TWI296622B - Dihydro-benzo[b][1,4]diazepin-2-one derivatives as mglur2 antagonists ii - Google Patents

Description

1296622 A7 B7 V. Description of invention (1)

Q

R° where \ X is a single bond or an acetylene diyl group; wherein -〇广,~f If X is a single bond, then R1 is a cyano group, a halogen, a lower alkyl group, a C3 -Cg -3⁄4• pit group, a low fluorene group, a fluoro-lower alkoxy group, a fluoro-lower alkyl group, a fluoren-1-yl group, which is unsubstituted or substituted with one to three substituents selected from the group consisting of Fluoro), emulsifier, gas, 丨 4 -trans, fluoro-lower alkyl, lower fluoro, n-lower methoxy, -(CH2)nC(〇)aR〃, -(CHdyNRir, hydroxy-lower alkoxy and -(CH2)n-CONR, Rn^. or phenyl which is unsubstituted or substituted by one or two substituents selected from , low-carbon alkyl, fluoro-lower alkyl, low carbon oxy, gas * low carbon pit based and gas base; -5- This paper scale applies to China National Standard (CNS) A4 specification (210x 297 PCT) 1296622 A7 B7 V. INSTRUCTIONS (2) Right * X is an ethylidene diyl group, then R1 is a phenyl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of Low beeswax, fluorine-low carbon base, C3-C6-cycloalkyl, lower alkane And fluorine-lower alkoxy; R2 is -NR'R,,, fluoro-lower alkoxy or 3-keto-hexahydropyrazine, tetrahydrop, p, small or hexahydro p is more than a decyl group, the ring is optionally substituted by R" 'R' is hydrogen, lower alkyl, -C3 -Cg -year alkyl' fluorine-low carbon alkyl, or 2-low carbon Alkoxy lower alkyl group;

Rn is hydrogen, lower alkyl, C3-C6-cycloalkyl, fluoro-lower alkyl, 2-lower alkoxy lower alkyl, -(CH2)2_4-di lower alkylamino, - (CH2)2-4-morpholinyl, -(CH2)2_4-tetrahydropyrrolyl, -(CH2)2_4-hexahydropyridyl, or 3-hydroxy-lower alkyl; Y is -CH= Or; R3 is halogen, lower alkyl, this paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 B7 V. Description of invention (3) Gas-low carbon alkyl, low carbon alkoxy , cyano, -(CH2)nC(0)-0R", -(CH2)nC(0)-NR, R丨', or a five-membered aromatic heterocyclic ring which may be substituted as appropriate , fluorine-lower alkyl, fluoro-lower alkoxy, cyano, -^!^:^-^^^", -(CH2)nc(〇)-〇RM > ^cu2)n ^c(〇ym:Rn > -(ch2)^802^^1 > -(CH2)nC(NH2)=NRn, hydroxy, lower alkoxy, lower alkylthio substituted, or low carbon An alkyl group, which is optionally substituted with a fluoro group, a hydroxy group, a lower alkoxy group, a cyano group or an amine mercaptooxy group; η is 0, 1, 2, 3 or 4; Accepted addition salts. It has been surprisingly discovered The compound of formula I is a metabolically shifting glutamate receptor antagonist. The compound of formula I is characterized by the therapeutic properties of valuable quinones. In the central nervous system (CNS), the transmission of stimuli is by neurotransmitters (which are Occurs by interactions with neuroreceptors. L-glutamic acid is the most frequently occurring neurotransmitter in the CNS and plays an important role in a large number of physiological processes. The stimulation of the acid ester is divided into two main groups by the system. The first main group forms the ion channel controlled by the ligand. The metabolic shifting surface: the amine ester receptor (mGluR) forms the second main group. Groups, and further belonging to the group of G-protein coupled receptors. Currently, eight different member lines of these mGluRs are known, and some of them even have subtypes. With structural parameters, for secondary metabolic products _-7- _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622, A7 B7 V. Description of invention (4) Different orientations and differences in low molecular weight chemical compounds Based on affinity, you can make this eight The receptor is subdivided into three subgroups: mGluR1 and mGluR5 are assigned to group I, mGluR2 is responsible for group MGhiR3, and mGluR4, mGluR6, mGluR7 and mGluR8 are assigned to group III. The metabolically shifting glutamate receptor ligands of the group can be used to treat or prevent acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits. In this connection, other treatable-adapted signs are brain function limitation due to shunt surgery or grafts, poor blood supply to the brain, spinal cord injury, head injury, hypoxia caused by pregnancy, Cardiac arrest and hypoglycemia. Other treatable indications are chronic and acute pain, Huntington's disease, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye damage, retinopathy, and spontaneous Parkinson's syndrome Or Bajinsheng's syndrome caused by medicinal agents, and symptoms that cause glutamate deficiency, such as muscle cramps, cramps, migraine, urinary incontinence, convulsions, opioid addiction, anxiety, vomiting, difficulty in movement, and depression . The object of the invention is a compound of the formula I and a pharmaceutically acceptable salt itself, and as a pharmaceutically active substance, a medicament, a medicament based on the compound according to the invention and its manufacture, and a compound according to the invention in a controlled or Prevent the aforementioned types of diseases and the use of the respective pharmaceuticals. The compounds of formula I can also be used in their prodrug form. Examples thereof are esters, N-oxides, phosphoric acid vinegars, exemplified by ethyl sulphate g, and co-consumers of glycerol. Such prodrugs may increase the price of the compounds of the invention in terms of absorption, distribution, and kinetics of delivery to the brain. • _-^8-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 B7 V. Description of the invention (5) All tautomeric forms of the compounds of the invention are also included herein. Preferred are compounds of formula I wherein X is a single bond. Exemplary preferred compounds are those wherein R1 is trifluoromethyl, and especially wherein R3 is cyano, for example the following compound: 4-(4-keto-8-tetrahydro-l-l-yl-7- Trifluoromethyl·4,5-dihydro_3H•benzo[b][i,4]diazepine-2-yl)-pyridine-2-carbonitrile, 4-[8-(cyclopropyl) Methyl-methyl-amino) mercapto 7-trifluoromethyldihydro-3H-benzo[b][M]diazepine-2-yl]-pyridine-2-carbonitrile, 4 -[8-(cyclopropylindolyl-amino)-glycosyl-t-trifluoromethyl-4,5-dihydro- 3 benzo[b][l,4]diazepine-2-yl ]-pyridine-2·carbonitrile, 4-[4-keto-8-(2,2,2-trifluoro-ethoxy)-7-trifluoromethyl-4,5-dihydrogen Benzo[b][l,4]diazepine]-pyridine-2-carbonitrile, and 4-[8-(isopropyl-methyl-amino)butanyl-7-trifluoromethyl Base 4,5-dihydro-3H-benzo[b][l,4]diazepine-2-yl]-mouth ratio-2-method. Further preferred compounds are those wherein X is a single bond, R1 is a trifluoromethyl group and p3 is optionally substituted with a five-shell aromatic heterocyclic ring which can be substituted by _, fluoro-low carbon, fluorine-low carbon Oxyl, Daichi, -(CH2)n-NRfRn, <(3Η^η_(Χ〇>ΟΚ/, , -(C^rrCiOH^'R", -(CH2)nS〇2-NR'R ", -(CH2)nC(NH2)=NR,,, per-base, low-carbon enthalpy gas radical, low-carbon pit sulfur-substituted, or substituted by low-carbon alkyl, which is optionally fluorine-based, hydroxyl-based, low- Carbon alkoxy, cyano or amine fluorenyloxy. Examples of such compounds are the following: 7-Dimethylamino-4-[3-(3-methyl-isoxazol-5-yl) -phenyl]·8_trifluoromethyl-indole, 3·dihydro-muco[b][l,4]diazepine-2-indole, 7-dimethylamino-4-indole (2) _Methyl-2H-pyrazol-3-yl)-phenyl]trifluoromethyl-i,3- -9 - The paper scale is suitable for @@家标准(CNS) A4 specification (210 X 297 public) ) "~ 1296622 A7 ____B7 V. Description of the invention (6~" Dihydro-benzo[b][l,4]diazepine-2-indole, 7-dimethylamino-4-(3- Mimi-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][l,4]diazepine-2-one, 4 -[3-(3-Methyl-iso-(n-5-yl)-phenyl]-7-(methyl-propyl-amino)-8-trifluoromethyl-1,3-dihydro- Benzo[b][l,4]diazepin-2-one, isopropyl isobutyl-methyl-amino)-4-[3-(3-methylisoisoxazol-5yl) -phenyl]-8-trifluoromethyl-I,3-dihydro-benzo[b][l,4]diazepin-2-one, 7-(isopropyl-methyl-amino group )-4-[3-(3-methyl-yl-iso-sigma. sit-5-yl)-phenyl]-8-trifluoromethyl-U-dihydro-benzo[b][l,4 Diazepine-2-one, 7-(isobutyl-methyl-amino)-4-(3-{5-[(isopropyl-methyl-amino)-methyl]_[ Io,2,3] di-l-yl}-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine-2-indole Same as, 7-(isopropyl-methyl-amino)-4-[3-(5-tetrahydrop-pyr-1-ylmethyl-[ι,2,3]III. )-phenyl] each trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine, 7-(methyl-propyl-amino)-4- (3-[1,2,3]tris-l-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine-2 -ketone, 7-(isobutyl-methyl-amino)-4-(3-[1,2,3]tris.-1-yl-phenyl)trifluoromethyl_1,3- Dihydro-benzo[b ][l,4]diazepine-2-one, 4-(3-imithio-1-yl-phenyl)-7-isobutylamino-8-trifluoromethyl 4,3-di Hydrobenzo[b][l,4]diazepine-2-indole, 7-methylamino-4-[3-(4-methyl-P-plug. Sodium-2-yl)-phenyl]trifluoromethyldihydro-benzo[b][l,4]diazepine-2-one, 7-dimethylamino-4-[3-( 4-hydroxymethyl-oxazol-2-yl)-phenyl]|trifluoromethyl",3-dihydro-benzo[b][l,4]diazepine-2-one, -10 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) ' - 1296622 A7 B7 V. Description of invention (4-[3-(4-light methyl-thiazolidine-2-yl)> benzene 7-(methyl-propyl-amino)trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepin-2-one, and 4- [3-(5-Carbendyl-[1,3,4]thiadiazol-2-yl)-phenyl]-7-(methyl-propyl-amino)trifluoromethyl-1, 3-Dihydro-benzo[b][i,4]diazepine-2.one. Further preferred compounds are those wherein X is a single bond and R1 is a chloro group, for example the following compounds: 8-apartyl- 7-Isobutylamino-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydrobenzo[b][l,4]diazepine Hetero-2-one, _-8-chloro-7-(methyl-propyl-amino) ice [3-(5-tetrahydropyrroleylmethyl][H3]tris-yl-1-yl )-phenyl]-1,3·dihydro-benzo[b][1,·4]diazepine, 8-carbyl-7-(isopropyl-methyl-amino) [3_(5-tetrahydropyrrole small group methyl·[U3]tris-l-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepine· 2. 8-Chloro-7-(isobutyl-methyl-amino) ice [3_(5-tetrahydropyrrolidinylmethyl my diin-1-yl)-phenyl]-1,3 -Dihydro-benzo[b][i,4]diazepin-2-one, 8-carbyl-4-[3-(5-diamidinomethylazol-1-yl)benzene Isobutyl-methyl-amino)-1,3-dihydro-benzo[1,4]diazepine-2·酉, 4-[3-(5-azatetraindole-1) -ylmethyl-[丨,2,3]triazol-1·yl)·phenyl]|gas group; (isopropyl-methyl-amino group>1,3-dihydro-benzo[b] ][l,4]diazepine·2·one, 4-[3-(5--azinotetrakisylmethyl-H3]triazole+yl)phenyl]each gas group_7_(isobutyl) -methyl-amino)-1,3-dihydro-benzo[b][l,4]diazepine-2-g, 8-chloro-7-(isobutyl-methyl -amino): 4-[3-(5-hexahydrop-Bitter-1-ylmethyl-[ι,2,3]tris-l-yl)-phenyl]-1,3-dihydro -Benzo[b][l,4]diazepine-2-g, 8-chloro-7-(isopropyl-methyl-amino)-4-(3_{5-[(different Propylmercaptopurine)-methyl]-[1,2,3]triazole-l-yl}-phenyl)-1,3-dihydro-benzo-indole 54] Nitrogen leather l, -11 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 ___ B7 V. Description of invention (8) 8-Chloro-4-(3-{5- [(Isobutyl-methyl-amino)-indenyl]-[1,2,3]triazole small phenyl)-7-(isopropyl-methyl-amino)-1,3 -dihydro^-benzo[b][l,4]diazepine-2-S, 8-chloro-7-isopropylamino-4-[3-(3-methyl-iso Suzol-5-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepin-2-one, 8-carbyl-7-(isobutyl- Methyl-amino) winter (3-[1,2,3]triazol-1-yl-phenyl)-l,3-dihydro-benzo[b][l,4]diazepine- 2-ketone, 8-oxyl (3-imidazol-1-yl-phenyl)-7-isobutylamino-i,3-dihydro-benzo[b][l,4]diazepine Leather-2-ketone, 1-octyl-8-(ethyl-methyl-amino)-4-[3-(4-and fluorenyl...serzolyl)-phenyl]-1,3 -dihydro-benzo[b][l,4]diazepine-2·one, 8-carbyl-4-[3-(4-glycosylmethylpyrazole-2-yl)-phenyl ]-7-(Methyl-propyl-amino)-1,3-dihydro-benzo[b][l,4]diazepine, 8-carbyl-4-[3-( 4-Glysylmethyl-2-yl)-phenyl]K-isopropyl-methyl-amino H ,3-dihydro-benzo[b][l,4]diazepine-2-one, 8-oxo-4-indole (4-hydroxymethyl-thiazol-2-yl)-phenyl] -7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][l,4]diazepin-2-one, 8-carbyl-7-(B --methyl-amino)-4-[3-(4-methyl-methyl -2-yl)-phenyl]-1,3-dihydro-benzo[b][l,4] Diazepine-2-one, 8-chloro-4-[3-(4-hydroxymethyl]oxazol-2-yl]phenyl]-7-(methyl-propyl-amino 1 ,3-dihydro-benzo[b][l,4]diazepin-2-one, 8-chloro-m-[3-(4-hydroxymethyl]carbazole-2-yl)-benzene -7-(isopropyl-methyl-amino H,3-dihydro-benzo[b][l,4]diazepine-2-one, and 8-chloro-4-[ 3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-7-(isobutylmethyl-amino)-1,3-dihydro-benzo[b][l, 4] Diazepine-2-one. -12- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) ------ 1296622 A7 B7 V. Description of invention (9) Further preferred compound is where X is a single bond And R1 is a cyano group. Examples of such compounds are the following: 8-diethylamino-2-[3-(3-methyl-isocyton w--5-yl)-phenyl]-4-mercapto-4,5-di Chloro-3H-benzo[b][l,4]diazepine-7-indenecarbonitrile with 2-[3-(3-methyl-isoxazol-5-yl)-phenyl]butanone Base-8-hexahydropyridin-1-yl-4,5-dihydro-3H-benzo[b][l,4]diazepine-7-carbonitrile. Further preferred compounds of formula I are those wherein R3 is optionally substituted as a five membered aromatic heterocyclic ring which may be substituted by S, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, -(CH2) Nm, R", -(CH2)nC(0)-0R, ·, -(CH2)nC(0(10)(CH2)n-S02-NR'R", -(CH2)nC(NH2)=NR,,, The hydroxy, lower alkoxy, lower alkylthio group is substituted or substituted by a lower alkyl group, which is optionally substituted by a fluorine group, a hydroxyl group, a lower alkoxy group, a cyano group or an amine mercaptooxy group. Particularly preferred are compounds of formula I wherein R3 is optionally substituted as a five member aromatic heterocycle selected from the group consisting of thiazolyl, oxazolyl, isoxazolyl, imidazolyl, 2H-pyrazolyl, [1,2, 3] triazolyl, [1,2,4]triazolyl, [1,3,4]thiadiazolyl and [1,3,4]oxadiazolyl. Examples of such compounds are as follows. 7-Dimethylamino-8-phenylethynyl-4-(3-[1,2,3]triazol-1-yl-phenyl H,3-dihydro-benzo[b][l, 4] diazepine-2-one, 8-(2-fluorophenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-7-(2,2 ,2-trifluoro-ethoxy)-1,3-dihydro-benzo[b][l,4]diazepin-2-one, 7-(ethyl-methyl-amino)- 8-methyl -4: [3-(3-Methyl-isoxazol-5-yl)-phenyl]-I,3-dihydro-benzo[b][l,4]diazepaconone, 7 -Dimethylaminomethyl-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3·dihydro-benzo[b][l,4] Diazepine-2-one, -13- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 _______B7_._ V. Description of invention (1〇) Η isobutyl-A Methyl-amino)methylpipe [3-(3-methylisoxazolinyl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepine , 7-(isobutyl-methyl-amino) each of indole-4-[3-(5-tetrahydropyrrol-1-ylmethyl-[1,2,3]triazin-1-yl) -phenyl]-1,3-dihydro-benzo[b^M]diazepin-2-one, and 4-(3-{5-[(cyclopropylmethyl-amino)-A扣7-(isobutyl-fluorenyl-amino)-8-mercapto-1,3-dihydro-benzo[b][l,4]diazepine Hetero-2-one. Preferred other compounds are those wherein R 2 is _N(CH 3 ) 2 or tetrahydropyrrole. Preferred compounds are those wherein R 2 is isopropyl-amine-based, isopropyl-methyl-amine Base, isobutyl-amino or isobutyl-methyl-amine. ! Within the scope of the compounds of formula * was preferred, in which further] ^ 3 is a cyano group or optionally substituted aromatic heterocyclic ring of five, which may be 〇H or -CH2 - ch2n (ch3) 2 group. As used in this specification, the term "lower alkyl" means a straight or branched saturated residue having 1 to 7 carbon atoms, preferably having one carbon atom, such as methyl, ethyl, or positive. The term propyl, iso-propyl, etc. π low carbon alkoxy refers to a lower alkyl residue having the meaning previously defined and bonded via an oxygen atom. Examples of the "lower alkoxy" residue include a methoxy group, an ethoxy group, an isopropoxy group and the like. The term 'halogen' includes fluorine, gas, bromine and iodine. The term "π-low carbon alkyl" means a lower alkyl residue in which one or more hydrogen atoms may be replaced by a fluorine group. The term "fluoro-lower alkoxy" denotes a lower alkoxy residue having the meaning of the preceding meaning t, wherein one or more hydrogen atoms may be substituted by a fluoro group. The term C3 -c0-%alkyl" It means a cycloalkyl group containing 3 to 6 carbon atoms, _______ -14 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1296622

For example, cyclodecyl, 'cyclohexyl, cyclopentyl or cyclohexyl. , 立-犬犬瓜基碉 represents a low-carbon base residue, which has the above definition "heart" bound via a sulfur atom, such as methylthio. / Five members of the aromatic heterocyclic ring, the wording includes 吱 ” "cement, (four) "bilo, benzoxazole, pyrrol", carbazole, isoxazole, triazole ... diazole "sedazol and four. Sit. The preferred heterocyclic ring is Sanjun, U4-Sans, Iso, 1,3-thiazole, 1,3,4-oxadiazole or imidazole. Substituting " means that a group may or may not be substituted by one or more two preferably - or two substituents independently selected from a particular group. The term "pharmaceutically acceptable addition salt" means any salt derived from an inorganic or organic enemy. The compound of formula I, and pharmaceutically acceptable salts thereof, are prepared according to a number of methods which comprise a) bringing a compound of formula II

II reacts with a compound of formula IV or IVa

R

-15- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 V. Description of invention (12 where R is an alkyl group, preferably an ethyl or butyl group, which is a compound of the formula ΙΠ

R m followed by deprotection of the amine group and cyclization to obtain the compound of the formula

R° wherein R1, R2, R3, and oxime are as defined above, and if necessary, converts the obtained compound into a pharmaceutically acceptable acid addition salt.

Figure A R1

IV

Co2r toluene reflux -NHBoc

General procedure: Et, Βυ1 Μ X, ^ ^ 'NHBoc 冚

TFA R1

[A clumsy]. General procedure N

0

According to the formula A, a compound of the formula i, wherein χ, γ, R1, R2 and R3 are all 1296622 V. Description of the invention (13 A7 B7

As described above, "through deuteration - deprotection - cyclization sequence from a compound of formula II: for example, a compound of formula II is reacted with dioxanthone, wherein both ruthenium and RJ are as described above, In the inerting agent, such as toluene or xylene, at a high (f), preferably between 8 (TC and · · C, to obtain a general oxime compound ^ or a compound of the formula III may also be passed, for example, by the formula η The reaction of a compound with a ketone ester (Formula IVa) wherein ruthenium and ruthenium 3 are as described above, using the same conditions as described for the reaction with dioxostrenone. The B0C protecting group is cleaved, and the cyclization of the removed moieties is accompanied to produce the desired oxime compound. Any other suitable amine protecting group, such as Fm〇c or 芊oxycarbonyl (7), may alternatively be used. In place of BOC. The one-acting-cyclization step can be carried out by treating the compound of the general formula III with, for example, a bronzee acid such as difluoroacetic acid, in an inert solvent such as dichloromethane (DCM). The best is in the 〇. 〇 and 5 〇. It is advantageously carried out at a temperature. It is also advantageous to use toluene or hydrazine, hydrazine dimethoxybenzene as a carbocation scavenger in the reaction mixture. L__ - 17-degree suitable for si?i^(CNS) A4 size (10) X 297 mm )

Binding

1296622 A7 B7 V. Description of invention (14)

Figure B female. >彳彡 κ^〇

Via KOAc, PdCI2(PPh3)2 a dioxin garden.100 eC general then procedure

R1-!, Ν^003 D

PdCI2(PPh3)2

V or R, B(0H)2

Pd(丨丨)· a.PPh3 program

狯 E

Reduction by (General Procedure J) ·· a.) Catalytic argonization with Pd/C or Sonny-Ni b. ) SnCI2*2H20

c. ) Zn, NH4CI according to formula B, a compound of formula II wherein R1 is phenyl, optionally substituted as described above for a compound wherein X is a single bond, and R2 is as previously described, which may be via a different route, Depending on the nature of R1, it is prepared from a compound of the formula V iodine wherein R2 is as described above. As shown in Figure B, the key step is a Suzuki type coupling reaction to produce a compound of the formula Via. A compound of the formula II wherein R1, R2 and X are as defined above, which can be prepared according to the formula B, by reduction of a nitro group in the compound of the formula Via to an amine group. This reduction can be carried out, for example, using hydrogen in the presence of a suitable catalyst such as Raney nickel or |bar/carbon. Another possible reduction method is the use of vaporized stannous (II) (SnC12 · 2H2 0) in ethanol at temperatures between 70 ° C and 80 ° C (as in

Tetrahedron L 198 · 198 tip 25, 839), or, in a polar aprotic solvent, such as DMF, DMA or NMP, etc., optionally in the presence of a base, such as pyridine or triethylamine, etc. It is carried out at a temperature between 0 ° C and 80 ° C. Another -18- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (15) An appropriate method is to use zinc powder in the presence of vaporized ammonium in proton The solvent is, for example, water or ethanol at a temperature between 20 ° C and 80 ° C. For the exact conditions of the individual compounds of formula II, see the experimental section. Compounds of the general formula V, wherein R2 is as defined above, may be prepared by different routes depending on the individual residue R2:

Schema C

No2 NHBoc B1 ία CI^^NH2 NaOAc/ HOAc General Procedure

GP B, Method a: diphosgene, EtOAc, 77 ° C; then t-BuOH GP B, Method b: Boc20, CS2C03, 2-butyl copper, 52 ° C GP B, Method c: i) Boc20, DMAP, THF; ii) TFA, DCM, 0 °C

A. As shown in the formula C, the compound B1 can be obtained from the commercially available 5-chloro-2-nitroaniline by cleavage, thereby obtaining a synthetic intermediate A1, which in turn can be protected, and Compound B1 is produced. This step of decomposing can be carried out, for example, by using a gasification solution in acetic acid in the presence of sodium acetate. This reaction can be carried out, for example, at a temperature between 20 ° C and 80 ° C.

The protection of the amine functional group can be applied to a variety of commercially available starting materials or compounds synthesized by those skilled in the art to produce the corresponding formula VII -19 - the paper scale applicable to the Chinese National Standard (CNS) A4 size (210X 297 mm) 1296622 A7 B7 V. 2-Nitroaniline of (16), wherein X is a single bond, and R1 is as described above. This conversion will result in the primary intermediate of formula VIb, and the exact conditions for the individual compounds used in the present invention can be found in the experimental section. One possibility for the protection of the amine functional group is, for example, by reacting a compound of the formula VII with di-tert-butyl carbonate, in the presence of a base such as cesium carbonate. This reaction can be carried out in a polar solvent such as acetone or methyl ethyl ketone at a temperature between 20 ° C and 60 ° C. Alternatively, the protection of the amine group can be achieved by treating the compound of the formula VII with a phosgene to prepare an isocyanate intermediate, preferably in a protic solvent such as ethyl acetate or 1,4-dioxane. , at a temperature of 0 ° C to 100 ° C, followed by treatment of the isocyanate with a third - butanol, in a solvent such as dichloromethane or 1,2-dichloroethane, at 20 ° C and 85 ° The reaction is carried out at a temperature between C to give the desired compound of the formula VIb. Another suitable method for achieving this protection step is the formation of an intermediate of a bis-BOC compound by treating the compound of formula VII with di-tert-butyl carbonate in the presence of DMAP in an aprotic solvent such as Performing in tetrahydrofuran or the like, followed by selective removal of a single Boc-group by treatment with a brownitate such as TFA in a protic solvent such as dichloromethane, gas or 1,2-dichloroethane. It is carried out at a temperature between 0 ° C and 20 ° C to obtain the desired compound of the formula VIb. According to the formula D, a compound of the formula VII, wherein R1 is a pyrrol-1-yl group which is optionally substituted as described above, X is a single bond 'and R is a chloride, and can be produced from a known 5-nitro-2-nitro group. -1,4-phenylenediamine [CAS No. 26196-45-2] by selective condensation of a 4-amino group with an appropriately substituted 2,5-dimethoxytetrahydrofuran of the formula VIII, It is carried out as described in J. Heterocycl. Chem. 1988, 25, 1003. -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622

Schema D

Preferably, the reaction is carried out in an acid a/f raw medium, such as acetic acid or propionic acid, and the cup is formed at a temperature between 4 ° C and ioo ° C. The conditions can be found in the experimental section. Μ The corresponding substituted 2,5-dimethoxytetrahydrofuran of the formula VIII, wherein R, R and R are as described above in the general request for pyrha-based compounds Said to be commercially available or synthesized from an appropriately substituted furan, as shown in the formula, wherein the substituents may be protected by suitable protecting groups known to the artist, or It can be introduced after the synthesis of the pyrrole ring. The two-step sequence includes reacting furan with bromine in Me〇H at a low temperature such as _35. ' followed by, for example, triethylamine or potassium carbonate or hydrogencarbonate. The treatment is carried out. The 2,5-dimethoxydihydrofuran of the formula VIII is formed, wherein Ra, Rb and Rc are all as described above, and can be reduced by catalytic hydrogenation, preferably in Me〇H. Using a catalyst such as palladium on carbon or Raney nickel to produce the desired 2,5-dimethoxytetrahydrofuran of the formula VIII An example of this sequence can be found in Tetrahedron 1971, 27, 1973-1996. -21 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mm).

