 g, 104 mmol) was added to 3,4-dihydro-2H-pyran (29.3 mL, 320 mmol) in dichloromethane (360 mL) / THF (300 mL) for 20 hours at 23 ° C. And reacted with a catalytic amount of p-TsOH.H 2 O and purified by column chromatography on silica gel (toluene / ethyl acetate 1: 1) to give a light brown oil] (16.6 g, 52.3 mmol) from lithium tert Prepared by treatment with .-butyl acetate. Obtained as a light yellow oil (14.3 g, 68%).
    [667] MS (ISP) 400.4 [(M − H) − ].
    [668] Example K25
    [669] 3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert.-butyl ester
    [670] The title compound was prepared according to general procedure K (method b) methyl 3- [1,2,4] triazol-1-yl-benzoate [CAS-No. 167626-27-9 from Lithium tert.-Butyl acetate. Obtained as an orange liquid (2.41 g).
    [671] MS (EI) 287 (M + ).
    [672] Example K26
    [673] 3- (3-imidazol-1-yl-phenyl) -3-oxo-propionic acid tert.-butyl ester
    [674] The title compound was prepared according to general procedure K (method b) methyl 3- (1H-imidazol-1-yl) benzoate [which is 3- (1H-imidazol-1-yl) benzoic acid (see J. Med. Chem 1987, 30, 1342 "; prepared by reducing concentrated H 2 SO 4 / MeOH from CAS-No. [108035-47-8]] with lithium tert.-butyl acetate. Orange-brown oil Obtained as
    [675] MS (ISP) 287 [(M + H) + ].
    [676] Example K27
    [677] 3-oxo-3- [3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester
    [678] a) 3- (4-hydroxymethyl-thiazol-2-yl) -benzoic acid methyl ester
    [679] A mixture of 3-thiocarbamoyl-benzoic acid methyl ester (7.8 g), 1,3-dichloro-2-propanone (8.4 g) and NaHCO 3 (8.4 g) in 1,4-dioxane (180 mL) was added to 24 Heated to 60 ° C. for hours. The reaction mixture was cooled to 20 ° C. and added to a stirred solution of NaOMe (5.4 g) in MeOH (200 mL). Stirring was continued for 0.5 hours. The mixture was poured into ice cold 2N HCl (200 mL) and the product was extracted with AcOEt. The organic layer was washed with brine, dried and evaporated in vacuo. The residue was crystallized from CH 2 Cl 2 / hexanes to give 3- (4-hydroxymethyl-thiazol-2-yl) -benzoic acid methyl ester (7.5 g) as light-brown crystals (mp 115-117 ° C.) .
    [680] b) 3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -benzoic acid methyl ester
    [681] A mixture of material (7.5 g), dihydropyran (4.1 mL) and p-toluenesulfonic acid hydrate (0.19 g) prepared in a) in AcOEt (50 mL) was stirred at 20 ° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO 3 solution and brine, dried over Na 2 SO 4 and evaporated in vacuo. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 2) as eluent 3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl]- Benzoic acid methyl ester (9.6 g) was obtained as a pale yellow oil.
    [682] c) 3-oxo-3- [3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester
    [683] A sample of the material prepared in b) (3.3 g) was treated with lithium tert.-butyl acetate according to general procedure K (method b) to give 3-oxo-3- [3- [4- (tetrahydro-pyran-2 -Yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester (3.25 g) was obtained as a pale yellow oil. MS (ISP) 418.2 [(M + H) + ].
    [684] Example K28
    [685] 3-oxo-3- [3- (2-bromo-1,1-dimethoxy-ethyl) -phenyl] -propionic acid tert.-butyl ester
    [686] a) 3- (2-bromo-1,1-dimethoxy-ethyl) -benzoic acid methyl ester
    [687] 3- (2-Bromo-acetyl) -benzoic acid [CAS-No 62423-73-8] (2.43 g), 4-toluenesulfonic acid hydrate (0.38 g) and trimethyl orthoformiate in MeOH (40 mL) 5.5 mL) was heated at reflux for 20 h. The cooled solution was diluted with AcOEt (0.15 L), washed with 5% NaHCO 3 solution and brine, dried and evaporated under vacuum to afford 3- (2-bromo-1,1-dimethoxy-ethyl) -benzoic acid. Methyl ester (3.0 g) was obtained as a pale yellow oil.
    [688] b) 3-oxo-3- [3- (2-bromo-1,1-dimethoxy-ethyl) -phenyl] -propionic acid tert.-butyl ester
    [689] 3- (2-Bromo-1,1-dimethoxy-ethyl) -benzoic acid methyl ester (3.9 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to give 3-oxo-3- [3- (2-Bromo-1,1-dimethoxy-ethyl) -phenyl] -propionic acid tert.-butyl ester (2.8 g) was obtained as a yellow oil.
    [690] Example K29
    [691] 3-oxo-3- [3- (2-methyl-oxazol-4-yl) -phenyl] -propionic acid tert.-butyl ester
    [692] a) 3- (2-methyl-oxazol-4-yl) -benzoic acid
    [693] A mixture of 3- (2-bromo-acetyl) -benzoic acid (2.43 g) and acetamide (1.77 g) was heated to 130 ° C. with stirring for 40 minutes. The mixture was cooled, diluted with H 2 O (30 mL) and the formed precipitate was collected by filtration to give 3- (2-methyl-oxazol-4-yl) -benzoic acid (1.51 g) as a brown solid.
    [694] b) 3- (2-methyl-oxazol-4-yl) -benzoic acid methyl ester
    [695] A solution of 3- (2-methyl-oxazol-4-yl) -benzoic acid (1.42 g) in a mixture of MeOH (30 mL) and 4NHCl / Et 2 O (6 mL) was heated to 40 ° C. for 4 h. . The solution was evaporated in vacuo, the residual oil was stirred with H 2 O (30 mL) and saturated NaHCO 3 solution was added to bring the pH of the mixture to about 6. The precipitate was isolated by filtration to give 3- (2-methyl-oxazol-4-yl) -benzoic acid methyl ester (1.18 g) as a light brown solid.
    [696] MS (ISP) 218.2 [(M + H) + ].
    [697] c) 3-oxo-3- [3- (2-methyl-oxazol-4-yl) -phenyl] -propionic acid tert.-butyl ester
    [698] 3- (2-Methyl-oxazol-4-yl) -benzoic acid methyl ester (1.02 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to give crude 3-oxo-3- [ 3- (2-Methyl-oxazol-4-yl) -phenyl] -propionic acid tert.-butyl ester (1.50 g) was obtained as a pale yellow oil.
    [699] Example K30
    [700] 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -phenyl} propionic acid tert.-butyl ester
    [701] a) 3- (N'-tert.-butoxycarbonyl-hydrazinocarbothioyl) -benzoic acid methyl ester
    [702] A mixture of 3- (N'-tert.-butoxycarbonyl-hydrazinocarbonyl) -benzoic acid methyl ester (1.47 g) and Lawesson reagent (1.62 g) in toluene (30 mL) was prepared. Heated to ° C. The mixture was concentrated in vacuo for 1.5 h, followed by chromatography on silica gel using AcOEt / hexane (1: 2) as eluent to afford 3- (N'-tert.-butoxy-carbonyl-hydrazinoca. Bothioyl) -benzoic acid methyl ester (1.31 g) was obtained as a yellow solid. MS (ISP) 328.3 [(M + NH4)].
    [703] b) 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate
    [704] A solution of 3- (N'-tert.-butoxy-carbonyl-hydrazinocarbothioyl) -benzoic acid methyl ester (0.93 g) in TFA (9 mL) / anisole (2 mL) at 0 ° C. for 1 hour Was stirred. The solvent was evaporated under vacuum to afford crude 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.98 g) as crystalline oil.
    [705] c) 3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -benzoic acid methyl ester
    [706] A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.49 g) and 2-chloro-acetimide acid ethyl ester hydrochloride (0.47 g) in EtOH (6 mL) was heated to 80 ° C. . The mixture was diluted with AcOEt for 2.5 hours and washed with 1N HCl and brine. The organic layer was dried and evaporated. Residual oil (0.8 g) was dissolved in MeOH (5 mL), MeONa (0.08 g) was added and the solution was heated to 65 ° C. The mixture was diluted with AcOEt for 0.5 h and washed with 1N HCl and brine. The organic layer is dried, evaporated and the residue is crystallized from AcOEt / hexanes to afford 3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -benzoic acid methyl ester (0.15 g). Obtained as a white solid. MS (ISP) 251.2 [(M + H) + ].
    [707] d) 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester
    [708] 3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -benzoic acid methyl ester (7.8 g), dihydropyran (5.6 mL) and p-toluene in AcOEt (80 mL) The mixture of sulfonic acid hydrate (0.59 g) was stirred at 20 ° C. for 1 hour. The solution was diluted with AcOEt, washed with 5% NaHCO 3 solution and brine, dried and evaporated in vacuo. The residual oil was chromatographed on silica gel with AcOEt / hexane (1: 2) as eluent to give 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazole. 2-yl] -benzoic acid methyl ester (5.85 g) was obtained as a pale yellow oil.
    [709] e) 3-oxo-3- [3-5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester
    [710] 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester (5.85 g) was prepared according to general procedure K (method b ) Crude 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazole-2- treated with lithium tert.-butyl acetate Ill-phenyl} -propionic acid tert.-butyl ester (8.9 g) was obtained as a pale yellow oil.
    [711] Example K31
    [712] 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -phenyl) -propionic acid tert.-butyl ester
    [713] a) 3- [5- (2-hydroxy-ethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester
    [714] A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.45 g) and 3-hydroxypropionimide ethyl ester hydrochloride (0.35 g) in pyridine (5 mL) was heated to 100 ° C. Heated. Dilute the mixture with AcOEt for 1.5 h. Washed with 1N HCl and brine. The organic layer is dried, evaporated and the residual oil is chromatographed on silica gel using AcOEt / hexane (1: 1) as eluent to give 3- [5- (2-hydroxy-ethyl)-[1, 3,4] thiadiazol-2-yl] -benzoic acid methyl ester (0.37 g) was obtained as a white solid. MS (ISP) 265.3 [(M + H) + ].
    [715] b) 3- [5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester
    [716] 3- [5- (2-hydroxy-ethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester (1.86 g) in AcOEt (25 mL), dihydropyran (0.95 mL) ) And p-toluenesulfonic acid hydrate (0.13 g) were stirred at 20 ° C for 1 hour. The solution was diluted with AcOEt, washed with 5% NaHCO 3 solution and brine, dried and evaporated in vacuo. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 2) as eluent to afford 3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1, 3,4] thiadiazol-2-yl} -benzoic acid methyl ester (1.60 g) was obtained as a pale yellow oil.
    [717] c) 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -phenyl- Propionic acid tert.-butyl ester
    [718] 3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -benzoic acid methyl ester (1.60 g) was subjected to the general procedure K. According to (method b) 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3, 4] thiadiazol-2-yl} -phenyl) -propionic acid tert.-butyl ester (2.1 g) was obtained as a pale yellow oil.
    [719] Example K32
    [720] 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] oxadiazol-2-yl] -phenyl} -propionic acid tert.-butyl ester
    [721] a) 3- (5-hydroxymethyl- [1,3,4] oxadiazol-2-yl) -benzoic acid methyl ester
    [722] A mixture of 3-hydrazinocarbonyl-benzoic acid methyl (0.97 g) and 2-chloro-acetimide acid ethyl ester hydrochloride (0.95 g) in EtOH (20 mL) was heated to 80 ° C. for 1 hour. The mixture was diluted with AcOEt and washed with 1N HCl and brine. The organic layer was dried, evaporated and residual oil (1.1 g) was dissolved in DMF (4 mL). The mixture was stirred at 100 ° C. for 0.5 h while AcOK (0.59 g) and KI (0.07 g) were added. After cooling to 20 ° C., MeOH (10 mL) and NaOMe (0.14 g) were added and stirring continued at 65 ° C. for 0.5 h. The mixture was diluted with AcOEt and washed with 1N HCl and brine. The organic layer is dried, evaporated and the residue is crystallized from AcOEt / hexanes to give 3- (5-hydroxymethyl- [1,3,4] oxadiazol-2-yl) -benzoic acid methyl ester (0.72 g). Obtained as a white solid. MS (ISP) 235.3 [(M + H) + ].
    [723] b) 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester
    [724] 3- (5-hydroxymethyl- [1,3,4] oxadiazol-2-yl) -benzoic acid methyl ester (9.8 g), dihydropyran (7.7 mL) and p-toluene in AcOEt (100 mL) The mixture of sulfonic acid hydrate (0.80 g) was stirred at 20 ° C for 1 hour. The solution was diluted with AcOEt and washed with 5% NaHCO 3 solution and brine, dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 2) as eluent to give 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thia Diazol-2-yl] -benzoic acid methyl ester (12.6 g) was obtained as a pale yellow oil.
    [725] c) 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] oxadiazol-2-yl] -phenyl} -propionic acid tert.- Butyl ester
    [726] 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -benzoic acid methyl ester (12.6 g) was prepared according to general procedure K (method b ) Crude 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] oxadiazole-2- by treatment with lithium tert.-butyl acetate Il] -phenyl} -propionic acid tert.-butyl ester (17.0 g) was obtained as a pale yellow oil.
    [727] Example K33
    [728] 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] oxadiazol-2-yl} -phenyl) -propionic acid tert.-butyl ester
    [729] a) 3- [5- (2-hydroxy-ethyl)-[1,3,4] oxadiazol-2-yl] -benzoic acid methyl ester
    [730] A mixture of crude 3-hydrazinocarbonyl-benzoic acid methyl (2.90 g) and 3-hydroxypropionimide ethyl ester hydrochloride (2.76 g) in pyridine (10 mL) was heated to 100 ° C. for 2 hours. It was. The mixture was diluted with AcOEt and washed with 1N HCl and brine. The organic layer is dried, evaporated and the residual oil crystallized from Et 2 O to methyl 3- [5- (2-hydroxy-ethyl)-[1,3,4] oxadiazol-2-yl] -methyl benzoate Ester (2.5 g) was obtained as a white solid. MS (ISP) 249.1 [(M + H) + ].
    [731] b) 3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -benzoic acid methyl ester
    [732] 3- [5- (2-hydroxy-ethyl)-[1,3,4] oxadiazol-2-yl] -benzoic acid methyl ester (7.45 g) in AcOEt (80 mL), dihydropyran (4.1 mL) ) And p-toluenesulfonic acid hydrate (0.57 g) were stirred at 20 ° C. for 2 hours. The solution was diluted with AcOEt, washed with 5% NaHCO 3 solution and brine, dried and evaporated in vacuo. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 2) as eluent to obtain 3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1, 3,4] thiadiazol-2-yl} -benzoic acid methyl ester (8.2 g) was obtained as a pale yellow oil.
    [733] c) 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] oxadiazol-2-yl} -phenyl) Propionic acid tert.-butyl ester
    [734] 3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -benzoic acid methyl ester (8.2 g) was subjected to General Procedure K. Treatment with lithium tert.-butyl acetate according to (method b) gave crude 3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1, 3,4] oxadiazol-2-yl} -phenyl) -propionic acid tert.-butyl ester (11.6 g) was obtained as a pale yellow oil.
    [735] Example K34
    [736] 3- (3-Oxazol-4-yl-phenyl) -3-oxo-propionic acid tert.-butyl ester
    [737] a) 3-oxazol-4-yl-benzoic acid methyl ester
    [738] A mixture of 3- (2-bromo-acetyl) -benzoic acid (1.94 g) and formamide (1.08 g) was heated to 130 ° C. with stirring for 3 hours. The mixture was partitioned between AcOEt and brine, the organic layer was dried, evaporated and the residual oil dissolved in a mixture of MeOH (30 mL) and 4NHCl / Et 2 O (8 mL). After holding at 20 ° C. for 18 hours, the solution was concentrated in vacuo, diluted with AcOEt, washed with saturated NaHCO 3 solution and brine, dried and evaporated. The residue was chromatographed on silica gel using AcOEt / hexane (1: 3) as eluent to afford 3-oxazol-4-yl-benzoic acid methyl ester (0.85 g) as a grayish white solid. MS (ISP) 204.1 [(M + H) + ].
    [739] b) 3- (3-oxazol-4-yl-phenyl) -3-oxo-propionic acid tert.-butyl ester
    [740] 3-oxazol-4-yl-benzoic acid methyl ester (0.85 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to yield crude 3- (3-oxazol-4-yl-phenyl ) -3-oxo-propionic acid tert.-butyl ester (1.46 g) was obtained as a pale yellow oil.
    [741] Example K35
    [742] 3-oxo-3- (3-thiazol-4-yl-phenyl) -propionic acid tert.-butyl ester
    [743] a) 3-thiazol-4-yl-benzoic acid methyl ester
    [744] A solution of 3- (2-bromo-acetyl) -benzoic acid (1.22 g) and thioformamide (0.46 g) in EtOH (5 mL) was heated to 80 ° C. for 1 hour. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated. The residual oil was dissolved in a mixture of MeOH (20 mL) and 4NHCl / Et 2 O (5 mL). After holding at 20 ° C. for 18 hours, the solution was concentrated in vacuo, diluted with AcOEt, washed with saturated NaHCO 3 solution and brine, dried and evaporated. The residue was subjected to chromatography on silica gel using AcOEt / hexane (1: 3) as eluent to afford 3-thiazol-4-yl-benzoic acid methyl ester (0.98 g) as a grayish white solid. MS (ISP) 220.2 [(M + H) + ].
    [745] b) 3-oxo-3- (3-thiazol-4-yl-phenyl) -propionic acid tert.-butyl ester
    [746] 3-thiazol-4-yl-benzoic acid methyl ester (0.91 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to yield crude 3-oxo-3- (3-thiazole-4 -Yl-phenyl) -propionic acid tert.-butyl ester (1.54 g) was obtained as a pale yellow oil.
    [747] Example K36
    [748] 3- [3- (5-Methyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [749] a) 3-tert.-butoxycarbonylacetyl-benzoic acid methyl ester
    [750] Dimethyl isophthalate (67.9 g) was treated with lithium tert.-butyl acetate according to General Procedure K (method b) to give crude 3-tert.-butoxycarbonylacetyl-benzoic acid methyl ester (74.5 g) as a pale yellow oil. Obtained as
    [751] b) 3-propionyl-benzoic acid methyl ester
    [752] To a stirred solution of 3-tert.-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and MeI (2.2 mL) in DMF (40 mL) at 0 ° C. NaH (55% dispersion in mineral oil, 1.4 g) Was added dropwise. Stirring was continued at 0 ° C. for 15 minutes and at 20 ° C. for 30 minutes. The mixture was partitioned between AcOEt and brine and the pH was brought to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residue was stirred in a mixture of CH 2 Cl 2 (30 mL) and TFA (30 mL) at 20 ° C. for 40 minutes. After evaporating the solvent, a solution of the residue in AcOEt was extracted with ice cold saturated Na 2 CO 3 solution, the aqueous extract was immediately acidified with 3N HCl and extracted with AcOEt. The solution of this extract was evaporated and the residue was heated to 100 ° C. for 1 hour in a mixture of toluene (40 mL) and 3N HCl (3 mL). The cooled mixture was diluted with AcOEt, washed with saturated NaHCO 3 and brine, dried and evaporated to afford 3-propionyl-benzoic acid methyl ester (3.87 g) as a white solid. MS (ISP) 193.2 [(M + H) + ].
    [753] c) rac-3- (2-bromo-propionyl) -benzoic acid methyl ester
    [754] A mixture of 3-propionyl-benzoic acid methyl ester (3.6 g) and CuBr 2 (7.45 g) in AcOEt (45 mL) was heated at reflux for 2 hours. The insoluble material was filtered off from the cooled mixture and the clear solution was washed with brine, dried and evaporated to yield crude rac-3- (2-bromo-propionyl) -benzoic acid methyl ester (5.0 g) as pale yellow oil. Obtained as
    [755] d) 3- (5-methyl-oxazol-4-yl) -benzoic acid methyl ester
    [756] rac-3- (2-bromo-propionyl) -benzoic acid methyl ester (5.42 g) and formamide (3.6 mL) were heated together to 130 ° C. for 5 hours. The mixture is partitioned between AcOEt and brine, the organic layer is dried and evaporated and the residual oil is chromatographed on silica gel using AcOEt / hexane (1: 4) as eluent 3- (5-methyl- Oxazol-4-yl) -benzoic acid methyl ester (2.52 g) was obtained as a white solid.
    [757] e) 3- [3- (5-methyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [758] 3- (5-methyl-oxazol-4-yl) -benzoic acid methyl ester (0.87 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to give crude 3- [3- (5 -Methyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (1.46 g) was obtained as a pale yellow oil.
    [759] Example K37
    [760] 3- [3- (2-Methyl-5-propyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [761] a) 3-pent-4-enoyl-benzoic acid methyl ester
    [762] To a stirred solution of 3-tert.-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and allyl bromide (3.0 mL) in DMF (40 mL) at 0 ° C. NaH (55% dispersion in mineral oil, 1.44 g) Dropwise). Stirring was continued at 0 ° C. for 20 minutes and at 20 ° C. for 30 minutes. The mixture was partitioned between AcOEt and brine and the pH was brought to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residual oil was stirred in a mixture of CH 2 Cl 2 (30 mL) and TFA (30 mL) at 20 ° C. for 40 minutes. The solvent was evaporated. The solution of the residue in AcOEt was extracted with an ice cold saturated Na 2 CO 3 solution, the aqueous extract was immediately acidified with 3N HCl and extracted with AcOEt. The solvent of this extract was evaporated and the residue was heated to 100 ° C. for 1 hour in a mixture of toluene (40 mL) and 3N HCl (2 mL). The cooled mixture was diluted with AcOEt, washed with saturated NaHCO 3 and brine, dried and evaporated to give 3-pent-4-enoyl-benzoic acid methyl ester (5.11 g) as a pale yellow oil. MS (ISP) 236.2 [(M + NH4)].
    [763] b) rac-3- (2-bromo-pentanoyl) -benzoic acid methyl ester
    [764] Samples of 3-pent-4-enoyl-benzoic acid methyl ester (3.93 g) were hydrogenated in AcOEt (50 mL) in the presence of 5% Pd-C (190 mg) at 20 ° C. for 30 minutes. The catalyst was filtered off, CuBr 2 (4.44 g) was added to the solution and the mixture was heated at reflux for 1 h. Insoluble material was filtered off from the cooled mixture and the clear solution was washed with 1N HCl and brine, dried and evaporated to afford crude rac-3- (2-bromo-pentanoyl) -benzoic acid methyl ester (3.6 g). Obtained as a pale yellow oil.
    [765] c) 3- (2-methyl-5-propyl-oxazol-4-yl) -benzoic acid methyl ester
    [766] Samples of rac-3- (2-bromo-pentanoyl) -benzoic acid methyl ester (1.50 g) and acetamide (0.89 g) were heated together to 130 ° C. for 15 hours. The mixture is partitioned between AcOEt and brine, the organic layer is dried and evaporated and the residual oil is chromatographed on silica gel using AcOEt / hexane (1: 3) as eluent 3- (2-methyl- 5-propyl-oxazol-4-yl) -benzoic acid methyl ester (0.47 g) was obtained as a light yellow oil.
    [767] d) 3- [3- (2-methyl-5-propyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [768] 3- (2-Methyl-5-propyl-oxazol-4-yl) -benzoic acid methyl ester (0.47 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to give crude 3- [ 3- (2-Methyl-5-propyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (0.58 g) was obtained as a light brown oil.
    [769] Example K38
    [770] 3- [3- (5-Methyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [771] a) 3- (5-methyl-thiazol-4-yl) -benzoic acid methyl ester
    [772] A solution of crude rac-3- (2-bromo-propionyl) -benzoic acid methyl ester (2.71 g) and thioformamide (1.83 g) in EtOH (20 mL) was heated at reflux for 1 hour. The mixture is partitioned between AcOEt and brine, the organic layer is dried and evaporated and the residual oil is chromatographed on silica gel using AcOEt / hexane (1: 4) as eluent 3- (5-methyl- Thiazol-4-yl) -benzoic acid methyl ester (2.41 g) was obtained as a white solid.
    [773] b) 3- [3- (5-methyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [774] A sample of 3- (5-methyl-thiazol-4-yl) -benzoic acid methyl ester (1.05 g) was treated with lithium tert.-butyl acetate according to General Procedure K (Method b) to give crude 3- [3- (5-Methyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (1.9 g) was obtained as a pale yellow oil.
    [775] Example K39
    [776] 3- [3- (2,5-Dimethyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [777] a) 3- (2,5-dimethyl-thiazol-4-yl) -benzoic acid methyl ester
    [778] A mixture of rac-3- (2-bromo-propionyl) -benzoic acid methyl ester (6.78 g) and thioacetamide (5.63 g) was heated to 130 ° C. for 20 minutes. The mixture was partitioned between AcOEt and H 2 O, the organic layer was dried and evaporated, and the residual oil was chromatographed on silica gel using AcOEt / hexane (1: 4) as eluent 3- (2, 5-Dimethyl-thiazol-4-yl) -benzoic acid methyl ester (4.97 g) was obtained as a yellow oil.