Line 1296622 A7 B7 V. Description of invention (18)

Scheme E R*

Br2, MeOH •35 *C and then 狯

For the exact conditions of the individual compounds to be synthesized, reference is made to Experimental Part 0. As shown in Formula F, a compound of the formula Vic-, wherein R2 is attached via a nitrogen atom and is as described above, can be prepared from the formula VIb. The intermediate compounds - their individual synthesis can be referred to the experimental part - by nucleophilic substitution reaction with the guanidine amines, in the presence of an appropriate assay. Schema F

No2 NHBoc R'R-NH DMS〇 or

R = Cl, F

Et3N/DMS〇 Δ General Procedure C

Vic R2 = NR'FT This reaction is preferably carried out in a polar aprotic solvent such as dimethylformamide, N-methyl-tetrahydropyrrolidone or diterpenoid; The base may be selected from sterically hindered amines such as triethylamine or Hunig, burned oxides such as sodium methoxide and sodium tributoxide, or hydrides such as sodium hydride. This reaction can be carried out at a temperature between 20 ° C and 110 ° C depending on the individual compound to be synthesized. -22- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (19)

Schema G

R

N02 NHBoc V

Ar—= Pda2(pphj2, pph3 Cul, E^N

THF 60 eC

VId Ar-X A program

Me, Si—= PdCI2(PPh3)2, PPhg Cul, EtgN

H

SnCl^^O EtOH 70 eC program j, method b R;»! NHj NHBoc Π

THF, 50 eC general course shore Η then NaOH, ΜθΟΗ

PdCI2(PPh3)2, PPhg Cul, EtgN THF 60 eC General. Procedure Η

According to the formula G, a compound of the formula II, wherein R1 is as described above for a compound wherein X is an acetylenediyl group, can be prepared from the iodine compound V by a different route depending on the nature of R1 and R2. As shown in Scheme G, this transformation can be carried out, for example, in the following manner: a) via a Sonogashira type coupling, the R1 - alkynediyl-substituent is directly attached to the compound of formula V to yield a compound of formula VId, followed by nitrate Substituting, or b) by two stepwise Sonogashira type couplings, wherein the trimethyl oxalyl acetylene is first coupled to a compound of formula V, which is dealkylated with sodium hydroxide in methanol to produce an intermediate X, which can then be converted to the compound of formula VId and the reduction of the nitro group via the second Sonogashira type coupling using the appropriate reactants R1 -I, R1 -Br or R1 -OS〇2 CF3, resulting in the desired a compound of formula II. See the experimental section for the exact conditions for individual compounds. -23- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (2Q)

Method a) K,0· A^c〇2r R* - Et, Bu*

MgCI2. E^N CH3CN Method b)

Jf LDA· UOBu丨 Calcium Bul THF, -78 eC

IVa R* = H, Et, Bu1 Y = CHt N

R = Cl, OH, OMe, OEt method c) Y = CH, N

Me3Si02C>^C02SiMe3

1.) LiBr, EtgN, CH3CN or 2.) BuLi, EtjO General Procedure

K

IV Y = CH,N

R' = Η, Bul Y =CH, N Method a) Isopropyl ketone acetate concentrated k2 S〇4 Method b) TFAA, TFA, acetone

General-Procedure L According to the formula Η, the dioxetosterone and /?-ketoester structural units of the formulae IV and IVa can be prepared from the corresponding carboxylic acid derivatives by methods known to those skilled in the art. R3 -COR, meaning free acid, methyl or ethyl ester and gasified hydrazine. The exact conditions of the corresponding compounds can be found in the experimental section. The pharmaceutically acceptable salt can be readily prepared according to methods known per se, and the nature of the compound to be converted into a salt. Inorganic or organic acids such as 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-toluene An acid or the like is suitable for forming a pharmaceutically acceptable salt of a basic compound of formula I. A compound of formula I, and a pharmaceutically acceptable salt thereof, are metabolically shifting glutamate receptor antagonists and are useful in the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, arz Hermes Disease, Recognition - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7

Know the illness and lack of memory. Other treatable indications are brain function limitation due to shunter I or graft, poor blood supply to the brain, spinal cord injury, head injury, hypoxia caused by pregnancy, and cardiac arrest: And low blood sugar. Other treatable indications are acute and chronic pain with Duns' chorea, ALS, dementia caused by AIDS, eye injury: retinopathy, spontaneous Bajinsheng's syndrome or caused by medication Birth's sign (4), sputum and can lead to (four) acid-supplemented disorders, chain 2 muscle spasm, phlegm, migraine, urinary incontinence, cravings, psychosis, addiction, anxiety, vomiting, difficulty in sports and depression. The phantom compound and its pharmaceutically acceptable salt can be used as a medicament, for example, in the form of a main pharmaceutical preparation. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, sugar-coated labels, hard and soft gelatin capsules, solutions, emulsifiers or dance floats. However, administration can also be effected rectally, for example in the form of a test, or parenterally, for example in the form of an injection solution. The compound of formula I, and pharmaceutically acceptable salts thereof, can be treated with a pharmaceutically inert, inorganic or organic carrier to produce a pharmaceutical preparation. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as such carriers in tablets, coated tablets, dragees and hard gelatin capsules. Suitable gelling agents for soft gelatin capsules are, for example, vegetable oils, terpenes, fats, semi-solid and liquid polyols, etc., depending on the nature of the active substance. However, in the case of soft gelatin capsules, a carrier is generally not required. For the preparation of solutions and syrups Z suitable carriers are, for example, water, polyols, sucrose, invert sugar, glucose, and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used for the aqueous solution of the compound hydrazine salt and the aqueous solution, but are usually not required. Suppositories -25 - 5. Description of the invention (22 appropriate carriers, such as natural or hard), liquid or liquid polyols, etc., one / master, wax, fat, half, in addition, such pharmaceutical preparations Us,,, wetting agent, emulsification, &quot; A 蜊, solubilizer, stabilizer, osmotic pressure: slow two doses, coloring agents, flavoring agents, substances used to change the price of osmotic treatment. ^ can contain the following:::, containing the compound! or its pharmacologically inert excipient drug Nanshi (Luohe / oral preparation h*, #明之-project, this medicine </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; - The dosage of the galenical agent can be varied within a wide range of conditions, and of course, in accordance with the specific requirements of the individual conditions. In general, the effective dose for oral or parenteral administration is 0. _mg/kg/day, where 〇1_1〇mg/kg/day full dose, for all The application system is preferred. The daily dose for an adult weighing 70 kg is therefore between 0.7 and 1400 mg per day, preferably between 7 and 7 mg per day. Use of a compound of I and a pharmaceutically acceptable salt thereof for the manufacture of a medicament, in particular for the control or prevention of an acute and/or chronic neurological disorder of the type mentioned hereinbefore. The compound of the invention is a Group II mGlu receptor Antagonists. These compounds, when measured in the assays described below, exhibit activity of 10 AM or less, '-...one..... ----——--^一——一- ^ , typically 1/M or less, and ideally 〇.3 &quot;Μ or smaller. One, /.〆·.. -26- This paper scale applies to China National Standard (CNS) A4 Specification (210 x 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (23) In the following table, some specific Ki値 of the preferred compounds are described. Compound Kj mGlu2(//M) 3-(8-Dimethylamino) 4-keto-7-phenylethylidene-4,5-dihydro-3H-benzo[b][l,4]diazepine-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][l,4]diazepine-2-one 0.070 8- Chloroyl-7([2-methoxy-ethyl)-methyl-amino]-4_[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3 -Dihydro-benzo[b][l,4]diazepine-2-one 0.025 8-chloro-7-dimethylamino-4-[3-(2-methyl-2H-pyrazole 3-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine-2-one 0.023 8-chloro-7-dimethylamino-4- [3-(4-Hydroxymethyl-thiazol-2-ylphenyl H,3-dihydro-benzo[b][l,4]diazepine-2-one 0.030 8-(2-gas winter -4-[3-(3-methyl-isosaki 17-spin-5-yl)-private]-7-(2,2,2-trifluoro-ethoxy)-1,3-di Hydrogen-benzo[b][l,4]diazepine-2-one 0.03 8-chloro-7-dimethylamino-4-[3-(4-hydroxymethyl-carbazole-2- -phenyl-H,3-dihydro-benzo[b][l,4]diazepine-2-one 0.039 8-chloro-7-(mercapto-propyl-amino)-4 -[3-(5-hydroxymethyl-[1,2,3]triazole small)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine- 2-ketone 0.030 8-chloro-7-(diethyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl] -U-dihydro-benzo[b][l,4]diazepine Leather-2-ketone 0.044 8-carbo-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-tetrahydropyrrole-1- -1,3-dihydro-benzo[b][l,4]diazepine-2-one 0.019 8-carbyl-7-(cyclopropyl-methyl-amino) ice [3- (5-Hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine-2- 0.1同0.16 8-chloro-7-dimethylamino-4-(3-pyrazole small-phenyl)-1,3-dihydro-benzo[b](l,4]diazepine 2-ketone 0.11 7-dimethylamino-4-[3-(3-morpholine-4-ylmethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl- 1,3-dihydro-benzo[b][l,4]diazepine-2-one 0.125

Binding

_-27- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ______B7 V. Description of invention (24) Compound K: mGIu2(//M) 7--Methylamino- 4_[3-(2-Methylthio-mi-sodium-based small base) 'Benzene 1 : Dunmethyl-1,3-dihydro-benzo[b][l,4]diazepine: '-two I \8 , 0.019 4-[8-(cyclopropylmethyl-methyl-aminopurine-5-dihydro-3H-benzo[b][l,4]diazepine-ylpyridine/carbonitrile &lt; - 0.005 4-[3-(5-Cyclopropylaminomethyl-[1,2,3]triazole-monomethylamino-8-triisodecyl-1,3-dihydro-benzo41 - Noisy-2-ketone L - chaotic 0.049 4-[4-keto group (2,2,2-difluoro-ethoxy]7-iTtr?^4;5. monohydro-3H- And [b][l,4] diazepine, 2-yl 1-p ratio dimeronitrile 0.004 3-[7-fluorenyl-8-(methyl-propyl-amino)-4" 4·5-diox-3Η-benzo[b][l,4]diazepine-2-yl]-benzonitrile'-&amp; · 0.025 8-gasyl-4-[3- (5-Methyl-[1,2,3]di-n-yl)-phenyl]·7·( butyl-methyl-amino)-1,3-dipho-benzo[ b][l,4]diazepine-2-one-anthracene 0.02 8-monoethylamino-2-[3-(3-methyl-isoxazol-5-yl) -phenyl] mercapto-4,5-dihydro-3H-benzo[b][l,4]diazepine π-compensation 0.009 4-[3-(5·-nitrotetradecyl) Base-[1,2,3]trixyl]yl]-7-(indolyl-propyl-amino)-1,3-dihydro-benzo-j 41 -ketone' 0.015 8-chloro-4-[3-(5-permethyl-[1,2,4"tris.-l-yl)-phenyl]winter (isobutyl-methyl-amine ))-1,3-dihydro-benzo[b][l,4]diazepine-2-indole. 0.089 7-(methyl-propyl-amino)-4-(3- [1,2,4]triazol-1-yl-phenyl&gt;8-difluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine-2-one 0.027 Ηisobutyl-methyl-amino)-4-(3-[1,2,4]tricate-phenyl) 8-trifluoromethyl-1,3-dihydro-benzo[b ][l,4]diazepine-2-one 0.012 8-carbyl-4-[3-(4-||methylpyrazol-2-yl)-phenyl]-7-(isobutyl -methyl-amino)-1,3-dihydro-benzo[b]indene 1,4]diazepine-2-one 0.003 8-chloro-7-didecylamino 4-[3 -(2-ethylaminomethylpyrazole-4-yl)-phenylindole,3-dihydro-benzo[b][l,4]diazepine-2-one 0.48 ___-28- paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A 7 B7 V. DESCRIPTION OF THE INVENTION (25) Chemical complex Kj mGlu2(//M) 7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,3,4]thiadiazole- 2-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine aspartame with 0.017 7-dimethylamino-4- [3-(2-Mercapto-5-propyl-oxazol-4-yl)-phenyl]-8·trifluoromethyl-1,3-dihydro-benzo[b][l,4] Diazepine-2-one 0.046 4-[3-(5-Hydroxymethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-7-(methyl-propyl- Amino)-8-dimethyl-1,3-1,3-diaza-benzo[b][l,4]-azaindole-2-one 0.008 PH1-LY354740 binds to mGlu2 transfected CHO cell membrane Infection and cell culture The cDNA encoding the mouse mGlu2 receptor protein in pBluescript II was obtained from S. Nakanishi (Sakamoto Kyoto) and subcultured asexually from Invitrogen (NV Leek, Netherlands). The nucleus cell expression vector pCDNA I-amp. This vector construct (pcDlmGR2) was co-transfected into CHO cells with the psvNeo plasmid encoding this gene to provide neomycin resistance, as modified by the calcium phosphate method described by Chen &amp; Okayama (1988). These cells were maintained in Dulbecco's Denature Eagle Medium with reduced L-Wei S-amine (2 mM final concentration) and 10. . Bovine fetal serum obtained from Gibco BRL (Basel, Switzerland) was dialyzed. The selection was carried out in the presence of G-418 (final 1000 μg/ml). The clonal propagation line was confirmed by a total of 5 μg of RNA reverse transcription, followed by PCR using the mGlu2 receptor-specific primer 5'-atcactgcttgggtttctggcactg-3· and 5'-agcatcactgtgggtggcataggagc-3, in 60 mM TrisHCl (pH 10). , 15mM (NH4)2S04, 2mMMgCl2, 25 units / ml Taq polymerase, 30 cycles of tempering at 60 ° C, after 1 minute, extended at 72 ° C for 30 seconds, and 1 minute 95 ° C Denaturation. — ___ -29-__ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (26) Cell membrane preparation The cells cultured as described above were washed three times with cold PBS. And freeze at -80 °C. The pellet was resuspended in cold 20 mM HEPES-NaOH buffer (pH 7.4) containing 10 mM EDTA and homogenized for 10 seconds at 10,000 rpm with a Polytron (Kinematica, AG, Littau, Switzerland). 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 (pH 7.4) containing 0.1 mM EDTA. The Pierce method (Socochim, Lausanne, Switzerland) was used to measure the protein content and bovine serum albumin was used as a standard. [3H]-LY354740 After thawing, the cell membrane was resuspended in cold 50 mM Tris-HCl buffer (pH 7) (binding buffer) containing 2 mM MgCl2 and 2 mM CaCl2. The final concentration of cell membrane in these assays was 25 micrograms protein per milliliter. An inhibition experiment was carried out in which the cell membrane was cultured at 10 nM [3H]-LY354740 at room temperature for 1 hour in the presence of various concentrations of the test compound to be tested. After the incubation, the cell membrane was filtered on a Whatmann GF/C glass fiber filter and washed 5 times with a cold binding buffer. The non-specific combination is measured by 10 //M DCG IV. After the filter was transferred to a plastic vial containing 10 ml of Ultima-Gold scintillation fluid (Packard, Zurich, Switzerland), it was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zurich, Switzerland). Radioactive. Data analysis The inhibition curve is consistent with the four-parameter calculation equation, and the Kj値 and Hill coefficients are obtained. __-30- This paper size is applicable to China National Standard (CNS) Δ4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (27) Example

General Procedure A Preparation of 4-iodo-2-nitroaniline f by iodination of 2-nitroaniline according to Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983, 365 2317-25 Add HOAc (300 ml) to 2-nitroaniline (1.0 mol) in a stirred solution of anhydrous NaOAc (93-103 g, 1.125-1.25 mol) in HOAc (500 mL) over 60 min. Iodine monochloride (59-66 ml, 1.125-L25 mol). The reaction mixture is heated to a specific temperature until thin layer chromatography (TLC) shows complete conversion of the starting material, stirring at 23 ° C for an additional 30 minutes, then slowly diluting with Η 2 Ο (1000 ml), which will Causes separation of crystalline products. The mixture was continuously stirred for 1 hour, and the product was filtered off, washed with HOAc, and dried in a hollow and at 60 °C. Example A1 5_Gasyl-4-Grytyl-2-Sytyl-Winterylon The title compound is iodized in HOAc/NaOAc according to the general procedure A (80 ° C), iodine, in 5-Ac Keto-2-nitroaniline. Obtained an orange solid. MS (EI) 298 (M+) and 300 [(M+2)+]; mp. 202-203. General procedure B: Preparation of 2-nitroaniline from 2-nitroaniline (2-nitro-phenyl)-amine carbamic acid Third-butyryl method Method a (from 2-nitroaniline): in diphosgene (4.1 ml) , 34.1 mmol, a solution of 2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL) in EtOAc (40 mL) Heat to reflux for 18 hours. The solvent was removed in the air, leaving a brown solid which was triturated with hot hexane (200 mL). Filtration of solid matter and filtration _-31 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (28) The liquid is concentrated under reduced pressure, leaving The pure 2-nitrophenyl isocyanate is a yellow solid. This material was refluxed in excess of a mixture of the third-BuOH in CH2C12 for 2.5 hours. The solvent was removed, leaving an orange solid, which was purified using hexane/EtOAc eluting with EtOAc EtOAc. It is a yellow solid. Method b (from 2-nitroaniline): in a mixture of 2-nitroaniline (142 mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 ml) A solution of Boc2(R) (37.8 g, 173 mmol) in 2-butanone (170 mL) was added dropwise, and the resulting mixture was stirred at 50 ° C to 80 ° C until TLC showed complete conversion. The residue was taken up in EtOAc (EtOAc) (EtOAc) The combined hexane layers were washed with brine (200 mL) and then evaporated and evaporated. The combined calcined layers were dried over MgSO4, filtered, and evaporated in vacuo to afford crystals eluted with EtOAc EtOAc EtOAc Phenyl) amidinoic acid tert-butyl ester as a yellow solid. Method c (from 2-nitroaniline): in 2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23 ° C A solution of Boc20 (246 g, 1128 mmol) in THF (500 mL) was added dropwise over 70 min. The bulk mixture was evaporated to dryness and dried under HV to leave a dark brown solid. This material was dissolved in DCM (1100 mL), cooled to EtOAc (EtOAc) The mixture was stirred at 〇 ° C for 2 hours, poured into ice-cold saturated NaHC03 solution, extracted with DCM, washed with brine-32- This paper scale was applied to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (29) Polyester and dehydrated and dried with MgS04. The solvent was removed in the sputum, leaving a dark brown solid which was applied to EtOAc (EtOAc) elute The third-butyl ester of the acid is a yellow solid. Method d (from 2-nitroacetanilide): 2-nitroacetanilide (1 mmol) with DMAP (122 mg, 1 mmol) in THF (100 mL) In a solution at ° C, a solution of Boc2(R) (22.92 g, 105 mmol) in THF (100 mL) was added dropwise over 15 min, and stirring was continued at 23 ° C until TLC showed complete Conversion so far. The bulk mixture was evaporated to dryness and dried under HV to leave a dark brown solid. This material was dissolved in THF (200 mL) and 25% NH4OH (77 mL, 500 mM) was added dropwise. The mixture was stirred at 23 °C until TLC showed complete conversion, poured into &lt;EMI ID&gt;&gt; The solvent was removed in the sputum to leave a yellow-brown solid which was substantially pure enough for further conversion or, if necessary, applied to the ruthenium and hexane/ EtOAc via a ruthenium tube column Purification afforded (3-nitro-phenyl)-amine methyl acid as a yellow solid. Example B1 (5-fluorenyl-2-stone succinyl)-amine methyl acid succinimide The title compound is according to the general procedure B (method a), via isocyanate, from 5-chloro-4-iodo- 2-Nitro-aniline (Example Α 1) (7.5 g, 23.45 mmol) with diphosgene (2.12 mL, 17.6 mmol) in EtOAc (30 mL) then CH2CI2 Made in the third -BuOH (100 ml) of the milliliters -33- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 ____ B7 V. Invention description (30) ' ' &quot;~ . Obtained as a yellow solid (7.1 g, 76%). MS (EI) 398 (M+) with 400 [(M+2)+]; m.p. 82-84 ° C. Example B2 (4,5-dichloro-2-nitro-phenyl)-amine methyl acid The tri-butyl ester title compound is based on the general procedure B (method c), via the bismuth (&gt; compound, commercially available 4,5-diox-2-nitroaniline (15 g, 72.5 mil). Mol) was prepared with Boc20 (32.4 g, 148.5 mmol) eluting with 2 eq. of TFA in CH.sub.2 C12 to afford a brown solid (21.63 g, 97 〇 / 〇). MS (ISN) 305 [ (Μ-Η)-]; Melting point 68-73 ° C. Example Β3·Pan: _Fluoro-2-nitro-4-trifluoromethyl-phenyl y-amine methyl acid tert-butyl ester title compound According to the general procedure 方法 (Method c), via the bis-B〇c_compound 'from 5-fluoro-2-nitro-4-trifluoromethyl-aniline (5.21 g, 23.2 mmol) [ Prepared from commercially available 4-amino-2-fluorobenzotrifluoride, which is acetonitrile at 23 ° C via AC 2 oxime in toluene. , nitration at 1 〇 23 ° C, and in THF at 5 ° ° C, with 2N NaOH to remove the B S stidid] and Bobo (10.63 g, 48.7 mmol), followed by in CH2C12 2 when Prepared by TFA to give a pale-yellow solid (6 33 g, 84 〇 /.) MS (ISN) 323 [(M-Η).]; melting point l 〇 4 ° C. Example B4 任:换基-2 -Saki-based-5-(2,2,2-trifluoro-ethoxy group of 1-aminomethyl acid tert-butyl ester. The title compound is according to the general procedure B (method c) via di-Boc- Compound 'from 4-bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-aniline (10.41 g, 29 Amor) [via DMSO (60 mL) 5-Alkyl-4-iodo-2-nitrophenyl-34· This paper scale is suitable for 0 g home (CNS) Α4·(21〇X 297 public) ' 1296622 A7 B7 V. Description of invention ( 31) Amine (by example Al) (8.95 g, 30 mmol), 2,2,2-trifluoroethanol (3 liters) and hydrazine (4.36 g, 66 mmol) at 23 (: made under stirring for 35 days) and b〇c2〇 (12.87 g, 59 mmol), followed by treatment with 2 equivalents of TFa in 2%. Obtained a yellow solid (13.34 g, 100%) MS(ISN)461 [(MH)-]· Example B5 Pan: Oxyoxo-l-fluoromethyl-phenylamine methyl acid Tri-butyl ester The title compound is based on the general procedure (Method c ), via the second seven (&gt; 5-purchase-nitrosomethyltrifluoroaniline [CAS-No. 35375-74·7] (22.61 g, 94 mmol) and Boc20 (42.06 g) , 193 millimoles) 'Subsequently treated with 2 equivalents of TFA in CH2 〇2. Obtained a yellow solid (31.82 g, 99.). MS (ISN) 339.1 [(M-Η)·] and 341 [(M+2-H)-]; melting point 113-115 ° C. Example B6 (5-Alkyl-4-fluoro-2-nitro -Phenyl)-Aminomethyl Acid The third title compound is a commercially available 3,-chloro-4f-fluoro group according to the general procedure B (Method d), via the di-B〇c-compound'. Base-6,-nitroacetanilide [CAS-No. 81962-58-5] (59 g, 254 mmol) and b〇c20 (58.13 g, 266 mmol) 'Next NH4 OH (25 .., 77.5 ml, 507 mmoles. Obtained a yellow solid (73.53 g, 100%). MS (ISN) 289 [(M-Η)·] and 291 [(M+2'H)-melting point 73-74 Ό. Example B7 -H2,2,2-tris-ethoxy-H-trifluoromethyl -Stupid 1-Aminomethyl Acid Third - Ding Yu-35- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1296622 A7 B7 V. DESCRIPTION OF THE INVENTION (32) The standard 4 compound is based on the general procedure B (method c), via a di-Boc compound, from 4-iodo-2-nitro-5-(2,2,2 -Trifluoro-ethoxy)-aniline [via &gt; chloro-4-iodo-2-nitrophenylamine (example Al), 2,2,2-trifluoroethanol and KOH in DMSO, This was prepared by stirring at 23 ° C for 32.5 days to give Boc 20 followed by treatment with 2 equivalents of TFA in CH 2 C 12 . Obtained a yellow solid (18.955 g). MS (ISN) 403 [(MH)·]· Example B8 (5-Alkyl-4-methyl-2-nitro-phenylamine methyl acid, the third-butyl hydrazine title compound is based on the general procedure B (method c), commercially available 5-chloro-4-methyl-2-nitroaniline (1 〇. gram, 53.6 mmol) and Boc20 (23.9 g) via di-Boc-compound Prepared by treatment with 2 equivalents of TFA in CH.sub.2.sub.2.sub.sub.sub.sub.sub.sub. 285.1 [(MH)·]. Example B9 (4-cyano-5-fluoro-2-nitro-phenyl)-amine methyl acid tert-butyl ester The title compound is based on the general procedure B (method c ), via bis-B〇(&gt; compound, from 4-cyano-5-l-yl-2-nitroaniline (24.9 g '137 mM Moer et al., J. Med. Chem. 1994, 37, 467-475] and Boc20 (61.5 g, 282 Torr), followed by treatment with 2 of CH2Cl in f TFA. Obtained by column chromatography (hexane / ethyl acetate 4:1) f color solid (14.5 g, 390 〇) MS (ISN) 280.1 [(MH)*]· General procedure C: 5-N-substituted-(2-nitro-stupyl V amine methyl acid third-butyl Ester production difference" • 36·

Thai Paper Scale Qualification® Home Standard (CNS) A4 Specification (21Gx297 Θ 1296622 A7 B7 V. Invention Note (33) Will (5-Alkyl or -Fluoro-2-nitro-phenyl) Amine The third acid of the base acid and the desired amine, optionally accompanied by DMS0, DMF, DMA, Guan or thf and / or DIPEA or EtgN, stir at 23 ° C to 130 ° C until TLC shows The gas or fluoride ruthenium disappears completely. The reaction is cooled to, poured into ice water, the precipitate is taken out, washed with water, and dried in the air. If the product is not precipitated, the mixture is extracted with Et0Ac. Washed with water and brine, dried over Na~SO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compound. Example C1·I-oxy-5-dimethylamino i-nitro-p-styl-v-amine methyl acid tert-butyl ester The title compound was obtained from DMSO at 23 ° C according to General Procedure C ( 35 liters of (4,5-dichloro-2-nitro-phenyl)-amine methyl acid tert-butyl ester (example Β 2) (3.0 g, 9.77 mmol) and dimethyl Amine (5 .6 N, 8.7 ml, 48.8 mmol in EtOH. Obtained a yellow solid (2·81 g). MS (ISP) 316 [(Μ+Η)+] and 318 [(Μ+2+Η) +]; melting point 136-138 Ό · Example C2 (5-dimethylamino-4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester The title compound is according to the general procedure C, In a sealed tube, tris-butyl (5-carbyl-4-iodo-2-nitro-phenyl)-amine methylate (example Β1) (399 mg, 1 mmol) and dimethyl Amine (5·6 Ν, EtOAc (3 mL), EtOAc (EtOAc) EI) 407 (M+); Melting point 120-122°C . -37- This paper size is applicable to China National Standard (CNS) A4 size (210X297 mm) Binding

Line 1296622 A7 ____ B7 V. Inventive Note (34) Example C3 H: Chloryl·5·Π&gt;Methoxy-ethyl)-indenyl-amine-based ι·2_nitro-jamman-aminomethyl The acid tert-butyl ester title compound was prepared according to the general procedure C, (4,5-di-2-nitro-phenyl)-amine methyl acid in DMSO (20 mL) at 23 °C. Third-butyl ester (Example B2) (3.07 g, 1 mmol), N-(2-methoxyethyl)decylamine (2.43 mL, 23 mmol) and Ets N (4.2 mL) , 30 millimoles). Obtained brown oil (3·57 g). MS (ISP) 360 [(M+H)+] and 362 [(M+2+H)+]· Example C4 (5-dimethylamino-2-nitro-4-trifluoromethyl-phenyl) Aminomethyl acid tert-butyl ester The title compound was prepared from DMSO (10 tL) (5-fluoro-2-nitro-4-trifluoromethyl) at 23 ° C according to General Procedure C. -Phenyl)amine methyl acid third-butan (Example B3) (1.62 g, 5.0 mmol) and dimethylamine (5.6 N in EtOH, 4.47 mL, 25.0 mmol). (1·48 g) MS (ISN) 348 [(Μ-Η)·]; melting point 1 l〇 ° C. Example C5 [4-Chloro-5-(ethyl-methyl-amino)-2 -Nitro-p-butyl 1-aminomethyl acid tert-butyl ester The title compound was prepared from DMSO (35 mL) at room temperature according to General Procedure C (4,5-diox-2-nitrogen) Base-phenyl)-amine methyl acid third-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-ethyl-methylamine (2.89 g, 48.8 mmol). Solid (3.12 g), MS (ISP) 330.3 [(Μ+Η)+]; melting point 94 ° C · Example C6 "4-chloro-5-(methyl-propyl-amino)-2 -nitro-phenyl 1-amine methyl acid third-butyl ester-38- This paper scale applies to China Household Standard (CNS) A4 Specification (210 X 297 mm) 1296622 A7 B7 V. Description of Invention (35) The title compound is prepared from DMSO (30 ml) at room temperature according to the general procedure C (4,5) -Dichloro-2-nitro-phenyl)-amine mercapto acid tert-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-mercapto-propyl-amine (2.50 g, 34.2 Obtained as a pale brown solid (3.58 g). MS (ESI) 344.3 [(M+H)+]; mp 68 ° C · Example C7 [4-carbyl-5-(diethyl-amino) -2-Nitro-phenyl 1-aminomethyl acid tert-butyl hydrazine titled compound (4,5-dichloro) from DMSO (35 ml) at 60 ° C according to the general procedure C 2-Nitro-phenyl)-amine mercapto acid tert-butyl ester (Example B2) (3.0 g, 9.77 mmol) and diethyl-amine <3.57 g, 48.8 mmol). Solid (2.63 g) MS (ISP) 344.3 [(M+H)+]; mp. 95 ° C. Example C8 (jb oxy-2-nitro-5-tetrahydropyrrol-1-yl-phenyl) Aminomethyl acid tert-butyl ester The title compound was prepared according to the general procedure C from (4,5-di-nitro-2-phenyl-phenyl)-amine methyl acid in DMSO at 23 °C. three· Ester (Example B2) and pyrrolidine. A yellow solid (6.65 g) was obtained. MS (ISP) 342 [(M+H)+] and 344 [(M+2+H)+]; mp 157-158 ° C. Example C9 Iji-Keki-5-(cyclopropyl--amino) · 2 nitro-stupyl &gt; Amino acid tert-butyl ester The title compound is prepared from DMSO (30 liters) at 23 ° C according to the general procedure C (4,5-II) Gas-2-decyl-phenyl)-amine methyl acid tert-butyl ester (Example B2) (3.07 g, 1 〇 mmol) and cyclopropyl-methyl hydrochloride (3 22 g, 3 〇 millimoles) and EtsN (6.97 ml, 50 millimoles). A yellow solid (325 g) was obtained. -39-

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Line 1296622 A7 ____B7 V. Description of invention (36) MS (ISP) 342·2 [(Μ+ΗΠ and 344 [(Μ+2+ΗΠ; melting point l〇4_106°C ·

Example CIO Tetrahydropyrrole small base trifluoromethyl-phenyl)-Aminomethyl acid tert-butyl ester The title compound was prepared from DMSO (70 mL) at 23 ° C according to General Procedure C ( 5-oxo-2-nitro-4-trifluoromethyl phenyl)-amine methyl acid third · butyl vinegar (example Β 5) (6·81 g, 20 mmol) and tetrahydropyrrole ( 8.27 ml, 1 〇〇 millimolar). Obtained as a yellow solid (7.35 g). MS (ISN) 374 [(M-Η)·]; mp 138-141 ° C. Example C11 dimethylamino-4-fluoro-2-nitro-phenyl-V-amine methyl acid tert-butyl ester The title compound is (5-chloro-4-fluoro-2-nitro-phenyl)-amine methyl acid in DMSO (35 liters) at 23 ° C according to the general procedure C. -butyl ester

Example Β6) (4·94 g, 17 mmol) with Me2NH (40 〇., in H20, 7.9 M ' 10.9 mL, 86 mmol). Obtained a yellow solid (4·93 g). MS (ISP) 303 [(Μ+Η)+ ]; melting point 144-148 ° C · Example C12 (!: _ gas-based 2-nitro-hexahydropyridine small-phenylamine methyl acid third - butyl ester title compound is based on general procedure C, at 4 ° C, from (4,5-di- 2 -nitro-phenyl)-amine methyl acid, third-butyl ester (in the case of DMSO) B2) with hexahydropyridine. Obtained as a yellow solid (U.sub.73 g). MS (ESI) 356 [(M+H)+] and 358 [(M+2;fH)+]; melting point 132-133 ° C · Example C13 (4-Fluoro-2-nitro-5-tetrahydropyrrole-1-yl-p-stylamine methyl acid tert-butyl ester The title compound was prepared from DMSO at 23 ° C according to General Procedure C ( 40 -40-I paper size suitable for SS standard (CNS) A4 specification (210 X 297 public) &quot;&quot; 1296622 A7 ________B7_ · _ V. Invention description (37) ML) (5-chlorine ice Fluoryl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Β6) (5·81 g, 20 mmol) and tetrahydropyrrole (8.27 ml, 1 〇〇 mmol) Obtained a yellow solid (6.42 g).

.I MS (ISP) 326 [(M+H)+]; melting point 188-193 ° C. Example C14 ubi-di iljzg圜_i-base carbyl-2-nitro-phenylamine A 篥 篥 - The title compound of butyl ester was prepared according to the general procedure C at 23 ° C in DMSO (40 mL) (4,5-dichloro-2-nitro-styl) &gt; Ester (Example B2) (6.14 g '20 mmol), nitrous tetramine (2.33 mL, 34 mmol) and Ets N (8.4 mL, 60 mmol) afforded an orange solid (5.85 g). MS (EI) 327 (M+) and 329 [(M+2)+ ]· Example C15 (g_Diazinium-tetradecyl-1 yl 2-nitro-t-trifluoromethyl-phenylamine methyl acid The third-butyl ester title compound was prepared from DMSO in the foot (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-amine methyl acid according to the general procedure C at 23 °C. Third butyl ester (Example B5), nitrous tetramine and ε^Ν. Obtained a yellow solid (6. 925 g). MS (ISN) 360 [(MH)·]· Example C16 propylmethyl bis-A Benzyl-amino)-2-nitro-trifluoromethyl- phenyl hydrazine-aminomethyl acid tert-butyl ester The title compound is based on the general procedure ,C, at 23 (:, from DMSO (50) Pen liter) (5-chlorine Benzyl-2-succinyl-4-trifluoromethyl-phenyl&gt; Aminomethyl acid, third butyl hydrazine (conventional Β5) (5·11 g 153⁄4 mol), cyclopropylmethyl-methyl _ Amine hydrochloride (5.47 g '45 φ mol) and EtsN (10·5 ml, 75 mmol). Obtained yellow-41 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210X297 mm) —- 1296622 A7 ___ B7 V. INSTRUCTIONS (38 ) &quot; Colour solids (5.73 g) MS (ISN) 388 [(Μ_ΗΠ ; melting point 51 ° C. Example C17

Jj-(cyclopropyl-methyl-amino)-2-nitro-4-trifluoromethyl- oxa-1 amine methyl acid tert-butyl ester The title compound is according to the general procedure C at 23 ° (5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-aminomethyl acid tert-butyl ester (Example B5) (3.40 g) from DMSO (50 mL) , 10 mmol) with cyclopropylmethyl-amine hydrochloride (3.22 g, 30 mmol) and Et3N (6.97 mL, 50 mmol). A yellow solid (3.74 g) was obtained. MS (ISP) 374.2 [(M+H)+]· Example C18 [2-Dimethylamino 1fluoro-5-nitro-biphenyl-4-yl)-amine mercapto acid tert-butyl ester The compound was prepared according to the general procedure C from (2-chloro-2,-fluoro-5-nitro-biphenyl-4-yl)-aminomethyl in DMSO (87 mL) at 23 °C. Acid third, butyl ester (Example D3) (9.568 g, ca. 26 mmol) with Me2NH (6 〇〇 /., in H2 hydrazine, 12 mL). A yellow solid (4.54 g) was obtained. MS (ISP) 376.3 [(M+H)+]. Example C19 (_5-dimethylamino-4-methyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester title compound (5-Gas-based methyl-2-nitro-phenyl)-amine methyl acid, third-butyl ester, prepared from DMSO (35 ml) at 50 ° C according to the general procedure C (example) Β8) (3.5 gram, 12.2 mmol) with dimethylamine (11 ml, 33 〇, in EtOH, 61.0 mmol). Obtained a yellow solid (3.50 g, 970 /.). -42- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (39) MS (ISP) 296.3 [(M+H)+]. Example C20 (4 -Cyano-5-dimethylamino-2-nitro-phenyl)-amine methyl acid tert-butyl ester The title compound was obtained from DMSO (30 mL) at room temperature according to General Procedure C. (4-cyano-5-fluoro-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Β9) (2.0 g, 7.11 mmol) and dimethyl Amine (6.3 ml, 33% in EtOH, 35.0 mmol). Obtained as a yellow solid (1.87 g, 86%). MS (ISP) 307.3 [(M+H)+]. · Example C21 [4_indolyl-5·(methyl-propyl-amino)-2-nitro-phenyl-1-amine methyl acid The tri-butyl ester title compound was prepared according to the general procedure C, (5-carbyl-4-methyl-2-nitro-phenyl)-aminomethyl in DMSO (35 mL) at 55 °C. Acid tri-butyl ester (Example Β 8) (3.5 g, 12.2 mmol) with N-methyl propylamine (6.5 mL, 61.0 mmol). Obtained yellow oil (3.89 g, 98%). MS (ISP) 324.4 [(Μ+Η)+]· Example C22 [5-(Ethyl-methyl-amino)-4-methyl-2-stone-chryptyl-styl 1-amine methyl acid - The title compound is (5-chloro-4-methyl-2-nitro-phenylamine methyl acid third) from DMSO (35 ml) at 55 ° C according to the general procedure C. - butyl ester (Example Β 8) (3.5 g, 12.2 mmol) and N-ethyl decylamine (5.5 mL, 61.0 mmol). Obsed as a yellow solid (3.58 g: 95%). MS (ISP) 310.3 [(M+H)+]. Example C23

If-murine_5-(isopropyl-methyl-amino)-2-nitro-phenylamine methyl acid third · vinegar-43- } paper scale suitable for g 0 standard (CNS) Α4 specifications (21G X 297 public fantasy)

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Line 1296622 A7 B7 V. Description of the invention (4〇) The title compound is prepared according to the general procedure C at 750 ° C in DMSO (50 mL) (4,5-di-nitro-2-phenyl-phenyl) )-Aminomethyl-tert-butyl ester (Example B2) (5.0 g, 16.3 mmol) with N-iso-yl-methylamine (5.95 g, 81.4 mmol). A yellow solid (4.07 g, 73 〇 /.) was obtained. MS (ISP) 344·3 [(Μ+Η)+]· Example C24 [4-Chloro-5-(isobutyl-methyl-amino)-2-nitro-phenyl 1-aminomethyl The acid tert-butyl ester title compound was prepared according to the general procedure C, (4,5-dichloro-2-nitro-phenyl)-amine methyl acid in DMSO (50 mL) at room temperature. Tri-butyl ester (Example B2) (5.0 g, 16.3 mmol) with N-isobutyl-methylamine (7.09 g, 81.4 mmol). Obtained brown oil (5.79 g, 990 / 〇). MS (ISP) 358.2 [(Μ+Η)+]· Example C25 (4-cyano-2-nitro-5-tetrahydropyrroleyl-phenyl)-amine methyl acid tert-butyl ester title compound Based on general procedure C, (4-cyano-5-fluoro-2-nitro-phenyl)-amine methyl acid, tert-butyl ester, from DMSO (30 mL) at room temperature ( Example Β 9) (2.0 g, 7.11 mmol) with tetrahydropyrrole (2.94 mL, 35.6 mmol). A yellow solid (1.97 g, 830 /.) was obtained. MS (ISP) 331.2 [(M-Η)-]. Example C26 II-Cyano-5-(methyl-propyl-amino)-2-nitro-phenyl 1-amine methyl acid - The title compound of butyl ester is the third (4-cyano-5-fluoro-2-nitro-phenyl)-amine methyl acid in DMSO (20 mL) at room temperature according to the general procedure C. -Butyl ester (Example Β9) (1.95 g, 6.93 mmol) and N-methyl-propylamine (3.72 ml, 34·7 -44- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) binding

Line 1296622 A7 _B7 V. Invention Description (41) &quot;' Miller. Obtained as a yellow solid (1.75 g, 75%). MS (ISP) 333.3 [(MH)*]. Example C27 (1-Cyano-5-diethylamino-2-nitro-phenyl)-amine mercapto acid tert-butyl ester The title compound is based on general Procedure C, (4-cyano-5-fluoro-2-nitro-phenyl)-aminomethyl acid tert-butyl ester (Example Β 9) in DMSO (20 mL) at room temperature (1·95 g, 6.93 mmol) with N,N-diethylamine (3.60 mL, 34.7 mmol) afforded a yellow solid (1.78 g, -77%) MS (ISP) 333.2 [(MH) -]. Example C28 II: oxy-indole isopropyl-methyl-amino)_2-nitrophenylamine methyl acid tert-butyl ester The title compound was prepared according to the general procedure C at room temperature. (4-cyano-5-fluoro- 2-nitro-phenyl&gt;-aminomethyl acid tert-butyl ester (Example Β9) (1·95 g, 6.93) from DMSO (30 ^: liter) Milliol) with hydrazine-isopropylmethylamine (3.60 ml, 34.7 mmol). Obtained a yellow solid (m. 84 g, 790 / s). MS (ISP) 333.3 [(MH)&quot;]. C29 Ι·4τ夜基-5-(isobutyl-methyl-amino)-2-nitro-phenyl------------------ Warm, made from DM (4-cyano-5-fluoro-2-nitro-phenyl&gt;-aminomethyl acid tert-butyl ester in SO (20 ml) (Example Β9) (1.95 g, 6.93 mmol) ) N-isobutyl-N-methylamine (3.02 g, 34.7 mmol). Obtained as a yellow solid (1.87 g, 770.) MS (ISP) 347.4 [(MH)·]. Example C30 - 45- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (42) (4-cyano-2-nitro-5-hexahydrop ratio - 1-Base-styl)-Aminomethyl Acid The third title compound was prepared according to the general procedure C in DMSO (20 mL) at room temperature (4-cyano-5-fluoro- 2-Nitro-phenyl)-amine mercapto acid tert-butyl ester (Example Β9) (2.0 g, 7.11 mmol) and hexahydropyridine (3·51 mL, 35.6 mmol). Yellow solid (1.94 g, 79%) MS (ISP) 345.3 [(MH)-]. f Example C31 (i-chloro-5-isobutylamino-2-nitro 'stupyl)-amine A The third-butyl ester of the acid is the title compound (4,5-dichloro-2-nitro-phenyl)-amine in DMSO (20 liters) at 55 ° C according to the general procedure C. Acid-third (Example B2) (3.0 g of 'Mao 9.77 mole) and isobutylamine (3.57 g, 48.8 mmol). Obtained as a brown solid (2·26 g, 67%). MS (ISP) 344.2 [(M+H)+]. Example C32, 1 (Methyl-propyl-yl-amino)-2-nitro-4-trifluoromethyl]-amine methyl acid, The title compound is based on the general procedure c, and is prepared from DMS(3〇mL) (5·glycol-2-nitro-glacial trifluoromethyl-phenyl)amine methyl acid at room temperature. • Butyl ester (Example Β 5) (4·00 g, 11.7 mmol), N-methyl-propylamine ML, 17.6 moles, and diethylamine (5.73 liters, 4 U millimolar). Obtained a yellow solid (4.04 g, 91%). MS (ISP) 378.3 [(M+H)+]. Example C33 benzyl-amino)-2-nitrophenyl-1-amine A 醴__ -46- f paper scale applicable towel gg standard (CNS Μ Specifications (4) 297 297 DON) ----

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1296622 A7 B7 V. INSTRUCTIONS (43) The title compound is prepared according to the general procedure c, at room temperature, from DMS (3 liters). Trifluoromethyl-phenyl)-amine methyl acid third-butyl vinegar (example Β5) (4·00 g, 1 L7 mmol), isobutyl-decylamine (154 g ' 17.6 mmol) And triethylamine (5.73 ml, 41·1 mmol). Obtained as a yellow solid (4.18 g, 91 〇 /.) MS (ISP) 390.3 [(MH)']. Example C34 propyl-methyl-amine The base compound of 2-nitro-4-trifluoromethyl-phenylamine methyl acid is according to the general procedure C, at 5 (TC, from DMSO (30 liters) (5-gas) Benzyl-2-nitro-4-trifluoromethyl-phenyl)amine methyl acid, third-butyl vinegar (conventional Β5) (4·00 g, 11.7 mmol), N-isopropyl-A Base-amine (3.67 ml '35.2 mmol) and triethylamine (5.73 mL, 41.1 mmol) afforded a yellow solid ( 3.27 g, 74 〇 /.) MS (ISP) 376.3 [(MH)-] Example C35 IKliT-methyl-amine A V4-methyl-2-nitro-phenyl 1-amine methyl acid tert-butyl ester The title compound is according to the general procedure C, (5-Alkyl-4·methyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (conventional B8) (3.01) prepared from DMSO (30 ml) at 55 °C克, ΐ〇·5 mmoles, with N-isobutyl-methylamine (4.56 g, 52.3 mmol). Obtained yellow oil (184 g, 52 〇.) MS (ISP) 336.3 [( Μ-Η)']. Example C36 ___ -47- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210χ 297 mm) 1296622 A7 B7 V. Invention description (44) Zhuang Methyl-2-nitro-5 - tetrahydropyrrol-1-yl-phenylamine methyl acid tert-butyl ester The title compound was obtained from DMSO (30 mL) (5-chloro-4) at 55 ° C according to General Procedure C. -Methyl-2-nitro-phenyl)-amine methyl acid, third-butyl ester (Example Β8) (3.11 g, 10.5 mmol) and tetrahydropyrrole (4.33 mL, 52.3 mmol) Obtained a yellow solid (3.27 g, 97%). MS (ESI) 320.3 [(Μ-Η)·]; melting point 145 ° C · Example C37 (_4_ gas--5-isopropylamino-2 -Nitro-phenyl-V-amine methyl acid, the third title compound, according to the general procedure C, at 550 ° C, from DMSO (35 ml) (4,5 · dichloro-2-nitrate) - phenyl) - carbamic acid tert - butyl ester (Example B2) (5.0 g, 16.3 mmol) and isopropylamine (7.0 mL, 81.4 mmol). Obtained as a brown solid (3.95 g, 73.). MS (ISP) 330·2 [(Μ+Η)+]· Example C38 (5·•Isobutylamino-2·nitro-4-trifluoromethyl·styl)-amine methyl acid - The title compound is based on the general procedure C, at room temperature, from DMSO (35 liters) of (5-chloro-2-ethyl-4-trifluoromethyl-phenyl)aminomethyl Acidic third-butyl ester (Example Β 5) (5·00 g, 14·7 mmol), isobutylamine (7·36 ml, 73.4 mmol). A yellow solid (5·39 g, 970 〇) was obtained. MS (ISP) 376.3 [(Μ-Η)&quot;]. General procedure D: by (4-c-yl-2-nitro-phenyl)-amine methyl acid, tert-butyl ester and aryl Direct Suzuki coupling of shy borane to prepare (4-aryl-2-nitro-phenyl)-amine methyl acid tert-butyl ester-48-^ paper scale for Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; 1296622 A7 B7 V. Description of Invention (45) Let (4. iodo-2-nitro-phenyl)-aminomethyl acid tert-butyl ester (3 〇 millimolar), a mixture of aryl dihydroxyborane (4.5 mM) and PdCl 2 (PPh3) 2 (2 mM) in hydrazine, 4-oxoindole (25 ml) and 2M Na2 C03 solution (7· 5 ml) [or 'iMNaHC03 solution (7.5 ml), LiCl (6.0 Amol) and (phs p) 4pd (3 mol%) used in DME (30 liters); can also be used in DMp (1 In 〇ml), reflux at 100 ° C in Et3N (9.0 mmol), Pd (〇Ac) 2 (3 mol %), PPh3 (6 mol %)] until TLc shows complete conversion of iodide until. The mixture was transferred to a sep. funnel, EtOAc (EtOAc) The combined organic layers were washed with brine (50 mL) and dried over Na. The solvent was removed, and the title compound was purified eluting eluting eluting eluting Example D1 ^ Monomethylamino, 3- 1 -nitro-5-nitrobiphenyl-4-yl)-amine methyl acid 3 - butyl hydrazine The title compound was prepared according to the general procedure D from (5-dimethylamino) 4-Iodo-2-nitro-phenyl)amine decyl acid tert-butyl ester (Example C2) and 2,3-difluorophenyl dihydroxyborane. A yellow solid (3.096 g) was obtained. MS (ISN) 392 [(MH)·]. Example D2 [2'-Fluoro-5-nitro-2-(2,2,2-trifluoro-ethoxy hydrazinyl 1-aminomethyl) The acid No. 3 - butyl hydrazine title compound is prepared according to the general procedure D from [4-iodo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenyl]monoamine Tri-butyl methacrylate (Example B4) and 2-fluorophenyl dihydroxyborane. Obtained a yellow solid (1.39 g). -49- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (46) MS (ISP) 491 [(M+H)+]; melting point 73-75 ° C. Example D3 (2-carbyl-2'-fluoro-5 -Nitro-Lycosyl V-Amino Acid Tri-Butyl Ester The title compound is prepared according to the general procedure D from (5-methyl-4-iodo-2-nitro-phenyl)-aminemethyl Acidic third-butyl ester (Example Bl) (30 g, 75·3 mmol) and 2-fluorophenyldihydroxyborane (13.82 g, 98.8 mmol). Obtained yellow gum (1.39 g). (ISN) 365.0 [(Μ-ΗΠ· General Procedure E: by (4-iodo-2-nitro-p-stylamine methyl acid, third-butyl ester and bis (pin 呐美)) Suzuki coupling, and the subsequent reaction with aryl halides Should be prepared (4) Mannyl 1 nitrophenyl)aminomethyl acid tert-butyl ester (4-picyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (2 〇 〇 Moer), bis(pinyl)diboron (2.2 mmol), KOAc (6.0 mmol) and PdCl2 (PPI13 &amp; (3 moles/〇) in 1,4-dioxane Mixture in (25 ml), stir at 10 ° C until TLC shows complete conversion of iodide [Review

Tetr. Lett. 1997, 38, 3841-3844]. After adding aryl halide (4 〇 millimolar), PdCl2 (PPI13 h (3 mol%) and 2M Na2 C03 solution (7.5 ml), the mixture was stirred at 100 ° C until the butyl LC showed an intermediate The dihydroborane ester was converted. The mixture was transferred to a separatory funnel, h2 hydrazine (3 liters) was added, and the product was extracted with ether or EtOAc (3×5 mL). 〇〇ml) Wash and dry with Na2S〇4. Remove the solvent, leave a brown residue, and use cyclohexane / _ or cyclohexane / Et〇Ac, and purify by column chromatography. Title compound. 50

1296622 A7 B7 V. INSTRUCTIONS (47) General procedure F: Preparation of 5-chloro-2-nitrate by condensation of 5-methyl-2-nitrophenylenediamine with 2,5-dimethoxytetrahydrofuran Base-4-exo b-h-yl-phenylamine [Ref. J. Heterocyd. Chem. 1988, 25, 1003-1005]: 5-Gas-2-nitro-1,4-phenylenediamine (4.69 g, 25 mmol), a mixture of 2,5-dimethoxytetrahydrofuran (26-32.5 mmol) in HOAc (150 mL), stirred at 60-120 ° C until TLC showed benzene The diamine is completely converted. After cooling to 23 &lt;0&gt;C, the mixture was poured into EtOAc EtOAc m. The combined organic layers were washed with brine (300 mL) and dried with EtOAc. The solvent was removed, the title compound was obtained eluted eluted elut elut elut General procedure G: Preparation of 2,5-dimethoxy dihydrofuran by bromination of furan in MeOH [see Tetrahedron 1971, 27, 1973-1996]: in furan (177.5 mmol) in anhydrous ether ( In a mixture of 54 ml) and dry MeOH (79 mL), EtOAc (EtOAc &lt;RTIgt; The reaction mixture was stirred for 30 minutes, saturated with a gaseous NH3 to pH 8, and allowed to warm to 23 °C. Pour into ice water, extract with ether (3 x 400 mL), wash with brine and dry with Na2SO. The bolus was evaporated to leave a yellow liquid which was purified by EtOAc to afford title compound. General procedure Η : by (4-iodo-2-nitro-phenyl)-amine methyl acid, tert-butyl ester and acetylene combination -51 - This paper scale applies to China National Standard (CNS) Α 4 specifications ( 210X 297 mm) 1296622 A7 B7 Description of the invention jl^ Sonogashka coupling reaction preparation (4-alkynyl-2-nitro-anisylamine A certain third butyl ester; also carried out (4-ethynyl-2-nitrate) Sonogashira coupling of a third-butyl ester of amino-benzoquinone-amino acid with an aryl halide: the halide (3.0-4.5 millimolar), an octal compound (3·〇_4·5 毫Mixture of Et3N, Et3N (13.5 mM), PdCl2(PPh3)2 (5 mM) and PPh3 (2.5 mil) in THF (12 mL) [Addition of insoluble materials (Nanda) 12 c|: liter)]' stir at 20 C for 20 minutes while argon gas. Add Cul (L2 mol%) and continue to stir at 6 (TC and argon atmosphere until TLC shows less &lt;Completely converted to &quot;complete [see j 〇rg Chem 1998, 咚 8551]. Transfer the mixture to a separatory funnel, add 5 〇 / citric acid (5 mM) and extract the product with EtOAc ( 2 X 100 ml) The combined organic layers were washed with EtOAc EtOAc (EtOAc)EtOAc. Purification by hydrazine column chromatography and/or trituration with hexane or EtHH to give the title compound. Example H1 light methyl-2-nitro-bromo-ethynyl-phenyl)-amine methyl acid - butyl ester title compound was prepared according to the general procedure from (5. dimethylamino iodonyl winter nitro-phenyl) amine methyl acid tert-butyl ester (example C2) (386 mg, 〇·97 Milliol) with phenyl bromide (149 mg, L46 Comool). Obtained an orange solid (37 mg). MS (EI) 381 (M+); melting point i41-149 ° C. General procedure J:

1296622 A7 B7 V. INSTRUCTION DESCRIPTION (49) Preparation of (2-amino-phenyl)-amine methyl acid by reduction of (2-nitro-phenyl)-amine methyl acid tert-butyl ester Tri-Butyl ester: Method a · Catalytic hydrogenation Nitro compound (1.0 mmol) in MeOH or EtOH with THF (1:1, ca. 20 mL) [or EtOAc as a separate EtOAc] ), with a mixture of 10% palladium on carbon (20 mg), monni-Ni (20 mg) or 5% platinum/carbon, vigorously stirred at 23 ° C under a hydrogen atmosphere until TLC showed complete conversion. The catalyst was filtered off and washed with MeOH or EtOAc (EtOAc) (EtOAc) (EtOAc) elute elute elute Hot hexane crystallizes. Method b: a mixture of a nitro compound (1.0 mmol) and SnCl 2 ·2Η2Ο (5·0 mmol) using a reduction of SnC^.21^0, either at 70-80 ° C in EtOH (30 ml), or at 23 ° C under argon atmosphere, stir in pyridine (3 ml) and DMF (12 ml) until TLC shows complete conversion [see Tetr. Lett. 1984, 25, 839] . The reaction mixture was brought to pH 8 and EtOAc (2 X 100 mL). The combined organic layers were washed with brine and dried over Na 2 EtOAc. The solvent is removed to leave a yellow solid which can be purified by hexane column chromatography if necessary. Method c · Adding zinc to a mixture of nitro compound (1.0 mmol) in EtOH / THF / saturated NH4C1 solution (1 ··1 : 1,30 ml) using a reduction of hydrazine and NH^Cl· Powder (3.0 mmol) and the mixture was stirred at 70 ° C under argon until TLC showed complete conversion. The aqueous solution treatment is as described in method b. -53- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (50) Example J1 (2-Amine base 氪-5-dimethylamino-benzene The title compound of the amino-tert-decyl acid tert-butyl ester was prepared according to the general procedure J (method b) by reduction with SnCl 2 ·2Η2〇 from (4-carbyl-5-dimethylamino-2) -Nitro-phenyl)-amine mercapto acid tert-butyl ester (Example Cl) (2.76 g, 8.74 mmol). Obtained an orange solid (2.3 g). MS (ISP) 286 [(Μ+Η)+ ] and 288 [(Μ+2+Η)+]; melting point 96-101 ° C. Example-J2 (2-amino-5-dimethylamino ice benzene Ethyl ethynyl-lamyl)-amino hydrazide tert-butyl ester The title compound was prepared according to the general procedure J (method b) by reduction with SnCl 2 · 2H 2 0 from (5-diamidino-2 -Nitro- ice phenylethynylphenyl)-amine methyl acid tert-butyl ester (Example H1). Obtained as a brown solid (1.927 g). MS(ISP) 352 [(M+H)+]· Example J3 (5-aminodimethylamine H3'-difluoro-biphenyl glacial amine methyl acid butyl ester title compound according to the general procedure j (Method b), by (N-dimethylamino 2,, 3,-difluoro-5-nitro-biphenyl-based hydro-amine methyl acid, third, via the reduction of SnCh 2 - butyl ester (Example D1). Obtained an orange solid (2.2 〇 6 g). MS (ISP) 364 [(M+H)+]· Example Jf Qin-4-yl-amino- 1-- The amine-methyl-butyrate-based title compound is based on the general procedure; (method b), via the reduction of 5 •·玛0, from {4-carbyl-5.methoxy-ethyl Base-Amine Rape Nitrogen This paper scale applies to China National Standard (CNS) A4 specification (210X297 Gongfu Factory -----

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Base-phenyl-b-amino acid second-butyl ester (Example C3) (3 46 g, 9.62 mmol). A yellow solid (2.25 g) was obtained. MS (ISP) 330 [(M+H)+] and 332 [(M+2+H)+]; (: Example J5

- The butyl vinegar title compound is prepared according to the general procedure J (method a), by hydrogenation with 1% pd/c, from [2··fluoro]-5-nitro·2·(2,2,2- Trifluoro-ethoxy)biphenyl yl]-amine methyl acid tert-butyl ester (Example D2). A grey solid (117 g) was obtained. MS (ISP) 401 [(M+H)+]. Example J6 This:.----5-diaminoamine-4-trifluoromethyl-p-stylamine methyl acid tert-butyl ester According to the general procedure J (method a), by hydrogenation, (5-dimethylamino-2-nitro-t-trifluoromethylphenyl)-amino acid tert-butyl ester (example) C4) Obtained amorphous yellow material (1.34 g) MS (ISP) 320 [(M+H)4·]. Example J7 Amino-4-carbyl-5-(ethyl-methyl-amine )-Phenyl 1-aminomethyl acid tert-butyl ester The title compound was prepared from [4-carbyl-5-(ethyl) by reduction with SnC12·2Η2 根据 according to General Procedure J (Method b). -Methyl-amino>&gt; 2-nitro-phenyl]-aminocarbamic acid tert-butyl ester (Example C5) (3:0 g, 9.09 mmol) afforded pale brown solid (2.64 g) MS (ISP) 300.3 [(M+H)+]; Melting point 81°C · Example J8 -55- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

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Line 1296622 A7 B7 V. Description of the invention (52) "2-Amino-4-carbyl winter (methyl-propyl-amino)-phenyl 1-amine mercapto acid tert-butyl ester The title compound is based on General Procedure J (Method b), based on the reduction of SnCl 2 · 2H 2 0, from [Woyl-based 5-(methyl-propyl-amino)-2-nitro-phenyl]-amine methyl acid Third-butyl ester (Example C6) (3.15 g, 9:16 mmol). Obtained as a pale brown solid (2.58 g). MS (ISP) 314.3 [(M+H)+]; m.p. 92 ° C. Example J9 Γ2-amino-4-carbyl-5-(diethyl-amino)-phenylamine decanoic acid -Butyl ester title compound was prepared from [4-chloro-5-(diethyl-amino)- 2-nitro-benzene by reduction with SnCl2 · 2H2 0 according to General Procedure J (Method b) Amino-tert-methyl-acid-tert-butyl ester (Example C7) (2.25 g, 6.54 mmol). Obtained orange solid (1.55 g) MS (ISP) 314_3 [(M+H)+]; 110X: · Example J10 (2-Amino-4-carbyl-5-tetrahydropyrrole-1-yl-phenyl Vaminemethyl acid tert-butyl ester) The title compound is according to the general procedure J (Method b), From (4-chloro-2-nitro-5-tetrahydrop-pyrrolidino-phenyl)-amine methyl acid tert-butyl ester (Example C8) via reduction with SnCl 2 · 2H 2 0 Obtained a red solid (4·8 gram) MS (ISP) 312 [(M+H)+] and 314 [(M+2+H)+]; melting point 136-138 ° C · , Example J11 2- Amino-4-carbyl-5-(cyclopropyl-methyl-amino)-p-stylamine methyl acid tert-butyl ester The title compound is according to the general procedure J (method b), via SnCl2 · 2H2 The reduction of 0, produced from [4-gasyl-5·( Propyl-methyl-amino)-2-nitro-phenyl]-amine mercapto acid tert-butyl ester (Example C9) (3.2 g, 9.36 mmol). Obtained brown-56- paper scale Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 ____ B7_ V. Invention description (53) Color solid (2.00 g) MS (ISP) 312 [(M+H)+] and 314 [( M+2+H)+]. Example J12 position: thiol-5-tetrahydropyrrole small group-4-trifluoromethyl-phenyl)-amine hydrazinoic acid tert-butyl ester title compound according to general procedure J (method a), produced by the hydration of 1 〇〇 /.pd / c '2-nitro-5-tetrahydro ρ pyridyl-1 yl-4-trifluoromethylphenyl) Amine methyl ketone second-butyl vinegar (Example C10) (7.35 g, 19.75 mmol). Obtained a pale orange solid (6.75 g). _ - MS (ISP) 346 [(M+H)+]; Melting point l〇ll 〇 3 ° C · Example J13 (2-amino-5-dimethylamino fluorophenyl V amine methyl acid third _ _ _ cool title compound according to the general procedure J (method a), via Hydrogenation by 1〇% pd/c 'from (5-dimethylaminofurfuryl-2-nitro-phenyl)-amine methyl acid second beta vinegar (C1) (4.88) Grams, 16 millimoles . Obtained a green solid (4.55 g). MS (ISP) 270 [(M+H)+]; m.p. 120-123 ° C. Example J14 (2-ife•yl-4-milyl·5·ττ wind P than phospho-1-yl)-amine The methyl acid:r__Dingxi target super compound is prepared according to the general procedure j (method b) by the reduction of gnci2 · 2Η2 , from (4-carbyl-2-nitro-5-hexahydro) Ττ ratio bite_1_yl_phenyl)_amine methyl fe: second-butyr (example C12). Danced as a light brown solid (747 mg).

MS (ISP) 326 [(M+H)+] and 328 [(M+2+H).]; melting point 149-15rC Example J15 (2-amino-4-carbyl-5-tetrazine p 嘻·1·基·麦基)·Aminomethyl acid II·丁j—57· This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296622

‘The sputum is based on the general procedure j (method a), via ι〇σ/. Hydrogenation of pd/c 'made from (4-fluoro-2-nitrotetrahydropyrrole small group -phenyl)amine methyl acid tert-butyl ester (example C13) (6.37 g, 2 〇 millimol ). Obtained as a grey solid (5.92 g). MS (ISP) 296 [(M+H)+]; melting point 75-76 ° C · Example J16 g-based-5-azachlorophenyl-v-amino acid 3-butyrate 椽 4 compound based on general private Sequence j (method a), via 5〇/. Hydrogenation of pt/c from (5--azatetraindole-:[-carbandyl 1nitro-phenyl&gt;-aminomethyl acid-second-butyl ester (Example C14). Obtained white solid (3 · 664 g) MS (ISP) 298 [(Μ+Η)+] and 300 [(Μ+2+Η)+]; melting point 176-179°C · Example J17 L? Diterpene-yl-5-I The title compound of the title compound is according to the general procedure j (method a), via 5 〇. Hydrogenation of Pt/C from (5--azatetraindole-yl-2-nitro-trifluoromethyl-phenyl)-aminomethyl acid tert-butyl ester (Example C15). White solid (5173 g). MS (ESI) 332 [(M+H)+]; mp 166-167 ° C. Example J18 [2-1-5-(cyclopropylmethyl-methyl-amino) ) Ice trifluoromethyl-phenyl iminomethyl acid tert-butyl ester The title compound was prepared from [5-(cyclopropyl) according to the general procedure j (method b) by reduction with SnCl 2 · 2 Η 20 Methyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example C16) (5.66 g, 14.5 mmol). Yellow solid (4.7g) -58- This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) Binding

Line 1296622 A7 B7 V. Description of the invention (55) MS (ISP) 360 [(M+H)+]; melting point 56. (: Example J19 II-Amino-5-(cyclopropylmethyl-amino V4-trifluoromethyl-phenyl1-aminemethyltri-butyl ester) The title compound is according to the general procedure J (Method b) , by [5-(cyclopropyl-indenyl-amino)-2.nitro-4-trifluoromethyl-phenyl]-amine methyl acid by third reduction with SnCl 2 ·2Η2〇 - butyl ester (Example C17) (3.74 g, 9.96 mmol). Obtained an orange semi-solid (2.00 g).-MS (ISP) 346.4 [(Μ+Η)+]· Example J20 Amino-2- Dimethylamino-2f-fluoro-biphenylidylamine methyl acid tert-butyl ester The title compound was prepared according to the general procedure J (method a) by hydrogenation at 1 〇〇/.Pd/C. (2-Dimethylamino-2,-fluoro-5-nitro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example C18) (4.54 g, 12.1 mmol). Obtained as a light brown solid (3.324 g). MS (ESI) 346.4 [(M+H)+]. Example J21 [2-amino-5-(2,2,2-trifluoro-ethoxy)-4- The title compound of the trifluoromethyl-p-pyraminopyridinic acid tert-butyl ester is prepared according to the general procedure J (method a), via hydrogenation with 50/.Pt/C, from [2-nitro- 5-(2,2,2-trifluoro-ethoxy)-4 -Trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example B7). Obtained a yellow solid (17.374 g). MS (ISP) 375 [(M+H)+]· Example J22

-59- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (56 ) (2-Amino-5-dimethylamine-4·methyl-benzene The title compound of the amino acid tert-butyl ester is prepared from (5-dimethylamino chloromethyl-2) by hydrogenation with 1% Pd/C according to the general procedure J (method a). -Nitro-phenyl)-aminomethyl acid tert-butyl ester (Example C19) (3.22 g, 10.9 mmol). Obtained a gray solid (2. 05 g, 58%). MS (ISP) 266.3 [(Μ+Η)+]; m.p. 78 ° C. Example J23 (2-amino-4-cyano-5-dimethylamino)-aminomethyl acid - The title compound of butyl ester is prepared from (4-cyano-5-dimethyl-amino-2-nitro-phenyl)-amine by reduction with SnCl 2 · 2H 2 0 according to the general procedure J (method b). Tri-butyl methacrylate (Example C20) (3.9 g, 12.7 mmol). Obtained a light brown solid (2.05 g, 58.,.). MS (ISP) 277·2 [(M+H)+]; m.p. 120° C., ???J24 [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl 1-Aminomethyl acid tert-butyryl title compound was prepared from [4-methyl-5-(methyl-propyl) by hydrogenation with 10% Pd/C according to General Procedure J (Method a). 3-Amino-phenyl]-aminomethyl acid tert-butyl ester (Example C21) (3.59 g, 11.1 mmol). Obtained a purple solid (3.23 g, 99%). MS (ISP) 294.4 [(M+H)+]. Example J25 [2-Amino-5-(ethyl-methyl-amino)-4-methyl-phenyl 1-amine decyl acid - The title compound is based on the general procedure J (method a), via 1 〇〇 /. Hydrogenation of Pd/C from [5-(ethyl-methyl-amino)-4-methyl-2-nitro-phenyl]-amine-60- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 1296622 A7 B7 V. Description of invention (57) Third-butyl methacrylate (Example C22) (3.28 g, 10.6 mmol). Obtained as a purple solid (2.94 g, 99%). MS (ISP) 280.3 [(M+H)+]. Example J26 "2-Amino-4-carbyl-5-(isopropyl-methyl-amino)-phenyl 1-aminemethyl acid The title compound of tris-butyl hydrazine is prepared from [4-chloro-5-(isopropyl-methyl-amino)-2- via the reduction of SnCl2 · 2Η2 根据 according to the general procedure J (method b). Nitro-phenyl]-amine methyl acid tert-butyl ester (Example C23) (4.07 g, 11.8 mmol). Obtained as a pale brown solid (3.08 g, 83%).

MS (ISP) 314·3 [(M+H)+]; melting point 116 ° C Example J27 [2-Amino-4-carbyl-5-(isobutyl-methyl-amino-V-methyl- 1- Aminomethyl-tert-butyl-tert-butyl ester The title compound was prepared from [4-chloro-5-(isobutyl-methyl-amine) by reduction with SnCl 2 · 2 Η 2 根据 according to General Procedure J (Method b). Tris-butyl 2-phenyl-phenyl]-amine methyl acid (Example C24) (5.55 g, 15.5 mmol) afforded pale brown solid (3.98 g, 78%). 328.3 [(M+H)+]· Example J28 (2-Amino-4-cyano-5-tetrahydrop-pyridin-1-yl-phenylaminemethyl acid tert-butyryl title compound) According to the general procedure J (method b), from (4-cyano-2-indolyl-5-tetrahydropyrrole small-phenyl)amine methyl acid by the reduction of SnCl2 · 2Η2 第三 - Butyl ester (Example C25) (1.82 g, 5.48 mmol) afforded a pale brown solid ( 1.27 g, 77.) MS (ISP) 303.2 [(M+H)+]. -61 - This paper size applies China National Standard (CNS) A4 specification (210 X 297 public love ^ ' 1296622 A7 B7 V. Description of invention (58 ) Example J29 [2-selective 4-cyano-5-(methyl-propyl-amine )·Phenyl &quot;μ Aminomethyl acid tert-butyl ester The title compound is prepared from [4-cyano-5-(methyl-propyl-amino) via a reduction of SnCl 2 · 2H 2 oxime according to the general procedure j (method b). 2-nitro-phenyl]-amine methyl acid tert-butyl ester (Example C26) (1.64 g, 4.90 mmol). Obsed dark red oil (1.24 g, 830 /.) MS. (ISP) 305.3 [(M+H)+]. Example J30 · [?_: Amino- glacial cyanyl-5-diethylamino-phenylamine methyl acid, the third butyl ester, the title compound is based on the general procedure j (method b), from (4-cyano-5-diethylamino-2-nitro-phenyl)amine methyl acid by the reduction of SnC12 · 2H2 oxime, the second-butan Example C27) (1.66 g, 4.96 mmol) obtained as an off-white solid (1.38 g, 910 〇) 〇MS (ISP) 305·3 [(M+H)+]; melting point 151 ° C · Example J31 ( g diamino-4-cyanomethicone dimethylamino)· 笨 I I·amine methyl acid tert-butyl ester The title compound is based on the general procedure j (method b), via SnC12 ·2Η2〇 The reduction was carried out from [4-cyano-5-(isopropyl decylamino)&gt;2 nitro-phenyl]-amine methyl acid tert-butyl ester (Example C28) (1) .73 grams, 5.17 millimoles). Obtained as an off-white solid (1.56 g, 99%). MS (ISP) 305.3 [(Μ+Η)+]; melting point 77°ρ · Example J32 benzyl-amino)-benzene 1-aminomethyl acid tert-butyl ester The title compound is based on the general procedure j (method b), from [4-cyano-5-(isobutyl-methyl-amino) by reduction with Μ% ·2Η2〇-62-1296622 A7 _ ____B7 _2_Nitro-phenyl]-aminomethyl acid tert-butyl ester (Example C29) (1.76 g, 5.05 mmol). Obtained as a pale brown solid (1. 55 g, 96%). MS (ISP) 319.5 [(Μ+Η)+]; melting point 88 ° C · Example J33 (2-amino-4-cyano-5-hexahydropyridin-1-yl-phenylamine methyl acid third The title compound of butyl ester is prepared according to the general procedure J (method b) by reduction with SnCl2 · 2Η2 Ο from 4-(4-yl-2-nitro-5-hexahydropyranyl small base phenyl) - Aminomethyl 3-butyrate (Example C30) (2.08 g, 5.71 mmol). Obtained as an off-white solid (1.67 g, 990 / 〇). MS (ISP) 317·2 [(Μ+Η)+ Melting point 86 ° C · Example J34 (2-Amino-4-chloro-5-isobutylamino-phenyl)-amine methyl acid Third · vinegar The title compound is based on the general procedure J (method b), made from (4-carbyl-5-isobutylamino-2-nitro-phenyl)amine methyl acid tert-butyl ester via a reduction with SnCl 2 · 2Η2 ( (Example C31) (1.93 g, 5.61 mmol). Obtained a brown solid (1.30 g, 74%). MS (ISP) 314.3 [(Μ+Η)+]· Example J35 J&gt; Amino-5-(methyl- Propyl-amino)-4-trifluoromethyl·phenyl 1-amine methyl acid butyl butyl ester The title compound is hydrogenated via 1 〇〇.pd/c according to the general procedure J (method a). effect, Preparation of [5-(methyl-propyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-amino acid tert-butyl ester (Example C32) (3.78 g, 10.0) Obtained __ _ -63- This paper scale applies to Chinese g standard (CNS) A4 specification (21G x 297 public) &quot; 1296622 A7 B7 V. Invention description (60) Red oil (3.40 g, 98%) MS (ISP) 248.4 [(M+H)+]. Example J36 Amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyli-amine A A certain 醢m tri-butyl ester shows that the compound is based on the general procedure J (method a) 'by hydrogenation of 1 〇., pwc, from [5-(isobutylmethyl-amino)-2·nitrate _4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example G33) (3.88 g, 9.91 mmol). Obtained orange oil (2.70 g, 75%). ISP) 362.3 [(M+H)+ ]. Example J37 [2 diamino-5-(isopropyl-methyl-amino) ice trimethylmethyl- stupid i-amine methyl acid third - The title compound of butyl ester is prepared according to the general procedure j (method a) by hydrogenation of 1 〇〇.Pd/C from [5·(isopropyl-methyl-amino)-2-nitroindole Fluoromethyl-phenyl]-amine methyl acid Three - butyl ester (Example C34) (2.98 g, 7.90 mmol). Obtained orange oil (2.42 g, 88%). MS (ISP) 348.5 [(M+H)+j. Example J38 [2-Amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl 1-aminemethyl acid The tri-but m_ title compound is based on the general procedure j (method a), via 10 〇 /. Hydrogenation of Pd/C from [5-(isobutyl-methyl-amino)-4-methyl-2-nitro-phenyl]-amine methyl acid tert-butyl ester (example C35 ) (1.48 grams, 4.39 millimoles). Obtain white __ -64- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1296622 A7 B7 V. Description of the invention (61 Ί _ color solid (1.08 g, 80%). MS (ISP) 308.3 [(Μ+Η)+ ]; melting point 71 ° C · Example J39 (2-Amino Winter A Benz-5-tetrahydropyrrol-1-yl-benzene I Vte: tert-butyl ester of hydrazine acid The title compound was prepared according to the general procedure J (method a) via hydrogenation with 10% Pd/C. 4-Methyl 2-nitro-5-tetrahydropyha-μ-yl-phenyl)amine methyl acid tert-butyl ester (Example C36) (3.27 g, 1 〇·2 mmol). Light brown solid (2.48 g, 83%). - MS (ISP) 292·3 [(Μ+Η)+]; melting point 115 ° C · Example J40 (2-Amino-4-chloro-5 -Isopropylamino-phenyl-V-aminomethyl acid tert-butyl hydrazine The title compound was prepared according to the general procedure J (Method b) via a reduction with SnCl 2 · 2 Η 2 Ο from 4-(milyl-5-) Isopropylamino-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example C37) (3.75 g, 11.3 mmol) afforded a brown solid (2.90 g, 86.). MS (ISP) 303.3 [(M+H)+]. Example J41 [2-Amine--5--(isobutyl-amino)-tert-trifluoromethyl-phenyl-l-amino acid · Butyl ester title combination The system was prepared according to the general procedure j (method a) from [5-(isobutyl-amino)-2_nitro-trifluoromethyl-phenyl]-amine A by hydrogenation with pj/C. Third acid butyl acrylate (Example C38) (5:28 g, 13.99 mmol). Obtained as a pale yellow solid ( 3.69 g, 76 〇 /.) MS (ISP) 348.5 [(Μ+Η) +]; melting point 141 ° C. The following shell example is related to 4 3-aryl-3-keto-propionic acid ethyl ethane or third - butyl g (general-65- this paper scale suitable for SS Family Standards 3) 8 4 Specifications (21 (^297 public) 1 - 1296622 A7 ____ ___ B7 V. Inventive Note (62) Preparation of IVa), which is compounded as a standard compound (synthetic pattern H The structural unit in the middle:

General course K keto-ethyl propionate or tri-butyl ester floes ^ According to the synthetic journal, 1993, 290, 3-aryl-3-keto-propionic acid B g or third Butyl ester is aryl carbamide and propyl acrylate or third-butyl acrylate (CAS-numbers 6148-64-7 and 75486_33-8) made from Ch3CN under TC to 23 ,, and Ε^Ν and MgCl2. If the free aryl carboxylic acid is recovered in this reaction, it is first passed through 〇 ° C to chloroformic acid in THF/CHsCN before reacting with the malonate salt. The ethyl ester is activated by treatment with Et3N. Friend b) Preparation of 3-aryl-3-keto-propionic acid tert-butyl ester or 3-aryl-3-keto-propionic acid third-butyl The ester is treated according to the Synthetic Journal, 1985, 45' in the presence of lithium-butoxide, via a third butyl butyl acetate [via lithium diisopropylamine in THF at -78 ° C It is prepared by treating acetic acid to the third butyl vinegar, and is prepared from an aryl methyl ester or an ethyl ester. If the product after the treatment contains residual starting material, it can be removed by selective deuteration in THF/MeOH/% 0 at THF/MeOH/% 0 at 23 °C. Process c) Preparation of 3-aryl-3-keto-propionic acid 3-aryl-3-keto-propionic acid from aryl hydrazine and malonic acid bis(trimethyldecyl)g According to Synth. Commun. 1985, 15, 1039 (method ci), using EyN and LiBr in CI^CN under 〇°c, or according to Synthetic Journal, 1979, 787 (method c2), at -60Ό At 0 ° C, n_BULi in ether was used. Example K1 Μ同基-3-(3-Π, 2,31 triazole small group-phenyl V propane boat-66- This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1296622 A7 ___B7 V. Inventive Note (63) The title compound is prepared according to the general procedure K (Method a) from 3-[1,2,3]tris-l-yl-benzoic acid [the preparation method is 3-layer Methyl benzobenzoate [CAS-No. 93066-93-4] is refluxed in trimethyldecyl acetylene, followed by saponification with aqueous NaOH at reflux EtH, and via ethyl chloroformate / % n Activated and reacted with Et3N and MgCl2 in CH3CN with ethyl malonate potassium salt to give a pale-yellow solid (2.22 g). MS (EI) 259 (M+); mp. 72-74 ° C. Example K2 3 -(3-Cyano-phenyl)-3-keto-propionic acid tert-butyl ester The title compound was prepared according to the general procedure K (method b), eluted with tris-butyl acetate, from 3- Methyl cyanobenzoate [CAS-No. 13531-481]. Obtained as a light brown oily semi solid. MS (EI) 245 (M+). Example K3 3-(2-cyano-p-biti-4-yl a 3-keto-propionic acid tert-butyl ester title compound according to the general procedure K (method b), via - butyl butyl acetate, mp. mp. ·]. Example K4 3-『3-(3-Methyl-isoxazol-5-yl)-phenylindol-3-one-propionic acid Third-buty §1 The title compound is based on the general procedure K ( Process b), prepared from 3-(3-methyl-isoxazol-5-yl)-benzoic acid ethyl ester via treatment with lithium tributyl-butyl acetate [according to Tetrahedron 1984, 40, 2985-2988, via Ethyl 3-ethynylbenzoate [CAS- _ - 67 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (64) No. 178742-95- 5] A mixture with NCS, acetaldoxime, Et3N and a catalytic amount of pyridinium, prepared in CHCI3 at 5 (TC). Obtained a yellow solid (2.54 g)., * MS (ISP) 302 [( M+H)+]; m.p. 50-56°C. Example K5(RS)-3-g-yl-3-"3-"5-(tetrahydro-bran-2-yloxymethyl)41 2,31 triazole small 11-phenyl-1-propionic acid tert-butyl ester The title compound was prepared according to the general procedure κ (method b) by treatment with tri-butyl acetate. RS)-3_[5·(tetrahydro-pipelanyloxymethyl)^2,3]tris-l-yl]-benzoic acid methyl ester [made by the following order: 丨) Methyl 3-azidobenzoate [CAS-No. 93066-93·4] (15.55 g, 88 mmol) with (RS)-Second-butyl-dimethylindole tetrahydro- shout喃-2-yloxy)-prop-1-ynyl]-decane [CAS- No. 135294-85-8] (33.50 g '132 mmol) heated to 60 ° C for 1 day; ϋ·) The obtained material (48·2 g, about 88 mmol) was placed in TBAF (300 ml, 1 Μ in THF) at 70. (: stirring for 6 days, followed by reflux in s1NHCi (400 ml) for 2 hours; out) the obtained material (1615 g, 74 mmol) in Me0H (400 ml) and concentrated H2S04 (3 ml) , at 23. (: stirring for 11 days; IV·) to obtain a substance obtained by Shao (4 6 g, 19 7 m) and 3,4-dihydro-2H- shout (2.67 ml, 29.5 mmol) And the catalytic amount of _Ts0H · Η 2 〇 in DCM (383⁄4 liters), reaction at 23 ° C for 20 hours] (6 · 20 grams, 19. 5 millimoles). Obtained yellow oil (8.47 g). MS (ISP) 402 [(M+H)+ ]. Example K6 Methyl-iso-yl)·Pyridinyl-ketone-keto-propenyl-tert-butyl ester _______ -68- This paper scale applies to Chinese national standards (CNS) Α4 size (210X297 mm) 1296622 A7 _-___B7 V. Description of the invention (65) The title compound is prepared according to the general procedure K (method b) by treatment with tri-butyl acetate. 3·Methyl-isoxazole·5-based&gt; Methyl isonicotinate [made by the following method, i.) According to a dance procedure, methyl 2-iodo-isonicotinate [CAS- No. 134579-47-8] reacted with trimethyldecyl acetylene; π.) was reacted with catalyzed & C03 in MeOH at 〇 ° C for 4 hours to carry out de-sintering; iii· A cycloaddition of NCS, acetaldehyde oxime, Et3N and a catalytic amount of pyridine 'in CHCI3 at 5 ° C, according to Tetrahedron 1984, 40, 2985-2988]. A brown solid (517 g) was obtained. MS (EI) 302 (M4*); mp. 59-67 ° C. Example K7 · Methylpyrazole-3-yl-phenyl- 1-3-keto-propionic acid tert-butyl ester The title compound is based on general Procedure K (Method b), prepared from tris-butylacetate 11 from methyl 3-(2-methyl-2H-pyrazol-3-yl)-benzoate (made by the following method) , i·) 1-(3-bromophenyl) 3-dimethylaminopropenone [CAS-No. 163852-04-8] and methyl hydrazine, in EtOH, reacted at 23 Torr for 2.5 days; Ii.) Chromatographic separation of the obtained isomers; treatment of the pure isomers in n-BuLi in THF at -78 °C for one hour, followed by quenching with a c〇2 stream, followed by MeOH and Concentrated H2 S04, esterified at 23 ° C for 48 hours]. Obtained yellow oil (5.96 g). MS (EI) 300 (M+). Example K8 3-[3-(5-Dimethylaminoindenyl·π,2,31 triazol-1-yl)-phenyl1-3-keto-propionic acid The third - Ding Yu title compound is based on the general procedure 方法 (Method b), via the third-butyl • 69 - this paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ______B7 five , Description of the invention (66) Lithium acetate treatment, prepared from 3-(5-dimethylaminomethyl m3]triazole small base &gt; methyl benzoate [synthesis step L as described in the preparation of Example K5) To m), prepared from 3-fluorenylcarbomethyl ester, and reacted the obtained product with s〇ci2 in THF at 0 to 23 C for 1 hour, followed by the addition of dimethylamine (7·9) M is in the crucible) and stirred at 23 to 70 ° C for 1 hour] (2·ΐ4 g, 8.22 mmol). Obtained yellow oil (2.90 g). MS (ISP) 345 [(M+H)+], Example K9 methoxymethyl-isoxazol-5-yl V phenyl 1-3-keto-propionic acid tert-butyl ester General procedure Κ (Method b), prepared from 3·(3-methoxymethyl-isoxazol-5-yl)-benzoic acid methyl ester via treatment with lithium-tert-butyl acetate [via 3- a mixture of ethyl ethynylbenzoate [CAS-No. 178742-95-5] with NCS, 2-methoxyacetaldehyde oxime [CAS-No. 71494-93-4], Et3N and a catalytic amount of pyridine, in CHC13, It was prepared by reacting at 50 ° C according to Tetrahedron 1984, 40, 2985-2988]. A pale yellow liquid (ι·548 g) was obtained. MS (EI) 331 (M+). Example K10 酉同基-3_{3-"4-(tetrahydro-pyran-2-yloxymethyl)-p-indole-2-yl 1-phenyl} - Propionic acid tert-butyl ester The title compound was prepared according to the general procedure K (method b) by treatment with tris-butyllithium acetate from (RS&gt;3-[4-(tetrahydro-p-pyran-2) -yloxymethyl&gt;pyrimidin-2-yl]-benzoic acid methyl ester [made by the following sequence: i.) 3-Aminothiomethyl- benzoic acid methyl ester [CAS-No. 106748 a mixture of -27-0](7·8 g), 1,3-dialdehyde-2-propanone (8.4 g) and sodium bicarbonate (8.4 g) in 1,4-dioxane (180 ml) , -70- _ This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) Ϊ296622 A7 r—^___ V. Description of invention (67) Heating to 60 ° C for 24 hours. Cooling the reaction mixture To 2 ° C, and added to a stirred solution of sodium decoxide (5.4 g) in decyl alcohol (200 ml). Stirring was continued for 0.5 h. The mixture was poured into ice cold 2 Ν HCl (200 mL). The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was crystallized from di-methane / hexane to give methyl 3-(4-hydroxymethyl-thiazol-2-yl)-benzoate (7.5 g) as pale brown crystals, 115-117 C. a mixture of this material (7.5 g), dihydrogen (4·1 ml) and p-toluenesulfonic acid hydrate (0.19 g) in ethyl acetate (50 ml) After 1 hour, the solution was diluted with ethyl acetate, washed with sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated in the thunder. The residue was purified by chromatography on silica gel using ethyl acetate. /hexane (1:2) as a dissolving agent to obtain (RS)-3-[4-(tetrahydro-pyran-2-yloxymethyl P-pyrazol-2-yl]-benzoic acid methyl ester ( 9.6 g), as a pale yellow oil] (3.5 g, 11 mmol). Obsed pale oil (3.8 g) MS (ISP) 418.2 [(M+H)+]. Example Kll (RS)-3- Keto-3-yl-3-{3-indoletetrahydro-m-butan-2-yloxymethyl)-oxazol-2-yl-l-mu-propionic acid tert-butyl ester The title compound is based on the general procedure ( Method b), by treatment with tri-butyllithium acetate, from (RS&gt;3-[4-(tetrahydro-ttan-2-yloxy) Methyl)-carbazol-2-yl]-benzoic acid [made by the following sequence... i.) 3-Aminomethylmercapto-benzoic acid methyl ester [CAS-No. 1〇6748-24- 7] (17.9 g) and a mixture of 1,3-dialdehyde-2-propanone (14.0 g), heated to 140 ° C for 1.5 hours. The mixture was cooled to 20 °C and concentrated sulfuric acid (12 mL) was carefully added. Stir the mixture for 10 minutes, -71 - China National Standard (CNS) A4 size (210 X 297 mm Γ

Binding

Line 1296622 A7 B7 V. Description of invention (68) and then pour into ice water. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on Shiqi gum, and ethyl 3-(4-chloromethyl-oxazol-2-yl)-benzoic acid was obtained using ethyl acetate/hexane (1:1) as solvent. Ester (1 18g) as a light yellow oil. MS (ISP) 252.2 [(M+H)+]. ii.) This material (7·6g) and hydrated monohydrate (5.0g) in DMSO The solution in (30 ml) was heated to 6 ° C for 7 hours. 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 the addition of 6N HCl, and the formed precipitate was collected by filtration and crystallised from di-methane/hexane. The pale yellow crystals (5.5 g) were dissolved in DMSO (25 ml), and then added with hydrazine, hydrazine, hydrazine, hydrazine*-tetramethyl-hydrazine (4.4 ml) and pyrifos (2.2 ml). The mixture was stirred at 20 ° C for 1 hour. Ethyl acetate was added and the mixture was washed successively with water, 1 HCl and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate / hexane (1:1) as eluting solvent, and the purified product was crystallised from diethyl ether/hexane to give 3-(4-hydroxymethyl-indole). Methyl oxazol-2-yl)-benzoate (2.1 g), m.p. Iii.) a mixture of this material (2.1 g), dihydropyran (1.2 ml) and p-toluenesulfonic acid hydrate (〇·ι) in ethyl acetate (15 ml) at 2 (TC) After stirring for 1 hour, the solution was diluted with ethyl acetate, washed with sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated in the sputum. Acetic acid B S / / : fe (1: 2) as a dissolving agent, and (RS)-3-[4-(tetrahydro-indol-2-yloxymethyl)-oxazol-2-yl ]-Methyl benzoate (3.5 g), light yellow oil] (3.5 g, 11 mmol). Obtained light yellow oil (3.8 g). -72- This paper scale applies to Chinese national standards. (CNS) Α4 size (210X 297 mm) 1296622 A7 B7 V. Description of invention (69) MS (ISP) 402.5 [(Μ+Η)+]. Example 迟12 late g)-3-keto-3-{3 - 丨3-(tetrahydro-pyran-2-yloxymethyl isoxazolyl phenylpropanoic acid tert-butyl ester title compound according to the general procedure 方法 (method b), via third-but Acetic acid surface treatment, prepared from (RS&gt;3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole -5-yl]-methyl benzoate [made by the following procedure: hydrazine) 4-(3-bromophenyl) 2,4-dione-butyric acid ethyl ester [CAS-No. 1-51646- 31-0] (7.55 g, 23 mmol) and HCl (4.74 g, 68 mmol) in EtOH for 1 hour; ii.) The obtained ester (5.94 g, 20) Millol). Reduction of .LiAlH4 (761 mg, 20 mmol) in THF at -1 °C for 1 hour; in·) to obtain the alcohol (49 g, 19 ¢: Mohr) With 3,4-dihydro-2H-furan and a catalytic amount of _Ts〇H · Η2 Ο, react in DCM at 23 ° C for 20 hours; iv ·) The obtained THP-ether (5.24克, 15 mmol) treated with n-BuLi at -78 °C for 45 minutes, followed by C02 sludge; ν·) obtained crude acid in MeOH (90 mL) with concentrated H.sub.2. In the mixture, stir at 50 ° C for 12 hours; vi ·) to obtain the material (2 · 〇 ι 克 ' 8.62 mAh) and 3,4- dihydro - 2 Η - brim (1.17 ml, 12.9 mmol The ear and the catalytic amount of -Ts0H.H20 in DCM (17 ml), at 23. (: 5 hours under reaction) (2.44 g, 7.7 mmol). Obtained yellow oil (3·06 g). MS (ISP) 402 [(M+H)4*]. Example K13 (RS)-3- {3-『3-Methyl-4-(tetrahydro-pyran-2-yloxymethyl)_iso 4-position-5-yl i-phenyl}-3-keto-propionic acid third - Butyl ester title compound is bound according to the general procedure 方法 (Method b) by applying the Chinese National Standard (CNS) A4 specification (210X297 mm) on the third-butyl-73- paper scale.

Line 1296622 A7 B7 V. Description of the invention (7(3) Lithium acetate treatment from (RS)-3-[3-methylidene (tetrahydro-pyran-2-yloxymethyl)-isoxazole -5-yl]-methyl benzoate [made by the following procedure: i.) to give (3-bromophenyl)-3-keto-propionic acid ethyl ester [CAS-No. 21575-91-7] , tetrahydropyrrole and TMSOTf are refluxed in benzene for 16 hours (〇rg· Synth. 53, 59); ii.) 3-(3-bromophenyl)-3-tetrahydropyrrole-1-yl obtained Ethyl acrylate is reacted with nitroethane, p〇ci3 and Et3N at 23 ° C; iii ·) the obtained 5-(3-bromophenyl)-3-methyl-isoxazole-4-carboxylate The ethyl ester was reduced with LiAlH4 in THF at -10 °C for 1 hour; iv.) The obtained [5-(3-bromophenyl)-3-methyl-isoxazol-4-yl group - methanol and 3,4-dihydro-2H-pyran and catalytic amount of -TsOH · H2 0, in DCM, reacted at 23 ° C for 20 hours; iv ·) the obtained THP-ether n-BuLi, at -78. (: the next treatment for 45 minutes, followed by the CO 2 gas stream; ν·) The obtained crude acid was stirred in MeOH and concentrated H 2 S04 at 50 ° C for 18 hours; Vi.) obtained 3-(4- Hydroxymethylmethyl-isoxazol-5-yl)-benzoic acid methyl ester with 3,4-dihydro-2H-pyran and a catalytic amount of -TsOH · Η2 Ο in DCM at 23° Reaction at C for 1 hour]. Obtained a pale yellow oil (972 mg). MS(EI)416[(M+H)+]· Example K14(RS)-3-{3-[2-Methyl-5-(tetrahydro-pyran-2-yl-methyl)-21 ^Bijun-3-yl 1-phenylindole-3-keto-propionic acid tert-butyl ester The title compound is prepared according to the general procedure K (method b) via treatment with tris-butyl acetate. (RS)-3-[2-methylindole-5-(tetrahydro-bran-2-yloxymethyl)-2H-pyrazol-3-yl]-benzoic acid methyl ester [by the following sequence Preparation: 卩 4-(3•Bromophenyl)-2,4-dione-butyric acid ethyl ester [CAS-No. 151646-31-0] (6.135 g, 21 mmol), MeNHNH2 (1.296 ml, 25 mmol) and HC1 (4Μ, in the second-74- this paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public) '~1129662 A7 _____B7 V. Invention description ( 3~^~—Oxygen sputum, 6·25 liters, 25 moles in EtOH (35 ml), refluxing for u hours; η·) to obtain the obtained 5_(3-bromophenylindolyl-1H • Pyrazole glacial carboxylic acid ethyl ester (7.02 g, 22.7 Torr) in LiAiH4 (862 mg, 22 7 mmol) in THF (60 mL). [5 bromophenyl)-1-methyl-1H-pyrazol-3-yl]-methanol obtained 6.34 g, 24 mmol) and 3,4-thiopyran K a hydrogen (3.25 liters Mao, 36 mmol) and a catalytic amount of a square of -TSQH · Η2, in DCM (50 mL) at 23. The reaction underarm for 23 hours; iv) the obtained (RS)-[5-(3-&gt;odorophenyl)-i-methyl each (tetrahydrofuranyloxymethyl)·1Η•峨嗤 (8.64 g, 25 mmol) was treated with π Βϋ for 45 minutes, followed by C 〇 2 gas; V·) The crude acid obtained was in Me〇H (9 〇 ml) and concentrated H2S 〇 4 (6.5 ml), the mixture was stirred at 5 (rc for 5 hours; vi.) to obtain the obtained hydrazine (5-hydroxymethyl-2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (3.41 g, 13.85 mmol) with 3,4-dihydro-2-indole-pentan (1.75 ml, 20.77 mmol) and a catalytic amount of -TsOH*H2 in DCM (28 mL), at 23 The reaction was carried out at ° C for 18 hours. ] (3.93 grams, 11.9 millimoles). Obtained a yellow oil (4.90 g). MS (ISP) 415 [(Μ+Η)+]. Example Κ15 (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-iso 4 s--3-yl-V-phenyl}-propionic acid tert-butyl ester The title compound was prepared according to the general procedure K (method b) from (RS)-3-[ Methyl 5-(tetrahydro-pyran-2-yloxymethyl)isoxazol-3-yl]-benzoate [produced from (Z)-3-(hydroxyiminomethyl)-benzoic acid Methyl ester [CAS-No. 91186-80-0], treated in CHC13 via NCS, catalytic amount of pyridine, followed by addition of (RS)-tetrahydro-2-(2-propynyloxy)-2H -pyran, and slow addition -75- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 __ V. Description of invention (72) Add Et3N in CHC13 at 23 °C Under proceed]. Obtained yellow oil (3·〇〇). MS (ISN) 400.5 [(M-Η)&quot;]. Example Klg 3-keto-3-(3-pyrazol-1-yl-phenyl acid tert-butyl ester The title compound is based on the general procedure K ( Method b) 'Prepared from 3-pyrazole small-methyl benzoate [CAS_No. 168618-35-7] by treatment with lithium-tert-butyl acetate. Obtained a yellow oil (5.00 g). ) 286 (M+)· -- Example K17 (RS)-3-keto-3-{3-『4-(tetrahydrotetram-2-yloxymethyl-V pyrazol-1-yl 1- stupid A certain title compound of propionate tri-butyl ester is prepared according to the general procedure 方法 (method b), by treatment with a third-butyl vinegar clock, from [RS)-3-[4-(w-nitrogen-methane -2-yloxymethyl)p ratio also -1·yl]-benzoic acid methyl ester [made by the following sequence: i·) to give methyl 3-mercaptobenzoate hydrochloride [CAS-number 16762626-8] (15·14 g, 75 mmol), 2-cyano-3-ethoxy benzyl acrylate [CAS-No. 32016-27-6] (17·36 g, 75 mmol) And a mixture of EtsN (10.53⁄4 liters '75 mmol) in isopropanol (115 ml) 'reflow L5 hr; ϋ·) to give the obtained 5-amino methoxycarbonyl-phenyl 1H-pyrazole- Benzyl 4-carboxylate (26. gram, 74 mmol) and nitrous acid Amyl ester (3() pen liter, 225 mmol; 1 〇 ml) was refluxed in THF (2 mL) for 22 hours, iii·) to give the obtained 1-(3-methoxycarbonyl-benzene Base) is more than sucrose (18.98 g, 56 mmol) in Pd/C (1 〇. pd/c 6 〇〇 mg, 丨mol.) in the presence of EtOAc (350 ml) ) with THF (250 ml), at 23. Hydrogenation under the arm for 16 hours; iv·) to obtain the obtained oxime-bumethoxycarbonyl·phenyl>lH_pyrazole·4•carboxylic acid ______-76- This paper scale applies to the Chinese National Standard (CNS) Α4 Specifications (21〇χ297 mm)---- 1296622 A7 B7 V. Description of the invention (13.70 g '55.6 mmol) to · SMe2 (28.46 ml, 278.2 mmol) in THF (364 ml), at 5 Reduction to 2 yC for 16 hours; V·) to obtain the obtained 3-(4-light methyl-pyrazole+ylbenzoic acid methyl ester (1〇·66 g, 45 9 mmol) and 3,4-di Hydrogen-2Η-pyran (6.24 ml, 68.9 mmol) and a catalytic amount of p-TsOH*H2 in DCM (91 mL) at 22 ° C for 22 hours] (14.18 g, 44.8 mmol) Obtained a yellow oil (15.87 g). MS (ISN) 399 [(MH)-]. 实-例 K18 迅 g) z.3_ keto-3·{3·“4-(tetra-argon-pyran) The title compound of a gas-methyl succinyl sulphate methyl 3- succinyl}-propionic acid tert-butyl ester is prepared according to the general procedure 方法 (method b) by treatment with tris-butyl acetate. (RS>3-[4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-benzoic acid methyl ester [made by the following sequence] i } (z); (hydroxyiminomethyl-methyl)-benzoic acid methyl ester [CAS-No. 91186-80-0] treated with NCS, catalytic amount of pyridinium, in CHCI3, followed by (E)-3 - tetrahydropyrrole small group · second butyl acrylate [CAS-No. 340257-76-3], and slowly add EyN in CHC13 at 23 ° C; ii ·) 3-(3-A obtained) Oxycarbonyl-phenyl)-isoxazole·4·carboxylic acid tert-butyl ester in formic acid, stirred at 50 ° C for 18 hours; iii ·) obtained 3-(3-methoxycarbonyl-benzene -isoxazole ice carboxylic acid with BH3 · SMe2, reduced in THF at 5 to 23 ° C for 16 hours; iv ·) obtained 3-(4-methylisosaki. sitting -3 Methyl-benzoic acid and 3,4-dihydrogen: 2H-mole and a catalytic amount of -Ts〇h · AO, reacted in DCM at 23 ° C for 1 hour]. Obtained yellow oil (丨817 g). MS (ISN) 400 [(Μ-ΗΠ. -77- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) binding

Line 1296622

Example K19 (g^H3-[2-methyl·4_(tetrahydro-piperidin-2-yloxymethyl_3_ylbupyridin-3-S synthyl-propionic acid third-butyl) 1 The title compound was prepared according to the general procedure κ (method b) by treatment with a third-butyl lithium acetate from (RS&gt;3-[2-indoleyl (tetrahydro-pyran-2-yloxy-Z) 2H-pyrazol-3-yl]-benzoic acid oxime ester [made by the following sequence: L) 3-bromobenzamide and 3_isopropyl according to Synthetic Journal 1982, 318 Methylamino-propionate [CAS-No. 89895-40-9] is reacted in 曱_Benzene_ with Ets N; 仏) according to Synthetic Journal 1982, 318, 2_(3·Bromo·Benzene) obtained Methyl isopropylamino group

Methyl propyl decanoate and methyl hydrazine are reacted in an ether at 23 〇c; the obtained 5-(3-bromophenyl)-1·methyl-1H-pyrazol carboxylic acid is obtained. The methyl ester was reduced with LiA1H4 in THF at -10 °C for 1 hour; iv·) the obtained [5-(3-bromophenyl)succinymethyl-1H-pyridinyl]-methanol 3,4-Dihydro-2H-pyran and the catalytic amount of _Ts〇h • % Ο, in DCM, react at 23 C for 20 hours; ν·) will obtain (RS)-5-( 3-bromophenyl)methanol (tetrahydro-pyran-2-yloxymethyl) 1 Η-pyrazole, treated with n-BuLi at -78 ° C for 45 minutes, followed by c 〇 2 The gas stream; vi) the obtained crude acid in MeOH and concentrated H2S04$, stirred at 5 (TC for 18 hours; vii·) to obtain 3-(4·methoxymethyl-m-methyl-2-pyridinium Oxazol group &gt; methyl benzoate and ΙΜΒΒι*3 solution, reacted in DCM at -78 to 23 ° C for 1 hour ' viii ·) to obtain the crude bromide and kqac, in DMF, at 60 The reaction was carried out for 30 minutes at C, ix.) The obtained crude acetate and Na〇Me solution were reacted in MeOH at 23 ° C for 20 minutes, and X·) was obtained by 3-(4·). Lean methyl-2-methyl-2H- Methyl pyrazol-3-yl)benzoate and 3,4-dihydro-2H-pyrene and a catalytic amount of -TsOH ·%0 were reacted in DCM at 23 ° C for 1 hour]. -78- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). Binding line 1296622 A7 B7 V. Inventive Note (75) Obtained a yellow solid (11.106 g). MS (ISN) 413 [(MH)·]. Example K20 keto-3-(3-{2-|~2-(tetrahydrotetram-2-yloxy oxime 2 Η·pyrazole·3_ The title compound of the group - phenyl)-propionic acid tert-butyrate is prepared according to the general procedure 方法 (method b), by treatment with a third butyl acetonide II from (RS)-3-{2-[ 2-(Tetrahydro-fluoren-2-yloxy)ethyl]-2H·methyl benzyl-3-ylbenzoate [made by-down-method, L) makes phenyl) 3-diamino-propenone [CAS-No. 163852-04-8] was reacted with 2-hydroxyethyl, in EtOH at 230 ° C for 2.5 days; ii ·) The obtained pyrazole mixture (1236 g, 35.19 mmol) and 3,4-dihydro-2H-pyran (4.79 ml, 52.8 mmol) and a catalytic amount of -TsOH*H2 〇 in DCM (70 mL) Reaction at 2 yC for 20 hours; Hi.) chromatographic separation of the obtained isomer; iv) pure isomer (7.35 g, 73.7 mmol) as n-BuLi (13.08 liter, 20.9 mmol) Treated in THF (42 ml) at -78 ° C for 45 minutes, followed by a c〇 2 gas stream, V·) to obtain the obtained (RS)-3-{2-[2-(tetrahydro---- -2-yloxy)-ethyl]-2H-exoxazol-3-yl}-benzoic acid (4.56 g, 14.1 mmol) with KHC03 (2.89 g, 28.8 mmol) and Mel (0.99 mL, 15.9 mmol) in DMF (29 mL) for 2 hours at 23 ° C] (2.96) Gram, 8.96 millimoles). Obtained yellow oil (3.00 g). MS (ISP) 415 [(M+H)+]., Example K21 delayed 8)-3-keto-3-(3-{542-(tetrahydro-pyran-2-yl)-ethyl 1-[~1,2,31-triazol-1-ylbuphenylpropionic acid tert-butyl ester-79- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) Binding

Line 1296622 A7 B7 V. INSTRUCTIONS (76) The title compound is prepared according to the general procedure K (method b) via a third-butyl acetate clock, from (RS)-3-{5-[2-(four Hydrogen-pyrano-2·yloxy)·ethyl]·[1,2,3]triazole-i-yl}-benzoic acid methyl ester [made by the following sequence...) 3 - methyl azidobenzoate [CAS-No. 93066-93-4] and (RS)-T-butyl-dimercapto-[4-(tetrahydro-pyran-2-yloxy)- But-1-ynyl]-decane [CAS-No. 198411-20-〇] heated to 60 ° C for 10 days; ii.) The obtained material was in tbAF (1M in THF) at 70° C fell for 6 days, followed by reflux in in HC1 for 2 hours; iii.) 3-[5-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl obtained ]-benzoic acid was stirred in MeOH and concentrated H 2 SO 4 at 23 ° C for 11 days; iv·) 3-[5-(2-hydroxy-ethyl)-[1,2,3]triazole obtained Methyl -1-yl]-benzoate and 3,4-dihydro-2H-pyran and a catalytic amount of p-TsOH·Η20 were reacted in DCM at 23T: for 20 hours]. Obtained yellow oil (6.748 g). MS (ISP) 416 [(M+H)+]· Example K22 (RS)-3-g-yl-3-{3-"5-(tetrahydro-pyran-2-yloxymethyl)- The pyrazol-1-yl 1-phenyl-propionate ethyl ester standard compound is prepared according to the general procedure 方法 (Method a) from (RS)-3-[5-(tetrahydro-pyran-2-yloxy) Methyl)-pyrazol-1-yl]-benzoic acid [produced by the following sequence: i·) to give 3-mercaptobenzoic acid [CAS-No. 38235-71-1], 4-dimethyl a mixture of amino-2-keto-but-3-enoate [CAS-No. 67751-14-8] in acetic acid, refluxing for 15.5 hours; ii·) 2-(3-) Ethyl carboxy-phenyl)-2H-pyrazole-3-carboxylate and DMF-di-tertiary-butyl acetal, stirred at 80 ° C for 45 hours in toluene; iii ·) Ethyl 2-(3-t-butoxycarbonyl-phenyl)-2H-pyrazole-3-carboxylate was saponified with 3N NaOH in THF at 0-23 ° C for 16 h; iv.) 80- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 ___B7_ ___ V. Description of invention (77) 2-(3-Terti-butoxy-carbonyl-benzene obtained Base &gt; 2H_pyrazol carboxylic acid, reduced in BH3 · SMe? in THF at 5 to 23 Torr for 18 hours; V.) 3·(5·Hydroxymethyl 4 azole small group)-hydrazinic acid tert-butyl ester (3.188 g, 1 L 62 mmol) was stirred in formic acid (22 ml) at 50 ° C for 5 hours; Vi·) The obtained crude acid was stirred in MeOH (50 ml) and S0C12 (1.54 ml, 21.25 mmol) at 23 ° C for 6·5 hours; vii·) obtained 3 (5) · light methyl-pyrazol-1-yl)-benzoic acid methyl ester (2.84 g, 12.2 mmol) and 3,4-dihydro-2-indole-piperane (1.66 ml, 18·3 mmol) and The catalytic amount of _Ts〇H · η2〇, in DCM (25 ml), reacted at 23 ° C for 3 days; viii.) the obtained (RS) -3- [5- (tetrahydro- shout Methyl-2-methyloxymethyl)-p-butyryl-benzoic acid methyl ester (2.926 g, 9.25 mmol) was saponified with 6N NaOH (5 mL) in THF (20 mL) 3 hours] (1.90 g, 6.3 mmol), via ciC02Et (0.63 liter, 6.6 mmol) with Et3N (1 mL, 7.0 mmol) in THF (9 mL) / 03⁄4 CN (7 ml), activated at 〇 ° C for 2 hours, followed by potassium monoethyl malonate (2.15 g, 12.6 mmol), MgCl 2 (1.5 g, 15.8 Mole) and EtsN (2.9 mL, 20.8 mmol) at-23 billion. (: The next reaction was carried out for 2 days. A pale yellow oil (1.124 g) was obtained. MS (ESI) 373.4 [(M+H)+]. Example K23 3- keto-3·(3-indole, 2,31 triazole- 1-Benzyl-phenylpropanoic acid tert-butyl ester The title compound was prepared according to the general procedure (Method a) from 3-[1,2,3]triazol-1-yl-benzoic acid [via 3 - Azidobenzoic acid methyl ester [CAS-No. 93〇66-93-4] Refracted in dimethyl acetonitrile block followed by saponification with aqueous NaOH solution in refluxing EtOH] (10.0 g, 52.86 m Mohr), which is based on the Chinese National Standard (CNS) A4 specification (210X 297 mm) on the scale of chlorine-81 - paper. 1296622 A7 B7 V. Description of invention (78 ethyl formate / Et3N activation, and with C Acid mono-tert-butyl ester potassium salt was reacted with MgCl2 in CHgCN using Ε^Ν to obtain an orange oil (11·55 g). MS (ISP) 288 [(M+H)+]. Example K24 (RS -3 - keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl Hl, 2,41 triazol-1-yl 1-phenylpropanoic acid third - The title compound of the butyl ester is prepared from (RS)-3-indole (tetrahydro-pyran-2-yloxymethyl) by treatment with tri-butylacetic acid according to the general procedure K (Method b). 1,2,4]three -1-yl]-benzoic acid oxime ester [made by the following sequence: i.) 3-(lH-l,2,4-triazole small)-benzoic acid methyl ester [CAS-No. 167626 -27-9] (39·4 g, 194 mmol) Heated at 150 ° C for 41 hours in a hot press at 36 ° / formaldehyde-water (250 ml). The ester/hexane (1:1) crystallized to give a pale brown solid (24.3 g, 54°), m.p. 164 ° C; ii.) </ RTI> (24.3 g, 104 mM) and 3,4 - dihydro-2H-pyran (29.3 ml, 320 mmol) and a catalytic amount of p-TsOH · Η2 Ο in 2 gas (360 ml) / THF (300 ml) at 23 ° C The reaction was carried out for 20 hours. Purification on silica gel eluting with EtOAc (EtOAc/EtOAc (EtOAc:EtOAc) %) MS (ISP) 400.4 [(MH)*]. Example K25 3-keto-3-(3-"1,2,41-triazol-1-yl-phenyl)-propionic acid tert-butyl § The title compound is prepared from 3-[1,2,4]triazole-based-benzoic acid methyl ester according to the general procedure K (method b) via tris-butyllithium acetate [CAS-No. 167626 -27-9 ]. Obtained an orange liquid (2.41 g). -82- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm).