    [779] b) 3- [3- (2,5-dimethyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [780] A sample of 3- (2,5-dimethyl-thiazol-4-yl) -benzoic acid methyl ester (0.99 g) was treated with lithium tert.-butyl acetate according to General Procedure K (method b) to give 3- [3- (2,5-Dimethyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (1.12 g) was obtained as a pale yellow oil.
    [781] Example K40
    [782] 3-oxo-3- [3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester
    [783] a) 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester
    [784] A solution of rac-3- (2-bromo-propionyl) -benzoic acid methyl ester (2.71 g) and 2- (tert.-butylcarbonyloxy) thioacetamide (2.1 g) in EtOH (20 mL) was refluxed. Under heating for 6 hours. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. A solution of residual oil and NaOMe (0.54 g) in MeOH (20 mL) was stirred at 60 ° C. for 1 h. The solution was diluted with AcOEt, washed with IN HCl and brine, dried and evaporated to afford 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester (1.17 g). Obtained as a crystal. MS (ISP) 264.1 [(M + H) + ].
    [785] b) 3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -benzoic acid methyl ester
    [786] 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester (1.05 g), dihydropyran (0.73 mL) and p-toluenesulfonic acid hydrate in AcOEt (10 mL) 0.07 g) was stirred at 20 ° C. for 1 h. The solution was diluted with AcOEt and washed with 5% NaHCO 3 solution and brine, dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 3) as eluent 3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazole-4 -Yl] -benzoic acid methyl ester (1.45 g) was obtained as a pale yellow oil.
    [787] c) 3-oxo-3- [3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester
    [788] 3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -benzoic acid methyl ester (1.45 g) was added to lithium tert. According to General Procedure K (Method b). Treated with -butyl acetate to give crude 3-oxo-3- [3- [5-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert .-Butyl ester (2.13 g) was obtained as a pale yellow oil.
    [789] Example K41
    [790] 3-oxo-3- [3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester
    [791] a) 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester
    [792] A sample of rac-3- (2-bromo-pentanoyl) -benzoic acid methyl ester (0.60 g) and 2- (tert.-butylcarbonyloxy) thioacetamide (0.36 g) in EtOH (4 mL) was refluxed. Under heating for 5 hours. The mixture was partitioned between AcOEt and 5% NaHCO 3 solution and the organic layer was washed with brine, dried and evaporated. A solution of residual oil and NaOMe (0.13 g) in MeOH (10 mL) was stirred at 60 ° C. for 30 minutes. The solution was diluted with AcOEt, washed with 1N HCl and brine, dried and evaporated to afford 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester (0.44 g). Obtained as
    [793] b) 3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -benzoic acid methyl ester
    [794] 3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -benzoic acid methyl ester (0.38 g), dihydropyran (0.73 mL) and p-toluenesulfonic acid hydrate in AcOEt (10 mL) 0.07 g) was stirred at 20 ° C for 1 h. The solution was diluted with AcOEt and washed with 5% NaHCO 3 solution and brine, dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 3) as eluent 3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazole-2 -Yl] -benzoic acid methyl ester (0.36 g) was obtained as a pale yellow oil.
    [795] c) 3-oxo-3- [3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert.-butyl ester
    [796] 3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -benzoic acid methyl ester (0.34 g) was added to lithium tert. According to General Procedure K (Method b). Treated with -butyl acetate to give crude 3-oxo-3- [3- [5-propyl-4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert .-Butyl ester (0.42 g) was obtained as a pale yellow oil.
    [797] Example K42
    [798] 3-oxo-3- [3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester
    [799] a) 3- (5-bromomethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester
    [800] 3- (2,5-Dimethyl-thiazol-4-yl) -benzoic acid methyl ester (3.96 g), N-bromosuccinimide (3.13 g) and α, α'-bis in CCl 4 (60 mL) A mixture of (isobutyronitrile) (0.02 g) was heated at reflux for 30 minutes. The cooled mixture was filtered and the solvent evaporated to afford crude 3- (5-bromomethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester (6.2 g) as an oil.
    [801] b) 3- (5-hydroxymethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester
    [802] 3- (5-Bromomethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester was stirred with KOAc (2.35 g) in DMF (16 mL) at 20 ° C. for 20 minutes. MeOH (32 mL) and NaOMe (0.86 g) were added and stirring continued at 50 ° C. for 30 minutes. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 1) as eluent to afford 3- (5-hydroxymethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester (2.93 g) was obtained as a white solid.
    [803] c) 3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl-benzoic acid methyl ester
    [804] 3- (5-hydroxymethyl-2-methyl-thiazol-4-yl) -benzoic acid methyl ester (0.38 g), dihydropyran (2.01 mL) and p-toluenesulfonic acid hydrate in AcOEt (25 mL) 0.21 g) was stirred at 20 ° C for 1 h. The solution was diluted with AcOEt and washed with 5% NaHCO 3 solution and brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt / hexane (1: 3) as eluent to afford 3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazole- 4-yl] -benzoic acid methyl ester (3.8 g) was obtained as a pale yellow oil.
    [805] d) 3-oxo-3- [3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester
    [806] 3- [2-Methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -benzoic acid methyl ester with lithium tert.-butyl acetate according to general procedure K (method b). Treated to give crude 3-oxo-3- [3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester (5.45 g) was obtained as a pale yellow oil.
    [807] Example K43
    [808] 3-oxo-3- [5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl] -propionic acid tert.-butyl ester
    [809] a) 3- (5-bromomethyl-thiazol-4-yl) -benzoic acid methyl ester
    [810] 3- (5-Methyl-thiazol-4-yl) -benzoic acid methyl ester (2.40 g), N-bromosuccinimide (2.01 g) and α, α'-bis (iso) in CCl 4 (40 mL) Butyronitrile) (0.02 g) was heated at reflux for 30 minutes. The cooled mixture was filtered and the solvent evaporated to afford crude 3- (5-bromomethyl-thiazol-4-yl) -benzoic acid methyl ester (3.36 g) as an oil.
    [811] b) 3- (5-hydroxymethyl-thiazol-4-yl) -benzoic acid methyl ester
    [812] 3- (5-Bromomethyl-thiazol-4-yl) -benzoic acid methyl ester was stirred with KOAc (1.52 g) in DMF (10 mL) at 20 ° C. for 30 minutes. MeOH (20 mL) and NaOMe (0.84 g) were added and stirring continued at 50 ° C. for 30 minutes. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 2) as eluent to afford 3- (5-hydroxymethyl-thiazol-4-yl) -benzoic acid methyl ester (1.43 g). Obtained as a solid.
    [813] c) 3- [5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -benzoic acid methyl ester
    [814] 3- (5-hydroxymethyl-thiazol-4-yl) -benzoic acid methyl ester (1.25 g), dihydropyran (0.84 mL) and p-toluenesulfonic acid hydrate (0.10 g) in AcOEt (12 mL) Stir at 20 ° C. for 3 hours. The solution was diluted with AcOEt and washed with 5% NaHCO 3 solution and brine, dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt / hexane (1: 3) as eluent 3- [5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl]- Benzoic acid methyl ester (1.60 g) was obtained as a pale yellow oil.
    [815] d) 3-oxo-3-{[5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl} -propionic acid tert.-butyl ester
    [816] 3- [5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -benzoic acid methyl ester was treated by lithium tert.-butyl acetate according to general procedure K (method b) to give crude 3-Oxo-3-{[5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl} -propionic acid tert.-butyl ester (2.3 g) was obtained as a pale yellow oil. It was.
    [817] Example K44
    [818] 3- [3- (2-Isopropyl-3H-imidazol-4-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester
    [819] a) 3-dihydroxyacetyl-benzoic acid methyl ester
    [820] A mixture of 3- (2-bromo-acetyl) -benzoic acid (2.43 g), DMSO (17 mL) and 48% HBr (3.4 mL) was heated to 55 ° C for 30 minutes. The mixture was partitioned between AcOEt and H 2 O and the organic layer was washed with brine, dried and evaporated to give 3-dihydroxyacetyl-benzoic acid methyl ester (1.06 g) as a white solid.
    [821] b) 3- (2-isopropyl-3H-imidazol-4-yl) -benzoic acid methyl ester
    [822] A solution of 3-dihydroxyacetyl-benzoic acid methyl ester (0.36 g) and 2-methyl-propionaldehyde (0.24 mL) in 5% aqueous NH 3 (6 mL) was heated to 100 ° C. for 1 h. The mixture was evaporated in vacuo and the residue solution in a mixture of MeOH (10 mL) and 4NHCl / Et 2 O (2 mL) was heated to 40 ° C. for 18 h. The solution was concentrated in vacuo, diluted with AcOEt, washed with saturated Na 2 CO 3 solution and brine, dried and evaporated. The residue was chromatographed on silica gel with AcOEt as eluent to afford 3- (2-isopropyl-3H-imidazol-4-yl) -benzoic acid methyl ester (0.37 g) as a pale yellow oil.
    [823] General procedure M
    [824] (2-amino-phenyl) -carbamic acid tert.-butyl ester with ethyl or tert.-butyl 3-aryl-3-oxo-propionate or 6-aryl-2,2-dimethyl- [1,3] di Preparation of {2- [3-aryl-3-oxo-propionylamino] -phenyl} -carbamic acid tert.-butyl ester by reaction with auxin-4-one
    [825] (2-Amino-phenyl) -carbamic acid tert.-butyl ester (1.0-1.2 mmol) and ethyl or tert.-butyl 3-aryl-3-oxo-propionate or 6-aryl-2,2-dimethyl- A mixture of [1,3] dioxin-4-one (1.0-1.5 mmol) was heated in toluene (4-8 mL) to 80 ° C. to 120 ° C. until the low tlc indicated complete consumption of the component. The solution is cooled to 23 ° C., at which time the product is generally crystallized (if crystallization does not appear, crystallization is induced by addition of hexane or ether, or the reaction mixture is directly subjected to silica gel column chromatography). The solid was filtered off, washed with ether or ether / hexane mixtures and dried in vacuo to afford {2- [3-aryl-3-oxo-propionylamino] -phenyl} -carbamic acid tert.-butyl ester It was used directly in the next step or purified by recrystallization or silica gel chromatography if necessary.
    [826] Example M1
    [827] {4-Chloro-2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5-dimethylamino-phenyl] -carbamic acid tert.-butyl ester
    [828] The title compound was converted to (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (0.5 mmol) and 3- (3-cyano-phenyl) -3- Oxo-propionic acid ethyl ester [CAS-No. 62088-13-5; Prepared according to general procedure K from 3-cyanobenzoyl chloride, according to general procedure M from method a] (0.55 mmol). Obtained as a white solid (160 mg).
    [829] MS (ISP) 457 [(M + H) + ]; mp 159-163 ° C.
    [830] Example M2
    [831] {4-Chloro-5-dimethylamino-2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -phenyl} -carbamic acid tert .-Butyl ester
    [832] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-oxo-3- (3- [ 1,2,3] from triazol-1-yl-phenyl) -propionic acid ethyl ester (Example KI) (150 mg, 0.58 mmol) according to General Procedure M. Obtained as a beige solid (160 mg).
    [833] MS (ISP) 499 [(M + H) + ] and 501 [(M + 2 + H) + ]; mp 136-137 ° C.
    [834] Example M3
    [835] (RS)-[4-Chloro-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] tria Zol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [836] The title compound was converted to (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (250 mg , 0.62 mmol), according to General Procedure M. Obtained as a yellow oil (257 mg).
    [837] MS (ISP) 613 [(M + H) + ] and 615 [(M + 2 + H) + ].
    [838] Example M4
    [839] {2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -5-dimethylamino-4-phenylethynyl-phenyl} -carbamic acid tert.-butyl ester
    [840] The title compound was prepared as (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J2) and 3- (2,2-dimethyl-6-oxo-6H- [1 , 3] dioxine-4-yl) -benzonitrile (Example L1) was prepared according to general procedure M. Obtained as an orange solid (108 mg).
    [841] MS (ISP) 523 [(M + H) + ].
    [842] Example M5
    [843] {5-Dimethylamino-2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-phenylethynyl-phenyl} -car Chestnut acid tert.-butyl ester
    [844] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J2) and 3-oxo-3- (3- [1,2,3] tria Prepared according to General Procedure M from Zol-1-yl-phenyl) -propionic acid ethyl ester (Example K1). Obtained as an orange solid (148 mg).
    [845] MS (ISP) 565 [(M + H) + ].
    [846] Example M6
    [847] (4-Chloro-5-dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert. -Butyl ester
    [848] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3- [3- (3methyl-isomeric Prepared according to General Procedure M from Sazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (450 mg, 0.75 mmol). Obtained as a white solid (136 mg).
    [849] S (ISP) 513 [(M + H) + ] and 515 [(M + 2 + H) + ]; mp 109-114 ° C.
    [850] Example M7
    [851] (RS)-[2-Dimethylamino-2 ', 3'-difluoro-5- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [852] The title compound was converted to (5-amino-2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example J3) and (RS) -3- Oxo-3- {3- [5-tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) From General Procedure M from Obtained as a yellow solid (253 mg).
    [853] MS (ISP) 691 [(M + H) + ].
    [854] Example M8
    [855] {2-Dimethylamino-2 ', 3'-difluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino]- Biphenyl-4-yl} -carbamic acid tert.-butyl ester
    [856] The title compound was converted to (5-amino-2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example J3) and 3-oxo-3- Prepared according to General Procedure M from (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid ethyl ester (Example K1). Obtained as a yellow solid (253 mg).
    [857] MS (ISP) 577 [(M + H) + ].
    [858] Example M9
    [859] {5- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl} -carbamic acid tert .-Butyl ester
    [860] The title compound was purified from (5-amino-2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example J3) and 3- (2,2 Prepared according to General Procedure M from -dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example L1). Obtained as a yellow solid (145 mg).
    [861] MS (ISP) 535 [(M + H) + ].
    [862] Example M10
    [863] (4-Chloro-5-dimethylamino-2- {3- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl] -3-oxo-propionylamino} -phenyl)- Carbamic acid tert.-butyl ester
    [864] The title compound was purified from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3- [2- (3-methyl- Isoxazol-5-yl) -pyridin-4-yl] -3-oxo-propionic acid tert.-butyl ester (Example K6) (170 mg, 0.56 mmol) was prepared according to General Procedure M. Obtained as a brown solid (206 mg).
    [865] MS (ISP) 514 [(M + H) + ] and 516 [(M + 2 + H) + ]; mp 181-183 ° C.
    [866] Example M11
    [867] (4-Chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo- Propionylamino} -phenyl) -carbamic acid tert.-butyl ester
    [868] The title compound was taken as {2-amino-4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol ) And 3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (165 mg, 0.55 mmol) to General Procedure M Prepared accordingly. Obtained as an amorphous yellowish substance (207 mg).
    [869] MS (ISP) 557 [(M + H) + ] and 559 [(M + 2 + H) + ].
    [870] Example M12
    [871] (4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- {3- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl]- 3-oxo-propionylamino} -phenyl) -carbamic acid tert.-butyl ester
    [872] The title compound was taken as {2-amino-4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol ) And 3- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl] -3-oxo-propionic acid tert.-butyl ester (Example K6) (151 mg, 0.5 mmol) Prepared according to General Procedure M. Obtained as a yellow solid (190 mg).
    [873] MS (ISP) 558 [(M + H) + ] and 560 [(M + 2 + H) + ]; mp 148 ° C.
    [874] Example M13
    [875] (RS)-[4-Chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yl Oxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [876] The title compound was taken as {2-amino-4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol ) And (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid Prepared according to general procedure M from tert-butyl ester (Example K5) (200 mg, 0.5 mmol). Obtained as an amorphous yellowish material (160 mg).
    [877] MS (ISP) 657 [(M + H) + ] and 659 [(M + 2 + H) + ].
    [878] Example M14
    [879] {4-Chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -Propionylamino] -phenyl} -carbamic acid tert.-butyl ester
    [880] The title compound was taken as {2-amino-4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol ) And 3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid ethyl ester (Example K1) (165 mg, 0.5 mmol) according to General Procedure M It was. Obtained as an amorphous yellowish substance (167 mg).
    [881] MS (ISP) 543 [(M + H) + ] and 545 [(M + 2 + H) + ].
    [882] Example M15
    [883] {4-Chloro-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-dimethylamino-phenyl} -carbamic acid tert.-butyl ester
    [884] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3- (2-cyano-pyridine- Prepared according to General Procedure M from 4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol). Obtained as a yellow solid (155 mg).
    [885] MS (ISP) 458 [(M + H) + ] and 460 [(M + 2 + H) + ]; mp 110 ° C.
    [886] Example M16
    [887] (4-Chloro-5-dimethylamino-2- {3- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert.-butyl ester
    [888] The title compound was purified from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3- [3- (2-methyl- Prepared according to General Procedure M from 2H-pyrazol-3-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K7) (180 mg, 0.6 mmol). Obtained as an amorphous yellowish material (160 mg).
    [889] MS (ISP) 512 [(M + H) + ] and 514 [(M + 2 + H) + ].
    [890] Example M17
    [891] (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole-1- Ill-phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [892] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and (RS) -3-oxo -3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) Prepared according to General Procedure M from (201 mg, 0.5 mmol). Obtained as an amorphous yellowish substance (247 mg).
    [893] MS (ISP) 647 [(M + H) + ].
    [894] Example M18
    [895] (5-Dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl-phenyl) -car Chestnut acid tert.-butyl ester
    [896] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3- [3- (3 -Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (151 mg, 0.5 mmol) was prepared according to general procedure M. Obtained as an amorphous yellowish substance (94 mg).
    [897] MS (ISP) 547 [(M + H) + ].
    [898] Example M19
    [899] (4-chloro-5-dimethylamino-2- {3- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionylamino } -Phenyl) -carbamic acid tert.-butyl ester
    [900] The title compound was purified from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3- [3- (5-dimethylamino Prepared according to general procedure M from methyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol). . Obtained as an amorphous yellowish substance (176 mg).
    [901] MS (ISP) 556 [(M + H) + ] and 558 [(M + 2 + H) + ].
    [902] Example M20
    [903] (4-Chloro-5-dimethylamino-2- {3- [3- (3-methoxymethyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert.-butyl ester
    [904] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) and 3- [3- (3-methoxymethyl-isoxazole-5- Ill-phenyl] -3-oxo-propionic acid tert.-Butyl ester (Example K9) was prepared according to general procedure M. Obtained as a yellow solid (205 mg).
    [905] MS (ISP) 543 [(M + H) + ] and 545 [(M + 2 + H) + ].
    [906] Example M21
    [907] {2- [3- (2-Cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-dimethylamino-4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [908] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3- (2-cyano Prepared according to General Procedure M from Pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (246 mg, 1.0 mmol). Obtained as an amorphous yellowish substance (297 mg).
    [909] MS (ISP) 492 [(M + H) + ].
    [910] Example M22
    [911] [2'-Fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -2- (2,2,2-trifluoro-ethoxy) -Biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [912] The title compound was converted to [5-amino-2'-fluoro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example J5). ) (200 mg, 0.5 mmol) and 6- (3-imidazol-1-yl-phenyl) -2,2-dimethyl- [1,3] dioxin-4-one (Example L3) (160 mg, 0.5 mmol) according to General Procedure M. Obtained as an amorphous brown material (167 mg).
    [913] MS (ISP) 492 [(M + H) + ].
    [914] Example M23
    [915] [2'-Fluoro-5- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -2- (2,2,2-tri Fluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [916] The title compound was converted to [5-amino-2'-fluoro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example J5). ) (200 mg, 0.5 mmol) and 3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (160 mg, 0.53 mmol), according to General Procedure M. Obtained as a white solid (40 mg).
    [917] MS (ISN) 626 [(M − H) − ]; mp 121-123 ° C.
    [918] Example M24
    [919] [2'-Fluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -2- (2,2,2- Trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [920] The title compound was converted to [5-amino-2'-fluoro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example J5). ) (200 mg, 0.5 mmol) and 3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid ethyl ester (Example K1) (150 mg, 0.57 mmol) From General Procedure M from Obtained as a light yellow solid (110 mg).
    [921] MS (ISP) 614 [(M + H) + ]; mp 54-56 ° C.
    [922] Example M25
    [923] (RS)-[2'-fluoro-5- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole-1 -Yl] -phenyl} -propionylamino) -2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester
    [924] The title compound was converted to [5-amino-2'-fluoro-2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example J5). ) (200 mg, 0.5 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole-1- Prepared according to General Procedure M from Ill-phenyl} -propionic acid tert-butyl ester (Example K5) (220 mg, 0.55 mmol). Obtained as a yellow oil (100 mg).
    [925] Example M26
    [926] (RS)-[4-Chloro-5- (ethyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [927] The title compound was converted to [2-amino-4-chloro-5- (ethyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J7) (300 mg, 1.0 mmol) and (RS) -3- Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5 ) (402 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow foam (500 mg).
    [928] MS (ISP) 627.1 [(M + H) + ].
    [929] Example M27
    [930] (RS)-[4-Chloro-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [931] The title compound was converted to [2-amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J8) (310 mg, 1.0 mmol) and (RS) -3- Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5 ) (402 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow foam (410 mg).
    [932] MS (ISP) 641.3 [(M + H) + ].
    [933] Example M28
    [934] (RS)-[4-Chloro-5- (diethyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [935] The title compound was converted to [2-amino-4-chloro-5- (diethyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J9) (310 mg, 1.0 mmol) and (RS) -3-oxo -3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) From (402 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow foam (530 mg).
    [936] MS (ISP) 641.3 [(M + H) + ].
    [937] Example M29
    [938] (RS)-[4-Chloro-5-dimethylamino-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl]- Phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [939] The title compound was converted to (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and (RS) -3-oxo-3- General procedure from {3- [3-tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -propionic acid tert.-butyl ester (Example K12) (201 mg, 0.5 mmol) Prepared according to M. Obtained as a yellow foam (530 mg).
    [940] MS (ISP) 613.1 [(M + H) + ] and 615 [(M + 2 + H) + ].
    [941] Example M30
    [942] (RS)-[4-chloro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl ] -Phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert.-butyl ester
    [943] The title compound was converted to (2-amino-4-chloro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example J10) and (RS) -3-oxo-3- {3 General procedure M from-[5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K5) It was prepared according to. Obtained as a yellow foam (228 mg).
    [944] MS (ISP) 639 [(M + H) + ] and 641 [(M + 2 + H) + ].
    [945] Example M31
    [946] (5-dimethylamino-2- {3- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl-phenyl) -Carbamic acid tert.-butyl ester
    [947] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3- [3- (2 -Methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K7) (150 mg, 0.5 mmol) was prepared according to general procedure M. Obtained as a yellow foam (90 mg).
    [948] MS (ISP) 546.2 [(M + H) + ].
    [949] Example M32
    [950] (RS)-[4-Chloro-5-dimethylamino-2- (3- {3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl]- Phenyl} -3-oxo-propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [951] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) and (RS) -3- {3- [3-methyl-4- ( Tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -3-oxo-propionic acid tert.-butyl ester (Example K13) was prepared according to General Procedure M. Obtained as a light yellow solid (187 mg).
    [952] MS (ISN) 626 [(MH ) -] and 628 [(M + 2-H ) -].
    [953] Example M33
    [954] (RS)-[4-Chloro-5- (cyclopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [955] The title compound was taken from [2-amino-4-chloro-5- (cyclopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and (RS)- 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester ( Prepared according to General Procedure M from Example K5) (250 mg, 0.62 mmol). Obtained as a yellow solid (215 mg).
    [956] MS (ISN) 637.1 [(MH ) -] and 639 [(M + 2-H ) -]; mp 47-49 ° C.
    [957] Example M34
    [958] (5-dimethylamino-2- {3- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionylamino} -4- Trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester
    [959] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3- [3- (5 -Dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol) to General Procedure M Prepared accordingly. Obtained as an amorphous yellow substance (195 mg).
    [960] MS (ISN) 588 [(M − H) − ].
    [961] Example M35
    [962] (RS)-[4-Chloro-5-dimethylamino-2- (3- {3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl ] -Phenyl} -3-oxo-propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [963] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (200 mg, 0.7 mmol) and (RS) -3- {3- [ 2-Methyl-5- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -phenyl} -3-oxo-propionic acid tert.-butyl ester (Example K14) (290 mg , 0.7 mmol), according to General Procedure M. Obtained as an amorphous yellow substance (329 mg).
    [964] MS (ISN) 624.0 [(MH ) -] and 626 [(M + 2-H ) -].
    [965] Example M36
    [966] {2- [3- (2-Cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [967] The title compound was purified from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and 3- Prepared according to General Procedure M from (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol). Obtained as a yellow solid (140 mg).
    [968] MS (ISP) 518 [(M + H) + ].
    [969] Example M37
    [970] (RS)-[2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl-phenyl}- Propionylamino) -5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [971] The title compound was purified from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and (RS ) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl Prepared according to general procedure M from ester (Example K5) (250 mg, 0.62 mmol). Obtained as an orange foam (168 mg).
    [972] MS (ISP) 673 [(M + H) + ].