1296622 A7 B7 V. INSTRUCTIONS (79) MS (EI) 287 (M+). Example K26 3-(3-Imidazolyl-phenyl)-3-keto-propionic acid tert-butyl ester The title compound is based on General Procedure K (Method b), prepared from 3-(1Η-imidazolidinyl)benzoic acid methyl ester by treatment with a third-butyl lithium acetate [via reflux in concentrated H2S04/Me0H, from 3-(1) -Imidazolyl-1-yl)benzoic acid (j Med. Chem. 1987, 30, 1342; CAS-No. [108035-47-8]]. Obtained an orange-brown oil. MS (ISP) 287 [(M+H) +]· - Example K27 3-indenyltetrahydro-pyran-2-yloxymethyl ρ π sitting -2 yl phenylpropionic acid tert-butyl ester a) 3-(4. hydroxy Methyl-pyrazol-2-yl)-benzoic acid methyl ester 3-methylthiomethyl benzoyl-benzoic acid methyl ester (7.8 g), 1,3-dialdehyde-2-propanone (8.4 g) and A mixture of NaHC03 (8.4 g) in 1,4-dioxane (180 mL) was heated to 60 ° C for 24 hours. The reaction mixture was cooled to 20 &lt;0&gt;C and added to a stirred solution of NaOMe (5·4 g) in MeOH (200 mL). The mixture was poured into ice cold 2N EtOAc (EtOAc) (EtOAc). The organic layer was washed with brine, dried and dried in vacuo. The residue was crystallized from CH.sub.2Cl.sub.2/hexanes to afford (3,4-hydroxymethyl-thiazol-2-yl)-benzoic acid methyl ester (7.5 g) as pale brown crystals. . , b) 3-"4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl 1-benzoic acid oxime ester. The material prepared in a) (7.5 g), a mixture of hydroperidine (4.1 ml) and p-toluenesulfonic acid hydrate (0.19 g) in AcOEt (50 ml) at -3 °C

Binding line The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ______B7 __ V. Invention description (80) Dissipate for 1 hour. This solution was diluted with Ac0Et, &amp; 5% NaHC 3 solution and washed with brine to dryness with Na &lt;RTIgt; The residual oil was purified by chromatography on ruthenium using Ac〇Et/hexane (1:2) as the eliminant to give 3-[4-(tetrahydro-methane-2-yloxy fluorenyl p-plug Zyridin-2-yl &gt; methyl benzoate (9·6 g) as a pale yellow oil. c) ^^3-[3-(4-hydrogen-pyranyloxymethylazole_2_ Base 1-phenyl decanoic acid tert-butyl ester according to the general procedure 方法 (Method b), - a sample of the material prepared in b) (3.3 g) was treated with a second-butyl acetate to obtain a ketone group. Tetrahydro-pyranyloxyindenyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (3·25 g), pale yellow oil, MS (ISP) 418.2 [(M +H)+]· Example K28 perketo-343-(2-bromo-1,1-dimethoxy-ethyl)-phenyl·[·propionic acid tert-butyl ester a) Μ2·bromine 3-(2-bromo-ethenyl)-benzoic acid [CAS-No. 62423-73-8] (2.43 g) , a mixture of 4-toluenesulfonic acid hydrate (〇·38 g) and tridecyl orthoformate (5 5 ml) in Me〇H (4 mL), heated under reflux for 20 hours. Dilute with AcOEt (0.15 L), wash with 5% NaHCO3 solution and brine. Dehydration drying and evaporation in the oxime to give methyl 3-(2-bromo-1,1,dimethoxy-ethyl)-benzoate (3.0 g) as a pale yellow oil. Keto-343-(2-bromo-1,1-dimethoxy-yl-ethyl phenyl 1-propionic acid tert-butyl ester according to the general procedure 方法 (method b), 3-(2- Methyl bromo-i,l-dimethoxy-ethyl)-benzoate (3.9 g) was treated with lithium tris-butyl acetate to give 3-keto-3-[3-(2- Moji-1,1-dimethoxy-ethyl)-phenyl]-propionic acid third-butyr (2.8 g), -84- This paper is suitable for China i standard (CNS) A4 specification ( 210 X 297 mm) 1296622 A7 B7 V. Description of the invention (for yellow oil. Example K29 3-ketomethyl- ketone 4-yl)-phenyl 1-propionic acid tert-butyl ester a) 3-( 2-Methyl-indazole base V茇A 醢 A mixture of 3-(2-bromo-ethenyl)-benzoic acid (2.43 g) and acetamide (1.77 g) was heated to 130 ° C and stirred. After 40 minutes, the mixture was cooled and diluted with h20 (30 ml), and the formed precipitate was collected by filtration to give 3-(2-methyl^ σ s--4-yl)-benzoic acid ( 51 g) _, a brown solid. b) 3-(2-A - carbazol-4-yl-4-benzoic acid methyl 3-(2-methyl^oxazolyl)-benzoic acid (1.42 g) in MeOH (30 mL) EtOAc. The solution is heated to 40. . After 4 hours. The solution was evaporated in the sputum, and the residual oil was stirred with Η2 Ο (30 ml), and the pH 値 of the mixture was set to about 6 by adding a saturated NaHC03 solution. The precipitate was isolated by filtration to give 3-(2-methyl-indazol-4-yl)-benzoic acid methyl ester (1.18 g) as pale brown solid, MS (ISP) 218·2 [(M+H) +]·. c) 3-keto-3-"3-(2-mercapto, oxazol-4-yl)-phenyl-1-propionic acid tert-butyl ester according to the general procedure 方法 (method b), 3-(2-Methyl-oxazol-4-yl)-benzoic acid methyl vinegar (L02 g) was treated with a tri-butyl acetate clock to give a crude 3- keto-3-[3-(2- Methyl-noxazol-4-yl)-phenyl]-propionic acid tert-butyl ester (ι·5 g) as a pale yellow oil. Example Κ30 3-keto-3-{345-(tetrahydro-pyran-2-yloxyindenyl)-indole, 3,4&gt;sedazol-2-ylf-ylindole-propionic acid -Butyl ester a) 3-(Ν·-T-butoxycarbonyl-fluorenylcarbothio)-benzoic acid methyl ester 3-(Nf-T-butyl-butoxycarbonyl-fluorenylcarbonyl)-benzoic acid Ester (ι·47g) and -85- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) Binding

1296622 A7 — B7 1. Description of invention (82) —

A mixture of Lawesson's reagent (1. 62 g) in toluene (30 mL) was heated to 7 ° C for 1.5 h. The mixture was concentrated in a helium atmosphere and then subjected to chromatography on a gel. Using AcOEt / hexane (1:2) as a leaver, 3 (N--T-butoxy-carbonyl-oxime) was obtained. (Carbothio)-benzoic acid methyl g (m3 g), as a yellow solid, MS (ISP) 328.3 [(M+NH4)+]. b) 3-mercaptothiocarbonyl-benzoic acid methyl ester Fluoroacetate 3-(Nf-T-butoxy-carbonyl-fluorenylcarbyl)-benzoic acid methyl ester (〇·93 g) in D-FA (9 ml) / phenyl ether (2 ml) The solution was stirred at 〇 ° C for 1 hour. The solvent was evaporated in vacuo to give crude 3-mercaptothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.98 g) as crystal oil. c) 3-(5-Hydroxymethyl-"1,3,4"-sedazol-2-yl)-benzoic acid methyl ester 3-mercaptothiocarbonyl-benzoic acid methyl ester trifluoroacetate (〇· 49 g), a mixture of ethyl 2-chloro-acetimidate hydrochloride (0.47 g) in EtOH (6 mL). The mixture was diluted with AcOEt and washed with 1N HCl and brine. The organic layer was dehydrated, dried and evaporated. Residual oil (0.8 g) was taken in MeOH (5 mL), EtOAc (0.08 g). The mixture was diluted with AcOEt and washed with 1N HCl and brine. The organic layer was dehydrated to dryness and evaporated, and the residue was crystallised from AcOEt /hexane to afford 3-(5-hydroxymethyl-[1,3,4] pyrazol-2-yl)-benzoic acid methyl ester ( 0.15 g) as a white solid, MS (ISP) 251. 2 [(M+H)+]. d) 3-(5-hydroxymethyl- [1,3,4]Methylpyrazol-2-yl)-benzoic acid methyl ester (7.8 g), dihydropyran (5.6 ml) and p-toluene acid hydrate (〇·59 g) in AcOEt ( The mixture in 80 ml) was stirred at 20 ° C for 1 hour. This solution is diluted with AcOEt -86- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Invention description (83, washed with 5% NaHC03 solution and brine, dehydrated and dried And evaporating in the air. The residual oil was purified by chromatography on the Shixi gum, using AcOEt / hex (1: 2) as the falling agent' to obtain 3-[5-(tetrahydro------ Benzyloxymethyl)-[l,3,4]p-oxadiazol-2-yl]-benzoic acid decyl ester (5·85 g) as a pale yellow oil. e) 3-keto-3- 3-"4-(tetrahydro-pyran-2-yloxymethyl)-"1,3,41-pyrazol-2-yl-1-molyl-propionic acid tert-butyl ester according to the general procedure K (Method b), 3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]pyrazol-2-yl]-benzoic acid methyl ester (5.85 (g) treated with tri-butyllithium acetate to give crude 3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4 Thiazol-2-yl]-phenyl}-propionic acid tert-butyl ester _ (8.9 g), light yellow oil. Example K31 3-keto-3-(3-{5-[2- (tetrahydro-bromo-2-yloxy)-ethyl]-[1,3,4&gt; stopper II. sit-2-yl V phenyl)-propionic acid third-butyl vinegar a) 345-(2-Hydrogen-ethyl)-"1,3,4"; cediazol-2-yl 1-benzoic acid methyl ester 3-mercaptothiocarbonyl-benzoic acid methyl ester trifluoroacetate (〇· 45 g), a mixture of ethyl 3-hydroxy-propionimidate hydrochloride (35 g) in pyridine (5 ml), heated to 100 ° C for 1.5 h. The mixture was diluted with AcOEt. The organic layer was dehydrated, dried and evaporated, and the residual oil was chromatographed on silica gel, using AcOEt / hexane (1 ··1) as the dissolving agent' to obtain 3-[5 -(2-carbyl-ethyl)-[1,3, servazol-2-yl]-benzoic acid methyl ester (0.37 g) as a white solid, MS (ISP) 26} 3 [(M+ 11) [5-[2-(tetrahydro-pyran-2-yloxy)-ethyl 1-indole 1,3,4&gt;sedazol-2-one}-benzoic acid A Vinegar 3-(5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.86 g) -87 - This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 1296622

Hydrogen wave south (0.95 liters) and p-toluene sulfonic acid hydrate (〇 i3 gram) in AcOEt (25 liters) <mixture, simmered for 1 hour. The solution was diluted with AcOEt, washed with 5% NaHC 3 solution and brine, dried and evaporated. The residual oil was purified by chromatography on a silica gel using AcOEt /hexane (1:2) as a solvent to give 3-{5-[2-(tetrahydro-pyranyloxy)-ethyl]- [1,3,4] thiadiazole 1 benzyl benzoate (1 6 g), a pale yellow oil. C) M?1yl-3-(3-{5-f2-(tetrahydro-pyro--2. base gas v-ethyl ether 1,3,4&gt;soxadiazole-2-yl}-benzene Base)-propionic acid tert-butyl ester 3-{5-[2-(tetrahydro-piperidin-2-yloxy)-ethyl]-[1,3 according to the general procedure K (method b) , 4&gt;sodium π-spin-2-yl}-benzoic acid methyl ester (1 60 g) was treated with tri-butyl acetate to give 3-keto-3-(3-{5-[2- (tetrahydro-piperidin-2-yloxy)-ethyl]-[1,3,4]thiadioxa-2-yl}-phenyl)-propionic acid tert-butyl ester (21 g), It is a pale yellow oil. Example K32 3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethylv) l,3,41 oxadiazol-2-yl 1- Phenylpropionic acid tert-butyl ester a) 3-(5-hydroxymethyl 4U, servodiozol-2-yl)-benzoic acid methyl ester 3-mercaptocarbonyl-benzoic acid decyl ester (0.97 g) Mixture with 2-oxo-ethyl acetimidate hydrochloride (0.95 g) in EtOH (20 mL), warm to 80 ° C for 1 hour. The mixture was diluted with AcOEt and taken with IN HC1 and The organic layer was dehydrated, dried, evaporated, evaporated, and evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Stir at 100 ° C for 0.5 hours. After cooling to 20 ° C, add MeOH (10 ml) and NaOMe (0.14 g), and continue stirring at 65 ° C for 5 hours. Mix -88 - paper scale Applicable to China National Standard (CNS) Α 4 specifications (210χ 297 public)

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Line 1296622 A7 ____ B7____; _ V. INSTRUCTION DESCRIPTION (85) The compound was diluted with AcOEt and washed with in HC1 and with brine. The organic layer is dehydrated and evaporated, and the residue is crystallized from EtOAc / hexane to give 3-(5-methyl-[l,3,4p-diazole-2-yl)-benzoic acid Ester (0.72 g) as a white solid, MS (ESI) 235.3 [(Μ+Η)+]. b) 3-[5-(tetrahydro-pyran-2-yloxymethyl V[l,3 ,41-Myrazolyl-2-yl-benzoic acid methyl ester 3-(5-hydroxymethyl-[ι,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (9·8 g , a mixture of dihydropyran (7.7 ml) and p-toluenesulfonic acid hydrate (〇·8 g) in AcOEt (100 ml), stirred at 2 (TC for 1 hour). This solution was diluted with AcOEt It was washed with 5% NaHCO3 solution and brine, dried over water and evaporated. The residue was purified by chromatography on silica gel, using Ac0Et / hexane (1: 2) as the dissolving agent to give 3-[5-(four Hydrogen-piperidin-2-yloxymethyl)-[1,3,4]pyrimidin-2-yl]-benzoic acid methyl ester (12.6 g) as a pale yellow oil. -{3-f5-(four discs ▲•piperidin-2-yloxymethyl)-indole, 3,41 oxadiazol-2-ylindole-phenylindole-propionic acid tert-butyl ester according to general Procedure Κ (Method b), 3-[5-(tetrahydro-pyran-2-yloxy) Methyl)-[1,3,4&gt;-dioxa-2-yl]-benzoic acid methyl ester (12.6 g) was treated with tri-butyl acetate to give crude 3-keto-3- 3-indole (tetrahydro-bran-2-yloxymethyl)-[1,3,4]oxadiazol-2-yl]-phenylpropanoic acid tert-butyl ester (170 g) , light yellow oil. Example K33 heptaerythryl tetrahydro-pyroyloxy)-B H1,3,4~|oxadiazole-2- phenyl)-propionic acid tert-butyl ester a ) St. [5-(2-Hydroxy-ethyl Hl, 3,41 oxadiazole-2-methane-gcarboxylic acid methyl ester to crude 3-mercaptocarbonyl-benzoic acid methyl (2·90 g)) - Mixture of hydroxypropyl imidate ethyl ester hydrochloride (2.76 g) in pyridine (1 mL), heated to -89 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) ) '~' ----- 1296622 A7 -------B7 V. Description of invention (86) 100 C calendar, 2. 2 hours. Dilute the mixture with heart (10) and wash with IN brain and saline The organic layer is dehydrated, dried and evaporated, and the residual oil is obtained from Et20, '3'[5&lt;2-methyl-ethyl&gt;[1,3,4]oxadiazole-2- Methyl benzoate (2·5 g) as a white solid MS (ISP) 249.1 [(M+H)+]. b&gt;M5:H(tetra)yloxyethyl hydrazine-hydrazine 1,3, carbazide 2 benzyl benzoate methyl ester 3-[5-( 2-peryl-ethyl hydrazine. Methyl carbazol-2-yl]-benzoic acid methyl ester (7.45 g) A mixture of gas Chennan (4.1 ml) and p-toluene acid hydrate (0.57 g) in AcOEt (80 liters) 2 (Stirring for 2 hours under rc. This solution was diluted with AcOEt), washed with 5% NaHC〇3 solution and brine, dehydrated and dried in sputum 2. The residual oil was purified by chromatography on silica gel using AcOEt. /hex (1: 2) as a dissolving agent to give 3-{5·[2-(tetrahydro-piperidinyloxyethyl]-[1,3,4]oxadiazolyl}- Methyl benzoate (82 g) is a pale yellow oil. c) 3-glH-3_(3-{^[2-(tetrahydro-indol-2-yl)-ethyl V"l, 3,41 oxadiazol-2-ylindole-phenyl)-propionic acid tert-butyl ester 3-{5-[2-(tetrahydro-pyran-2-) according to the general procedure K (method b) Methyloxy)-ethyl]-[1,3,4&gt;soxadiazolyl}-methyl benzoate (8.2 g) was treated with tri-butylacetic acid to give crude 3-keto-3. -(3-{5-[2-(tetrahydrofuran-2-yloxy)-ethylanthracene 1,3,4]5-.sodium-2-yl}-phenyl)-propionic acid third- Ding g (11·6 g), light yellow oil. Example K34 3-(3-oxazol-4-yl-phenyl)-3-one- Acid tri-butyl acrylate a) 3-oxazol-4-yl-benzoic acid methyl ester Mix 3-(2-bromo-ethenyl)-benzoic acid (1.94 g) with formamide (1.08 g) -90- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (87)

The material was heated to 130 ° C and stirred for 3 hours. The mixture was partitioned between AcOEt and brine. The organic layer was dried <RTI ID=0.0>: </RTI> EtOAc (EtOAc) After 18 hours at 20 ° C, the solution was concentrated in sputum, diluted with AcOEt, washed with saturated NaHC03 solution and brine, dried and evaporated. The residue was chromatographed on silica gel, using AcOEt /hexane (1:3) as a solvent to give 3-sodium succinyl-benzoic acid decyl ester (0.85 g) as an off-white solid, MS (ISP) 204.1 [(_)+]·- b) 3-(3-oxazol-4-yl-phenyl)-3-keto-propionic acid tert-butyl ester according to the general procedure K (method b), 3 - oxazole-based-methyl benzoate (0.85 g) was treated with lithium tris-butyl acetate to give crude 3-(3-oxazol-4-yl-phenyl)-3- keto-propionic acid The third-butyl ester (1.46 g) was a pale yellow oil. Example K35 3·酉同基-3-(3-Buten-4-yl-yl)-propyl-feet II-butyr a) 3-thiazol-4-yl-benzoic acid methyl ester 3-( A solution of 2-bromo-ethenyl)-benzoic acid (1.22 g) and thioformamide (0.46 g) in EtOH (5 mL). The mixture was partitioned between AcOEt and brine, and the organic layer was dried and evaporated. The residual oil was dissolved in a mixture of MeOH (20 mL) and 4N EtOAc /EtOAc. After 18 hours at 20 ° C, the solution was concentrated in the sputum, diluted with AcOEt, washed with saturated NaHC03 solution and brine, dried and evaporated. The residue was chromatographed on silica gel eluting with EtOAc (EtOAc: EtOAc (EtOAc) 220·2 [(M+H)+ ]· -91 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 __B7_____ V. Description of invention (88) b) 3-ketone 3-(3-indol-4-yl-phenyl)-propionic acid tert-butyl ester 3-thiazol-4-yl-benzoic acid methyl ester (0.91 g) according to the general procedure K (method b) Treated with a third-butyl acetate clock to give a crude 3-keto-3-(3-0-beta-pyridyl-4-yl-phenyl)-propanthine-di-butyl group (1.54 g), It is light yellow oil. Example K36 3_『3·(5-Methyl-oxazol-4-yl)-phenyl-1-keto-propionic acid tert-butyl ester a) 3-second-butoxycarboxyethyl hydrazide- Methyl benzoate according to the general procedure K (Method b), dimethyl isophthalate (67.9 g) was treated with lithium tris-butyl acetate to give crude 3-tris-butoxycarbonylethyl · Methyl benzoate (74.5 g) as a pale yellow oil. b) 3-propenyl-benzoic acid methyl ester in a stirred solution of 3-tris-butoxycarbonylethyl-benzoic acid methyl ester (111 ml) in DMF (40 ml) NaH (55% dispersion in mineral oil, 1.4 g) was added in portions. Continue to agitate for 15 minutes at 〇 ° C and 30 minutes at 20 ° C. The mixture was partitioned between Ac〇£t and brine. The pH 値 was set to 7 by the addition of 3N HC1'. The organic layer is dehydrated, dried and prepared. The residue was stirred at 20 ° C for 40 minutes in a mixture of CH 2 C 2 (30 mL) and EtOAc (3 mL). After evaporating the solvent, a solution of the residue in EtOAc (EtOAc) was evaporated. The solvent of the extract was evaporated, and the residue was evaporated, mjjjjjjjjjj The chilled mixture was diluted with EtOAc (EtOAc) EtOAc (EtOAc) EtOAc (EtOAc) -92- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) '~' -- 1296622 A7 B7 V. Description of invention (89 ) [(m+h)+]· c) Bromine Propionyl-v-benzoic acid methyl ester A mixture of 3-propenyl-benzoic acid methyl ester (3.6 g) and CuBr2 (7.45 g) in AcOEt (45 ml). The undissolved material was filtered off from the cooled mixture, and the clear solution was washed with brine, dried over water and evaporated to give crude tris-tris--3-(2-bromo-propenyl)-benzoic acid methyl ester (5· 0 g) 'Ma light yellow oil. d) Κ5-methyl 号 坐 )) _ benzoic acid methyl ester oxalo-3-(2-bromo-propenyl) benzoic acid oxime ester (5.42 g) together with formamide (3.6 ml) Heat to 130 ° C for 5 hours. The mixture was partitioned between AcOEt and brine, the organic layer was dehydrated and evaporated, and the residual oil was chromatographed on silica gel using AcOEt /hexane (1: 4) as the dissolving agent to give 3-( Methyl 5-methyl-oxazol-4-yl)-benzoate (2.52 g) was obtained as a white solid. e) M3-(5-methyl-carbazole yl)-phenyl-1-keto-propionic acid tert-butyl ester 3-(5-methyl- according to the general procedure K (method b) Methyl benzoate)-methyl benzoate (0.87 g) was treated with tris-butyllithium acetate to give crude 3·[3-(5-methyl·呤呤冰基)-phenyl]-3- G-same-propionic acid tert-butyl ester (ι·46 g), light yellow oil 0 Example Κ37 3-ΙΜ2·methyl-5-propan-oxazole ice-based V-based 1-3-keto- Third-butyl propionate a) 3-pent-4-mercapto-benzoic acid methyl ketone in 3·t-butoxycarbonylethenyl-benzoic acid oxime ester (111 g) and hydrazine bromopropene (3.0 In a stirred solution of DMF (40 ml), NaH (55% dispersion in mineral oil, 4 g) was added in portions. Continued at 〇°c -93-

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This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public attack) 1296622 A7 _____B7 V. Invention description (90) Stir for 20 minutes, and at 20. (The next 3 minutes. The mixture was partitioned between Ac〇a and brine. By adding 3N HCl, the pH was set to 7. The organic layer was dehydrated and evaporated. The residual oil was taken in CH2Cl2 (30 mL) Mix with TFA (3 mL) wa at 40 C for 40 minutes. Evaporate the solvent. The residue in AcOEt was extracted with ice-cold saturated Na2c 〇3 solution, and the aqueous extract was acidified immediately with 3NHC1. And extracting with Ac0]Et. Evaporating the solvent of the extract, and heating the mixture in toluene (4 mL) and 3NHC1 (2 mL) to 1 〇〇C for 1 hour. The mixture was diluted with Ac EtOAc, washed with EtOAc EtOAc EtOAc (EtOAc m. Isp) 2362 [(M+NH4)+]. b) &gt; Xiaoxuan-3_(2_bromo-indenyl)-methyl benzoate methyl 3-pent-4-enyl-benzoic acid methyl ester ( A sample of 3.93 g) in Ac〇Et (5 mL) at 5. . Hydrogenation was carried out at 20 ° C for 30 minutes in the presence of Pd-C (190 mg). The catalyst was decanted, CuBr2 (4.44 g) was added to the solution, and the mixture was heated under reflux for 1 hour. The undissolved material was filtered out from the cooled mixture and the clear solution was washed with IN HCl and brine, dried and evaporated to give crude <RTIgt; </RTI> <RTIgt; 3.6 g), light yellow oil. c) Μ?·Methyl-5-propyl-carbazole-tungyl)-benzoic acid methyl ester will be a sample of racemic-3-(2-bromo-pentyl)-benzene and methyl ester (丨. 50 g) was heated to 130 ° C with acetamide (0.89 g) for 15 hours. The mixture was partitioned between Ac〇Et and brine, the organic layer was dehydrated and evaporated, and the residual oil was chromatographed on silica gel using Ac〇Et/hexane (1:3) as the dissolving agent-94. - The paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 __B7 _ V. Invention description (91 ) ^, and 3-(2-methyl-5-propyl-sodium azole) Methyl benzoate (〇·47 g) is a pale yellow oil. d) Chiba: [3-(2_methyl-5-propyl] oxazolyl chlorpyrifos ^ 3 ketone _ propionic acid third · butyl g according to the general procedure K (method b) 'will 3- (2-Methyl-l-propyl-oxazol-4-yl)-benzoic acid methyl ester (0.47 g) was treated with tris-butyllithium acetate to give crude 3-[3-(2-methyl-5-) Propyl-carbazole-based)-phenyl]-3-ketopropionic acid, third butyl ester (〇58 g), as pale brown oil. t^LK38 3-[3-(5-methyl- Soul-4-yl&gt;•phenyl l-3-g homo-propyl-butane-butyrate a) 3-(5-methyl-pyrazol-4-yl)-benzoic acid methyl cool- A solution of crude racemic -3-(2-bromo-propionyl)-benzoic acid methyl ester (2.71 g) and thioformamide (1.83 g) in EtOH (20 mL). The mixture is subjected to liquid separation between AcOEt and brine, the organic layer is dehydrated and evaporated, and the residual oil is chromatographed on silica gel, using Ac0Et / hexane (1: 4) as a dissolving agent. 3-(5-Methyl-methylpyrazol-4-yl)-benzoic acid methyl ester (2.41 g) as a white solid. b) 3-?~3-(5-methyl- ph-Shen-4-yl) -phenyl 1-3-keto-propionic acid third-butyr is based on the general procedure K (method) b), a sample of methyl 3-(5-methyl-thiazol-4-yl)-benzoate (1.05 g) was treated with a third-butyl lithium acetate to give a crude 3-[3-(5- Methyl-a-Shen-4-yl)-phenyl]-3-propenyl-propionic acid third-butyr S (1.9 g), light yellow oil 0 Example K39 3-[3-(2,5 -Dimethyl-g-Septen-4-yl)-phenyl1-3-mercapto-propionic acid Third-butyryl a) 3-(2,5-dimethyl-oroxazole ice-based)- Benzoic acid methyl vinegar _ -95- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

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F A7 B7 V. Description of the invention (92) A mixture of methyl 3-(2-bromo-propionyl)benzoate (6·78 g) and thioacetamide (5.63 g) is heated to I3〇°C, after 20 minutes. The mixture was subjected to liquid separation between AcOEt and 1^0, the organic layer was dehydrated and evaporated, and the residual oil was chromatographed on silica gel, using Ac0Et / hexane: 4) as a dissolving agent to obtain 3-( Methyl 2,5-dimethyl-oxazol-4-yl)-benzoate (4.97 g) was obtained as a yellow oil. b) 3-[3-(2 dimethyl dimethyl-P- oxazole-4-yl)- phenyl i-3-g homo-propionic acid tert-butyl ester according to the general procedure K (method b), _ A sample of methyl 3-(2,5-dimethyl-oxazol-4-yl)-benzoate (0.99 g) was treated with a third lithium butyl acetate to give 3 ρ·(2,5· Dimethyl 4 thiophen-4-yl)-phenyl]-3-g-iso-propionic acid tert-butyl ester (ι·12 g) was a pale yellow oil. Example Κ40 3-keto bis 3 bis |&gt;[5-Methyl-4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-4-yl 1-phenyl 1-propionic acid Third-butyl ester a) M2-hydromethyl-5-methyl-喧π-sitting) methyl benzoic acid methyl 3-(2-bromo-propenyl)-benzoic acid methyl ester (2) 71 g). A solution of 2-(t-butylcarbonyloxy)thioacetamide (2.1 g) in EtOH (20 mL). The mixture was partitioned between AcOEt and brine, and the organic layer was dried and evaporated. A solution of the residual oil and NaQMe (0.54 g) in MeOH (20 mL) (: stirring under! hours. This solution was diluted with AcOEt, washed with 1 NHC1 and hydrazine, dehydrated and evaporated to give 3-(2-hydroxymethyl-5-methyl------ Ester (U7 g), white crystals, MS (ISP) 264.1 [(M+H)+]· b) Mgr methyl-4-(tetrahydro-piperidin-2-yloxymethyl)- Methyl ester-96- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (93) 3-(2-3⁄4 methyl-5-methyl-violation a mixture of methyl benzoate-4-methyl)benzoate (1.05 g), dihydrogen (0.73 ml) and p-toluenesulfonic acid hydrate (7 g) in Ac0Et (1 mL) Stir at 2 ° C for 1 hour. This solution was diluted with AcOEt to 5. /. The NaHC03 solution was washed with brine, dried and evaporated. The residual oil was purified by chromatography on a silica gel using Ac0Et / hexane (1··3) as a solvent to give 3-[5-methyl-4-(tetrahydro- s. Methyl)-indazol-4-yl]-benzoic acid methyl ester (1.45 g) as a pale yellow oil. c) 3-keto-3-[3-『5-methyl-4-(tetrahydro^guaran-2-ylglyoximeyl)-thiazole-4_I.Phenyl 1-propene III - Ding, according to the general procedure K (Method b), 3-[5-methyl-ice (tetrahydro-piperidinyloxyindenyl)-thiazol-4-yl]-benzoic acid methyl ester (1.45 g) Treated with tri-butyllithium acetate to give crude 3-keto-3-[3-[5-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-carbazole 4-Benzyl]-phenyl]-propionic acid tert-butyl ester (2.13 g) as a pale yellow oil. Example K41 3-keto-3- "3-|~5-propyl-4-(tetrahydro-t-butyl-2-yloxymethyl)-carbazole-2-1 1-pyredyl 1-propanyl Acid tri-butyl ester a) 3-(2-hydroxymethyl-5-methyl-oxazol-4-ylbenzoic acid methyl vinegar to racemic-3-(2-bromo-pentamethylene)-benzoic acid A methyl ester sample (60 g) and 2-(t-butyl carbonyloxy) thioacetamide (36 g) were stirred in EtOH (4 mL) for 5 hr under reflux. The mixture was partitioned between AcOEt and 5 °. NaHC 〇3 solution, and the organic layer was washed with brine, dried, evaporated and evaporated. EtOAc EtOAc EtOAc The mixture was stirred for 30 minutes at 6 ° C. The solution was diluted with AcOEt, washed with in HCl and brine, dried over water and evaporated to give 3-(2-hydroxymethyl-5-methyl----- -Bug A-97- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1296622 ▼ A7 B7 V. INSTRUCTIONS (94) I &quot; Acid methyl ester (〇·44 g), an oily substance. b) 3-[5-propyl-4-(tetrahydro-methane-2-yloxymethyl)-thiazol-2-yl-1-benzoic acid methyl^ 3-(2-hydroxymethyl- 5-methyl-Oxazol-4-yl)-benzoic acid methyl ester (0.38 g), dihydropyran (0.73 ml) and p-toluenesulfonic acid hydrate (0.07 g) in Ac〇Et (1) In 〇 ml), stir at 20 ° C for 1 hour. This solution was diluted with Ac〇Et, washed with 5% NaHC03 solution and brine, dried and evaporated. The residual oil was purified by chromatography on a silica gel using AcOEt /hexane (1:3) as a solvent to give 3-[5-propyl-4-(tetrahydro-pyran-2-yloxy) Ethyl)-thiazol-2-yl]-benzoic acid oxime ester (0.36 g) as a pale yellow oil. c) 3-keto-3-s 3-"5-propyl-4-(tetrahydro-pyran-2-yl-ylmethyl)-soul-2-yl 1-phenyl-1-propionic acid Third-butyl ester according to the general procedure K (method b), 3-[5-propyl,4·(tetrahydro-blan-2-yloxymethyl)-carbazole-2.yl]-benzene Methyl formate (0.34 g) was treated with tri-butyllithium acetate to give crude 3- keto-3-[3-[5-propyl-4-(tetrahydro-pyran-2-yloxy). Methyl)-ρ stopper-2-yl]-phenyl]-propionic acid tert-butyr (0.42 g) was a pale yellow oil. Example K42 3-Regiving-3-"3-[2-Methyl-5-(tetra complex-pyran-2-yloxymethyl)-soul-4-yl 1-year ι_ propyl 1-propyl Acid tert-butyl ester a) 3-(5-bromomethyl-2-methyloxazol-4-yl V-formic acid methyl ester 3-(2,5-dimethyl-oxazol-4-yl) a mixture of methyl benzoate (3.96 g), hydrazine-bromosuccinimide (3.13 g) and a V-bis (, isobutyronitrile) (0.02 g) in CC14 (60 mM) The mixture was heated under reflux for 30 minutes. The cooled mixture was filtered, and then evaporated to give ethyl 3-(5-bromomethyl-2-methyl-carbazolyl)-benzoic acid ( 6.2 g). It is an oil. -98- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (95) b) 3-(5-Hydroxymethyl-2- Methyl sulfonate-methyl benzoate methyl ester 3·(5·Bromomethyl-2-methyl-propazol-4-yl)benzoic acid methyl ester in DMF (16 ml) 'with KOAc (2.35 g) The mixture was stirred for 20 minutes at 20 ° C. MeOH (32 ml) and NaOMe (0.86 g) were added, and stirring was continued for 30 minutes at 50 ° C. The mixture was partitioned between AcOEt and brine, and The layer is dehydrated, dried and evaporated. The residual oil is chromatographed on silica gel, and Ac〇Et / hex (1:1) is used as the dissolving agent to obtain 3-(5-glycolmethyl-2-methyl-π-su-jun- 4-Base)-methyl benzoate (2.93 g) as a white solid. c) Methyl-5-(tetrahydro-pyran-2-yloxymethyl)^Seijing ice-based 1-benzoic acid The ester will be 3-(5-hydroxyindol-2-methyl-thiazolyl)-methyl benzoate (〇·38 g), dihydropyran (2.01 ml) and p-toluenesulfonic acid hydrate (〇 2 gram of stirring in Ac〇Et (25 ml) at 20 ° C for 1 hour. This solution was diluted with Ac0Et, washed with 5 σ 〇 NaHC 〇 3 and washed with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt / hexane (1:3) as the solvent to give 3-[2-methyl-5-(tetrahydro-bromo-2-yloxymethyl) Methyl)-pyrazol-4-yl]-benzoic acid (3.8 g) as a pale yellow oil. d) g-keto-3-[3-[2-methyl·5-(tetrahydro-pyran-2-yloxymethyl V-thiazole winter 1-phenyl-1-propionic acid third-butyl Esters according to the general procedure 方法 (Method b), 3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester Treatment with lithium tributyl-butyl acetate gives crude 3-keto-3-indol[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)p-suppleyl-4-yl ]-Phenyl]-propionic acid tert-butyl ester (5.45 g) as a pale yellow oil. Example K43: </ RTI> </ RTI> </ RTI> </ RTI>唾-4-yl 1-stupyl 丨-Bingling-99- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1296622 A7 B7 V. INSTRUCTIONS (96) Third-Butyl ester a) 3-(5-Bromomethyl-thiazol-4-yl methacrylate methyl ester 3-(5-methyl-snose-4- a mixture of methyl benzoate (2.40 g), N-bromosuccinimide (2.01 g) and α,α,-bis(isobutyronitrile) (0.02 g) in CC14 (40 ml) The mixture was heated under reflux for 30 minutes. The cooled mixture was dried and evaporated to give ethyl 3-(5-bromomethyl-carbazole- yl)-benzoic acid methyl ester (3.36 g) as oil. b) 3-(5-Hydroxymethyl-thiazole ice V benzoyl-methyl ester 3-(5-bromomethyl-oxazol-4-yl)-benzoic acid methyl ester in DMF (10 In milliliters, 'with KOAc (1.52 g), stir for 30 minutes at 20 ° C. Add MeOH (20 ml) with NaOMe (0·84 g) and continue stirring at 50 ° C for 30 minutes. The separation between AcOEt and brine was carried out, and the organic layer was dehydrated, dried and evaporated. The residual oil was chromatographed on silica gel, using AcOEt / hexane (1: 2) as the glutarizer to give 3-(5) - seromethyl succin-4-yl)-benzoic acid § (1.43 g) as a white solid. c) 3-[5-( Tetrahydro-bromo-2-yloxymethyl)·soul-4-yl 1-benzoic acid methyl ester 3-(5-hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1 25 g), dihydropyran (0.84 ml) and p-toluenesulfonic acid hydrate (〇1 g) were stirred at 20 ° C for 3 hours in Ac〇Et (12 ml). This solution was diluted with AcOEt to 5. 〇 NaHC〇3 solution and washed with brine, dehydrated and evaporated. The residual oil was purified by chromatography on a silica gel using AcQEt / hexane (1··3) as a dissolving agent to give 3-indole (tetrahydro-pyran-2-yloxymethyl)-indole 7 Methyl 4-methyl]-benzoate (1.60 g) was obtained as a pale yellow oil. d) g-dione-3-(丨5-(tetrahydro-pyran-2-yloxymethyl)·thiazolyl phenyl hydrazide·-100- This paper scale applies to Chinese national standard (CNS) ) A4 size (210 X 297 mm)

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Line 1296622 A7 B7 V. INSTRUCTIONS (97) Acidic Tri-Butyl Ester 3-[5-(Tetrahydro-piperidin-2-yloxymethyl)-pyrimidine according to the general procedure K (Method b) Methyl 4-methyl]-benzoate, treated with lithium tri-butyl acetate to give crude 3-keto-3-{[5-(tetrahydro-pyran-2-yloxymethyl) Benzazole group] phenyl butyl propionate third · butyl ester (2.3 grams), a pale yellow oil. Example Κ 44 3-IHg: isopropyl-3 Η - imi _ 4- base stupid V3-S Same as its -tributyl-propionate a) 3-dihydroxyethyl-benzoic acid methyl ester - 3-(2-bromo-ethenyl)-benzoic acid (2.43 g), DMSO (17 ml) A mixture of 480 〇HBr (3.4 mL) was heated to 55 ° C for 30 minutes. The mixture was partitioned between AcOEt and H.sub.2, and the organic layer was washed with brine, dried, evaporated and evaporated to give ethyl 3-dihydroxyethyl- benzoate (1.06 g) as white solid. b) 3-(2-Isopropyl-3H-imidazol-4-yl)- benzoic acid methyl ester 3- hydroxyethyl hydrazino-benzoic acid oxime ester (0.36 g) and 2-methylpropanal (0.24 ML) at 5°/. The solution in NH3 aqueous solution (6 mL) was heated to 10 ° C for 1 hour. The mixture was evaporated in vacuo and a solution of EtOAc (EtOAc &lt;RTI ID=0.0&gt;0&gt; The solution was concentrated in the sputum, diluted with AcOEt, washed with saturated Na 2 C03 solution and brine, dried and evaporated. The residue was chromatographed on silica gel, using AcOEt as a solvent to give 3-(2-isopropyl-3H-imidazol-4-yl)-benzoic acid methyl ester (0.37 g) as pale yellow oil . c) 3-"3-(2-isopropyl-3H-imidazol-4-ylphenyl1-3-keto-propionic acid tert-butyl ester according to the general procedure K (method b), 3-( 2-isopropyl-3H-imidazol-4-yl)-benzene-101 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1296622 A7 B7 V. INSTRUCTIONS (98) Methyl ester, treated with tri-butyllithium acetate to give 3-[3-(2-isopropyl-3H-imidazol-4-yl)phenyl ]_3_keto-propionic acid tert-butyl ester (0.25 g), a pale yellow oil. .i The following examples relate to the preparation of 6-aryl-2,2-dimethyl-[1,3]dioxanthone (Formula IV), which is synthesized as a standard compound (synthesis diagram) The structural unit in the formula η):

General procedure for the preparation of L 6-aryl-2,2-dimethyl-π,31 dioxo-decen-4-one a) 6-aryl-2,2-dimethyl-[1, 3] Dioxinide-4-one is based on Chem. Pharm. Bull. 1983, 31, 1896 'under 23C' from 3-isopropyl phthalate Propionic acid and a catalytic amount of concentrated h2 S04 or trifluoroacetic acid (TFA). The final product was purified by column chromatography using hexane / EtOAc. Method b) 6-aryl-2,2-dimethyl-[1,3]dioxanthene-4-one according to Tetrahedr〇n Lett 1998, 39, 2253, at 23 ° C, Treatment with trifluoroacetic anhydride (TFAA) in a mixture of TFA and acetone from 3-aryl-3-keto-propionic acid tert-butyl ester. If necessary, the final product was purified by column chromatography using hexane/EtOAc. Example L1 lr(2,2-Methyl-6-keto-6Η·Π, 31 Dioxane 圜晞冰)-Benzyl Moontone 3-(3-Cyano-phenyl)-3-one The base-propionic acid was used according to the general procedure (method c2) using n-BuLi (1·6 Μ in hexane, 6.25 ml). c to the lower, gasification of 3-cyanobenzamide (828 mg, 5 mmol) and C-102- to this paper scale applicable to China National Standard (CNS) A4 specification (210X 297 PCT) 1296622 A7 B7 V. Description of the invention (99 bis(trimethyldecyl) g (2.56 ml, 10 mmol). According to the general procedure L (method a), via crude material (1·〇4)克) Stirring in isopropenyl acetate and TFA to convert it into a standard compound, obtaining a pale yellow solid (〇.8 g) MS (EI) 229 (M+); melting point 138 Ό (decomposition) · Example L2 4-( 2,2-Dimethyl-6-keto-6IH1,31 dioxordecen-4-yl)pyridine-2-carbonitrile The title compound is obtained according to the general procedure L (method b) in TFA / acetone The mixture was stirred with TFAA to give 3-(2-cyanopyridin-4-yl) 3-keto-propionic acid tert-butyl ester (Example M10). A brown solid (3.30 g) was obtained. MS (EI) 230 (M+); melting point 132 ° C (decomposition) · Example L3 f (3-imifen-1-yl-phenyl)-2,2-dimethyl-"1,31 dioxane Alkene-4-g with 3-(3-imiran-1-yl-phenyl)-3-keto-propionic acid, according to the general procedure κ (method cl) Using Ε^Ν and LiBr, at 0 ° C, in CH3CN, from gasification of 3_(1H-micidyl) benzamidine hydrochloride [via s〇Cl2 treatment 3-(1Η-咪 sniffing) -1-yl)-benzoic acid (J. Med. Chem. 1987, 30, 1342; CAS-No. [108035-47-8])] and bis(trimethyldecyl) malonate The crude material was converted to the title compound by stirring in EtOAc EtOAc EtOAc EtOAc (EtOAc) (M+)., Example L4 Tingdimethyl group: 6-(3-丨1,2,31tris-l-yl-phenyl-phenyl)_丨,3〗 Dioxanedecene carbone The title compound is based on General procedure L (method b), via the Chinese National Standard (CNS) A4 specification (210X 297 public) on the Tfa / Acetone-103- paper scale 1296622 A7 __ __ B7 V. Invention description (1QQ1 ~~ &quot;~~&quot;, mixed with TFAA, prepared from 3-keto-3-(3-[1,2,3]triazol-1-yl-phenyl)propyldi-butyl vinegar Example K23). Obtained a beige solid (7. (6) g) MS (EI) 271 (M+); mp 144-147 ° C (decomposition) · (2-Amino-phenyl)-amine methyl acid tert-butyl ester and fluorenyl ketone keto-propionic acid vinegar or second-butyr or 6-aryl·2,2-dimethyl Preparation of {2-[3-aryl-3-keto-propionylamino ρphenyl-p-butylamino acid tert-butyl ester by reaction of _[1,3]dioxanthene-4-one : . (2-Amino-phenyl)-amine methyl acid tert-butyl ester or (1 丨 2 mmol) and (1.0-1.5 mmol) 3-aryl-3-keto group - a mixture of propionic acid ethyl ester or a third butyl ester or 6-aryl 2,2-dimercapto-[1,3]dioxanthene ketone, heated in toluene...8 ml) 80 C to 120 C until the D-LC shows less consumption of the ingredients. The falling liquid is cooled to 23 Torr: wherein the product is substantially crystallized (in the case where crystallization does not occur, by adding hexane or ether, or directly, the reaction mixture is subjected to ♦ hose column chromatography) . The solid was filtered, washed with a mixture of ether or ether / hexanes and dried in sputum to give the title of [2_[3_ aryl-3- keto-propenylamino] phenyl phenylamino acid Butyl ester, which is used directly in the next step or, if necessary, by recrystallization or by gel column chromatography. Example M1 111Fluoro-2-indole-3-(ji-phenyl)_3·keto-propionylamino dimethylamine Some-芨 }}•Aminomethyl acid Third-butyrene title compound is based on General procedure Μ, from (2-aminopyridyl-5-dimethylaminophenyl)-amine methyl acid, third butyl ester (example η) (〇·5 mmol) and 3·(3 · -104 _ This paper ruler &amp; (4) a national standard (CNS) Μ · ((10) χ tear public love - a 1296622 A7 B7 V. Description of invention (101) Cyanophenyl)-3-keto-propionic acid Ethyl ester [CAS-No. 62008-13-5; from gasification of 3-cyanobenzidine according to the general procedure K method a] (〇.55 mmol). Obtained as a white solid (160 mg). MS (ISP) 457 [(M+H)+]; mp 159-163. Example M2 14-Gas-based net dimethylamino-243-keto-3-(341,2,31 triazole-based-phenyl-propionyl-amino-phenyl-phenyl-amine--an acid-third The title compound of butyl ester was prepared according to the general procedure from (2-aminopyridin-5-dimethylamino-phenyl)-amine methyl acid tert-butyl ester (example jl) (143 mg, 〇. 5 mM) with 3-keto-butyl (3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (example κ ΐ) (150 mg, 0.58 mmol). Obtained as a beige solid (160 mg). MS (ESI) 499 [(M+H)+] and 501 [(M+2+H)+]; melting point 136-13 TC. Example M3 (RS)-[4- 5--5-dimethylamino-2-(3-keto-3-indol-3-'5-(tetrahydro-pyran-2-yloxyf-yl)-[1,2,31 triazole 1-phenyl-propionylaminophenyl [amino acid tert-butyl ester) The title compound is prepared according to the general procedure from 2-amino-4-yl-5-dimethylamino Phenyl)-aminomethyl acid tert-butyl ester (example j1) (143 mg, 〇·5 mmol) and (RS) keto-3-(3-[5-(tetrahydro------ -2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example Κ5) (25 mg, 〇62 mmol) ) Obtained yellow oil (257 mg). w MS (ISP) 613 [(Μ+Η)+] and 615 [(Μ+2+Η)+]· Example Μ4 {2-[3-(3-Cyano-benzene) ))-3-keto-propionylaminopurine-5-dimethylamino-4-phenylethyl ______· 105- A paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 Binding)