    [973] Example M38
    [974] (RS)-[5-dimethylamino-4-fluoro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [975] The title compound was converted to (2-amino-5-dimethylamino-4-fluoro-phenyl) -carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS) -3-oxo-3 -{3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K5) ( 401 mg, 1.0 mmol), according to General Procedure M. Obtained as a yellow amorphous material (417 mg).
    [976] MS (ISN) 595 [(M − H) − ].
    [977] Example M39
    [978] (5-dimethylamino-2- {3- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionylamino} -4- Fluoro-phenyl) -carbamic acid tert.-butyl ester
    [979] The title compound was purified from (2-amino-5-dimethylamino-4-fluoro-phenyl) -carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and 3- [3- (5-dimethyl Prepared according to the general procedure M from aminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K8) (344 mg, 1.0 mmol) It was. Obtained as a yellow amorphous material (211 mg).
    [980] MS (ISN) 538 [(M − H) − ].
    [981] Example M40
    [982] (RS)-[5-dimethylamino-4-fluoro-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -Phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [983] The title compound was converted to (2-amino-5-dimethylamino-4-fluoro-phenyl) -carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS) -3-oxo-3 From-{3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -propionic acid tert.-butyl ester (Example K12) (401 mg, 1.0 mmol) Prepared according to General Procedure M. Obtained as a yellow amorphous material (360 mg).
    [984] MS (ISN) 595 [(M − H) − ].
    [985] Example M41
    [986] (RS)-[5-Dimethylamino-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -propy Onylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [987] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (565 mg, 1.77 mmol) and (RS) -3-oxo -3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -propionic acid tert.-butyl ester (Example K12) (710 mg, 1.77 mmol) From General Procedure M). Obtained as a yellow amorphous material (721 mg).
    [988] MS (ISN) 645 [(M − H) − ].
    [989] Example M42
    [990] (RS)-[5-dimethylamino-4-fluoro-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -Phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [991] The title compound was purified from (2-amino-5-dimethylamino-4-fluoro-phenyl) -carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and 3- [3- (3-methyl Prepared according to General Procedure M from -isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a yellow amorphous material (273 mg).
    [992] MS (ISP) 497 [(M + H) + ].
    [993] Example M43
    [994] (RS)-[4-Chloro-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl]- Phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [995] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) and (RS) -3-oxo-3- {3- [5- ( Tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester (Example K15) was prepared according to General Procedure M. Obtained as a yellow foam (232 mg).
    [996] MS (ISN) 611.1 [(MH ) -] and 613 [(M + 2-H ) -].
    [997] Example M44
    [998] (RS)-[4-chloro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl ] -Phenyl} -propionylamino) -5-piperidin-1-yl-phenyl] -carbamic acid tert.-butyl ester
    [999] The title compound was converted to (2-amino-4-chloro-5-piperidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example J14) and (RS) -3-oxo-3- {3 General procedure M from-[5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K5) It was prepared according to. Obtained as a yellow foam (257 mg).
    [1000] MS (ISP) 653.2 [(M + H) + ] and 655 [(M + 2 + H) + ].
    [1001] Example M45
    [1002] (RS)-[5-Dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propy Onylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1003] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3-oxo-3- {3- Prepared according to General Procedure M from [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester (Example K15). Obtained as a light yellow foam (224 mg).
    [1004] MS (ISP) 647.2 [(M + H) + ].
    [1005] Example M46
    [1006] {4-Chloro-5-dimethylamino-2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -phenyl} -carbamic acid tert.-butyl ester
    [1007] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) and 3-oxo-3- (3-pyrazol-1-yl-phenyl Prepared according to General Procedure M from) -propionic acid tert.-butyl ester (Example K16). Obtained as a light yellow solid (135 mg).
    [1008] MS (ISP) 498 [(M + H) + ] and 500 [(M + 2 + H) + ]; mp 148-149 ° C.
    [1009] Example M47
    [1010] {2- [3- (2-Cyano-pyridin-4-yl) -3-oxo-propionylamino] -4-fluoro-5-pyrrolidin-1-yl-phenyl} -carbamic acid tert. -Butyl ester
    [1011] The title compound was formulated as (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example J15) and 3- (2-cyano-pyridine-4 Prepared according to General Procedure M from -yl) -3-oxo-propionic acid tert.-butyl ester (Example K3). Obtained as a yellow solid (196 mg).
    [1012] MS (ISP) 468 [(M + H) + ]; mp 231 ° C. (dec.).
    [1013] Example M48
    [1014] (4-fluoro-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidin-1-yl-phenyl ) -Carbamic acid tert.-butyl ester
    [1015] The title compound was prepared as (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example J15) and 3- [3- (3-methyl-isomeric Prepared according to General Procedure M from Sazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4). Obtained as a light yellow solid (126 mg).
    [1016] MS (ISP) 468 [(M + H) + ]; mp 186 ° C.
    [1017] Example M49
    [1018] (RS)-[4-fluoro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole-1- Yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert.-butyl ester
    [1019] The title compound was converted to (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert.-butyl ester (Example J15) and (RS) -3-oxo-3- { General procedure from 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K5) Prepared according to M. Obtained as an orange viscous oil (268 mg).
    [1020] MS (ISP) 623 [(M + H) + ].
    [1021] Example M50
    [1022] {5-Azetidin-1-yl-4-chloro-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -phenyl} -carbamic acid tert.-butyl ester
    [1023] The title compound was formulated as (2-amino-5-azetidin-1-yl-4-chloro-phenyl) -carbamic acid tert.-butyl ester (Example J16) and 3- (2-cyano-pyridin-4-yl ) -3-oxo-propionic acid tert.-butyl ester (Example K3), according to General Procedure M. Obtained as a yellow solid (142 mg).
    [1024] MS (ISP) 470 [(M + H) + ] and 472 [(M + 2 + H) + ]; mp 168 ° C. (dec.).
    [1025] Example M51
    [1026] (RS)-[2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionylamino) -5 -Pyrrolidin-1-yl-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1027] The title compound was converted to (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J12) and (RS) -3-oxo-3 Prepared according to General Procedure M from-{3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester (Example K15) . Obtained as a yellow foam (522 mg).
    [1028] MS (ISN) 671.2 [(M − H) − ].
    [1029] Example M52
    [1030] {5-azetidin-1-yl-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert .-Butyl ester
    [1031] The title compound was prepared as (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J17) and 3- (2-cyano-pyridine- Prepared according to General Procedure M from 4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3). Obtained as a light yellow solid (131 mg).
    [1032] MS (ISP) 470 [(M + H) + ]; mp 166-167 ° C.
    [1033] Example M53
    [1034] (5-azetidin-1-yl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl- Phenyl) -carbamic acid tert.-butyl ester
    [1035] The title compound was prepared as (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J17) and 3- [3- (3-methyl- Isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) was prepared according to General Procedure M. Obtained as a light yellow foam (218 mg).
    [1036] MS (ISN) 557.2 [(M − H) − ]; mp 83-84 ° C.
    [1037] Example M54
    [1038] (RS)-[5-azetidin-1-yl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] tria Zol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1039] The title compound was converted to (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J17) and (RS) -3-oxo-3- General from {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K5) Prepared according to Procedure M. Obtained as a yellow foam (450 mg).
    [1040] MS (ISN) 657.1 [(M − H) − ]; mp 76-77 ° C.
    [1041] Example M55
    [1042] {5-Dimethylamino-2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [1043] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3-oxo-3- ( Prepared according to General Procedure M from 3-pyrazol-1-yl-phenyl) -propionic acid tert.-butyl ester (Example K16) (286 mg, 1.0 mmol). Obtained as a yellow amorphous material (485 mg).
    [1044] MS (ISN) 530 [(M − H) − ].
    [1045] Example M56
    [1046] {5-Dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-4-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl}- Carbamic acid tert.-butyl ester
    [1047] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (383 mg, 1.2 mmol) and 3-oxo-3- ( 3- [1,2,4] triazol-4-yl-phenyl) -propionic acid ethyl ester [CAS-No. 335255-97-5] (259 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow solid (290 mg).
    [1048] MS (ISP) 533.3 [(M + H) + ]; mp 58-62 ° C.
    [1049] Example M57
    [1050] {5-Dimethylamino-2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [1051] The title compound was prepared as (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and 6- (3-imidazol-1-yl-phenyl) Prepared according to General Procedure M from -2,2-dimethyl- [l, 3] dioxin-4-one (Example L3). Obtained as an orange oil (238 mg).
    [1052] MS (ISP) 432 [(M + H) + ].
    [1053] Example M58
    [1054] (RS)-[4-Chloro-5-dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl]- Phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester
    [1055] The title compound was converted to (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (429 mg, 1.5 mmol) and (RS) -3-oxo-3- General from {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K17) (601 mg, 1.5 mmol) Prepared according to Procedure M. Obtained as a yellow amorphous material (710 mg).
    [1056] MS (ISN) 610 [(MH ) -] and 612 [(M + 2-H ) -].
    [1057] Example M59
    [1058] (RS)-[5-Dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propy Onylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1059] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (479 mg, 1.5 mmol) and (RS) -3-oxo -3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propionic acid tert.-butyl ester (Example K17) (601 mg, 1.5 mmol) From General Procedure M). Obtained as a pink amorphous material (641 mg).
    [1060] MS (ISN) 644 [(M − H) − ].
    [1061] Example M60
    [1062] (RS)-[5-Dimethylamino-2- (3- {3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -3 -Oxo-propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1063] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3- {3- [3-methyl- Prepared according to General Procedure M from 4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl} -3-oxo-propionic acid tert.-butyl ester (Example K13). Obtained as a red oil (424 mg).
    [1064] MS (ISN) 626 [(M − H) − ].
    [1065] Example M61
    [1066] (RS)-[5-Dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propy Onylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1067] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3-oxo-3- {3- [ Prepared according to General Procedure M from 4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionic acid tert.-butyl ester (Example K18). Obtained as a light yellow solid (145 mg).
    [1068] MS (ISP) 647 [(M + H) + ].
    [1069] Example M62
    [1070] (RS)-(5-Dimethylamino-2- {3- [3- (2-methylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoro Methyl-phenyl) -carbamic acid tert.-butyl ester
    [1071] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3- [3- (2 -Methylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester [CAS-No. 335256-01-4] (432 mg, 1.3 mmol) according to General Procedure M. Obtained as a light brown amorphous material (493 mg).
    [1072] MS (ISP) 333.2 [(M + H) + ].
    [1073] Example M63
    [1074] (RS)-[5-Dimethylamino-2- (3- {3- [2-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -phenyl} -3-oxo-propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1075] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3- {3- [2-methyl- Prepared according to General Procedure M from 4- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] -phenyl} -3-oxo-propionic acid tert.-butyl ester (Example K19) It was. Obtained as a bright red solid (576 mg).
    [1076] MS (ISN) 658 [(M − H) − ].
    [1077] Example M64
    [1078] {4-Chloro-5-dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -phenyl} -carbamic acid tert .-Butyl ester
    [1079] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) and 3-oxo-3- (3- [1,2,4] tria Zol-1-yl-phenyl) -propionic acid tert.-butyl ester [CAS-No. 335255-88-4, according to General Procedure M. Obtained as a light yellow solid (427 mg).
    [1080] MS (ISN) 497 [(MH ) -] and 499 [(M + 2-H ) -].
    [1081] Example M65
    [1082] {5-Dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl}- Carbamic acid tert.-butyl ester
    [1083] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and 3-oxo-3- (3- [1,2, 4] triazol-1-yl-phenyl) -propionic acid tert.-butyl ester [CAS-No. 335255-88-4, according to General Procedure M. Obtained as a light red solid (502 mg).
    [1084] MS (ISN) 531 [(M − H) − ].
    [1085] Example M66
    [1086] {2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -5-dimethylamino-4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [1087] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (320 mg, 1.0 mmol) and 3- (2,2- Prepared according to general procedure M from dimethyl-6-oxo-6H- [1,3] dioxin-4-yl) -benzonitrile (Example L1) (275 mg, 1.2 mmol). Obtained as a red viscous oil (196 mg).
    [1088] MS (ISN) 489.1 [(M − H) − ].
    [1089] Example M67
    [1090] (RS)-[5- (cyclopropylmethyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2, 3] triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [1091] The title compound was collected from [2-amino-5- (cyclopropylmethyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example J18) (719 mg, 2.0 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert. Prepared according to general procedure M from butyl ester (Example K5) (803 mg, 2.0 mmol). Obtained as a yellow amorphous material (985 mg).
    [1092] MS (ISP) 687 [(M + H) + ].
    [1093] Example M68
    [1094] [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (cyclopropylmethyl-methyl-amino) -4-trifluoromethyl-phenyl]- Carbamic acid tert.-butyl ester
    [1095] The title compound was extracted with [2-amino-5- (cyclopropylmethyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example J18) (180 mg, 0.5 mmol) and Prepared according to General Procedure M from 3- (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol). Obtained as a yellow amorphous material (206 mg).
    [1096] MS (ISP) 532 [(M + H) + ].
    [1097] Example M69
    [1098] (RS)-{5-Dimethylamino-2- [3-oxo-3- (3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazole-3- Il} -phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [1099] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (639 mg, 2.0 mmol) and (RS) -3- Oxo-3- (3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazol-3-yl} -phenyl) -propionic acid tert.-butyl ester (Example K20) (829 mg, 2.0 mmol) according to General Procedure M. Obtained as a pink amorphous material (272 mg).
    [1100] MS (ISN) 658 [(M − H) − ].
    [1101] Example M70
    [1102] [2- [3- (2-Cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (cyclopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -car Chestnut acid tert.-butyl ester
    [1103] The title compound was extracted with [2-amino-5- (cyclopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example J19) (259 mg, 0.75 mmol) and 3 Prepared according to General Procedure M from-(2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (192 mg, 0.78 mmol). Obtained as a yellow solid (228 mg).
    [1104] MS (ISN) 516.2 [(M − H) − ]; mp 114-116 ° C.
    [1105] Example M71
    [1106] {2-Dimethylamino-2'-fluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -biphenyl-4 -Yl} -carbamic acid tert.-butyl ester
    [1107] The title compound was converted to (5-amino-2-dimethylamino-2'-fluoro-biphenyl-4-yl) -carbamic acid tert.-butyl ester (Example J20) (691 mg, 2.0 mmol) and 2,2 General from -dimethyl-6- (3- [1,2,3] triazol-1-yl-phenyl)-[1,3] dioxin-4-one (Example L4) (543 mg, 2.0 mmol) Prepared according to Procedure M. Obtained as a yellow solid (820 mg).
    [1108] Mp 125-135 ° C.
    [1109] Example M72
    [1110] (RS)-{5-dimethylamino-2- [3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,2,3] Triazol-1-yl} -phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester
    [1111] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,2,3] triazol-1-yl} -phenyl) -propionic acid tert.-butyl ester (Example K21) From General Procedure M from Obtained as a bright red oil (527 mg).
    [1112] MS (ISP) 577 [(M + H) + ].
    [1113] Example M73
    [1114] (RS)-[5-Dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propy Onylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester
    [1115] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) and (RS) -3-oxo-3- {3- Prepared according to General Procedure M from [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl} -propionic acid ethyl ester (Example K22). Obtained as a brown oil (179 mg).
    [1116] MS (ISP) 646 [(M + H) + ].
    [1117] Example M74
    [1118] {5-Dimethylamino-2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl}- Carbamic acid tert.-butyl ester
    [1119] The title compound was converted to (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert.-butyl ester (Example J6) (639 mg, 2.0 mmol) and 2,2-dimethyl- 6- (3- [1,2,3] triazol-1-yl-phenyl)-[1,3] dioxin-4-one (Example L4) (543 mg, 2.0 mmol) to General Procedure M Prepared accordingly. Obtained as a red solid (915 mg).
    [1120] MS (ISP) 533.3 [(M + H) + ]; mp 79-81 ° C.
    [1121] Example M75
    [1122] [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (2,2,2-trifluoro-ethoxy) -4-trifluoro Methyl-phenyl] -carbamic acid tert.-butyl ester
    [1123] The title compound was collected from [2-amino-5- (2,2,2-trifluoro-ethoxy) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example J21) and 3- Prepared according to General Procedure M from (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3). Obtained as a light brown solid (262 mg).
    [1124] MS (ISN) 545.0 [(M − H) − ]; mp 158 ° C. (dec.).
    [1125] Example M76
    [1126] [2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -4-dimethylamino-5-methyl-phenyl} -carbamic acid tert-butyl ester
    [1127] The title compound was prepared as (2-amino-5-dimethylamino-4-methyl-phenyl) -carbamic acid tert-butyl ester (Example J22) (300 mg, 1.0 mmol) and 3- (3-cyano-phenyl)- Prepared according to General Procedure M from 3-oxo-propionic acid tert-butyl ester (Example K2) (245 mg, 1.0 mmol). Obtained as a light brown foam (250 mg, 57%).
    [1128] MS (ISP) 437.4 [(M + H) + ].
    [1129] Example M77
    [1130] (RS)-[5-dimethylamino-4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] tria Zol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1131] The title compound was prepared from (2-amino-5-dimethylamino-4-methyl-phenyl) -carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and (RS) -3-oxo-3- { 3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol), according to General Procedure M. Obtained as a yellow foam (420 mg, 71%).
    [1132] MS (ISP) 593.5 [(M + H) + ].
    [1133] Example M78
    [1134] {5-Cyano-2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -4-dimethylamino-phenyl} -carbamic acid tert-butyl ester
    [1135] The title compound was converted to (2-amino-4-cyano-5-dimethylamino-phenyl) -carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and 3- (3-cyano-phenyl) Prepared according to General Procedure M from 3-oxo-propionic acid tert-butyl ester (Example K2) (245 mg, 1.0 mmol). Obtained as a brown foam (290 mg, 65%).
    [1136] MS (ISP) 448.3 [(M + H) + ].
    [1137] Example M79
    [1138] [2- [3- (3-Cyano-phenyl) -3-oxo-propionylamino] -5-methyl-4- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester
    [1139] The title compound was collected from [2-amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J24) (293 mg, 1.0 mmol) and 3- (3-sia Prepared according to General Procedure M from no-phenyl) -3-oxo-propionic acid tert-butyl ester (Example K2) (245 mg, 1.0 mmol). Obtained as a light brown oil (170 mg, 37%).
    [1140] MS (ISP) 463.3 [(M − H) − ].
    [1141] Example M80
    [1142] (RS)-[4-Methyl-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1143] The title compound was converted to [2-amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J24) (293 mg, 1.0 mmol) and (RS) -3- Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5 ) (402 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow foam (350 mg, 56%).
    [1144] MS (ISP) 621.2 [(M + H) + ].
    [1145] Example M81
    [1146] (RS)-[5- (ethyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1147] The title compound was converted to [2-amino-5- (ethyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert-butyl ester (Example J25) (279 mg, 1.0 mmol) and (RS) -3- Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5 ) (402 mg, 1.0 mmol) according to General Procedure M. Obtained as a yellow foam (400 mg, 66%).
    [1148] MS (ISP) 607.1 [(M + H) + ].
    [1149] Example M82
    [1150] (RS)-[4-cyano-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1151] The title compound was converted to (2-amino-4-cyano-5-dimethylamino-phenyl) -carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (402 mg , 1.0 mmol), according to General Procedure M. Obtained as a light brown foam (360 mg, 59%).
    [1152] MS (ISP) 602.1 [(M − H) − ].
    [1153] Example M83
    [1154] (RS)-[4-Chloro-5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1155] The title compound was converted to [2-amino-4-chloro-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J26) (300 mg, 0.96 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (383 mg, 0.96 mmol) according to General Procedure M. Obtained as a light yellow oil (530 mg, 86%).
    [1156] MS (ISP) 639.2 [(M − H) − ].
    [1157] Example M84
    [1158] [4-Methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino) -phenyl] -Carbamic acid tert-butyl ester
    [1159] The title compound was purified from [2-amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J24) (293 mg, 1.0 mmol) and 3- [3- ( 3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was prepared according to general procedure M. Obtained as a light yellow foam (340 mg, 65%).
    [1160] MS (ISP) 519.3 [(M − H) − ].
    [1161] Example M85
    [1162] (4-cyano-5-dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino] -1-phenyl) -car Chest acid tert-butyl ester
    [1163] The title compound was purified from (2-amino-4-cyano-5-dimethylamino-phenyl) -carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and 3- [3- (3-methyl- Isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was prepared according to General Procedure M. Obtained as a light brown foam (320 mg, 64%).
    [1164] MS (ISP) 504.3 [(M + H) + ].
    [1165] Example M86
    [1166] (5- (Ethyl-methyl-amino) -4-methyl-2- {3- [3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert-butyl ester
    [1167] The title compound was purified from [2-amino-5- (ethyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert-butyl ester (Example J25) (279 mg, 1.0 mmol) and 3- [3- ( 3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was obtained according to general procedure M. Obtained as a brown foam (390 mg, 77%).
    [1168] MS (ISP) 505.3 [(M − H) − ].
    [1169] Example M87
    [1170] (5-Dimethylamino-4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert- Butyl ester
    [1171] The title compound was purified from (2-amino-5-dimethylamino-4-methyl-phenyl) -carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and 3- [3- (3-methyl-isomeric Prepared according to General Procedure M from Sazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a brown foam (330 mg, 67%).
    [1172] MS (ISP) 491.3 [(M − H) − ].
    [1173] Example M88
    [1174] (RS)-[4-Chloro-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1175] The title compound was converted to [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to General Procedure M. Obtained as a light brown foam (330 mg, 50%).
    [1176] MS (ISP) 655.1 [(M + H) + ].
    [1177] Example M89
    [1178] (4-Chloro-5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl ) -Carbamic acid tert-butyl ester
    [1179] The title compound was purified from [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3- [3- Prepared according to General Procedure M from (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light yellow foam (360 mg, 65%).
    [1180] MS (ISP) 555.1 [(M + H) + ].
    [1181] Example M90
    [1182] (RS)-[4-cyano-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole-1- Yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert-butyl ester
    [1183] The title compound was converted to (2-amino-4-cyano-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester (Example J28) (302 mg, 1.0 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to General Procedure M. Obtained as a bright orange foam (380 mg, 60%).
    [1184] MS (ISP) 630.1 [(M + H) + ].
    [1185] Example M91
    [1186] (4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidin-1-yl-phenyl ) -Carbamic acid tert-butyl ester
    [1187] The title compound was purified from (2-amino-4-cyano-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butylester (Example J28) (302 mg, 1.0 mmol) and 3- [3- Prepared according to General Procedure M from (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (420 mg, 79%).
    [1188] MS (ISP) 530.2 [(M + H) + ].
    [1189] Example M92
    [1190] (RS)-[4-cyano-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1191] The title compound was converted to [2-amino-4-cyano-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to General Procedure M. Obtained as a bright red foam (440 mg, 70%).
    [1192] MS (ISP) 630.1 [(M + H) + ].
    [1193] Example M93
    [1194] [4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino) -phenyl ] -Carbamic acid tert-butyl ester
    [1195] The title compound was purified from [2-amino-4-cyano-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and 3- [3- Prepared according to General Procedure M from (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (370 mg, 70%).
    [1196] MS (ISP) 532.3 [(M + H) + ].
    [1197] Example M94
    [1198] (4-cyano-5-diethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert-butyl ester
    [1199] The title compound was purified from (2-amino-4-cyano-5-diethylamino-phenyl) -carbamic acid tert-butyl ester (Example J30) (304 mg, 1.0 mmol) and 3- [3- (3-methyl Prepared according to General Procedure M from -isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (360 mg, 68%).
    [1200] MS (ISP) 530.2 [(M + H) + ].
    [1201] Example M95
    [1202] (4-cyano-5- (isopropyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino}- Phenyl) -carbamic acid tert-butyl ester
    [1203] The title compound was purified from [2-amino-4-cyano-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J31) (304 mg, 1.0 mmol) and 3- [3. Prepared according to General Procedure M from-(3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (380 mg, 71%).
    [1204] MS (ISP) 530.2 [(M − H) − ].
    [1205] Example M96
    [1206] (RS)-[4-cyano-5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[ 1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1207] The title compound is taken from [2-amino-4-cyano-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J31) (304 mg, 1.0 mmol) and (RS)- 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester Prepared according to General Procedure M from Example K5) (401 mg, 1.0 mmol). Obtained as a yellow foam (460 mg, 73%).
    [1208] MS (ISP) 630.1 [(M − H) − ].
    [1209] Example M97
    [1210] (4-cyano-5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino}- Phenyl) -carbamic acid tert-butyl ester
    [1211] The title compound was purified from [2-amino-4-cyano-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and 3- [3. Prepared according to General Procedure M from-(3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (400 mg, 73%).
    [1212] MS (ISP) 544.3 [(M − H) − ].
    [1213] Example M98
    [1214] (RS)-[4-cyano-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[ 1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1215] The title compound was taken from [2-amino-4-cyano-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and (RS)- 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester Prepared according to General Procedure M from Example K5) (401 mg, 1.0 mmol). Obtained as a yellow foam (470 mg, 73%).
    [1216] MS (ISP) 644.2 [(M − H) − ].
    [1217] Example M99
    [1218] (4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-piperidin-1-yl-phenyl ) -Carbamic acid tert-butyl ester
    [1219] The title compound was purified from (2-amino-4-cyano-5-piperidin-1-yl-phenyl) -carbamic acid tert-butyl ester (Example J33) (316 mg, 1.0 mmol) and 3- [3- Prepared according to General Procedure M from (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light brown foam (420 mg, 77%).
    [1220] MS (ISP) 544.2 [(M + H) + ].
    [1221] Example M100
    [1222] (4-Chloro-5-isobutylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert -Butyl ester
    [1223] The title compound was purified from (2-amino-4-chloro-5-isobutylamino-phenyl) -carbamic acid tert-butyl ester (Example J34) (314 mg, 1.0 mmol) and 3- [3- (3-methyl- Isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was prepared according to General Procedure M. Obtained as a greyish white foam (340 mg, 63%).
    [1224] MS (ISP) 542.2 [(M + H) + ].
    [1225] Example M101
    [1226] (RS)-[4-Chloro-5-isobutylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1227] The title compound was converted to (2-amino-4-chloro-5-isobutylamino-phenyl) -carbamic acid tert-butyl ester (Example J34) (314 mg, 1.0 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg , 1.0 mmol), according to General Procedure M. Obtained as a red oil (180 mg, 28%).
    [1228] MS (ISP) 640.2 [(M − H) − ].
    [1229] Example M102
    [1230] (RS)-[5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [1231] The title compound was converted to [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J35) (380 mg, 1.09 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester ( Prepared according to General Procedure M from Example K5) (439 mg, 1.09 mmol). Obtained as a red foam (150 mg, 20%).
    [1232] MS (ISP) 675.4 [(M − H) − ].
    [1233] Example M103
    [1234] [2- {3- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino) -4-trifluoromethyl -Phenyl] -carbamic acid tert-butyl ester
    [1235] The title compound was extracted with [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J35) (360 mg, 1.04 mmol) and 3- [ Prepared according to General Procedure M from 3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (312 mg, 1.04 mmol). Obtained as a bright red foam (270 mg, 45%).
    [1236] MS (ISP) 573.2 [(M − H) − ].
    [1237] Example M104
    [1238] (RS)-[5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3 ] Triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [1239] The title compound was extracted with [2-amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J36) (370 mg, 1.02 mmol) and (RS ) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester Prepared according to General Procedure M from Example K5 (411 mg, 1.02 mmol). Obtained as a light brown foam (520 mg, 74%).
    [1240] MS (ISP) 687.2 [(M − H) − ].
    [1241] Example M105
    [1242] (5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoro Methyl-phenyl) -carbamic acid tert-butyl ester
    [1243] The title compound was extracted with [2-amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J36) (360 mg, 1.0 mmol) and 3- Prepared according to General Procedure M from [3- (3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (302 mg, 1.0 mmol). Obtained as a light brown foam (430 mg, 73%).
    [1244] MS (ISP) 587.3 [(M − H) − ].
    [1245] Example M106
    [1246] (RS)-[5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3 ] Triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester
    [1247] The title compound was extracted with [2-amino-5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J37) (340 mg, 0.98 mmol) and (RS ) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester Prepared from Example K5 (393 mg, 0.98 mmol) according to General Procedure M. Obtained as a light yellow foam (510 mg, 77%).
    [1248] MS (ISP) 673.3 [(M − H) − ].
    [1249] Example M107
    [1250] (5- (isopropyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoro Methyl-phenyl) -carbamic acid tert-butyl ester
    [1251] The title compound was collected from [2-amino-5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J37) (350 mg, 1.01 mmol) and 3- Prepared according to General Procedure M from [3- (3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (304 mg, 1.01 mmol). Obtained as a light brown foam (380 mg, 66%).
    [1252] MS (ISP) 573.2 [(M − H) − ].
    [1253] Example M108
    [1254] (RS)-[5- (isobutyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1255] The title compound was converted to [2-amino-5- (isobutyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to General Procedure M. Obtained as a light yellow foam (330 mg, 52%).
    [1256] MS (ISP) 635.2 [(M + H) + ].
    [1257] Example M109
    [1258] (5- (isobutyl-methyl-amino) -4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl ) -Carbamic acid tert-butyl ester
    [1259] The title compound was purified from [2-amino-5- (isobutyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and 3- [3- Prepared according to General Procedure M from (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol). Obtained as a light yellow foam (330 mg, 62%).
    [1260] MS (ISP) 535.4 [(M + H) + ].
    [1261] Example M110
    [1262] (RS)-[4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl ] -Phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert-butyl ester
    [1263] The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester acid tert-butyl ester (Example J39) (292 mg, 1.0 mmol) and ( RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl Prepared according to general procedure M from ester (Example K5) (401 mg, 1.0 mmol). Obtained as a light yellow foam (410 mg, 66%).
    [1264] MS (ISP) 619.3 [(M + H) + ].
    [1265] Example M111
    [1266] (4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidin-1-yl-phenyl) -Carbamic acid tert-butyl ester
    [1267] The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl) -carbamic acid tert-butyl ester (Example J39) (291 mg, 1.0 mmol) and 3- [3- ( 3-Methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was prepared according to general procedure M. Obtained as a light brown foam (330 mg, 64%).
    [1268] MS (ISP) 517.3 [(M − H) − ].
    [1269] Example M112
    [1270] (4-Chloro-5-isopropylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -carbamic acid tert -Butyl ester
    [1271] The title compound was purified from (2-amino-4-chloro-5-isopropylamino-phenyl) -carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) and 3- [3- (3-methyl- Isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) was prepared according to General Procedure M. Obtained as a light brown foam (169 mg, 32%).
    [1272] MS (ISP) 525.2 [(M − H) − ].
    [1273] Example M113
    [1274] (RS)-[4-Chloro-5-isopropylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1275] The title compound was converted to (2-amino-4-chloro-5-isopropylamino-phenyl) -carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) and (RS) -3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K5) (401 mg , 1.0 mmol), according to General Procedure M. Obtained as a light yellow foam (375 mg, 60%).
    [1276] MS (ISP) 625.1 [(M − H) − ].
    [1277] Example M114
    [1278] (RS)-[4-Chloro-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, 2,4] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1279] The title compound was converted to [2-amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J8) (1.0 g, 3.19 mmol) and (RS) -3- Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,4] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K24 ) (1.28 g, 3.19 mmol) according to General Procedure M. Obtained as a yellow foam (1.48 g).
    [1280] MS (ISP) 641.3 [(M + H) + ].
    [1281] Example M115
    [1282] (RS)-[4-Chloro-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1283] The title compound was converted to [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J24) (1.0 mg, 3.05 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,4] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K24) (1.22 g, 3.05 mmol) according to General Procedure M. Obtained as a light brown foam (620 mg, 31%).
    [1284] MS (ISP) 655.1 [(M + H) + ].
    [1285] Example M116
    [1286] (RS)-[5- (isobutyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,4] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester
    [1287] The title compound was converted to [2-amino-5- (isobutyl-methyl-amino) -4-methyl-phenyl] -carbamic acid tert-butyl ester (Example J38) (1.0 g, 3.25 mmol) and (RS) -3 -Oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,4] triazol-1-yl] -phenyl} -propionic acid tert-butyl ester (Example K24) (1.31 g, 3.25 mmol) according to General Procedure M. Obtained as a light yellow foam (970 mg, 47%).
    [1288] MS (ISP) 635.2 [(M + H) + ].
    [1289] Example M117
    [1290] [5- (Methyl-propyl-amino) -2-3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl -Phenyl} -carbamic acid tert-butyl ester
    [1291] The title compound was converted to [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo Prepared according to General Procedure M from 3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol). Obtained as a light yellow foam (320 mg, 57%).
    [1292] MS (ISP) 561.4 [(M + H) + ].
    [1293] Example M118
    [1294] [5- (Methyl-propyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-trifluoro Methyl-phenyl] -carbamic acid tert-butyl ester
    [1295] The title compound was converted to [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo Prepared according to General Procedure M from 3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol). Obtained as a light brown oil (340 mg, 61%).
    [1296] MS (ISP) 561.3 [(M + H) + ].
    [1297] Example M119
    [1298] 5- (Isobutyl-methyl-amino) -2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert-butyl ester
    [1299] The title compound was collected from [2-amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J40) (361 mg, 1.0 mmol) and 3- Prepared according to General Procedure M from oxo-3- (3-pyrazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K16) (286 mg, 1.0 mmol). Obtained as a light brown foam (500 mg, 87%).
    [1300] MS (ISP) 574.2 [(M + H) + ].
    [1301] Example M120
    [1302] [2- [3- (2-Cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -car Chest acid tert-butyl ester
    [1303] The title compound was extracted with [2-amino-5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J37) (500 mg, 1.44 mmol) and 3- Prepared according to General Procedure M from (2-cyano-pyridin-4-yl) -3-oxo-propionic acid tert-butyl ester (Example K3) (355 mg, 1.44 mmol). Obtained as a light orange oil (670 mg, 90%).
    [1304] MS (ISP) 518.1 [(M − H) − ].
    [1305] Example M121
    [1306] {4-Chloro-5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino]- Phenyl} -carbamic acid tert-butyl ester
    [1307] The title compound was converted to [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J27) (500 mg, 1.53 mmol) and 3-oxo-3 Prepared according to general procedure M from-(3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K25) (438 mg, 1.53 mmol). Obtained as a light orange foam (700 mg, 85%).
    [1308] MS (ISP) 539.2 [(M − H) − ].
    [1309] Example M122
    [1310] {5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoro Romethyl-phenyl} -carbamic acid tert-butyl ester
    [1311] The title compound was collected from [2-amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J36) (361 mg, 1.0 mmol) and 3- Prepared according to General Procedure M from oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol). Obtained as a bright red foam (490 mg, 85%).
    [1312] MS (ISP) 575.2 [(M + H) + ].
    [1313] Example M123
    [1314] {4-Chloro-5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino]- Phenyl} -carbamic acid tert-butyl ester
    [1315] The title compound was converted to [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3-oxo-3 Prepared according to General Procedure M from-(3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol). Obtained as an orange oil (250 mg, 46%).
    [1316] MS (ISP) 539.2 [(M − H) − ].
    [1317] Example M124
    [1318] {5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-trifluoro Romethyl-phenyl} -carbamic acid tert-butyl ester
    [1319] The title compound was collected from [2-amino-5- (isobutyl-methyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J41) (460 mg, 1.27 mmol) and 3- Prepared according to General Procedure M from oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K23) (364 mg, 1.27 mmol). Obtained as a light brown oil (480 mg, 69%).
    [1320] MS (ISP) 573.1 [(M − H) − ].
    [1321] Example M125
    [1322] {2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5-isobutylamino-4-trifluoromethyl-phenyl} -carbamic acid tert-butyl ester
    [1323] The title compound was extracted with [2-amino-5- (isobutyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3- (3 Prepared according to General Procedure M from -Imidazol-1-yl-phenyl) -3-oxo-propionic acid tert-butyl ester (Example K26) (286 mg, 1.0 mmol). Obtained as a light yellow foam (430 mg, 77%).
    [1324] MS (ISP) 558.2 [(M − H) − ].
    [1325] Example M126
    [1326] {4-Chloro-2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5-isobutylamino-phenyl} -carbamic acid tert-butyl ester
    [1327] The title compound was purified from (2-amino-4-chloro-5-isobutylamino-phenyl) -carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3- (3-imidazole-1- Prepared according to General Procedure M from mono-phenyl) -3-oxo-propionic acid tert-butyl ester (Example K26) (286 mg, 1.0 mmol). Obtained as a light yellow foam (330 mg, 63%).
    [1328] MS (ISP) 524.1 [(M − H) − ].
    [1329] Example M127
    [1330] {4-Chloro-5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -phenyl} -Carbamic acid tert-butyl ester
    [1331] The title compound was purified from [2-amino-4-chloro-5- (isobutyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-oxo-3- ( Prepared according to General Procedure M from 3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol). Obtained as a light brown foam (220 mg, 42%).
    [1332] MS (ISP) 525.1 [(M − H) − ].
    [1333] Example M128
    [1334] {5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl -Phenyl} -carbamic acid tert-butyl ester
    [1335] The title compound was converted to [2-amino-5- (isobutyl-amino) -4-trifluoro-methyl-phenyl] -carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-oxo Prepared according to General Procedure M from 3- (3- [1,2,3] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol). Obtained as a light yellow foam (340 mg, 60%).
    [1336] MS (ISP) 559.2 [(M − H) − ].
    [1337] Example M129
    [1338] {4-Chloro-5- (isobutyl-amino) -2- [3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -phenyl} -carbamic acid tert-butyl ester
    [1339] The title compound was purified from [2-amino-4-chloro-5- (isobutyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-oxo-3- ( Prepared according to General Procedure M from 3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol). Obtained as a light yellow foam (390 mg, 74%).
    [1340] MS (ISP) 525.1 [(M − H) − ].
    [1341] Example M130
    [1342] {5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl -Phenyl} -carbamic acid tert-butyl ester
    [1343] The title compound was converted to [2-amino-5- (isobutyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-oxo- Prepared according to General Procedure M from 3- (3- [1,2,4] triazol-1-yl-phenyl) -propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol). Obtained as a light yellow foam (430 mg, 77%).
    [1344] MS (ISP) 559.2 [(M + H) + ].
    [1345] General procedure N
    [1346] Preparation of 4-aryl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1347] {2- [3-aryl-3-oxo-propionylamino] -phenyl} -carbamic acid tert-butyl ester in CH 2 Cl 2 (5 mL) or {2- [3-aryl-3-oxo-propionyl A solution or suspension of amino] -phenyl} -carbamic acid tert-butyl ester (1.0 mmol) [addition of anisole or 1,3-dimethoxybenzene (5-15 mmol) if necessary] was added to TFA (0.5- 5.0 mL) and continued stirring at 23 ° C. until tlc indicated complete consumption of the starting material.
    [1348] Work-up Procedure a: The solvent was removed in vacuo and the residue was crystallized by treatment with a small amount of ether. The solid is stirred with saturated NaHCO 3 -solution or 1M Na 2 CO 3 -solution, filtered, washed with H 2 O and a mixture of ether or ether / ether / THF / MeOH and dried to afford the title compound, which if necessary Crystallized or purified from 1,4-dioxane and purified by silica gel column chromatography with cyclohexane / EtOAc or EtOAc / EtOH.
    [1349] Work-up procedure b: The reaction mixture was diluted with DCM or EtOAc, washed with saturated NaHCO 3 -solution or 1M Na 2 CO 3 -solution and brine and dried over MgSO 4 or Na 2 SO 4 . The solvent is removed in vacuo to give a material which is triturated with ether or a mixture of ether / THF / MeOH to give the title compound or, if necessary, by silica gel column chromatography with cyclohexane / EtOAc or EtOAc / EtOH. It can be purified.
    [1350] Example 1
    [1351] 3- (7-Chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -benzonitrile
    [1352] The title compound was taken from {4-chloro-2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5-dimethylamino-phenyl} -carbamic acid tert.-butyl ester (Example M1 ) Was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (85 mg).
    [1353] MS (ISP) 339 [(M + H) + ] and 341 [(M + 2 + H) + ]; mp> 250 ° C.
    [1354] Example 2
    [1355] 8-chloro-7-dimethylamino-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [1356] The title compound is {4-chloro-5-dimethylamino-2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -phenyl}- Prepared from carbamic acid tert.-butyl ester (Example M2) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (87 mg).
    [1357] MS (ISP) 381 [(M + H) + ] and 383 [(M + 2 + H) + ]; mp 222-225 ° C.
    [1358] Example 3
    [1359] 8-chloro-7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1360] The title compound was obtained from (RS)-[4-chloro-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2, 3] triazol-1-yl] -phenyl} -propionyl-amino) -phenyl] -carbamic acid tert.-butyl ester (Example M3) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N It was. Obtained as a beige solid (60 mg).
    [1361] MS (ISP) 411 [(M + H) + ] and 413 [(M + 2 + H) + ]; mp 210-214 ° C.
    [1362] Example 4
    [1363] 3- (8-Dimethylamino-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -benzonitrile
    [1364] The title compound is taken from {2- [3- (3-cyano-phenyl) -3-oxo-propionyl-amino] -5-dimethylamino-4-phenylethynyl-phenyl} -carbamic acid tert.-butyl ester ( Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from Example M4). Obtained as an orange solid (65 mg).
    [1365] MS (ISP) 405 [(M + H) + ]; mp 215-216 ° C.
    [1366] Example 5
    [1367] 7-dimethylamino-8-phenylethynyl-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [1368] The title compound is taken as {5-dimethylamino-2- [3-oxo-3- (3-triazol-1-yl-phenyl) -propionylamino] -4-phenylethynyl-phenyl} -carbamic acid tert.- Prepared from butyl ester (Example M5) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as an orange solid (76 mg).
    [1369] MS (ISP) 447 [(M + H) + ]; mp 185-186 ° C.
    [1370] Example 6
    [1371] 8-chloro-7-dimethylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine-2 -On
    [1372] The title compound is taken as (4-chloro-5-dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -ca Prepared by treatment with TFA in CH 2 Cl 2 according to the general procedure N from chest acid tert.-butyl ester (Example M6). Obtained as a light yellow solid (68 mg).
    [1373] MS (EI) 394 (M + ) and 396 [(M + 2) + ]; mp 212-215 ° C.
    [1374] Example 7
    [1375] 8- (2,3-Difluoro-phenyl) -7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1376] The title compound is (RS)-[2-dimethylamino-2 ', 3'-difluoro-5- (3-oxo-3- {3- [5-tetrahydro-pyran-2-yloxymethyl)- [1,2,3] triazol-1-yl] -phenyl} -propionylamino) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example M7) from CH according to general procedure N Prepared by treatment with TFA in 2 Cl 2 . Obtained as a yellow solid (26 mg).
    [1377] MS (ISP) 489 [(M + H) + ].
    [1378] Example 8
    [1379] 8- (2,3-difluoro-phenyl) -7-dimethylamino-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [ b] [1,4 diazepin-2-one
    [1380] The title compound is 2-dimethylamino-2 ', 3'-difluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino ] -Biphenyl-4-yl} -carbamic acid tert.-butyl ester (Example M8) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (47 mg).
    [1381] MS (ISP) 459 [(M + H) + ]; mp 197-199 ° C.
    [1382] Example 9
    [1383] 3- [7- (2,3-difluoro-phenyl) -8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Benzonitrile
    [1384] The title compound is {5- [3- (3-cyano-phenyl) -3-oxo-propionyl-amino] -2-dimethylamino-2 ', 3'-difluoro-biphenyl-4-yl} Prepared from carbamic acid tert.-butyl ester (Example M9) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (75 mg).
    [1385] MS (ISP) 417 [(M + H) + ]; mp 228-229 ° C.
    [1386] Example 10
    [1387] 8-chloro-7-dimethylamino-4- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl] -1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [1388] The title compound is (4-chloro-5-dimethylamino-2- {3- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl] -3-oxo-propionylamino}- Prepared from phenyl) -carbamic acid tert.-butyl ester (Example M10) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (111 mg).
    [1389] MS (ISP) 396 [(M + H) + ] and 398 [(M + H + 2) + ]; mp> 250 ° C.
    [1390] Example 11
    [1391] 8-chloro-7-[(2-methoxy-ethyl) -methyl-amino] -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1392] The title compound is taken as (4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3 Prepared from -oxo-propionylamino} -phenyl) -carbamic acid tert.-butyl ester (Example M11) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (115 mg).
    [1393] MS (EI) 438 (M + ) and 440 [(M + 2) + ]; mp 182 ° C.
    [1394] Example 12
    [1395] 8-chloro-7-[(2-methoxy-ethyl) -methyl-amino] -4- [2- (3-methyl-isoxazol-5-yl) -pyridin-4-yl] -1,3- Dihydro-benzo [b] [1,4] diazepin-2-one
    [1396] The title compound is (4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- {3- [2- (3-methyl-isoxazol-5-yl) -pyridine-4- Prepared from Ill] -3-oxo-propionylamino} -phenyl) -carbamic acid tert.-butyl ester (Example M12) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (106 mg).
    [1397] MS (ISP) 440 [(M + H) + ] and 442 [(M + H + 2) + ]; mp 213 ° C.
    [1398] Example 13
    [1399] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-[(2-methoxy-ethyl) -methyl-amino] -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1400] The title compound was obtained from (RS)-[4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- (3-oxo-3- {3- [5- (tetrahydro-pyran- 2-yloxymethyl)-[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M13) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a beige solid (50 mg).
    [1401] MS (ISP) 455 [(M + H) + ] and 457 [(M + H + 2) + ]; mp 185 ° C.
    [1402] Example 14
    [1403] 8-chloro-7-[(2-methoxy-ethyl) -methyl-amino] -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [1404] The title compound is {4-chloro-5-[(2-methoxy-ethyl) -methyl-amino] -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl -Phenyl) -propionylamino] -phenyl} -carbamic acid tert.-butyl ester (Example M14) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (69 mg).
    [1405] MS (ISP) 425 [(M + H) + ] and 427 [(M + H + 2) + ]; mp 156 ° C.
    [1406] Example 15
    [1407] 4- (7-Chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -pyridine-2-carbonitrile
    [1408] The title compound is {4-chloro-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-dimethylamino-phenyl} -carbamic acid tert.-butyl ester Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from Example M15. Obtained as a yellow solid (50 mg).
    [1409] MS (ISP) 340 [(M + H) + ] and 342 [(M + 2 + H) + ]; mp 216 ° C.
    [1410] Example 16
    [1411] 8-chloro-7-dimethylamino-4- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1412] The title compound is (4-chloro-5-dimethylamino-2- {3- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionylamino} -phenyl) Prepared from carbamic acid tert.-butyl ester (Example M16) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a grayish white solid (67 mg).
    [1413] MS (ISP) 394 [(M + H) + ] and 396 [(M + 2 + H) + ]; mp 225 ° C.
    [1414] Example 17
    [1415] 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1416] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole -1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M17) treated with TFA in CH 2 Cl 2 according to General Procedure N It was prepared by. Obtained as a grayish white solid (62 mg).
    [1417] MS (ISP) 445 [(M + H) + ]; mp 210 ° C.
    [1418] Example 18
    [1419] 7-dimethylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [1420] The title compound is taken as (5-dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl-phenyl Prepared from T-carbamic acid tert.-butyl ester (Example M18) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (28 mg).
    [1421] MS (ISP) 429 [(M + H) + ]; mp 223 ° C.
    [1422] Example 19
    [1423] 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1424] The title compound was purified by 3- (7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepine in 1,4-dioxane (15 mL). 2-yl) -thiobenzamide {3- (7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl Prepared from) -benzonitrile (Example 1) as follows: To a solution of hexamethyldisylthiane (0.55 mL, 2.6 mmol) in 1,3-dimethyl-2-imidazolidinone (2.6 mL) at 20 ° C. Sodium methoxide (0.13 g, 2.5 mmol) was added. The mixture was stirred for 15 minutes and then the blue solution formed was washed with 3- (7-chloro-8-dimethylamino-4-oxo-4,5-di in 1,3-dimethyl-2-imidazolidinone (2 mL). To a solution of hydro-3H-benzo [b] [1,4] diazepin-2-yl) -benzonitrile (Example 1) (0.34 g, 1.0 mmol). The mixture was stirred at 20 ° C. for 3 hours and then poured into water. The precipitate was isolated by filtration and triturated with acetone to give 3- (7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ) -Thiobenzamide (0.35 g) was obtained as a yellow solid. mp 234 ° C. dec. MS (ISP) 373.2 [(M + H) + ].} (0.71 g, 1.9 mmol), 1,3-dichloro-2-propanone (0.36 g, 2.85 mmol) and sodium bicarbonate (0.24 g, 2.85 mmol) Were heated to 60 ° C. for 48 h. The clear solution was evaporated in vacuo. To a solution of the residue in 1,4-dioxane (5 mL) was added 2N KOH (3.8 mL) and the mixture was stirred at 20 ° C. for 1 h. Water (100 mL) was added and the mixture was stirred for 0.5 h. The precipitate formed was collected by filtration and crystallized from dichloromethane to give the title compound (0.69 g) as a pale yellow solid.
    [1425] MS (ISP) 427.2 [(M + H) + ]; mp 134 ° C. dec.
    [1426] Example 20
    [1427] 8-chloro-7-dimethylamino-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1428] The title compound is (4-chloro-5-dimethylamino-2- {3- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo- Prepared from propionylamino} -phenyl) -carbamic acid tert.-butyl ester (Example M19) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a beige solid (34 mg).
    [1429] MS (ISP) 438 [(M + H) + ] and 440 [(M + 2 + H) + ]; mp 145-160 ° C.
    [1430] Example 21
    [1431] 8-chloro-7-dimethylamino-4- [3- (3-methoxymethyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1432] The title compound is (4-chloro-5-dimethylamino-2- {3- [3- (3-methoxymethyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) Prepared from carbamic acid tert.-butyl ester (Example M20) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (157 mg).
    [1433] MS (ISP) 425 [(M + H) + ] and 427 [(M + 2 + H) + ]; mp 191 ° C.
    [1434] Example 22
    [1435] 4- (8-dimethylamino-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -pyridine-2-carbo Nitrile
    [1436] The title compound was taken as {2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-dimethylamino-4-trifluoromethyl-phenyl} -carbamic acid tert. Prepared from -butyl ester (Example M21) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (158 mg).
    [1437] MS (ISP) 374 [(M + H) + ]; mp 248 ° C.
    [1438] Example 23
    [1439] 8- (2-Fluoro-phenyl) -4- (3-imidazol-1-yl-phenyl) -7- (2,2,2-trifluoro-ethoxy) -1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [1440] The title compound is taken as [2'-fluoro-5- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -2- (2,2,2-trifluoro- Prepared from ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example M22) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a brown solid (50 mg).
    [1441] MS (EI) 494 (M + ); mp 208-210 ° C.
    [1442] Example 24
    [1443] 8- (2-Fluoro-phenyl) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -7- (2,2,2-trifluoro-ethoxy) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1444] The title compound is taken as [2'-fluoro-5- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -2- (2,2, Prepared from 2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example M23) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (21 mg).
    [1445] MS (EI) 509 (M + ); mp 218-220 ° C.
    [1446] Example 25
    [1447] 8- (2-Fluoro-phenyl) -4- (3- [1,2,3] triazol-1-yl-phenyl) -7- (2,2,2-trifluoro-ethoxy)- 1,3] dihydro-benzo [b] [1,4] diazepin-2-one
    [1448] The title compound is [2'-fluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -2- (2,2 Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from, 2-Trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example M24). Obtained as an orange solid (45 mg).
    [1449] MS (EI) 495 (M + ).
    [1450] Example 26
    [1451] 8- (2-Fluoro-phenyl) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (2,2,2- Trifluoro-ethoxy) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1452] The title compound is (RS)-[2'-fluoro-5- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] tria Zol-1-yl] -phenyl} -propionylamino) -2- (2,2,2-trifluoro-ethoxy) -biphenyl-4-yl] -carbamic acid tert.-butyl ester (Example M25) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (10 mg).
    [1453] MS (ISP) 526 [(M + H) + ]; mp 232-234 ° C.
    [1454] Example 27
    [1455] 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1456] The title compound was converted to (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J2) (170 mg) and (RS) -3-oxo-3- {3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl} -propionic acid tert-butyl ester (Example K11) (270 mg). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (110 mg).
    [1457] MS (ISP) 411.2 [(M + H) + ]; mp 193-195 ° C.
    [1458] Example 28
    [1459] 8-chloro-7- (ethyl-methyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1460] The title compound is (RS)-[4-chloro-5- (ethyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)- [1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M26) (0.5 g, 0.8 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a greyish white solid (60 mg).
    [1461] MS (ISP) 425.4 [(M + H) + ]; mp 206 ° C. (dec.).
    [1462] Example 29
    [1463] 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1464] The title compound is (RS)-[4-chloro-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)- [1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M27) (0.41 g, 0.64 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a light yellow solid (110 mg).
    [1465] MS (ISP) 439.3 [(M + H) + ]; mp 178 ° C. (dec.).
    [1466] Example 30
    [1467] 8-chloro-7- (diethyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [1468] The title compound is (RS)-[4-chloro-5- (diethyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[ 1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M28) (0.53 g, 0.827 mmol) from CH according to General Procedure N Prepared by treatment with TFA in 2 Cl 2 . Obtained as a grayish white solid (210 mg).
    [1469] MS (ISP) 439.3 [(M + H) + ]; mp 208 ° C. (dec.).
    [1470] Example 31
    [1471] 8-chloro-7-dimethylamino-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1472] The title compound is (RS)-[4-chloro-5-dimethylamino-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazole-5- Prepared from Ill-phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M29) (81 mg, 0.13 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. . Obtained as a yellow solid (38 mg).
    [1473] MS (ISP) 411 [(M + H) + ] and 413 [(M + 2 + H) + ]; mp 132 ° C.
    [1474] Example 32
    [1475] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-pyrrolidin-1-yl-1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1476] The title compound is (RS)-[4-chloro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole- 1-yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert.-butyl ester (Example M30) according to General Procedure N, TFA in CH 2 Cl 2 Prepared by treatment with. Obtained as a yellow solid (58 mg).
    [1477] MS (ISP) 437 [(M + H) + ] and 439 [(M + 2 + H) + ]; mp 193-197 ° C.
    [1478] Example 33
    [1479] 7-dimethylamino-4- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1480] The title compound is (5-dimethylamino-2- {3- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl Prepared from -phenyl) -carbamic acid tert.-butyl ester (Example M31) (78 mg, 0.14 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a grayish white solid (48 mg).
    [1481] MS (ISP) 428 [(M + H) + ]; mp 225 ° C.
    [1482] Example 34
    [1483] 4- [7-Chloro-8- (cyclopropyl-methyl-amino) -4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl] -pyridine- 2-carbonitrile
    [1484] The title compound was purified from [2-amino-4-chloro-5- (cyclopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester (Example J11) (150 mg, 0.5 mmol) and 3- (2 Prepared according to General Procedure M from -cyano-pyridin-4-yl) -3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (69 mg).
    [1485] MS (ISN) 364.1 [(MH ) -] and 366 [(M + 2-H ) -]; mp 199-201 ° C.
    [1486] Example 35
    [1487] 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [1488] The title compound is (RS)-[4-chloro-5-dimethylamino-2- (3- {3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazole-5- Prepare from Ill-phenyl} -3-oxo-propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M32) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (60 mg).
    [1489] MS (ISP) 425 [(M + H) + ] and 427 [(M + 2 + H) + ]; mp 232-233 ° C.
    [1490] Example 36
    [1491] 8-chloro-7- (cyclopropyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [1492] The title compound was purified from [2-amino-4-chloro-5- (cyclopropyl-methyl-amino) -phenyl] -carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and 3- [3. Prepared according to General Procedure M from-(3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionic acid tert.-butyl ester (Example K4) (170 mg, 0.56 mmol). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (49 mg).
    [1493] MS (ISP) 421.3 [(M + H) + ] and 423 [(M + 2 + H) + ]; mp 195-197 ° C.
    [1494] Example 37
    [1495] 8-chloro-7- (cyclopropyl-methyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1496] The title compound is (RS)-[4-chloro-5- (cyclopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) General procedure N from-[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M33) (200 mg, 0.313 mmol) Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a light yellow solid (54 mg).
    [1497] MS (ISP) 437.3 [(M + H) + ] and 439 [(M + 2 + H) + ].
    [1498] Example 38
    [1499] 7-dimethylamino-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1500] The title compound is called (5-dimethylamino-2- {3- [3- (5-dimethyl-aminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionylamino } -4-Trifluoromethyl-phenyl) -carbamic acid tert.-butyl ester (Example M34) (126 mg, 0.214 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (23 mg).
    [1501] MS (ISP) 472 [(M + H) + ]; mp 200 ° C.
    [1502] Example 39
    [1503] 8-chloro-7-dimethylamino-4- [3- (5-hydroxymethyl-2-methyl-2H-pyrazol-3-yl) -phenyl] -1,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [1504] The title compound is (RS)-[4-chloro-5-dimethylamino-2- (3- {3- [2-methyl-5- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazole- 3-yl] -phenyl} -3-oxo-propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M35) (278 mg, 0.44 mmol) in CH 2 Cl 2 according to general procedure N. Prepared by treatment with TFA. Obtained as a light yellow solid (129 mg).
    [1505] MS (ISP) 424 [(M + H) + ] and 426 [(M + 2 + H) + ]; mp 184 ° C.
    [1506] Example 40
    [1507] 4- (4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl)- Pyridine-2-carbonitrile
    [1508] The title compound is {2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl} Prepared from carbamic acid tert.-butyl ester (Example M36) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as an orange solid (65 mg).
    [1509] MS (ISP) 400.4 [(M + H) + ]; mp 188 ° C. (dec.).
    [1510] Example 41
    [1511] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-pyrrolidin-1-yl-8-trifluoromethyl-1,3 -Dihydro-benzo [b] [1,4] diazepin-2-one
    [1512] The title compound is (RS)-[2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazol-1-yl] -Phenyl} -propionylamino) -5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M37) from CH 2 Cl according to General Procedure N Prepared by treatment with double TFA. Obtained as a light yellow solid (33 mg).
    [1513] MS (ISP) 471.2 [(M + H) + ]; mp 134 ° C.
    [1514] Example 42
    [1515] 7-dimethylamino-8-fluoro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1516] The title compound is obtained from (RS)-[5-dimethylamino-4-fluoro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionyl-amino) -phenyl] -carbamic acid tert.-butyl ester (Example M38) (375 mg, 0.63 mmol) from CH 2 according to General Procedure N Prepared by treatment with TFA in Cl 2 . Obtained as a yellow solid (115 mg).
    [1517] MS (ISP) 395 [(M + H) + ]; mp 75 ° C.
    [1518] Example 43
    [1519] 7-dimethylamino-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -8-fluoro-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1520] The title compound is called (5-dimethylamino-2- {3- [3- (5-dimethyl-aminomethyl- [1,2,3] triazol-1-yl) -phenyl] -3-oxo-propionylamino } -4-Fluoro-phenyl) -carbamic acid tert.-butyl ester (Example M39) (170 mg, 0.32 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (34 mg).
    [1521] MS (ISP) 422 [(M + H) + ]; mp 181 ° C.
    [1522] Example 44
    [1523] 7-dimethylamino-8-fluoro-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [1524] The title compound is (RS)-[5-dimethylamino-4-fluoro-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazole-5 -Yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M40) (314 mg, 0.53 mmol) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N It was. Obtained as a yellow solid (95 mg).
    [1525] MS (ISP) 395 [(M + H) + ]; mp 187 ° C.
    [1526] Example 45
    [1527] 8-chloro-7-dimethylamino-4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1528] The title compound is 8-chloro-7-dimethylamino-4- [3- (5-hydroxy-methyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro- SOCl 2 (0.044 mL) in CH 2 Cl 2 (2 mL) from benzo [b] [1,4] diazepin-2-one (Example 3) (123 mg, 0.3 mmol) at 23 ° C. under reflux for 15 minutes. , 0.6 mmol), and then evaporated to dryness. Crude chloride was dissolved in DMF (2 mL) and stirred with saturated amount of NaI and pyrrolidine (0.248 mL, 3.0 mmol) at 23 ° C. until tlc indicated complete conversion of chloride. The reaction mixture was taken up in EtOAc, washed with water and brine and dried over Na 2 SO 4 . The solvent was removed in vacuo to yield a yellow semisolid which was purified by silica gel column chromatography. Obtained as a yellow solid (101 mg).
    [1529] MS (ISP) 464 [(M + H) + ] and 466 [(M + 2 + H) + ]; mp 180-182 ° C.
    [1530] Example 46
    [1531] 7-dimethylamino-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1532] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [3- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl } -Propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M41) (680 mg, 1.05 mmol) treated with TFA in CH 2 Cl 2 according to General Procedure N It was prepared by. Obtained as a yellow solid (294 mg).
    [1533] MS (ISP) 455 [(M + H) + ]; mp 219 ° C.
    [1534] Example 47
    [1535] 7-dimethylamino-8-fluoro-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [1536] The title compound is (5-dimethylamino-4-fluoro-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl)- Prepared from carbamic acid tert.-butyl ester (Example M42) (233 mg, 0.47 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a tan solid (59 mg).
    [1537] MS (ISP) 379 [(M + H) + ]; mp 124 ° C.
    [1538] Example 48
    [1539] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7-dimethylamino-1, 3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [1540] The title compound is 8-chloro-7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 3) (123 mg, 0.3 mmol) from SOCl 2 (3 eq.) and trimethylene imine (10 eq. Prepared by treatment with). Obtained as a yellow solid (17 mg).
    [1541] MS (ISP) 450 [(M + H) + ]; mp 153 ° C.
    [1542] Example 49
    [1543] 8-chloro-7-dimethylamino-4- [3- (5-hydroxymethyl-isoxazol-3-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1544] The title compound was obtained from (RS)-[4-chloro-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazole-3- Prepared from I] -phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M43) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (113 mg).
    [1545] MS (ISP) 411.3 [(M + H) + ] and 413 [(M + 2 + H) + ]; mp 211 ° C. (dec.).
    [1546] Example 50
    [1547] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-piperidin-1-yl-1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1548] The title compound is (RS)-[4-chloro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole- 1-yl] -phenyl} -propionylamino) -5-piperidin-1-yl-phenyl] -carbamic acid tert.-butyl ester (Example M44) according to the general procedure N TFA in CH 2 Cl 2 Prepared by treatment with. Obtained as a light yellow solid (99 mg).
    [1549] MS (ISP) 451.3 [(M + H) + ] and 453 [(M + 2 + H) + ]; mp 246 ° C. (dec.).
    [1550] Example 51
    [1551] 7-dimethylamino-4- [3- (5-hydroxymethyl-isoxazol-3-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1552] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3yl] -phenyl} Prepared from -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M45) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (103 mg).
    [1553] MS (ISP) 445.3 [(M + H) + ]; mp 211 ° C. (dec.).
    [1554] Example 52
    [1555] 8-chloro-7-dimethylamino-4- (3-pyrazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1556] The title compound is taken as {4-chloro-5-dimethylamino-2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -phenyl} -carbamic acid tert.-butyl ester Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from Example M46. Obtained as a yellow solid (75 mg).
    [1557] MS (ISP) 380 [(M + H) + ] and 382 [(M + 2 + H) + ]; mp 231-234 ° C.
    [1558] Example 53
    [1559] 7-dimethylamino-4- [3- (3-pyrrolidin-1-ylmethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1560] The title compound was purified by 7-dimethylamino-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one (Example 46) (111 mg, 0.25 mmol) treated with SOCl 2 (3 eq.) And pyrrolidine (10 eq.) As described in Example 45. Prepared. Obtained as a yellow solid (28 mg).
    [1561] MS (ISP) 498 [(M + H) + ]; mp 160 ° C.
    [1562] Example 54
    [1563] 7-dimethylamino-4- [3- (3-morpholin-4-ylmethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1564] The title compound was purified by 7-dimethylamino-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] Diazin-2-one (Example 46) (53 mg, 0.12 mmol) was prepared by treatment with SOCl 2 (3 eq.) And morpholine (10 eq.) As described in Example 45. . Obtained as a yellow solid (33 mg).
    [1565] MS (ISP) 514 [(M + H) + ]; mp 165 ° C.
    [1566] Example 55
    [1567] 7-dimethylamino-4- [3- (3-dimethylaminomethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1568] The title compound was purified by 7-dimethylamino-4- [3- (3-hydroxymethyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one (Example 46) (53 mg, 0.12 mmol) as described in Example 45, SOCl 2 (3 eq.) And 40% Me 2 NH-aqueous solution (10 eq. Prepared by treatment with). Obtained as a light yellow solid (21 mg).
    [1569] MS (ISP) 472 [(M + H) + ]; mp 160 ° C.
    [1570] Example 56
    [1571] 4- (7-Fluoro-4-oxo-8-pyrrolidin-1-yl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -pyridine- 2-carbonitrile
    [1572] The title compound is taken as {2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -4-fluoro-5-pyrrolidin-1-yl-phenyl} -car Prepared by treatment with TFA in CH 2 Cl 2 according to the general procedure N from chest acid tert.-butyl ester (Example M47). Obtained as an orange solid (54 mg).
    [1573] MS (ISP) 350 [(M + H) + ]; mp 278-279 ° C.
    [1574] Example 57
    [1575] 8-fluoro-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -7-pyrrolidin-1-yl-1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [1576] The title compound is (4-fluoro-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidine-1- Prepared from mono-phenyl) -carbamic acid tert.-butyl ester (Example M48) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a brown solid (86 mg).
    [1577] MS (ISP) 405 [(M + H) + ]; mp 236 ° C.
    [1578] Example 58
    [1579] 8-fluoro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-pyrrolidin-1-yl-1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1580] The title compound is (RS)-[4-fluoro-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole -1-yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert.-butyl ester (Example M49) in CH 2 Cl 2 according to general procedure N. Prepared by treatment with TFA. Obtained as an orange solid (72 mg).
    [1581] MS (ISP) 421 [(M + H) + ]; mp 184-185 ° C.
    [1582] Example 59
    [1583] 4- (8-azetidin-1-yl-7-chloro-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -pyridine-2- Carbonitrile
    [1584] The title compound is {5-azetidin-1-yl-4-chloro-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -phenyl} -carbamic acid tert Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from .-butyl ester (Example M50). Obtained as an orange solid (66 mg).
    [1585] MS (ISP) 352 [(M + H) + ] and 354 [(M + 2 + H) + ]; mp 276 ° C.
    [1586] Example 60
    [1587] 4- [3- (5-hydroxymethyl-isoxazol-3-yl) -phenyl] -7-pyrrolidin-1-yl-8-trifluoromethyl-1, 3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1588] The title compound is (RS)-[2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl} -propionylamino Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N from the) -5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M51) It was. Obtained as a yellow solid (224 mg).
    [1589] MS (ISP) 471.2 [(M + H) + ]; mp 206-208 ° C.
    [1590] Example 61
    [1591] 4- (8-azetidin-1-yl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) -pyridine -2-carbonitrile
    [1592] The title compound is {5-azetidin-1-yl-2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -4-trifluoromethyl-phenyl}- Prepared from carbamic acid tert.-butyl ester (Example M52) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as an orange solid (51 mg).
    [1593] MS (ISN) 384.2 [(M − H) − ]; mp 241 ° C.
    [1594] Example 62
    [1595] 7-azetidin-1-yl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [1596] The title compound is called (5-azetidin-1-yl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoro Prepared from romethyl-phenyl) -carbamic acid tert.-butyl ester (Example M53) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (94 mg).
    [1597] MS (ISP) 441.3 [(M + H) + ]; mp 239 ° C. (dec.).
    [1598] Example 63
    [1599] 7-azetidin-1-yl-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1,3- Dihydro-benzo [b] [1,4] diazepin-2-one
    [1600] The title compound was obtained from (RS)-[5-azetidin-1-yl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2, 3] triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M54) from CH 2 Cl 2 according to General Procedure N It was prepared by treatment with TFA in water. Obtained as a yellow solid (182 mg).
    [1601] MS (ISP) 457.4 [(M + H) + ]; mp 202 ° C. (dec.).
    [1602] Example 64
    [1603] 7-dimethylamino-4- (3-pyrazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1604] The title compound was taken from {5-dimethylamino-2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert. Prepared from -butyl ester (Example M55) (438 mg, 0.82 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (238 mg).
    [1605] MS (ISP) 414 [(M + H) + ]; mp 176 ° C.
    [1606] Example 65
    [1607] 7-dimethylamino-4- (3- [1,2,4] triazol-4-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [1608] The title compound is {5-dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-4-yl-phenyl) -propionylamino] -4-trifluoromethyl- Prepared from phenyl} -carbamic acid tert.-butyl ester (Example M56) (280 mg, 0.526 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (121 mg).
    [1609] MS (ISP) 415.3 [(M + H) + ]; mp 247-250 ° C.
    [1610] Example 66
    [1611] 7-dimethylamino-4- (3-imidazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1612] The title compound was extracted with {5-dimethylamino-2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert. Prepared from -butyl ester (Example M57) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (132 mg).
    [1613] MS (ISP) 414 [(M + H) + ]; mp 203-205 ° C.
    [1614] Example 67
    [1615] 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-pyrazol-1-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [1616] The title compound is (RS)-[4-chloro-5-dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazole-1- Prepared from Ill-phenyl} -propionylamino) -phenyl] -carbamic acid tert.-butyl ester (Example M58) (642 mg, 1.05 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. . Obtained as a yellow solid (365 mg).
    [1617] MS (ISP) 410 [(M + H) + ]; mp 211 ° C.
    [1618] Example 68
    [1619] 7-dimethylamino-4- [3- (4-hydroxymethyl-pyrazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1620] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl } -Propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example M58) (590 mg, 0.91 mmol) was treated with TFA in CH 2 Cl 2 according to General Procedure N. Prepared. Obtained as a light yellow solid (299 mg).
    [1621] MS (ISP) 444 [(M + H) + ]; mp 175 ° C.
    [1622] Example 69
    [1623] 7-dimethylamino-4- [3- (4-hydromethyl-3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [1624] The title compound is (RS)-[5-dimethylamino-2- (3- {3- [3-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-5-yl] -phenyl } -3-oxo-propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M60) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. . Obtained as a light yellow solid (64 mg).
    [1625] MS (ISP) 459 [(M + H) + ]; mp 207-208 ° C.
    [1626] Example 70
    [1627] 7-dimethylamino-4- [3- (4-hydroxymethyl-isoxazol-3-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1628] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [4- (tetrahydro-pyran-2-yloxymethyl) -isoxazol-3-yl] -phenyl } -Propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M61) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (50 mg).
    [1629] MS (ISP) 445 [(M + H) + ]; mp 217-219 ° C.
    [1630] Example 71
    [1631] 7-dimethylamino-4- [3- (2-methylsulfanyl-imidazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1632] The title compound is called (5-dimethylamino-2- {3- [3- (2-methylsulfanyl-imidazol-1-yl) -phenyl] -3-oxo-propionylamino} -4-trifluoromethyl Prepared from -phenyl) -carbamic acid tert.-butyl ester (Example M62) (450 mg, 0.78 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (253 mg).
    [1633] MS (ISP) 460 [(M + H) + ]; mp 192 ° C.
    [1634] Example 72
    [1635] 7-dimethylamino-4- [3- (4-hydroxymethyl-2-methyl-2H-pyrazol-3-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [ b] [1,4] diazepin-2-one
    [1636] The title compound is (RS)-[5-dimethylamino-2- (3- {3- [2-methyl-4- (tetrahydro-pyran-2-yloxymethyl) -2H-pyrazol-3-yl] Treatment with TFA in CH 2 Cl 2 according to general procedure N from -phenyl} -3-oxo-propionyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M63) It was prepared by. Obtained as a yellow solid (272 mg).
    [1637] MS (ISP) 458 [(M + H) + ]; mp 243-244 ° C.
    [1638] Example 73
    [1639] 8-chloro-7-dimethylamino-4- (3- [1,2,4] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [1640] The title compound is {4-chloro-5-dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -phenyl}- Prepared from carbamic acid tert.-butyl ester (Example M64) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (316 mg).
    [1641] MS (ISP) 381 [(M + H) + ] and 383 [(M + 2 + H) + ]; mp 239-241 ° C.
    [1642] Example 74
    [1643] 7-dimethylamino-4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [1644] The title compound is {5-dimethylamino-2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl- Prepared from phenyl} -carbamic acid tert.-butyl ester (Example M65) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (269 mg).
    [1645] MS (ISP) 415 [(M + H) + ]; mp 228-230 ° C.
    [1646] Example 75
    [1647] 3- (8-Dimethylamino-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -benzonitrile
    [1648] The title compound is taken as {2- [3- (3-cyano-phenyl) -3-oxo-propionyl-amino] -5-dimethylamino-4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester Prepared from Example M66 (180 mg, 1.0 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (41 mg).
    [1649] MS (ISN) 371 [(M − H) − ]; mp 224-227 ° C.
    [1650] Example 76
    [1651] 7-dimethylamino-4- (3- {5-[(2,2,2-trifluoro-ethylamino) -methyl]-[1,2,3] triazol-1-yl} -phenyl)- 8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1652] The title compound is converted to 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-di SOCl 2 (3 eq.) And 2,2, as described in Example 45 from hydro-benzo [b] [1,4] diazepin-2-one (Example 17) (133 mg, 0.3 mmol) Prepared by treatment with 2-trifluoroethylamine (10 eq.). Obtained as a light yellow solid (19 mg).
    [1653] MS (ISP) 526 [(M + H) + ]; mp 168-170 ° C.
    [1654] Example 77
    [1655] 7- (cyclopropylmethyl-methyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1656] The title compound is (RS)-[5- (cyclopropylmethyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,3] triazol-1-yl] -phenyl} -propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M67) (939 mg, 1.37 mmol) Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (544 mg).
    [1657] MS (ISN) 483 [(M − H) − ]; mp 212 ° C.
    [1658] Example 78
    [1659] 4- [8- (cyclopropylmethyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Pyridine-2-carbonitrile
    [1660] The title compound is [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (cyclopropylmethyl-methyl-amino) -4-trifluoromethyl- Prepared from phenyl] -carbamic acid tert.-butyl ester (Example M68) (173 mg, 0.33 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (81 mg).
    [1661] MS (ISN) 412 [(M − H) − ]; mp 155 ° C.
    [1662] Example 79
    [1663] 4- [3- (4-cyclopropylaminomethyl-pyrazol-1-yl) -phenyl] -7-dimethylamino-8-trifluoromethyl- [1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [1664] The title compound was purified by 7-dimethylamino-4- [3- (4-hydroxymethyl-pyrazol-1-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one (Example 68) (133 mg, 0.3 mmol) treated with SOCl 2 (3 eq.) And cyclopropyl amine (10 eq.) As described in Example 45 Prepared. Obtained as a yellow solid (45 mg).
    [1665] MS (ISP) 483 [(M + H) + ]; mp 135 ° C.
    [1666] Example 80
    [1667] 4- [3- (5-cyclopropylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (cyclopropylmethyl-methyl-amino) -8-trifluoromethyl- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1668] The title compound is 7- (cyclopropylmethyl-methyl-amino) -4- [3- (5-hydromethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 78) (145 mg, 0.3 mmol) as described in Example 45 from SOCl 2 (3 eq. ) And cyclopropyl amine (10 eq.). Obtained as a yellow solid (97 mg).
    [1669] MS (ISP) 524 [(M + H) + ]; mp 35-46 ° C.
    [1670] Example 81
    [1671] 7-dimethylamino-4- {3- [2- (2-hydroxy-ethyl) -2H-pyrazol-3-yl] -phenyl} -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1672] The title compound is (RS)-{5-dimethylamino-2- [3-oxo-3- (3- {2- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-pyrazole 3-yl} -phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester (Example M69) (237 mg, 0.36 mmol) according to general procedure N Prepared by treatment with TFA in 2 Cl 2 . Obtained as a grayish white solid (48 mg).
    [1673] MS (ISP) 458 [(M + H) + ]; mp 138 ° C.
    [1674] Example 82
    [1675] 4- [3- (5-cyclopropylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7-dimethylamino-8-trifluoromethyl-1, 3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [1676] The title compound is converted to 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-di From hydro-benzo [b] [1,4] diazepin-2-one (Example 17) (444 mg, 1.0 mmol) SOCl 2 (3 eq.) And cyclopropyl amine as described in Example 45 ( 10 eq.). Obtained as a yellow solid (248 mg).
    [1677] Mp 145-148 ° C.
    [1678] Example 83
    [1679] 4- [8- (cyclopropyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -Pyridine-2-carbonitrile
    [1680] The title compound is [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (cyclopropyl-methyl-amino) -4-trifluoromethyl-phenyl ] -Carbamic acid tert.-butyl ester (Example M70) (215 mg, 0.42 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (87 mg).
    [1681] MS (ISP) 400.4 [(M + H) + ]; mp 200-205 ° C.
    [1682] Example 84
    [1683] 7-dimethylamino-8- (2-fluoro-phenyl) -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [1684] The title compound is ratio of {2-dimethylamino-2′-fluoro-5- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino]- Prepared from phenyl-4-yl} -carbamic acid tert.-butyl ester (Example M70) (810 mg, 1.45 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (61 mg).
    [1685] MS (ISP) 400.4 [(M + H) + ]; mp 225-230 ° C.
    [1686] Example 85
    [1687] 7-dimethylamino-4- {3- [5- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -phenyl} -8-trifluoromethyl-1,3 -Dihydro-benzo [b] [1,4] diazepin-2-one
    [1688] The title compound was obtained from (RS)-{5-dimethylamino-2- [3-oxo-3- (3- {5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,2 , 3] triazol-1-yl} -phenyl) -propionylamino] -4-trifluoromethyl-phenyl} -carbamic acid tert.-butyl ester (Example M72) from CH 2 Cl according to the general procedure N Prepared by treatment with double TFA. Obtained as a light yellow solid (179 mg).
    [1689] MS (ISP) 459 [(M + H) + ]; mp 172-175 ° C.
    [1690] Example 86
    [1691] 7-dimethylamino-4- [3- (5-hydroxymethyl-pyrazol-1-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1692] The title compound is (RS)-[5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -pyrazol-1-yl] -phenyl } -Propionylamino) -4-trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M73) prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (109 mg).
    [1693] MS (ISP) 444 [(M + H) + ]; mp 228-229 ° C.
    [1694] Example 87
    [1695] 7-dimethylamino-4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [1696] The title compound is {5-dimethylamino-2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl- Prepared from phenyl} -carbamic acid tert.-butyl ester (Example M74) (905 mg, 1.7 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (566 mg).
    [1697] MS (ISN) 413.2 [(M − H) − ]; mp 210-212 ° C.
    [1698] Example 88
    [1699] 4- [4-oxo-8- (2,2,2-trifluoro-ethoxy) -7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-2-yl] -pyridine-2-carbonitrile
    [1700] The title compound is [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (2,2,2-trifluoro-ethoxy) -4- Prepared from trifluoromethyl-phenyl] -carbamic acid tert.-butyl ester (Example M75) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (100 mg).
    [1701] MS (EI) 428.2 (M < + >); mp 252-255 ° C.
    [1702] Example 89
    [1703] 3- (8-Dimethylamino-7-methyl-4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -benzonitrile
    [1704] The title compound was taken as {2- [3- (3-cyano-phenyl) -3-oxo-propionyl-amino] -4-dimethylamino-5-methyl-phenyl} -carbamic acid tert-butyl ester (Example M76 (0.24 g, 0.55 mmol) from TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (114 mg, 59%).
    [1705] MS (ISP) 319.3 [(M + H) + ]; mp 257 ° C.
    [1706] Example 90
    [1707] 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-methyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1708] The title compound was obtained from (RS)-[5-dimethylamino-4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2, 3] triazol-1-yl] -phenyl} -propionyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example M77) (0.42 g, 0.71 mmol) from CH 2 Cl 2 according to General Procedure N It was prepared by treatment with TFA in water. Obtained as a pale yellow solid (200 mg, 72%).
    [1709] MS (ISP) 391.3 [(M + H) + ]; mp 190 ° C.
    [1710] Example 91
    [1711] 2- (3-cyano-phenyl) -8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1712] The title compound was taken as {5-cyano-2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -4-dimethylamino-phenyl} -carbamic acid tert-butyl ester (Example M78 ) (0.28 g, 0.63 mmol) by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (36 mg, 59%).
    [1713] MS (ISP) 328.3 [(M − H) − ]; mp 251 ° C.
    [1714] Example 92
    [1715] 3- [7-Methyl-8- (methyl-propyl-amino) -4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl] -benzonitrile
    [1716] The title compound is taken [2- [3- (3-cyano-phenyl) -3-oxo-propionylamino] -5-methyl-4- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester Prepared from Example M79 (0.17 g, 0.37 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (74 mg, 58%).
    [1717] MS (ISP) 347.4 [(M + H) + ]; mp 195 ° C.
    [1718] Example 93
    [1719] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-methyl-7- (methyl-propyl-amino) -1, 3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1720] The title compound is (RS)-[4-methyl-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)- [1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M80) (0.42 g, 0.71 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a pale yellow solid (200 mg, 72%).
    [1721] MS (ISP) 419.4 [(M + H) + ]; mp 186 ° C.
    [1722] Example 94
    [1723] 7- (ethyl-methyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-methyl-1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1724] The title compound is (RS)-[5- (ethyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)- [1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M81) (0.39 g, 0.64 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a greyish white solid (159 mg, 61%).
    [1725] MS (ISP) 405.5 [(M + H) + ]; mp 207 ° C.
    [1726] Example 95
    [1727] 8-dimethylamino-2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [ b] [1,4] diazepine-7-carbonitrile
    [1728] The title compound is (RS)-[4-cyano-5-dimethylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butylester (Example M82) (0.35 g, 0.58 mmol) from CH 2 Cl 2 according to General Procedure N It was prepared by treatment with TFA in water. Obtained as a yellow solid (149 mg, 64%).
    [1729] MS (ISP) 402.5 [(M + H) + ]; mp 234 ° C.
    [1730] Example 96
    [1731] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1732] The title compound is (RS)-[4-chloro-5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M83) (0.53 g, 0.83 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a greyish white solid (120 mg, 33%).
    [1733] MS (ISP) 439.5 [(M + H) + ]; mp 207 ° C.
    [1734] Example 97
    [1735] 8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -7- (methyl-propyl-amino) -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1736] The title compound is taken from [4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino) Prepared from -phenyl] -carbamic acid tert-butyl ester (Example M84) (0.33 g, 0.63 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (163 mg, 64%).
    [1737] MS (ISP) 403.4 [(M + H) + ]; mp 194 ° C.
    [1738] Example 98
    [1739] 8-dimethylamino-2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepine -7-carbonitrile
    [1740] The title compound is (4-cyano-5-dimethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl)- Prepared from carbamic acid tert-butyl ester (Example M85) (0.31 g, 0.62 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (171 mg, 72%).
    [1741] MS (ISP) 386.3 [(M + H) + ]; mp 248 ° C.
    [1742] Example 99
    [1743] 7- (ethyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1744] The title compound is (5- (ethyl-methyl-amino) -4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} Prepared from -phenyl) -carbamic acid tert-butyl ester (Example M86) (0.38 g, 0.75 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (160 mg, 55%).
    [1745] MS (ISP) 389.5 [(M + H) + ]; mp 198 ° C.
    [1746] Example 100
    [1747] 7-dimethylamino-8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine-2 -On
    [1748] The title compound is (5-dimethylamino-4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) -car Prepared by treatment with TFA in CH 2 Cl 2 according to the general procedure N from chest acid tert-butyl ester (Example M87) (0.32 g, 0.65 mmol). Obtained as a light yellow solid (140 mg, 57%).
    [1749] MS (ISP) 375.4 [(M + H) + ]; mp 204 ° C.
    [1750] Example 101
    [1751] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1752] The title compound is (RS)-[4-chloro-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M88) (0.32 g, 0.49 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a greyish white solid (107 mg, 48%).
    [1753] MS (ISP) 453.4 [(M + H) + ]; mp 201 ° C.
    [1754] Example 102
    [1755] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [1756] The title compound is (4-chloro-5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino } -Phenyl) -carbamic acid tert-butyl ester (Example M89) (0.35 g, 0.63 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (114 mg, 41%).
    [1757] MS (ISP) 437.4 [(M + H) + ]; mp 194 ° C.
    [1758] Example 103
    [1759] 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -4-oxo-8-pyrrolidin-1-yl-4,5-dihydro -3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1760] The title compound is (RS)-[4-cyano-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole -1-yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert-butyl ester (Example M90) (0.37 g, 0.59 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a yellow solid (140 mg, 56%).
    [1761] MS (ISP) 428.5 [(M + H) + ]; mp 241 ° C.
    [1762] Example 104
    [1763] 2- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -4-oxo-8-pyrrolidin-1-yl-4,5-dihydro-3H-benzo [b] [1 , 4] diazepine-7-carbonitrile
    [1764] (4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidin-1-yl-phenyl Prepared from) -carbamic acid tert-butyl ester (Example M91) (0.41 g, 0.77 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (90 mg, 28%).
    [1765] MS (ISP) 412.3 [(M + H) + ]; mp 267 ° C.
    [1766] Example 105
    [1767] 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8- (methyl-propyl-amino) -4-oxo-4,5-dihydro -3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1768] The title compound was obtained from (RS)-[4-cyano-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M92) (0.43 g, 0.68 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a yellow solid (100 mg, 34%).
    [1769] MS (ISP) 430.5 [(M + H) + ]; mp 221 ° C.
    [1770] Example 106
    [1771] 2- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -8- (methyl-propyl-amino) -4-oxo-4,5-dihydro-3H-benzo [b] [1 , 4] diazepine-7-carbonitrile
    [1772] The title compound is [4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino Prepared from) -phenyl] -carbamic acid tert-butyl ester (Example M93) (0.36 g, 0.68 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (94 mg, 34%).
    [1773] MS (ISP) 414.4 [(M + H) + ]; mp 133 ° C.
    [1774] Example 107
    [1775] 8-diethylamino-2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-7-carbonitrile
    [1776] The title compound is (4-cyano-5-diethylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl) Prepared from carbamic acid tert-butyl ester (Example M94) (0.35 g, 0.66 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (209 mg, 77%).
    [1777] MS (ISP) 414.4 [(M + H) + ]; mp 191 ° C.
    [1778] Example 108
    [1779] 8- (isopropyl-methyl-amino) -2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [ 1,4] diazepine-7-carbonitrile
    [1780] The title compound is taken from (4-cyano-5- (isopropyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionyl Prepared from amino} -phenyl) -carbamic acid tert-butyl ester (Example M95) (0.37 g, 0.70 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (219 mg, 76%).
    [1781] MS (ISP) 414.4 [(M + H) + ]; mp 197 ° C.
    [1782] Example 109
    [1783] 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8- (isopropyl-methyl-amino) -4-oxo-4,5-di Hydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1784] The title compound is (RS)-[4-cyano-5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl General procedure N from)-[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M96) (0.45 g, 0.71 mmol) Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a yellow solid (236 mg, 77%).
    [1785] MS (ISP) 430.5 [(M + H) + ]; mp 206 ° C.
    [1786] Example 110
    [1787] 8- (isobutyl-methyl-amino) -2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [ 1,4] diazepine-7-carbonitrile
    [1788] The title compound is referred to as (4-cyano-5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionyl Prepared from amino} -phenyl) -carbamic acid tert-butyl ester (Example M97) (0.39 g, 0.71 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (230 mg, 75%).
    [1789] MS (ISP) 428.5 [(M + H) + ]; mp 170 ° C.
    [1790] Example 111
    [1791] 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8- (isobutyl-methyl-amino) -4-oxo-4,5-di Hydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1792] The title compound is (RS)-[4-cyano-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl General procedure N from)-[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M98) (0.46 g, 0.71 mmol) Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a yellow solid (180 mg, 57%).
    [1793] MS (ISP) 444.4 [(M + H) + ]; mp 199 ° C.
    [1794] Example 112
    [1795] 2- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -4-oxo-8-piperidin-1-yl-4,5-dihydro-3H-benzo [b] [1 , 4] diazepine-7-carbonitrile
    [1796] The title compound is (4-cyano-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-piperidine-1- Prepared from mono-phenyl) -carbamic acid tert-butyl ester (Example M99) (0.41 g, 0.75 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (226 mg, 70%).
    [1797] MS (ISP) 426.4 [(M + H) + ]; mp 246 ° C.
    [1798] Example 113
    [1799] 8-chloro-7-isobutylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [1800] The title compound is (4-chloro-5-isobutylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl)- Prepared from carbamic acid tert-butyl ester (Example M100) (0.34 g, 0.63 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (216 mg, 81%).
    [1801] MS (ISP) 423.3 [(M + H) + ]; mp 249 ° C.
    [1802] Example 114
    [1803] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-isobutylamino-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1804] The title compound is (RS)-[4-chloro-5-isobutylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionyl-amino) -phenyl] -carbamic acid tert-butyl ester (Example M101) (0.17 g, 0.27 mmol) according to the general procedure NCH 2 Cl Prepared by treatment with double TFA. Obtained as a yellow solid (41 mg, 35%).
    [1805] MS (ISP) 439.4 [(M + H) + ]; mp 214 ° C.
    [1806] Example 115
    [1807] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1,3 -Dihydro-benzo [b] [1,4] diazepin-2-one
    [1808] The title compound is (RS)-[5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example M102) (0.15 g, 0.22 mmol) Prepared by treatment with TFA in CH 2 Cl 2 according to Procedure N. Obtained as a greyish white solid (31 mg, 30%).
    [1809] MS (ISP) 473.2 [(M + H) + ]; mp 230 ° C.
    [1810] Example 116
    [1811] 4- (3- (3-Methyl-isoxazol-5-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [1812] The title compound is taken as [2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5- (methyl-propyl-amino) -4-tri Prepared from fluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example M103) (0.26 g, 0.45 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (127 mg, 61%).
    [1813] MS (ISP) 457.4 [(M + H) + ]; mp 193 ° C.
    [1814] Example 117
    [1815] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1816] The title compound was obtained from (RS)-[5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, From 2,3] triazol-1-yl] -phenyl} -propionyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example M104) (0.51 g, 0.74 mmol) Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a grayish white solid (169 mg, 47%).
    [1817] MS (ISP) 487.3 [(M + H) + ]; mp 230 ° C.
    [1818] Example 118
    [1819] 7- (isobutyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1820] The title compound is (5- (isobutyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4- Prepared from trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example M105) (0.42 g, 0.71 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (161 mg, 48%).
    [1821] MS (ISP) 471.2 [(M + H) + ]; mp 195 ° C.
    [1822] Example 119
    [1823] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1824] The title compound was obtained from (RS)-[5- (isopropyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1, From 2,3] triazol-1-yl] -phenyl} -propionyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (Example M106) (0.50 g, 0.74 mmol) Prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (156 mg, 45%).
    [1825] MS (ISP) 473.3 [(M + H) + ]; mp 234 ° C.
    [1826] Example 120
    [1827] 7- (isopropyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [1828] The title compound is (5- (isopropyl-methyl-amino) -2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -4- Prepared from trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example M107) (0.37 g, 0.64 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (74 mg, 25%).
    [1829] MS (ISP) 457.4 [(M + H) + ]; mp 199 ° C.
    [1830] Example 121
    [1831] 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1832] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3 Reaction with thionylchloride in dichloromethane from dihydro-benzo [b] [1,4] diazepin-2-one (Example 29) (220 mg, 0.50 mmol) according to the method described in Example 45 The corresponding chloride was then prepared by treatment with pyrrolidine in DMF. Obtained as a yellow foam (63 mg, 26%).
    [1833] MS (ISP) 492.3 [(M + H) + ].
    [1834] Example 122
    [1835] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1836] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3 Reaction with thionylchloride in dichloromethane from dihydro-benzo [b] [1,4] diazepin-2-one (Example 29) (118 mg, 0.27 mmol) according to the method described in Example 45 The corresponding chloride was then prepared by treatment with trimethylene-imine in DMF. Obtained as a light yellow solid (65 mg, 50%).
    [1837] MS (ISP) 478.3 [(M + H) + ]; mp 169 ° C.
    [1838] Example 123
    [1839] 8-chloro-4- [3- (5-diethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (methyl-propyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1840] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3 Reaction with thionylchloride in dichloromethane from dihydro-benzo [b] [1,4] diazepin-2-one (Example 29) (219 mg, 0.50 mmol) according to the method described in Example 45 The corresponding chloride was then prepared by treatment with diethylamine in DMF. Obtained as a light yellow solid (123 mg, 50%).
    [1841] MS (ISP) 494.3 [(M + H) + ]; mp 151 ° C.
    [1842] Example 124
    [1843] 8-chloro-4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (methyl-propyl- Amino) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1844] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3 Reaction with thionylchloride in dichloromethane from dihydro-benzo [b] [1,4] diazepin-2-one (Example 29) (219 mg, 0.50 mmol) according to the method described in Example 45 The corresponding chloride was then prepared by treatment with N-isopropyl-methylamine in DMF. Obtained as a light yellow solid (129 mg, 52%).
    [1845] MS (ISP) 494.3 [(M + H) + ]; mp 148 ° C.
    [1846] Example 125
    [1847] 8-chloro-7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1848] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (219 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (157 mg, 64%).
    [1849] MS (ISP) 492.3 [(M + H) + ]; mp 172 ° C.
    [1850] Example 126
    [1851] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1852] The title compound was purified by 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 101) (226 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (163 mg, 64%).
    [1853] MS (ISP) 506.3 [(M + H) + ]; mp 190 ° C.
    [1854] Example 127
    [1855] 8-chloro-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1856] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 99) (219 mg, 0.50 mmol) according to the method described in Example 45; After the reaction, the corresponding chloride was prepared by treatment with dimethylamine in DMF. Obtained as a light brown solid (143 mg, 61%).
    [1857] MS (ISP) 566.3 [(M + H) + ]; mp 225 ° C.
    [1858] Example 128
    [1859] 8-chloro-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1860] The title compound was purified by 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 101) (226 mg, 0.50 mmol) according to the method described in Example 45; After the reaction, the corresponding chloride was prepared by treatment with dimethylamine in DMF. Obtained as a light brown solid (134 mg, 56%).
    [1861] MS (ISP) 480.5 [(M + H) + ]; mp 199 ° C.
    [1862] Example 129
    [1863] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isopropyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1864] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, From 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 99) (219 mg, 0.50 mmol) with thionylchloride in dichloromethane according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with trimethylene-imine in DMF. Obtained as a light brown solid (102 mg, 43%).
    [1865] MS (ISP) 478.3 [(M + H) + ]; mp 177 ° C.
    [1866] Example 130
    [1867] 4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isobutyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1868] The title compound was purified by 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 101) (220 mg, 0.49 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with trimethylene-imine in DMF. Obtained as a light brown solid (125 mg, 52%).
    [1869] MS (ISP) 492.3 [(M + H) + ]; mp 191 ° C.
    [1870] Example 131
    [1871] 8-chloro-4- [3- (5-methylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (methyl-propyl-amino) -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1872] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -1,3 Reaction with thionylchloride in dichloromethane from dihydro-benzo [b] [1,4] diazepin-2-one (Example 29) (230 mg, 0.52 mmol) according to the method described in Example 45 The corresponding chloride was then prepared by treatment with methylamine in DMF. Obtained as a light yellow solid (122 mg, 52%).
    [1873] MS (ISP) 452.4 [(M + H) + ]; mp 185 ° C.
    [1874] Example 132
    [1875] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [1876] The title compound was obtained from (RS)-[5- (isobutyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -[1,2,3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M108) (0.33 g, 0.52 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a light brown solid (188 mg, 79%).
    [1877] MS (ISP) 431.4 [(M − H) − ]; mp 198 ° C.
    [1878] Example 133
    [1879] 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8-methyl-7-pyrrolidin-1-yl-1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1880] The title compound is (RS)-[4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2,3] triazole- 1-yl] -phenyl} -propionylamino) -5-pyrrolidin-1-yl-phenyl] -carbamic acid tert-butyl ester (Example M110) (0.41 g, 0.66 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a light yellow solid (239 mg, 86%).
    [1881] MS (ISP) 417.3 [(M + H) + ]; mp 202 ° C.
    [1882] Example 134
    [1883] 7- (isobutyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [1884] The title compound is (5- (isobutyl-methyl-amino) -4-methyl-2- {3- [3 (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} Prepared from -phenyl) -carbamic acid tert-butyl ester (Example M109) (0.33 g, 0.62 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (136 mg, 53%).
    [1885] MS (ISP) 417.3 [(M + H) + ]; mp 187 ° C.
    [1886] Example 135
    [1887] 8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -7-pyrrolidin-1-yl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [1888] The title compound is (4-methyl-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -5-pyrrolidin-1-yl Prepared from -phenyl) -carbamic acid tert-butyl ester (Example M111) (0.33 g, 0.64 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (223 mg, 87%).
    [1889] MS (ISP) 401.5 [(M + H) + ]; mp 211 ° C.
    [1890] Example 136
    [1891] 4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1892] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 117) (300 mg, 0.62 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with dimethylamine in DMF. Obtained as a light brown solid (110 mg, 35%).
    [1893] MS (ISP) 514.3 [(M + H) + ]; mp 182 ° C.
    [1894] Example 137
    [1895] 8- (Isobutyl-methyl-amino) -4-oxo-2- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 4,5-dihydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1896] The title compound was collected from 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8- (isobutyl-methyl-amino) -4-oxo-4, Tea in dichloromethane according to the method described in Example 45 from 5-dihydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile (Example 111) (200 mg, 0.45 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (140 mg, 63%).
    [1897] MS (ISP) 497.3 [(M + H) + ]; mp 174 ° C.
    [1898] Example 138
    [1899] 7- (isobutyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoro Chloromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1900] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 117) (300 mg, 0.62 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light orange foam (80 mg, 24%).
    [1901] MS (ISP) 540.5 [(M + H) + ].
    [1902] Example 139
    [1903] 7- (isobutyl-methyl-amino) -8-methyl-4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1904] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1, From 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 132) (200 mg, 0.46 mmol) with thionylchloride in dichloromethane according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (50 mg, 22%).
    [1905] MS (ISP) 486.4 [(M + H) + ]; mp 177 ° C.
    [1906] Example 140
    [1907] 8- (isobutyl-methyl-amino) -2- (3- {5-[(isobutyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl)- 4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile
    [1908] The title compound was collected from 2- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -8- (isobutyl-methyl-amino) -4-oxo-4, Tea in dichloromethane according to the method described in Example 45 from 5-dihydro-3H-benzo [b] [1,4] diazepine-7-carbonitrile (Example 111) (220 mg, 0.50 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with N-isobutyl-methylamine in DMF. Obtained as a light yellow solid (100 mg, 39%).
    [1909] MS (ISP) 513.4 [(M + H) + ]; mp 169 ° C.
    [1910] Example 141
    [1911] 7- (isobutyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl)- 8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1912] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 117) (260 mg, 0.53 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with N-isopropyl-methylamine in DMF. Obtained as a light brown solid (70 mg, 24%).
    [1913] MS (ISP) 542.3 [(M + H) + ]; mp 157 ° C.
    [1914] Example 142
    [1915] 8-chloro-4- [3- (5-cyclopentylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1,3- Dihydro-benzo [b] [1,4] diazepin-2-one
    [1916] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with cyclopentylamine in DMF. Obtained as a light yellow solid (170 mg, 67%).
    [1917] MS (ISP) 506.3 [(M + H) + ]; mp 174 ° C.
    [1918] Example 143
    [1919] 4- (3- {5-[(cyclopropylmethyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isobutyl-methyl-amino) -8 -Methyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1920] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1, From 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 132) (250 mg, 0.58 mmol) with thionylchloride in dichloromethane according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with cyclopropylmethylamine in DMF. Obtained as a light yellow solid (50 mg, 18%).
    [1921] MS (ISP) 486.4 [(M + H) + ]; mp 184 ° C.
    [1922] Example 144
    [1923] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-piperidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1924] The title compound was purified by 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 101) (220 mg, 0.49 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with piperidine in DMF. Obtained as a light brown solid (250 mg, 99%).
    [1925] MS (ISP) 520.3 [(M + H) + ]; mp 169 ° C.
    [1926] Example 145
    [1927] 8-chloro-4- {3- [5- (isopropylamino-methyl)-[1,2,3] triazol-1-yl] -phenyl} -7- (isopropyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1928] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with isopropylamine in DMF. Obtained as a light yellow solid (160 mg, 67%).
    [1929] MS (ISP) 480.3 [(M + H) + ]; mp 208 ° C.
    [1930] Example 146
    [1931] 8-chloro-7- (isopropyl-methyl-amino) -4- [3- (5-{[(2-methoxy-ethyl) -methyl-amino] -methyl}-[1,2,3] tria Zol-1-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1932] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with N- (2-methoxyethyl) methylamine in DMF. Obtained as a light yellow solid (120 mg, 47%).
    [1933] MS (ISP) 510.4 [(M + H) + ]; mp 119 ° C.
    [1934] Example 147
    [1935] 8-chloro-4- (3- {5-[(cyclopropylmethyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isopropyl-methyl- Amino) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1936] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with aminomethyl-cyclopropane in DMF. Obtained as a light brown solid (150 mg, 61%).
    [1937] MS (ISP) 592.2 [(M + H) + ]; mp 151 ° C.
    [1938] Example 148
    [1939] 8-chloro-7- (isopropyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -Phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1940] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with N-isopropylmethylamine in DMF. Obtained as a light yellow solid (120 mg, 49%).
    [1941] MS (ISP) 494.3 [(M + H) + ]; mp 180 ° C.
    [1942] Example 149
    [1943] 8-chloro-4- (3- {5-[(isobutyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isopropyl-methyl -Amino) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1944] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with N-isobutylmethylamine in DMF. Obtained as a light yellow solid (190 mg, 75%).
    [1945] MS (ISP) 508.4 [(M + H) + ]; mp 182 ° C.
    [1946] Example 150
    [1947] 4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1948] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (200 mg, 0.42 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with dimethylamine in DMF. Obtained as a greyish white solid (80 mg, 38%).
    [1949] MS (ISP) 500.4 [(M + H) + ]; mp 197 ° C.
    [1950] Example 151
    [1951] 7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoro Chloromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1952] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (200 mg, 0.42 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light brown solid (140 mg, 63%).
    [1953] MS (ISP) 526.2 [(M + H) + ]; mp 175 ° C.
    [1954] Example 152
    [1955] 7- (isopropyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl)]-[1,2,3] triazol-1-yl} -phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1956] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (220 mg, 0.47 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with N-isopropylmethylamine in DMF. Obtained as a light yellow solid (110 mg, 45%).
    [1957] MS (ISP) 528.4 [(M + H) + ]; mp 182 ° C.
    [1958] Example 153
    [1959] 4- (3- {5-[(cyclopropylmethyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isopropyl-methyl-amino) -8 -Trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1960] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (210 mg, 0.44 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with aminomethyl-cyclopropane in DMF. Obtained as a light brown solid (110 mg, 47%).
    [1961] MS (ISP) 526.2 [(M + H) + ]; mp 152 ° C.
    [1962] Example 154
    [1963] 8-chloro-4- [3- (5-cyclopropylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1,3- Dihydro-benzo [b] [1,4] diazepin-2-one
    [1964] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with cyclopropylamine in DMF. Obtained as a light yellow solid (40 mg, 17%).
    [1965] MS (ISP) 478.4 [(M + H) + ]; mp 144 ° C.
    [1966] Example 155
    [1967] 4- {3- [5- (isopropylamino-methyl)-[1,2,3] triazol-1-yl] -phenyl} -7- (isopropyl-methyl-amino) -8-trifluoro Methyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1968] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (236 mg, 0.50 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with isopropylamine in DMF. Obtained as a light yellow solid (100 mg, 39%).
    [1969] MS (ISP) 514.4 [(M + H) + ]; mp 191 ° C.
    [1970] Example 156
    [1971] 8-chloro-4- {3- [5- (isobutylamino-methyl)-[1,2,3] triazol-1-yl] -phenyl} -7- (isopropyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1972] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 96) (220 mg, 0.50 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with isobutylamine in DMF. Obtained as a light yellow solid (160 mg, 65%).
    [1973] MS (ISP) 494.4 [(M + H) + ]; mp 182 ° C.
    [1974] Example 157
    [1975] 4- [3- (5-cyclopropylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl-1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1976] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isopropyl-methyl-amino) -8-trifluoromethyl Tea in dichloromethane according to the method described in Example 45 from -1,3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 119) (236 mg, 0.50 mmol) After reacting with onylchloride the corresponding chloride was prepared by treatment with cyclopropylamine in DMF. Obtained as a light yellow solid (70 mg, 27%).
    [1977] MS (ISP) 512.4 [(M + H) + ]; mp 178 ° C.
    [1978] Example 158
    [1979] 7- (isobutyl-methyl-amino) -8-methyl-4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,4] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [1980] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 132) (180 mg, 0.42 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a greyish white solid (106 mg, 52%).
    [1981] MS (ISP) 486.5 [(M + H) + ]; mp 164 ° C.
    [1982] Example 159
    [1983] 4- [3- (5-cyclopropylaminomethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1,3- Dihydro-benzo [b] [1,4] diazepin-2-one
    [1984] The title compound is 4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1, Thionylchloride in dichloromethane with 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 132) (180 mg, 0.42 mmol) according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with cyclopropylamine in DMF. Obtained as a light yellow solid (108 mg, 55%).
    [1985] MS (ISP) 472.4 [(M + H) + ]; mp 114 ° C.
    [1986] Example 160
    [1987] 8-chloro-7-isopropylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [1988] The title compound is (4-chloro-5-isopropylamino-2- {3- [3- (3-methyl-isoxazol-5-yl) -phenyl] -3-oxo-propionylamino} -phenyl)- Prepared from carbamic acid tert-butyl ester (Example M112) (0.16 g, 0.31 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (120 mg, 93%).
    [1989] MS (ISP) 409.4 [(M + H) + ]; mp 225 ° C.
    [1990] Example 161
    [1991] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,3] triazol-1-yl) -phenyl] -7-isopropylamino-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [1992] The title compound is (RS)-[4-chloro-5-isopropylamino-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,2 , 3] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M113) (0.37 g, 0.60 mmol) from CH 2 Cl 2 according to General Procedure N It was prepared by treatment with TFA in water. Obtained as a light yellow solid (209 mg, 82%).
    [1993] MS (ISP) 425.4 [(M + H) + ]; mp 250 ° C.
    [1994] Example 162
    [1995] 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [1996] The title compound is (RS)-[4-chloro-5- (methyl-propyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)- [1,2,4] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M114) (1.47 g, 2.29 mmol) according to General Procedure N Prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a pale yellow solid (1.0 g, 99%).
    [1997] MS (ISP) 439.5 [(M + H) + ]; mp 192 ° C.
    [1998] Example 163
    [1999] 8-chloro-4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [2000] The title compound is (RS)-[4-chloro-5- (isobutyl-methyl-amino) -2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl) -[1,2,4] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M115) (0.61 g, 0.93 mmol) to General Procedure N Thus prepared by treatment with TFA in CH 2 Cl 2 . Obtained as a light brown solid (290 mg, 69%).
    [2001] MS (ISP) 453.5 [(M + H) + ]; mp 195 ° C.
    [2002] Example 164
    [2003] 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,4] triazol-1-yl) -phenyl] -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2004] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -1,3 From dihydro-benzo [b] [1,4] diazepin-2-one (Example 162) (220 mg, 0.50 mmol) with thionylchloride in dichloromethane according to the method described in Example 45 The corresponding chloride was then prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (114 mg, 46%).
    [2005] MS (ISP) 492.3 [(M + H) + ]; mp 183 ° C.
    [2006] Example 165
    [2007] 8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,4] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2008] The title compound is combined with 8-chloro-4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, From 3-dihydro-benzo [b] [1,4] diazepin-2-one (Example 163) (200 mg, 0.44 mmol) with thionyl chloride in dichloromethane according to the method described in Example 45; After reaction the corresponding chloride was prepared by treatment with pyrrolidine in DMF. Obtained as a light yellow solid (99 mg, 44%).
    [2009] MS (ISP) 506.4 [(M + H) + ]; mp 164 ° C.
    [2010] Example 166
    [2011] 8-chloro-4- [3- (5-dimethylaminomethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (methyl-propyl-amino) -1,3-dihydro -Benzo [b] [1,4] diazepin-2-one
    [2012] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -1,3 From dihydro-benzo [b] [1,4] diazepin-2-one (Example 162) (220 mg, 0.50 mmol) with thionylchloride in dichloromethane according to the method described in Example 45 The corresponding chloride was then prepared by treatment with dimethylamine in DMF. Obtained as a light yellow solid (93 mg, 540%).
    [2013] MS (ISP) 466.4 [(M + H) + ]; mp 170 ° C.
    [2014] Example 167
    [2015] 8-chloro-4- [3- (5-cyclopropylaminomethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (methyl-propyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [2016] The title compound is 8-chloro-7- (methyl-propyl-amino) -4- [3- (5-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -1,3 From dihydro-benzo [b] [1,4] diazepin-2-one (Example 162) (220 mg, 0.50 mmol) with thionylchloride in dichloromethane according to the method described in Example 45 The corresponding chloride was then prepared by treatment with cyclopropylamine in DMF. Obtained as a light yellow solid (95 mg, 40%).
    [2017] MS (ISP) 478.4 [(M + H) + ]; mp 123 ° C.
    [2018] Example 168
    [2019] 4- [3-hydroxymethyl- [1,2,4] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -8-methyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2020] (RS)-[5- (isobutyl-methyl-amino) -4-methyl-2- (3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1 , 2,4] triazol-1-yl] -phenyl} -propionylamino) -phenyl] -carbamic acid tert-butyl ester (Example M116) (0.96 g, 1.51 mmol) according to the general procedure N CH 2 Prepared by treatment with TFA in Cl 2 . Obtained as a light brown solid (480 mg, 73%).
    [2021] MS (ISP) 433.6 [(M + H) + ]; mp 191 ° C.
    [2022] Example 169
    [2023] 7- (methyl-propyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2024] The title compound is {5- (methyl-propyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4- Prepared from trifluoromethyl-phenyl} -carbamic acid tert-butyl ester (Example M117) (0.31 g, 0.55 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (192 mg, 78%).
    [2025] MS (ISP) 443.4 [(M + H) + ]; mp 185 ° C.
    [2026] Example 170
    [2027] 7- (methyl-propyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2028] The title compound is {5- (methyl-propyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4- Prepared from trifluoromethyl-phenyl} -carbamic acid tert-butyl ester (Example M118) (0.33 g, 0.59 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (115 mg, 44%).
    [2029] MS (ISP) 443.4 [(M + H) + ]; mp 147 ° C.
    [2030] Example 171
    [2031] 7- (isobutyl-methyl-amino) -4- (3-pyrazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [2032] The title compound is {5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3-pyrazol-1-yl-phenyl) -propionylamino] -4-trifluoromethyl-phenyl } -Carbamic acid tert-butyl ester (Example M119) (0.49 g, 0.85 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (324 mg, 83%).
    [2033] MS (ISP) 454.4 [(M − H) − ]; mp 182 ° C.
    [2034] Example 172
    [2035] 4- [8- (isopropyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -Pyridine-2-carbonitrile
    [2036] The title compound is titled [2- [3- (2-cyano-pyridin-4-yl) -3-oxo-propionylamino] -5- (isopropyl-methyl-amino) -4-trifluoromethyl-phenyl ] -Carbamic acid tert-butyl ester (Example M120) (0.67 g, 1.29 mmol) was prepared by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (210 mg, 41%).
    [2037] MS (ISP) 400.3 [(M − H) − ]; mp 189 ° C.
    [2038] Example 173
    [2039] 8-chloro-7- (isobutyl-methyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2040] The title compound is taken as {4-chloro-5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionyl Prepared from amino] -phenyl} -carbamic acid tert-butyl ester (Example M121) (0.76 g, 1.41 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light orange solid (530 mg, 89%).
    [2041] MS (ISP) 423.4 [(M + H) + ]; mp 213 ° C.
    [2042] Example 174
    [2043] 7- (isobutyl-methyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [2044] {5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-trifluoro Prepared from romethyl-phenyl} -carbamic acid tert-butyl ester (Example M122) (0.50 g, 0.87 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (350 mg, 88%).
    [2045] MS (ISP) 457.5 [(M + H) + ]; mp 198 ° C.
    [2046] Example 175
    [2047] 8-chloro-7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2048] The title compound is referred to as {4-chloro-5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionyl Prepared from amino] -phenyl} -carbamic acid tert-butyl ester (Example M123) (0.17 g, 0.31 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (100 mg, 75%).
    [2049] MS (ISP) 423.5 [(M + H) + ]; mp 85 ° C.
    [2050] Example 176
    [2051] 7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [2052] The title compound is {5- (isobutyl-methyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4 Prepared from -trifluoromethyl-phenyl} -carbamic acid tert-butyl ester (Example M124) (0.44 g, 0.77 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (170 mg, 49%).
    [2053] MS (ISP) 457.5 [(M + H) + ]; mp 202 ° C.
    [2054] Example 177
    [2055] 4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2056] The title compound is {2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5-isobutylamino-4-trifluoromethyl-phenyl} -carbamic acid tert Prepared from -butyl ester (Example M125) (0.43 g, 0.77 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (260 mg, 76%).
    [2057] MS (ISP) 442.4 [(M + H) + ]; mp 221 ° C.
    [2058] Example 178
    [2059] 8-chloro-4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2060] The title compound is taken as {4-chloro-2- [3- (3-imidazol-1-yl-phenyl) -3-oxo-propionylamino] -5-isobutylamino-phenyl} -carbamic acid tert-butyl ester Prepared from Example M126 (0.33 g, 0.63 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (240 mg, 94%).
    [2061] MS (ISP) 408.4 [(M + H) + ]; mp 212 ° C.
    [2062] Example 179
    [2063] 8-chloro-7- (isobutyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2064] The title compound is {4-chloro-5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] Prepared from -phenyl} -carbamic acid tert-butyl ester (Example M127) (0.22 g, 0.42 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (90 mg, 53%).
    [2065] MS (ISP) 407.3 [(M − H) − ]; mp 249 ° C.
    [2066] Example 180
    [2067] 7- (isobutyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2068] The title compound is taken as {5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,3] triazol-1-yl-phenyl) -propionylamino] -4-tri Prepared from fluoromethyl-phenyl} -carbamic acid tert-butyl ester (Example M128) (0.34 g, 0.61 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (150 mg, 56%).
    [2069] MS (ISP) 443.4 [(M + H) + ]; mp 212 ° C.
    [2070] Example 181
    [2071] 8-chloro-7- (isobutyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2072] The title compound is {4-chloro-5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] Prepared from -phenyl} -carbamic acid tert-butyl ester (Example M129) (0.39 g, 0.74 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light orange solid (270 mg, 89%).
    [2073] MS (ISP) 407.3 [(M − H) − ]; mp 222 ° C.
    [2074] Example 182
    [2075] 7- (isobutyl-amino) -4- (3- [1,2,4] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2076] The title compound is taken as {5- (isobutyl-amino) -2- [3-oxo-3- (3- [1,2,4] triazol-1-yl-phenyl) -propionylamino] -4-tri Prepared from fluoromethyl-phenyl} -carbamic acid tert-butyl ester (Example M130) (0.43 g, 0.77 mmol) with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (270 mg, 61%).
    [2077] MS (ISP) 441.3 [(M − H) − ]; mp 191 ° C.
    [2078] Example 183
    [2079] 8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2080] The title compound was purified from [2-amino-4-chloro-5- (ethyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.23 g) (Example K27). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.14 g).
    [2081] MS (ISN) 439.2 [(M − H) − ]; mp 136-137 ° C.
    [2082] Example 184
    [2083] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2084] The title compound was purified from [2-amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.23 g) (Example K27). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.10 g).
    [2085] MS (ISN) 453.2 [(M − H) − ]; mp 211-213 ° C.
    [2086] Example 185
    [2087] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2088] The title compound was extracted with [2-amino-4-chloro-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3- [3 Prepared according to General Procedure M from-[4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (Example K27) (0.23 g). . The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light brown solid (0.05 g).
    [2089] MS (ISP) 455.2 [(M + H) + ]; mp 193-195 ° C.
    [2090] Example 186
    [2091] 8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2092] The title compound was extracted with [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3- [3 Prepared according to General Procedure M from-[4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.32 g) (Example K27). . The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.06 g).
    [2093] MS (ISP) 469.1 [(M + H) + ]; mp 135-136 ° C.
    [2094] Example 187
    [2095] 8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2096] The title compound was purified from [2-amino-4-chloro-5- (ethyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.22 g) (Example K11). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.10 g).
    [2097] MS (ISN) 423.1 [(M − H) − ]; mp 165-166 ° C.
    [2098] Example 188
    [2099] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl-7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [2100] The title compound was purified from [2-amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.22 g) (Example K11). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.10 g).
    [2101] MS (ISP) 437.2 [(M − H) − ]; mp 166-167 ° C.
    [2102] Example 189
    [2103] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2104] The title compound was extracted with [2-amino-4-chloro-5- (isopropyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3- [3 Prepared according to General Procedure M from-[4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.22 g) (Example K11). . The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.05 g).
    [2105] MS (ISP) 439.3 [(M + H) + ]; mp 143-145 ° C.
    [2106] Example 190
    [2107] 8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2108] The title compound was converted to [2-amino-4-chloro-5- (isobutyl-methyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3- [3 Prepared according to General Procedure M from-[4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.31 g) (Example K11). . The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.18 g).
    [2109] MS (ISP) 453.3 [(M + H) + ]; mp 166-167 ° C.
    [2110] Example 191
    [2111] 8-chloro-7-dimethylamino-4- [3- (4-methylaminomethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [2112] a) 8-chloro-4- [3- (4-chloromethyl-thiazol-2-yl) -phenyl] -7-dimethylamino-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [2113] 8-chloro-7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 in CH 2 Cl 2 , 4] A mixture of diazepin-2-one (0.38 g) (Example 19) and thionyl chloride (0.1 mL) was heated to 40 ° C. for 2 hours. The heterogeneous mixture was evaporated in vacuo and the residue was triturated with AcOEt to afford the title compound (0.44 g) as a light brown solid. MS (ISP) 445.1 [(M + H) + ].
    [2114] b) 8-chloro-7-dimethylamino-4- [3- (4-methylaminomethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [2115] 8-chloro-4- [3- (4-chloromethyl-thiazol-2-yl) -phenyl] -7-dimethylamino-1,3-dihydro in 8M solution of methylamine in EtOH (1 mL) A mixture of benzo [b] [1,4] diazepin-2-one (89 mg) and KI (3 mg) was stirred at 20 ° C. for 20 hours. H 2 O (25 mL) was added and 2N NaOH was added to set the pH of the mixture to 11. The precipitate was collected by filtration and purified by chromatography using MeOH as eluent on silica gel. The product was stirred with 20% aqueous MeOH (10 mL) and the solids were separated by filtration to give the title compound (49 mg) as a yellow powder.
    [2116] MS (ISP) 440.2 [(M + H) + ]; mp 129-130 ° C.
    [2117] Example 192
    [2118] 8-chloro-7-dimethylamino-4- [3- (4-morpholin-4-ylmethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [2119] 8-chloro-4- [3- (4-chloromethyl-thiazol-2-yl) -phenyl] -7-dimethylamino-1,3-dihydro-benzo [b] [1 in EtOH (0.5 mL) , 4] A mixture of diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) was stirred at 60 ° C. for 3 hours. H 2 O (25 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography using AcOEt / acetone (1: 1) as eluent on silica gel. The product was stirred with 20% aqueous MeOH (20 mL). The pH of the mixture was set to 11 by addition of 1N NaOH and the solids were separated by filtration to give the title compound (55 mg) as a yellow powder.
    [2120] MS (ISP) 496.2 [(M + H) + ]; mp 138-143 ° C.
    [2121] Example 193
    [2122] 8-chloro-7-dimethylamino-4- [3- (2-hydroxymethyl-thiazol-4-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine 2-on
    [2123] a) 4- (3-bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2124] 3-oxo-3- [3- (2-bromo-1,1-dimethoxy-ethyl) -phenyl] -propionic acid tert-butyl ester (2.34 g) in toluene (16 mL) (Example K28) and ( A solution of 2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J2) (1.57 g) was heated to 100 ° C. for 5 hours. The solvent was evaporated in vacuo and the crude product was purified by chromatography on silica gel using CH 2 Cl 2 / AcOEt (1:20) as eluent. A solution of purified material (2.4 g) in CH 2 Cl 2 / TFA (1: 1, 30 mL) was stirred at 20 ° C. for 15 minutes and then evaporated. The residue oil was dissolved in AcOEt and the solution was washed with 1N HCl and brine, dried and evaporated. The residue was crystallized from AcOEt / Et 2 O to give 4- (3-bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepine- 2-one was obtained as a light brown solid.
    [2125] b) 8-chloro-7-dimethylamino-4- [3- (2-hydroxymethyl-thiazol-4-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] Diazepine-2-one
    [2126] 4- (3-Bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one in EtOH (3 mL) 0.22 g) and a mixture of 2- (tert.-butylcarbonyl-oxy) thioacetamide (0.11 g) were heated at 80 ° C. for 0.5 h. The solution was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine, dried and evaporated. The residue was stirred at 20 ° C. for 20 minutes in a mixture of MeOH (8 mL) and 1.5N KOH (8 mL). H 2 O (30 ml) was added and the precipitated product was collected by filtration to give the title compound (0.9 g) as a yellow powder.
    [2127] MS (ISP) 427.3 [(M + H) + ]; mp 176-178 ° C.
    [2128] Example 194
    [2129] 4- [3- (2-amino-thiazol-4-yl) -phenyl] -8-chloro-7-dimethylamino-1, 3-dihydro-benzo [b] [1,4] diazepine-2 -On
    [2130] 4- (3-Bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one in THF (10 mL) 0.73 g) (Example 193a) and Thiourea (0.13 g) were heated to 60 ° C. for 15 minutes. The mixture was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine. The organic layer was dried, evaporated and the residue was stirred with CH 2 Cl 2 to afford the title compound (0.14 g) as a yellow solid.
    [2131] MS (ISN) 410.2 [(M − H) − ]; mp 247-248 ° C.
    [2132] Example 195
    [2133] 8-chloro-7-dimethylamino-4- [3- (2-ethylamino-thiazol-4-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on
    [2134] 4- (3-Bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one in THF (3 mL) 130 mg) (Example 193a) and N-ethyl-thiourea (31 mg) were heated at 60 ° C. for 15 minutes. The mixture was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine. The organic layer was dried, evaporated and the residue was purified by chromatography on silica gel using AcOEt / hexanes (1: 1) as eluent. The purified product was triturated with Et 2 O to afford the title compound (24 mg) as a yellow solid.
    [2135] MS (ISP) 440.3 [(M + H) + ]; mp 122-123 ° C.
    [2136] Example 196
    [2137] N- {4- [3- (7-Chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo [b] [1, 4] diazepin-2-yl) -phenyl] -Thiazol-2-yl} -guanidine
    [2138] 4- (3-Bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one in THF (3 mL) 130 mg) (Example 193a) and a mixture of N-amidino-thiourea (35 mg) were heated at 60 ° C. for 1 hour. The mixture was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine. The organic layer was dried and evaporated and the residue was purified by chromatography using AcOEt / MeOH (20: 1) as eluent on silica gel. The purified product was crystallized from acetone to give the title compound (22 mg) as a yellow solid.
    [2139] MS (ISP) 454.2 [(M + H) + ]; mp 221 ° C. dec.
    [2140] Example 197
    [2141] 8-chloro-7-dimethylamino-4- {3- [2- (pyridin-4-ylamino) -thiazol-4-yl] -phenyl} -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2142] 4- (3-Bromoacetyl-phenyl) -8-chloro-7-dimethylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one (130 mL in THF (3 mL)) mg) (Example 193a) and 1- (4-pyridyl) -2-thiourea (46 mg) were heated at 60 ° C. for 45 minutes. The mixture was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine. The organic layer was dried, evaporated and the residue triturated with Et 2 O to afford the title compound (55 mg) as a yellow solid.
    [2143] MS (ISP) 489.2 [(M + H) + ]; mp 231-234 ° C.
    [2144] Example 198
    [2145] 8-chloro-4- [3- (2-methyl-oxazol-4-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2146] The title compound was purified from [2-amino-4-chloro-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3- [3- Prepared according to General Procedure M from (2-methyl-oxazol-4-yl) -phenyl] -propionic acid tert-butyl ester (0.17 g) (Example K29). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.07 g).
    [2147] MS (ISP) 423.2 [(M + H) + ]; mp 163-164 ° C.
    [2148] Example 199
    [2149] 4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -8-methyl-7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2150] The title compound was extracted with [2-amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (Example K27) (0.31 g). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.09 g).
    [2151] MS (ISP) 435.3 [(M + H) + ]; mp 222-224 ° C.
    [2152] Example 200
    [2153] 4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -8-methyl-7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2154] The title compound was extracted with [2-amino-4-methyl-5- (methyl-propyl-amino) -phenyl] -carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3- [3- Prepared according to General Procedure M from [4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (Example K11) (0.31 g). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.16 g).
    [2155] MS (ISP) 419.3 [(M + H) + ]; mp 200-202 ° C.
    [2156] Example 201
    [2157] 7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2158] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- [3- [ Prepared according to General Procedure M from 4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (Example K27) (0.23 g). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.12 g).
    [2159] MS (ISP) 461.2 [(M + H) + ]; mp 198-199 ° C.
    [2160] Example 202
    [2161] 7-dimethylamino-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2162] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- [3- [ Prepared according to General Procedure M from 4- (tetrahydro-pyran-2-yloxymethyl) -oxazol-2-yl] -phenyl] -propionic acid tert-butyl ester (0.22 g) (Example K11). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.11 g).
    [2163] MS (ISP) 445.0 [(M + H) + ]; mp 197-198 ° C.
    [2164] Example 203
    [2165] 4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b ] [1,4] diazepin-2-one
    [2166] The title compound was extracted with [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3- [3- [4- (tetrahydro-pyran-2-yloxymethyl) -thiazol-2-yl] -phenyl] -propionic acid tert-butyl ester (Example K27) (0.23 g) according to General Procedure M Prepared. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.06 g).
    [2167] MS (ISP) 489.2 [(M + H) + ]; mp 177-180 ° C.
    [2168] Example 204
    [2169] 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [2170] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- {3- [ 5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -phenyl} -propionic acid tert-butyl ester (0.23 g) (Example K30) Prepared according to Procedure M. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.06 g).
    [2171] MS (ISP) 462.1 [(M + H) + ]; mp 242-246 ° C.
    [2172] Example 205
    [2173] 7-dimethylamino-4- {3- [5- (2-hydroxy-ethyl)-[1,3,4] thiadiazol-2-yl] -phenyl} -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2174] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- (3- { 5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -phenyl) -propionic acid tert-butyl ester (0.24 g) Prepared according to General Procedure M from Example K31). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.06 g).
    [2175] MS (ISN) 474.2 [(M − H) − ]; mp 234-237 ° C.
    [2176] Example 206
    [2177] 7-dimethylamino-4- [3- (5-hydroxymethyl- [1,3,4] oxadiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [2178] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (1.44 g) (Example J6) and 3-oxo-3- {3- [5 General procedure from (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] oxadiazol-2-yl] -phenyl} -propionic acid tert-butyl ester (2.17 g) (Example K32) Prepared according to M. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.88 g).
    [2179] MS (ISP) 463.2 [(M + NH 4 ) + ].
    [2180] Example 207
    [2181] 7-dimethylamino-4- {3- [5- (2-hydroxy-ethyl)-[1,3,4] oxadiazol-2-yl] -phenyl} -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2182] The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- (3- { 5- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] oxadiazol-2-yl} -phenyl) -propionic acid tert-butyl ester (0.23 g) Prepared according to General Procedure M from Example K33). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.88 g).
    [2183] MS (ISP) 460.2 [(M + H) + ]; mp 237 ° C. dec.
    [2184] Example 208
    [2185] 7-dimethylamino-4- (3-oxazol-4-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2186] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (96 mg) (Example J6) and 3- (3-oxazole-4- Prepared according to General Procedure M from mono-phenyl) -3-oxo-propionic acid tert-butyl ester (103 mg) (Example K34). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (50 mg).
    [2187] MS (ISP) 415.2 [(M + H) + ]; mp 218-219 ° C.
    [2188] Example 209
    [2189] 7-dimethylamino-4- (3-thiazol-4-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2190] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (96 mg) (Example J6) and 3-oxo-3- (3-thia Prepared according to General Procedure M from Zol-4-yl-phenyl) -propionic acid tert-butyl ester (109 mg) (Example K35). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a grayish white solid (61 mg).
    [2191] MS (ISP) 431.2 [(M + H) + ]; mp 200 ° C. dec.
    [2192] Example 210
    [2193] 7-dimethylamino-4- [3- (2-methyl-oxazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [2194] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3- [3- (2-methyl- Prepared according to General Procedure M from oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (0.18 g) (Example K29). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.04 g).
    [2195] MS (ISP) 429.3 [(M + H) + ]; mp 192-193 ° C.
    [2196] Example 211
    [2197] 7-dimethylamino-4- [3- (5-methyl-oxazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [2198] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3- [3- (5-methyl- Prepared according to General Procedure M from oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (0.18 g) (Example K36). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.13 g).
    [2199] MS (ISP) 429.3 [(M + H) + ]; mp 238-239 ° C.
    [2200] Example 212
    [2201] 7-dimethylamino-4- [3- (2-methyl-5-propyl-oxazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one
    [2202] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (80 mg) (Example J6) and 3- [3- (2-methyl- 5-Propyl-oxazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (103 mg) (Example K37) was prepared according to general procedure M. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a pale yellow solid (20 mg).
    [2203] MS (ISP) 471.2 [(M + H) + ]; mp 211-212 ° C.
    [2204] Example 213
    [2205] 7-dimethylamino-4- [3- (5-methyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one
    [2206] The title compound is taken as (2-amino-5-dimethylamino-4-trifluoro-methyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (0.19 g) (Example K38) From General Procedure M from The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.06 g).
    [2207] MS (ISP) 445.2 [(M + H) + ]; mp 214-215 ° C.
    [2208] Example 214
    [2209] 7-dimethylamino-4- [3- (2,5-dimethyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2210] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (48 mg) (Example J6) and 3- [3- (2,5- Methyl-thiazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (50 mg) (Example K39) was prepared according to general procedure M. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (38 mg).
    [2211] MS (ISP) 459.2 [(M + H) + ]; mp 208-209 ° C.
    [2212] Example 215
    [2213] 7-dimethylamino-4- [3- (2-hydroxymethyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2214] a) 4- (3-bromoacetyl-phenyl) -7-dimethylamino-8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2215] (2-Amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (Example J6) (0.32 g) and 3-oxo-3- [3 in toluene (3 mL) A solution of-(2-bromo-1,1-dimethoxy-ethyl) -phenyl] -propionic acid tert-butyl ester (0.43 g) (Example K28) was heated to 100 ° C. for 2 hours. The solvent was evaporated in vacuo and the crude product was purified by chromatography using AcOEt / hexanes (1: 3) as eluent on silica gel. A solution of purified material (0.57 g) in CH 2 Cl 2 / TFA (1: 1, 7 mL) was stirred at 20 ° C. for 15 minutes and then evaporated. The residue oil was dissolved in AcOEt and the solution was washed with 1N HCl and brine, dried and evaporated to afford crude 4- (3-bromoacetyl-phenyl) -7-dimethylamino-8-trifluoromethyl-1,3- Dihydro-benzo [b] [1,4] diazepin-2-one (0.22 g) was obtained as a light brown solid.
    [2216] b) 7-dimethylamino-4- [3- (2-hydroxymethyl-thiazol-4-yl) -phenyl] -8-trifluoro-methyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one
    [2217] 4- (3-Bromoacetyl-phenyl) -7-dimethylamino-8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepine-2 in EtOH (5 mL) A mixture of -one (0.40 g) and 2- (tert.-butylcarbonyloxy) thio-acetamide (0.21 g) was heated to 80 ° C. for 0.5 h. The solution was diluted with AcOEt and washed with saturated NaHCO 3 solution and brine, dried and evaporated. Stir at 20 ° C. for 20 minutes in a mixture of MeOH (5 mL) and 1.5N KOH (5 mL). H 2 O was added and the precipitated product was collected by filtration and purified by chromatography using AcOEt as eluent on silica gel to give the title compound (0.01 g) as a yellow solid.
    [2218] MS (ISP) 461.1 [(M + H) + ].
    [2219] Example 216
    [2220] 7-dimethylamino-4- [3- (2-hydroxymethyl-5-methyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2221] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- {3- [ 5-Methyl-2- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl} -propionic acid tert-butyl ester (0.26 g) from Example K40 according to General Procedure M Prepared. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a light yellow solid (0.11 g).
    [2222] MS (ISP) 475.2 [(M + H) + ]; mp 190-193 ° C.
    [2223] Example 217
    [2224] 7-dimethylamino-4- [3- (2-hydroxymethyl-5-propyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2225] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (79 mg) (Example J6) and 3-oxo-3- {3- [5 Prepared according to General Procedure M from -propyl-2- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl} -propionic acid tert-butyl ester (138 mg) (Example K41). It was. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (45 mg).
    [2226] MS (ISP) 503.2 [(M + H) + ]; mp 112-114 ° C.
    [2227] Example 218
    [2228] 7-dimethylamino-4- [3- (5-hydroxymethyl-2-methyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones
    [2229] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3- {3- [ 2-Methyl-5- (tetrahydro-pyran-2-yloxymethyl) -thiazol-4yl] -phenyl} -propionic acid tert-butyl ester (0.26 g) prepared according to General Procedure M from Example K42 It was. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.11 g).
    [2230] MS (ISN) 473.0 [(M − H) − ]; mp 226-227 ° C.
    [2231] Example 219
    [2232] 7-dimethylamino-4- [3- (5-hydroxymethyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one
    [2233] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.16 g) (Example J6) and 3-oxo-3-{[5- Prepared according to General Procedure M from (tetrahydro-pyran-2-yloxymethyl) -thiazol-4-yl] -phenyl} -propionic acid tert-butyl ester (0.25 g) (Example K43). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.08 g).
    [2234] MS (ISN) 459.3 [(M − H) − ].
    [2235] Example 220
    [2236] 4- (3- {5-[(cyclopropylmethyl-amino) -methyl] -thiazol-4-yl} -phenyl) -7-dimethylamino-8-trifluoromethyl-1, 3-dihydro- Benzo [b] [1,4] diazepin-2-ones
    [2237] 7-dimethylamino-4- [3- (5-hydroxymethyl-thiazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro in CH 2 Cl 2 (0.3 mL) A mixture of benzo [b] [1,4] diazepin-2-one (Example 219) (65 mg) and thionyl chloride (0.015 mL) was stirred at 20 ° C. for 1 hour. The heterogeneous mixture was evaporated in vacuo and the residue suspended in EtOH (0.5 mL). Aminomethyl-cyclopropane (0.12 mL) and KI (3 mg) were added and the mixture was stirred at 80 ° C. for 5 hours. The mixture was evaporated in vacuo and the residue was purified by chromatography on silica gel using AcOEt / MeOH (50: 1) as eluent. The resulting product was washed with 20% aqueous MeOH (10 mL), 1N NaOH was added to set the pH of the mixture to 11, and the solids were separated by filtration to give the title compound (44 mg) as a grayish white solid. Obtained.
    [2238] MS (ISP) 514.3 [(M + H) + ]; 157-158 ° C.
    [2239] Example 221
    [2240] 7-dimethylamino-4- [3- (2-isopropyl-1H-imidazol-4-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1, 4] diazepine-2-one
    [2241] The title compound was purified from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) -carbamic acid tert-butyl ester (0.13 g) (Example J6) and 3- [3- (2-isopropyl Prepared according to General Procedure M from -3H-imidazol-4-yl) -phenyl] -3-oxo-propionic acid tert-butyl ester (0.20 g) (Example K44). The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a greyish white solid (0.10 g).
    [2242] MS (ISP) 456.4 [(M + H) + ]; mp 150 ° C. dec.
    [2243] Example 222
    [2244] 4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-one
    [2245] The title compound was extracted with [2-amino-5- (methyl-propyl-amino) -4-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3- {3- [5- (tetrahydro-pyran-2-yloxymethyl)-[1,3,4] thiadiazol-2-yl] -phenyl} -propionic acid tert-butyl ester (0.23 g) (Example K30) according to General Procedure M. The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.02 g).
    [2246] MS (ISP) 490.2 [(M + H) + ]; mp 193-194 ° C.
    [2247] Example 223
    [2248] 8-chloro-7-dimethylamino-4- {3- [5- (2-hydroxy-ethyl)-[1,3,4] thiadiazol-2-yl] -phenyl} -1,3-di Hydro-benzo [b] [1,4] diazepin-2-one
    [2249] The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl) -carbamic acid tert.-butyl ester (Example J1) (0.15) and crude 3-oxo-3- (3- {5- [ 2- (tetrahydro-pyran-2-yloxy) -ethyl]-[1,3,4] thiadiazol-2-yl} -phenyl) -propionic acid tert-butyl ester (0.24 g) (Example K30) From General Procedure M from The material obtained was deprotected and cyclized by treatment with TFA in CH 2 Cl 2 according to General Procedure N. Obtained as a yellow solid (0.10 g).
    [2250] MS (ISN) 440.2 [(M − H) − ]; mp 198-200 ° C.
    [2251] Example I
    [2252] Tablets of the following composition were prepared in a conventional manner:
    [2253] mg / tablet Active ingredient100 Powdered lactose95 White corn starch35 Polyvinylpyrrolidone8 Na carboxymethyl starch10 Magnesium stearate2 Tablet weight250
    [2254] Example II
    [2255] Tablets of the following composition were prepared in a conventional manner:
    [2256] mg / tablet Active ingredient200 Powdered lactose100 White corn starch64 Polyvinylpyrrolidone12 Na carboxymethyl starch20 Magnesium stearate4 Tablet weight400
    [2257] Example III
    [2258] Capsules of the following composition were prepared:
    [2259] mg / capsules Active ingredient50 Crystalline lactose60 Microcrystalline cellulose34 talc5 Magnesium stearateOne Capsule Filling Weight150
    [2260] The active material, crystalline lactose and microcrystalline cellulose, having a suitable particle size are mixed homogeneously with each other, sieved and then admixed with talc and magnesium stearate. The final mixture is filled into hard gelatine capsules of suitable size.
    权利要求:
    Claims (21)
    [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable addition salt thereof:
    Formula I

    Where
    X is a single bond or ethyndiyl group;
    When X is a single bond, R 1 is cyano, halogen, lower alkyl, C 3 -C 6 -cycloalkyl, lower alkoxy, fluoro-lower alkoxy, fluoro-lower alkyl, or fluoro, chloro, cyano ,-(CH 2 ) 1-4 -hydroxy, fluoro-lower alkyl, lower alkyl,-(CH 2 ) n -lower alkoxy,-(CH 2 ) n -C (O) OR ",-(CH 2 ) 1-4 -NR'R ", hydroxy-lower alkoxy and-(CH 2 ) n -CONR'R", pyrrole-1-yl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: Phenyl unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, fluoro-lower alkoxy and cyano;
    When X is an ethyndiyl group, R 1 is 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, C 3 -C 6 -cycloalkyl, lower alkoxy and fluoro-lower alkoxy Substituted or unsubstituted phenyl;
    R 2 is —NR′R ″, fluoro-lower alkoxy or 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the ring is optionally defined as R ″ Substituted with;
    R 'is hydrogen, lower alkyl, C 3 -C 6 -cycloalkyl, fluoro-lower alkyl or 2-lower alkoxy lower alkyl;
    R ″ is hydrogen, lower alkyl, C 3 -C 6 -cycloalkyl, fluoro-lower alkyl, 2-lower alkoxy lower alkyl,-(CH 2 ) 2-4 -di-lower alkylamino,-(CH 2 ) 2-4 -morpholinyl,-(CH 2 ) 2-4 -pyrrolidinyl,-(CH 2 ) 2-4 -piperidinyl or 3-hydroxy-lower alkyl;
    Y is -CH = or = N-;
    R 3 is halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, cyano,-(CH 2 ) n -C (O) -OR ",-(CH 2 ) n -C (O) -NR'R "Or an optionally substituted 5-membered aromatic heterocycle [which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano,-(CH 2 ) n -NR'R",-(CH 2 ) n- C (O) -OR ",-(CH 2 ) n -C (O) -NR'R",-(CH 2 ) n -SO 2 -NR'R ",-(CH 2 ) n -C (NH 2 ) = NR ", hydroxy, lower alkoxy, lower alkylthio or lower alkyl, wherein lower alkyl is optionally substituted with fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy. ;
    n is 0, 1, 2, 3 or 4.
    [2" claim-type="Currently amended] The method of claim 1,
    X is a single bond.
    [3" claim-type="Currently amended] The method of claim 2,
    R 1 is trifluoromethyl.
    [4" claim-type="Currently amended] The method of claim 3, wherein
    R 3 is cyano.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    4- (4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl)- Pyridine-2-carbonitrile,
    4- [8- (cyclopropylmethyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl ] -Pyridine-2-carbonitrile,
    4- [8- (cyclopropylmethyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl]- Pyridine-2-carbonitrile,
    4- [4-oxo-8- (2,2,2-trifluoro-ethoxy) -7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-2-yl] -pyridine-2-carbonitrile, and
    4- [8- (isopropyl-methyl-amino) -4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] -A compound selected from the group consisting of pyridine-2-carbonitrile.
    [6" claim-type="Currently amended] The method of claim 3, wherein
    R 3 is an optionally substituted 5-membered aromatic heterocycle, which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano,-(CH 2 ) n -NR'R ",-(CH 2 ) n -C (O) -OR ",-(CH 2 ) n -C (O) -NR'R",-(CH 2 ) n -SO 2 -NR'R ",-(CH 2 ) n -C ( NH 2 ) = NR ", hydroxy, lower alkoxy, lower alkylthio or lower alkyl, wherein lower alkyl is optionally substituted with fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy .
    [7" claim-type="Currently amended] The method of claim 6,
    7-dimethylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one,
    7-dimethylamino-4- [3- (2-methyl-2H-pyrazol-3-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    7-dimethylamino-4- (3-imidazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    4- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    7- (isobutyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    7- (isopropyl-methyl-amino) -4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -8-trifluoromethyl-1, 3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    7- (isobutyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl)- 8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-trifluoro Rhomethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    7- (methyl-propyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-ones,
    7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -8-trifluoromethyl-1,3-dihydro-benzo [b ] [1,4] diazepin-2-one,
    4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one ,
    7-dimethylamino-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    7-dimethylamino-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -8-trifluoromethyl-1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-dihydro-benzo [b ] [1,4] diazepin-2-ones, and
    4- [3- (5-hydroxymethyl- [1,3,4] thiadiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -8-trifluoromethyl-1, 3-Dihydro-benzo [b] [1,4] diazepin-2-one.
    [8" claim-type="Currently amended] The method of claim 2,
    R 1 is chloro.
    [9" claim-type="Currently amended] The method of claim 8,
    8-chloro-7-isobutylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on,
    8-chloro-7- (methyl-propyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7- (isopropyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-4- [3- (5-dimethylaminomethyl- [1,2,3] triazol-1-yl) -phenyl] -7- (isobutyl-methyl-amino) -1,3-di Hydro-benzo [b] [1,4] diazepin-2-ones,
    4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isopropyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    4- [3- (5-azetidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl] -8-chloro-7- (isobutyl-methyl-amino) -1 , 3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7- (isobutyl-methyl-amino) -4- [3- (5-piperidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7- (isopropyl-methyl-amino) -4- (3- {5-[(isopropyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -Phenyl) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-4- (3- {5-[(isobutyl-methyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isopropyl-methyl -Amino) -1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7-isopropylamino-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine- 2-on,
    8-chloro-7- (isobutyl-methyl-amino) -4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    8-chloro-4- (3-imidazol-1-yl-phenyl) -7-isobutylamino-1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    8-chloro-4- [3- (4-hydroxymethyl-thiazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one,
    8-chloro-7- (ethyl-methyl-amino) -4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -1,3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (methyl-propyl-amino) -1, 3-dihydro-benzo [b] [1 , 4] diazepin-2-one,
    8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isopropyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one, and
    8-chloro-4- [3- (4-hydroxymethyl-oxazol-2-yl) -phenyl] -7- (isobutyl-methyl-amino) -1, 3-dihydro-benzo [b] [ 1,4] diazepin-2-one.
    [10" claim-type="Currently amended] The method of claim 2,
    R 1 is cyano.
    [11" claim-type="Currently amended] The method of claim 10,
    8-diethylamino-2- [3- (3-methyl-isoxazol-5-yl) -phenyl] -4-oxo-4,5-dihydro-3H-benzo [b] [1,4] dia Zepin-7-carbonitrile, and
    2- [3- (3-Methyl-isoxazol-5-yl) -phenyl] -4-oxo-8-piperidin-1-yl-4,5-dihydro-3H-benzo [b] [1 , 4] diazepine-7-carbonitrile.
    [12" claim-type="Currently amended] The method of claim 1,
    R 3 is an optionally substituted 5-membered aromatic heterocycle, which is halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano,-(CH 2 ) n -NR'R ",-(CH 2 ) n -C (O) -OR ",-(CH 2 ) n -C (O) -NR'R",-(CH 2 ) n -SO 2 -NR'R ",-(CH 2 ) n -C ( NH 2 ) = NR ", hydroxy, lower alkoxy, lower alkylthio or lower alkyl, wherein lower alkyl is optionally substituted with fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy .
    [13" claim-type="Currently amended] The method of claim 12,
    R 3 is thiazolyl, oxazolyl, isoxazolyl, imidazolyl, 2H-pyrazolyl, [1,2,3] triazolyl, [1,2,4] triazolyl, [1,3,4] thia A compound which is an optionally substituted 5-membered aromatic heterocycle selected from the group consisting of diazolyl and [1,3,4] oxadiazolyl.
    [14" claim-type="Currently amended] The method of claim 13,
    7-dimethylamino-8-phenylethynyl-4- (3- [1,2,3] triazol-1-yl-phenyl) -1,3-dihydro-benzo [b] [1,4] dia Zepin-2-one,
    8- (2-Fluoro-phenyl) -4- (3- [1,2,3] triazol-1-yl-phenyl) -7- (2,2,2-trifluoro-ethoxy)- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one,
    7- (ethyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4 ] Diazepin-2-one,
    7-dimethylamino-8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1,4] diazepine-2 -On,
    7- (isobutyl-methyl-amino) -8-methyl-4- [3- (3-methyl-isoxazol-5-yl) -phenyl] -1,3-dihydro-benzo [b] [1, 4] diazepine-2-one,
    7- (isobutyl-methyl-amino) -8-methyl-4- [3- (5-pyrrolidin-1-ylmethyl- [1,2,3] triazol-1-yl) -phenyl]- 1,3-dihydro-benzo [b] [1,4] diazepin-2-one, and
    4- (3- {5-[(cyclopropylmethyl-amino) -methyl]-[1,2,3] triazol-1-yl} -phenyl) -7- (isobutyl-methyl-amino) -8 -Methyl-1,3-dihydro-benzo [b] [1,4] diazepin-2-one.
    [15" claim-type="Currently amended] A medicament containing at least one compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.
    [16" claim-type="Currently amended] The method of claim 15,
    Drugs for the treatment or prevention of acute and / or chronic neurological disorders including psychiatric disorders, schizophrenia, Alzheimer's disease, cognitive impairment and memory loss.
    [17" claim-type="Currently amended] a) reacting a compound of formula (II) with a compound of formula (IV) or (IVa) to produce a compound of formula (III), followed by deprotection and cyclization of the amino group to give a compound of formula (I)
    If necessary, a process for preparing the compound of formula I as defined in claim 1 comprising converting the obtained compound into a pharmaceutically acceptable acid addition salt:
    Formula II

    Formula IV

    Formula IVa

    Wherein R is alkyl, preferably ethyl or butyl
    Formula III

    Formula I

    [Wherein R 1 , R 2 , R 3 , X and Y are as described in claim 1] [18" claim-type="Currently amended] The method according to any one of claims 1 to 14,
    A compound prepared by the method according to claim 17 or by an equivalent method.
    [19" claim-type="Currently amended] The method according to any one of claims 1 to 14,
    Compounds for use in the treatment or prevention of diseases.
    [20" claim-type="Currently amended] One or more of any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of acute and / or chronic neurological disorders including psychiatric disorders, schizophrenia, Alzheimer's disease, cognitive impairment and memory loss. Use of a compound and / or a pharmaceutically acceptable acid addition salt thereof.
    [21" claim-type="Currently amended] Invention as described herein.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-04-12|Priority to EP01109125.3
    2001-04-12|Priority to EP01109125
    2002-04-02|Application filed by 에프. 호프만-라 로슈 아게
    2002-04-02|Priority to PCT/EP2002/003644
    2003-11-12|Publication of KR20030087076A
    2006-03-29|Application granted
    2006-03-29|Publication of KR100566171B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP01109125.3|2001-04-12|
    EP01109125|2001-04-12|
    PCT/EP2002/003644|WO2002083652A1|2001-04-12|2002-04-02|DIHYDRO-BENZO [b] [1, 4] DIAZEPIN-2-ONE DERIVATIVES AS MGLUR2 ANTAGONISTS II|
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