Line 1296622 A7 B7 V. Description of the invention (1Q2) alkynyl-phenyl}-amine A 醢 三 - - 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 胺 胺 胺 胺 胺-Phenyl)-aminoglycolic acid tert-butyl ester (Example J2) and 3-(2,2-dimethylglycosyl-6Η-[1,3]dioxolyn-4-yl) Benzoonitrile (Example L1). Obtained an orange solid (108 mg). MS (ISP) 523 [(M+H)+]. Example M5 {5-dimethylamino-2-"3-keto-3-G-fl.2.31 triazole small-phenyl-propionyl Amine 1-4-phenylethynyl-phenylimamine-methyl-t-butyl ester The title compound is prepared according to the general procedure 2-·(2-aminopiperidin-5-dimethylamino- Phenyl)-aminomethyl acid tert-butyl ester (example J2) and ethyl 3-keto-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionate (Example Κ 1). Obtained an orange solid (148 mg). MS (ISP) 565 [(M+H)+]. Example M6 (4-carbyl-5-dimethylamino-2-indole-343-(3-methyl-isoxazol-5-yl stupyl 1 3-keto-p-propylaminomethyl hydrazine-phenyl)-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-4-yl-5-) Dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example Jl) (143 mg, 〇. 5 mmol) and 3-[3-(3·methyl-iso-w w-5 -yl)-phenyl]-3-yl-propionic acid ternary-butylic acid (Example K4) (450 mg, 0.75 mmol) afforded white solid (136 mg). MS (ISP) 513 [( Μ+Η)+ ] and 515 [(Μ+2~+Η)+]; melting point 109-114 ° C. Example M7 late S)-(2-dimethylamino 2',3,_difluoro- 5-(3-keto-3-{3-"5-(tetrahydro-t-butan-2-yloxymethyl-"1,2,31 triazol-1-yl-1-phenylpropanylamine某)·联笨冬基 i_胺甲-106- I paper scale applicable to China National Standard (CNS) Α4 specification (210 X 297 public) '&quot; A 1296622 A7 B7 V. Invention description (1G3 base acid third -Butyl ester title compound is prepared according to the general procedure from (5-amino-2-dimethylamino-2',3'-difluoro-biphenyl-4-yl)-amine methyl acid Third-butyl ester (Example J3) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3] Triazol-1-yl]•Phenylpropionic acid tert-butyl ester (Example K5) Obtained a yellow solid (253 mg). MS (ISP) 691 [(M+H)+]. Example M8 {2- Dimethylamino-27-difluoro-5-"3-keto-3-(3-"l,2,31 triazol-1-yl-phenylpropanylamino-5biphenyl-4-yl }-Aminomethyl acid, the third-butyl hydrazine title compound, according to the general procedure 制, from (5-amino-2-dimethylamino-2',3'-difluoro-biphenyl-4-yl --Amidinoic acid third butyl ester (Example J3) and 3-keto-3-(3-[1,2,3]triazol-1yl-phenyl)-propionic acid ethyl ester (example) Κ1). Obtained as a yellow solid (253 mg). MS (ESI) 577 [(M+H)4*]. Example M9 {543-(3-Cyano-phenyl)-3-one-propenylamine 1-2-Dimethylamino-2^3'-diqi_biphenyl-4-yl}-amine methyl acid, the third-butyl hydrazine title compound is prepared according to the general procedure, from 5-amino group 2-Dimethylamino-2',3'-difluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example J3) with 3-(2,2-dimethyl- 6-keto-6-[1,3]dioxolan-4-yl)-benzene Carbonitrile (Example L1). Obtained as a yellow solid (145 mg). MS (ISP) 535 [(M+H)+]. Example M10 (4-chloro-5-dimethylamino-2-(342-(3-methyl-isoxazole-5-ylpyridine)- 4-Base 1-3-keto-107- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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线1296622 A7 B7 V. INSTRUCTION DESCRIPTION (104) propyl propyl hydrazinyl hydrazide-styl)-Aminomethyl acid tert- butyl g The title compound is prepared according to the general procedure from 2-amino- 4-Actyl-5-dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example Jl) (143 mg, 0.5 mmol) and 3-[2-(3-methyl-) Isoxazol-5-yl)-pyridinyl]-3-keto-propionic acid tert-butyl vinegar (Example Κ6) (170 mg, 0.56 mmol). Obtained as a brown solid (206 mg). MS (ISP) 514 [(Μ+Η)+] and 516 [(Μ+2+Η)+]; melting point 181-183 °C. Example Mil (4_glycol-5-"(2-carbamoyl-ethyl)-methyl-amino 1-2-indole 343-(3-methyl-isoxazol-5-yl) benzene 1-3-keto-propionylamino hydrazine-phenyl)-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure Μ _, from {2-amino-4-chloro- 5-[(2-decyloxy-ethyl)-methyl-amino]-phenyl}-amine methyl acid tert-butyl ester (Example J4) (165 mg, 0.5 mmol) and 3- [3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example K4) (165 mg, 〇·55 mmol). Obtained an amorphous yellow material (207 mg) MS (ISP) 557 [(M+H)+] and 559 [(M+2+H)+]· Example M12 (4-Alkyl-5-"(2 -Methoxy-ethyl)-methyl-aminol-2-{3-"2-(3-methyl-isoxazolidinyl)pyridin-4-yl&gt;3-keto-propionium The amino-aminophenyl phenylamine methyl acid tert-butyl title compound is prepared from {2-amino-4-carbyl-5-[(2-decyloxy-ethyl)-oxime according to the general procedure. Benzyl-amino]-phenyl-p-methylamino acid tert-butyl ester (Example J4) (165 Aike '0.5 house Wuer) and 3-[2-(i-methyl·iso-p-jun-5 -yl)-p is more than -4-yl]* 3-keto-propionic acid third- Ester (Example Κ6) (151 mg, 0.5 mmol) afforded a yellow solid (190 mg). MS (ESI) 558 [(M+H)+] and 560 [(M+2+H)+]; 148 ° C. _ -108-____ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ____B7 V. Invention description (105) Example M13 Avoid)-[4_气基-5 ·[(2_Methoxy-ethyl)-methyl-aminol_2-(3-g-iso-3-yl-3-{3-"5-(四皇-喊喃-2-yloxymethyl) -[1,2,31 triazole oxime 苽篡 醯 醯 醯 胺 胺 笨 笨 1- 1- 1- 1- 1- 1- 1- 1- 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题4-Actyl-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl-p-methylamino acid tert-butyl ester (Example J4) (165 mg, 0.5 mmol) And (rs)-3-keto-3-{3-[5·(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]- Phenyl-propionic acid tert-butyl ester (Example Κ 5) (200 mg '〇·5 mmol). Obtained amorphous yellow material (16 mg) MS (ISP) 657 [(Μ+Η)+ ] with 659 [(Μ+2+Η)十]· Example Μ14 {4-Alkyl-54 (2-methoxyethylmethyl-amino-up-keto-3-(3-丨1,2,31Triazol-1-yl-phenyl)-propionylamino-1-phenylindole-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from {2- Amino-4-yl-5-[(2-methoxy-ethyl)methyl-amino]-phenyl}-amine methyl acid tert-butyl ester (Example J4) (165 mg, hydrazine · 5 mM) with 3-keto-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example Kl) (165 mg, 0.5 mmol) ear). An amorphous yellow material (167 mg) was obtained. MS (ISP) 543 [(Μ+Η)+] and 545 [(Μ+2+Η)+]· Example Μ15 {4-Alkyl-243-(2-cyano-pyridyl)-3-one Base-propionylamino 1-5-dimethylamino-phenyl}-amine methyl-acid-tert-butyl ester The title compound is prepared according to the general procedure from 2-amino-4-yl-- 5-Dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example jl) (143 mg, 0.5 mmol-109- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297) PCT) 1296622 A7 B7 V. INSTRUCTIONS (106 ears) and 3-(2-cyano-rhodium)-(3-keto-propionic acid tert-butyl ester (Example Κ3) (123 mg, 〇 · 5 亳 耳. Obtained a yellow solid (155 mg). MS (ISP) 458 [(Μ+Η)+] and 460 [(M+2+H)+]; melting point 1 l〇 ° C. Example M16 (4-Alkyl-5-dimethylamino-2-{3-丨3-(2-mercapto-2H-indole ratio. Sodium-3-yl)-phenyl 1-3-keto-no The title compound of the title compound is prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-amine according to the general procedure. Methyl acid third, butyl ester (example j1) (143 mg, 〇. 5 mmol) and 3-[3-(2-methyl-2H-pyridyl) -3-yl)-phenyl]-3-g-iso-propionic acid tert-butyl ester (Example K7) (180 mg, 0.6 mmol). Obtained amorphous yellow material (16 mg). (ISP) 512 [(M+H)+ ] and 514 [(M+2+H)+ ]. Example M17 (RSH5-dimethylamino-2-(3-keto-3-丨3-『5 -(tetrahydro-pyran-2-yloxymethyl)-"1,2,31 triazol-1-yl-1-phenylpropanylamino)-4-trifluoromethyl-phenyl 1- Aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid - Butyl ester (Example J6) (160 mg, 0.5 mmol) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[ 1,2,3] Triazole small group]-phenyl}-propionic acid tert-butyl ester (Example K5) (201 mg, 0.5 mmol). Obtained amorphous yellow material (24 mg). (ISP) 647 [(M+H)+]. Example M18 (5-dimethylamino-2-(343-(3-methyl-isoxazol-5-yl)-phenyl 1-3-one基·丙醯基-110- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1296622 A7 B7 V. INSTRUCTIONS (107) . r Amino V4-trifluoromethyl-phenyl)-amine methyl acid 3rd-butyl 11_ The title compound is prepared according to the general procedure from 2-amino 5-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl phthalate tri-butyl ester (example) (160 mg, 0.55 mmol) and 3-[3-( 3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (151 mg, 0.55 mmol). Obtained an amorphous yellow material (94 mg). MS (ISP) 547 [(Μ+Η)+ ]·实-例Μ19 (4-Chloro-5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[ U,3]triazol-1-yl)-phenyl 1-3-keto-propionylamino hydrazine-phenyl V amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure. (2-Amino-4-chloro-5-dimethylaminophenyl)-amine methyl acid, third butyl ester (example J1X143 mg, 0.5 mmol) and 3-[3-(5-two Methylaminomethyl-[1,2,3]triazoleyl)-phenyl] keto-propionic acid tert-butyl ester (Example K8) (172 mg, 0.5 mmol). Obtained amorphous Yellow substance (176 mg) MS (ISP) 556 [(M+H)+] and 558 [(M+2+H)+]· Example M20 (4-carbyl-5-dimethylamino-2 -〇-"3-(3-carbomethyl-isoxazol-5-styl 1-3-keto-propionylamino hydrazine-stupyl)-amine methyl hydrazine tert-butyl ester The title compound was prepared according to the general procedure from (2-aminopiperidin-5-dimethylaminophenyl)-amine methyl acid tert-butyl ester (example Chuan and 3-[3-(3- Methoxymethyliso-n-n-yt-5-yl)-phenyl]-3-keto-propionic acid ternary-butylidene (Example Κ9). Obtained as a yellow solid (205 mg). MS (ISP) 543 [(Μ+Η)+ ] and 545 [(Μ+2+Η)+ ]· -111- _ This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. DESCRIPTION OF THE INVENTION (108) Example M21 {2·[3-(2-Cyano-pyridin-4-yl V3-keto-propionylamino 14-dimethylamino-4-trimethyl-phenyl)丨-Aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid Tri-butyl ester (Example J6) (319 mg, 1·〇当莫耳) and 3-(2-Alkyl ratio-4-yl)-3-mercapto-propionic acid 2nd-butyr (example) Κ3) (246 mg, 1·〇 mmol). Obtained amorphous yellow material (297 mg) MS (ISP) 492 [(M+H)+]. Example M22 This-fluoro-543-(3 -imidazol-1-yl-phenyl)-3-keto-propionylamino 1-2-(2,2,2-triethoxyethoxy)-biphenyl-4-yl 1-aminomethyl The acid tert-butyl ester title compound was prepared according to the general procedure from [5-amino-2,-fluoro-2-(2,2,2-trifluoroethoxy)-biphenyldongyl]. Aminomethyl 3-butyrate (Example J5) (2 mg, 0.5 mmol) and 6-(3-imidazolyl-phenyl)_ 2,2-Dimethyl-[1,3]dioxolene-4-one (Example L3) (160 mg, 0.55 mmol). An amorphous brown material (167 mg) was obtained. MS (ISP) 492 [(Μ+Η)+ ]. Example Μ23 [^__Fluoro-isoxazole 4·yl)· Stupid base&gt;3·_yl-propionylamino group hM2,2, 2-Trifluoro-[iA-based)-dipyridyl-4-yl 1-aminemethyl acid tert-butyl ester "The title compound is prepared according to the general procedure from [5. Amino-2,-fluoro-- 2-(2,2,2-difluoro-ethoxy)-biphenyl-4-yl]-amino hydrazide tert-butyl ester (example J5) (200 mg '0.5 mmol) and 3_[ 3·(3_Mercapto-isoxazole|yl)-phenyl]_3-keto-propionic acid tert-butyl ester (Example Κ4) (160 mg, 〇·53 mmol). Obtained white-112 - This paper size applies to China National Standard (CNS) Α 4 specifications (210X297 public)

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1296622 A7 B7 V. INSTRUCTIONS (109) Colour solid (40 mg). MS (ISN) 626 [(M-H)·]; mp. 121-123. Example M24 [2-Alkyl-5-"3-indolyl-3-(3-"1,2,31-trisyl-phenyl-phenyl)-propanylamine ~[-91 (2,2, 2-Trifluoro-ethoxy)-biphenyl-4-yl 1-aminomethyl acid tert-butyl ester The title compound was prepared according to the general procedure from [5-amino-2'-fluoro fluorene ( 2,2,2-Trifluoro-ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example J5) (200 mg, 0.5 mmol) and anthranilyl-3 -(3-[1,2,3]triazol-1-yl-phenyl&gt;ethyl propionate (Example Kl) (150 mg, EtOAc······ MS (ISP) 614 [(M+H)+]; m.p. 54-56. (:. M.sup. M25 (_RS&gt;[2'-Fluoro-5-(3-keto-3-3-345-(4) Hydrogen-methane-2-ylyl-methyl)-"1.2.31 oxa-1-yl-phenyl}-propenylamino)-2-(2,2,2-trifluoro-ethoxy The title compound of the 1-aminomethyl acid tert-butyl ester is prepared according to the general procedure from [5-amino-2,-fluoro-2-(2,2,2-three). Fluorine-ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example J5) (200 mg, 0.5 mmol) and (RS)-3-keto-3- 3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl] -Phenyl}-propionic acid tert-butyl ester (Example K5) (22 mg, 0.55 mmol). Obtained yellow oil (1 mg). Example Μ26 (RS)-[4-carbyl-5 -(ethyl-methyl-amino)-2-(3-keto-3-(3-indole-5-(tetrahydro-pyran-2-yloxymethylHl,2,3]triazole -1-yl 1-phenylindole-propionylamino)-phenylamine methyl acid tert-butyl ester-113 This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (110) The title compound is prepared according to the general procedure from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-aminomethyl Acid tri-butyl ester (Example J7) (300 mg, 1.0 mmol) and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl) • [1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (example) (402 mg, 1. 〇 millimol). Obtained yellow foam (500 Mg) MS (ISP) 627.1 [(M+H)+]· Example M27 (RS)-[4-Chloro-5-(methyl-propylamino)-2-(3-keto-3-yl) 3-丨5·(tetrahydro-pyranomolyloxymethyl) 41,2,31 triazol-1-yl 1-phenylindole-propionylamino)-styl 1-aminemethanoic acid First - butyl ester title compound was prepared according to the general procedure from [2-aminopyridin-5-(methyl-propylamino)-phenyl]-amine methyl acid tert-butyl ester (example J8) (310 Mg, 1.0 mM) with (RS)-3-keto each {3-[5-(tetrahydro-pyran-2-yloxymethylhuj) triazole small group]-phenyl}propionic acid Third-butyl ester (Example K5) (402 mg, ΐ·〇 mmol). A yellow foam (410 mg) was obtained. MS (ISP) 641.3 [(M+H)+]. Example M28 (RS)-[4-Chloro-5-(diethyl-amino)-2-(3-keto-3-{3- 『5-(tetraj,-pyran-2-yloxymethyl)-[1,2,31triazol-1-yl-1-phenylindole-propenylamine-methyl-methyl-amine The acid tert-butyl ester title compound was prepared according to the general procedure from [2-aminopyridin-5-(diethyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (example) J9) (31 〇 mg, h 〇 millimol) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl Huy three-seat-1 -基]-Phenylpropionic acid third-butyl ester (example Κ5χ4〇2 mg, 1 〇mmol-114- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) Binding

Line 1296622 A7 B7 V. Description of invention (111) Ear). A yellow bath (530 mg) was obtained. MS (ISP) 641.3 [(M+H)+]. Example M29 (RS)-丨4-Gayl-5-&gt;-Methylamino-2-(3-indolyl-3-{3-[3 -(tetrakis-bran-2-yloxymethyl)-isoxazol-5-yl 1-phenylpropionylamino)-phenyl 1-amine methyl acid tert-butyl ester title compound According to the general procedure, it was prepared from (2-amino-4-carbyl-5-dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example J1) (143 mg, 0.5 mmol). And (RS)-3-keto-3-{3-[3-(tetrahydro-piperidin-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionic acid Third-butyl ester (Example Κ 12) (201 mg, 0.5 mmol). A yellow foam (530 mg) was obtained. MS (ISP) 613.1 [(Μ+Η)+] and 615 [(Μ+2+Η)+]· Example Μ30 (g^SH4-气基-2-(3-keto-3-丨3-『 5-(tetrahydro-pyran-2-yloxymethyl V丨1231 triazol-1-yl 1-phenylindole-propionylamino)-5-tetrahydropyrrole small group-phenyl&quot; The title compound of the third amine, butylamine, is prepared according to the general procedure, and is prepared from (2-aminopyridyl-5-tetrahydro^:l-l-ylphenyl)-amine methyl acid -丁g(Example jl〇) and (RS)-3-keto_3-{3-〇(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole- 1-Benzyl-p-phenyl-propionic acid tert-butyl ester (Example K5). Obtained yellow foam (228 mg) MS (ISP) 639 [(M+H)+] and 641 [(M+2fH) +]· Example M31 (5-Dimethylamino-2-{3-P-(2-methyl-2H-pyrazolyl V Momo 1-3-S homo-propyl-propionyl 1 base}-4 -Trifluoromethyl-p-stylamine methyl acid tert-butyl ester-115- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1296622 A7 B7 V. Description of the invention (112) The title compound was prepared according to the general procedure from (2-amino-5-dimethylamino 4-trifluoromethyl-phenyl)-amine methyl acid. -Butyl ester (Example J6) (i60 mg, 〇5 mmol) and 3-[3-(2-methyl-2Η-pyrazol-3-yl)-phenyl]-3-keto-propionic acid The first: a 丨 ~, butyl ester (example Κ 7) (150 mg, 〇 · 5 mmol). Obtained a yellow foam (9 gram). MS (ISP) 546.2 [(M+Hf]. Example M32 (RSH4-carbyl-5-dimethylamino-2-(3-{3-"3-methyl-4-(tetrahydro-pyran) -2-ylmethyl)-isoxazole-5-yl 1-phenylindol-3-one-propionylamino)-phenyl 1-amino acid tert-butyl ester The title compound is based on the general procedure Μ, produced from (2-aminopiperidyl j, methylamino-phenyl)-amine methyl acid tert-butyl ester (example J1) and (RS)-3-{3-[3-methyl 4-(tetrahydro-piperidin-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-one, acid tert-butyl ester (example K13). Yellow solid (187 mg). MS (ISN) 626 [(MH)·] and 628 [(M+2-H)·]· Example M33 (RS)-[4-carbyl-5-(cyclopropanyl) -amino)-2-G-keto-3-{3-f5-(tetrahydro-2-yloxymethyl)-fl, 2,31 tricen-1-yl 1-phenylindole-propion The title compound is the [2-aminopiperidinyl I(cyclopropyl-methyl-amino)-phenyl group according to the general procedure. ]-Aminomethyl, acid tert-butyl ester (example J11X156 gram, 〇·5 mmol) and (RS) ketone-3-{3-[5-(tetrahydro-furan-2_) Hydroxymethyl)-[1,2,3]triazole-1_yl]- Third butyl ketopropionate (Example Κ 5) (250 mg, 〇 · 62 mmol). Obtained a yellow solid (215 mg). -116- This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) binding

Line 1296622 A7 B7 V. INSTRUCTIONS (113) MS (ISN) 637.1 [(M-Η)·] and 639 [(M+2-H)-]; melting point 47-49 °C. Example M34 (5-Dimethylamino-243-ρ-(5.dimethylaminomethyl-indole 1,2,31 triazol-1-yl)-phenyl1-3-keto-propenyl Amino-p-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-aminodiamminyl- 4-trifluoromethyl) Phenyl)-aminomethyl acid tert-butyl ester (Example J6) (160 mg, 〇.5 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3 Triazol-1-yl)-phenyl]-3-ketopropionic acid tert-butyl ester (Example Κ 8) (172 mg, 0.5 mmol). Obtained an amorphous yellow material (195 mg). MS (ISN) 588 [(MH)·]. Example M35 (RSM4-qi-5-dimethylamino-2-(3]3-indole-2-methyl-5-(tetrahydro-pyran-2) -Meta. Its methyl)-2H-pyrazol-3-yl 1-phenylindol-3-one-propionylamino)-phenyl 1-amine-methic acid tri-butyl ester, title The compound was prepared according to the general procedure from (2-amino-4-carbylj dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example Jl) (200 mg, 0.7 mmol). And (RS)-3-{3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-2H-pyrazolyl]-phenyl}-3-one - Propionic acid third-butyl ester (Example K14) (290 mg, 0.7 mmol). Obtained amorphous yellow material (329 mg). MS (ISN) 624·0 [(MH)-] and 626 [( Μ+2-Η:Γ]. Example Μ36 {2-『3·(2-Cyano-pyridin-4-yl)-3-keto-propionylamino 1-5-tetrahydropyrrole-1 - benzyl-trifluoromethyl-phenyl hydrazine-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure, from (2-amino-5-tetrahydropyrrole- _ -117 - ____ This paper size applies to China National Standard (CNS) Α4 specification (210 X 297 mm) Binding

1296622 A7 B7 V. INSTRUCTIONS (114) 1-Phenyl-4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (example J12X173 mg, 〇·5 mmol) and 3-( 2-cyano-pyridin-4-yl)-3-hydroxyl-propionic acid tert-butyl ester (Example K3) (150 mg, 0.61 mmol). Obtained as a yellow solid (140 mg). MS (ISP) 518 [(M+H)+]· Example M37 (RSH2-(3-keto-34345-(tetrahydro-pyran-2-yloxymethyl)-oxime, 2,31 triazole -1-yl 1-phenylindole-propionylamino-based V5-tetrahydropyrrole-1-yltrifluoromethylphenyl 1-aminemethyl acid tert-butyl ester - the title compound is based on the general procedure , prepared from (2. Amino-5-tetrahydropyrrol-1-yl-4-trifluoromethyl-phenyl)-amine methyl acid, third-butyl ester (Example J12) (173 mg, 〇·5 Millol) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole-1- Base]-phenyl}-propionic acid tert-butyl ester (Example K5) (250 mg, 0.62 mmol). Obtained orange foam (168 mg) MS (ISP) 673 [(M+H)+ Example M38 (RSH5-dimethylamino-4-fluoro-2-(3-keto-3-{3_"5-(tetrahydro-indol-2-yloxyindenyl Hl, 2, 31 triazole small group 1-phenylidene propylamino)-phenyl 1-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-dimethylamino) 4-fluorophenyl)-amine methyl acid third-butyr (example J13) (269 mg, ΐ·〇 millimol) and (RS)-3-keto-3-{3-[5 -(tetrahydro-boranyloxy Base)-[1,2,3]triazol-1-yl]-phenyl]propionic acid tert-butyl ester (Example Κ5) (401 mg, 1.0 mmol). Obtained yellow amorphous material (417 Mg) MS (ISN) 595 [(MH)']. -118- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Invention description (115) Example M39 Enterprise II Amidino-2-{3_"3-(5-dimethylamine-methyl-"1,2,31-triazol-1-ylphenyl n-gg-propyl-propylamino-4-anthene Stupid-based V-aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-dimethylamino fine 4-fluorophenyl)-amine methyl acid. Ester (example jn) (269 mg, 1·〇 mmol) with 3-[3-(5-dimethylaminomethyl-[1,2,3]triazole)-phenyl]-3 - Keto-propionic acid tert-butyl ester (Example Κ 8) (344 mg, ΐ·〇 mmol). Obtained yellow amorphous material (211 mg). _ MS(ISN) 538 [(MH)·] Example M40 迅S)-[5-Dimethylamino fluoroyl 2-G-keto-3-{3-『3-(tetrahydro-pyranyl-hydrogen a certain j7 group) -5-ylyl-phenylphenyl-propionylamino)-phenyl 1-amine methyl acid third_ The title compound was prepared according to the general procedure from (2-amino Idimethylamino-4-pyrene)-amine methyl acid tert-butyl ester (example j13) (269 mg, 1·〇 Mos) with (RS)-3-keto-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)isoxazole·5-yl]·phenyl}-prop Acidic third-butyl ester (Example Κ 12) (401 mg, 1.0 mmol). Yellow amorphous material (360 mg) was obtained. MS (ISN) 595 [(Μ-Η)-]· Example M41 (RS)-[5-Dimethylaminoketo-3-ylidene-tetrahydro-pyran-2-yloxymethyl V Iso-N--5-yl-based oxime-propionylamino)-4-trifluoromethyl-phenyl 1-aminemethyl acid tert-butyl ester The title compound is obtained according to the general procedure. -Amino-5-dimethylamino-119- The paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) Binding 1296622 A7 B7 V. Description of invention (116) 4-Trifluoromethyl -Phenyl)-aminomethyl acid tert-butyl ester (Example J6) (565 mg, "77 mmol") and (RS)-3-keto-3-{3-[3-(tetrahydro- Piperidin-2-yloxymethyl)-isoindole-5-yl]-phenylpropionic acid tert-butyl ester (Example K12) (71 mg, 1.77 mmol). A yellow amorphous material (721 mg) was obtained. MS(ISN) 645 [(M-Η)·]· Example M42 (RSH5-dimethylamino-fylfluoro-2-(3-keto-_3_{3-ί3·(tetrahydro-pyran-2-)基 王 王 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基-amino-5-dimethylamino-4-fluorophenyl)-amine methyl acid, third butyl ester (example J13) (269 mg, 1 〇 millimolar) with 3-[3-(3- Methyl-isoxazole_5_yl>phenyl]keto-propionic acid tert-butyl ester (Example K4) (301 mg, ΐ·〇 mmol). Obtained yellow amorphous material (273 mg) MS (ISP) 497 [(M+H)+]. Example M43 Avoid)-[4-Alkyl-5-dimethylamino-2-indoloneyltetramine·Bane-2-Acyloxy Base) - different drinks. Sodium-3-yl]-phenylindole-propionylamino ν-decylamine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from (2-amino-4-chloro-5) -dimethylamino-phenyl)-amine methyl acid tert-butyl ester (example with (RS) ketone group ^(3-[5-(tetrahydro-pyran-2-yloxymethyl)) _isoxazol-3-yl]-phenylpropionic acid third-butyl vinegar (Example K15). Obtained yellow foam (232 mg). MS (ISN) 611.1 [(M-Η)·] and 613 [ (Μ+2-Η)-]· Example M44 迅习-屮气基 K2-keto-3-(345-(tetrahydro-mum-2-yloxymethyl)-oxime, 2,3] -120- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm)

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Line 1296622 A7 B7 V. Description of the invention (117, 1,1-yl)-phenylindole-propionylamino)-5-hexahydropyridine-1-yl-l-yl 1-amine methyl acid - The title compound of butyl ester is prepared according to the general procedure from (2-aminohydrocarbyl-hexahydro-p-m-phenyl)amine methyl acid to the third-butyl ester (Example J14) and (RS)-3-ketone. 3-(3-[5-(tetrahydropyran-2-yloxymethyl)-[1,2,3]triazole-μyl]-phenylpropanoic acid tert-butyl ester ( Example K5). Yellow foam (257 mg) was obtained. MS (ISP) 653.2 [(M+H)+ ] and 655 [(M+2+H)+ ]· Real-example M45 (RS)-[5-monomethylamino-2-(3-indenyl) -3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-iso-yl]-phenyl l-propionylamino)-4_trifluoromethyl- stupid The title compound of the 1-aminomethyl acid tert-butyl ester is prepared according to the general procedure from (2-amino-5-dimethylamino-4-difluoro-methyl-phenyl)-amine methyl Acid third-butyl vinegar (example brother) and (Rg)-3-keto-3-(3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl ]-Phenyl-propionic acid tert-butyl ester (Example K15). Obtained as a pale yellow foam (224 mg). MS (ISP) 647.2 [(M+H).]· Example M46-{4-Chloro-5-dimethylamino-2-[~3-g-yl-3-(3-p ratio -Phenylpropanylamino 1 benzyl}-aminomethyl acid tert-butyl hydrazine The title compound is prepared according to the general procedure from (2-aminopiperidin-5-diamidino-phenyl --Aminomethyl acid third-butyl ester (Example J1) and 3-keto 3-(3-exo I:pyridin-1-yl-phenyl)-propionic acid tert-butyl ester (Example K16) Obtained a pale yellow solid (135 mg) MS (ISP) 498 [(M+H)+] and 500 [(M+2+H)+]; mp 148-149 ° C. -121 National Standard (CNS) A4 Specification (210 X 297 mm)

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Line 1296622 A7 B7 V. Description of the invention (118 Example M47 {243-(2-Cyanyl-pyridyl)-3-one-propionyl-hydrazino-tetrahydro-p-butyr-1-yl-stupyl- Aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-aminopiperidin-5-tetrahydropyrrol-1-yl-phenyl)-amine methyl acid tert-butyl. Ester (Example J15) and 3-(2-cyano-exobutyl-4-yl)-3-mercapto-propionic acid tert-butyl vinegar (C3). MS (ISP) 468 [(M+H)+]; melting point 23 L ° C (decomposition) · Example M48 (4-fluoro-2-{3-"3-(3-methyl-isoxazole) -5-yl)-styl 1-3-keto-propionylamino}-5-tetrahydropyrrole small-styl)-aminomethyl acid tert-butyl ester The title compound is according to the general procedure Μ Made from (2-amino-4-fluoro-5-tetrahydropyrrole small-phenyl)-amine methyl acid tert-butyl ester (Example J15) with 3-[3-(3-methyl -isoxazole-5-yl)-phenyl-keto-propionic acid tert-butyl ester (Example Κ 4) gave a pale yellow solid (126 mg). MS (ISP) 468 [(M+H)+] Melting point 186 ° C. Example M49 (RSH 4-fluoro-2-(3-keto-3-indol-3-(5-(tetrahydro-pyran-2-yloxy) Methyl)-"1,2,31 tri-U-yl 1-phenyl}-propenylamino)-5-tetrahydropyrrole-1-yl-phenyl 1-amine methyl acid tert-butyl ester The title compound was prepared from (2-amino-4-fluoro-5-tetrahydro-exo-l-yl-1-yl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure. J15) and (RS)-3•keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethylhuj]triazol-1-yl]-phenylpropanoic acid Tri-butyl ester (Example K5). Obtained orange viscous oil (268 mg) -122 This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) Binding

Line 1296622 A7 B7 V. INSTRUCTIONS (119) MS (ISP) 623 [(M+H)+J. Example M50 azo-tetradec-1-yl-4-chloro-2-"3-(2- Cyano-pyridinone V3-keto-propionyl]]-phenylindole-amine methyl-acid-tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-- N-tetradec-1-yl-4-chlorophenyl)-amine methyl acid tert-butyl ester (example j16) and 3-(2-cyano-4-pyridin-4-yl)-3-keto-propionic acid Third-butyl ester (Example K3). Obtained as a yellow solid ( 142 mg) - MS (ESI) 470 [(M+H)+] and 472 [(M+2+H)+]; Decomposition) · Example M51 (inhibition)-[2-(3·keto-3-(345-(tetrahydro-pyran-2-yloxymethyl)-isosazol-3-yl) 奚}--propylaminomethyl)_5-tetrahydropyrroleyl-4-trifluoromethyl-benzene 1-acetic acid tert-butyl ester The title compound is prepared according to the general procedure from 2-amine -5-5-tetrahydropyrrol-1-yl-4-trifluoromethyl-phenyl)-amine methyl acid 3rd-butyr (example ji2) and (rs)-3-keto-3-13 -[5-(Tetrahydro-fluoren-2-yloxymethyl)-isoindole -3-yl]-phenyl}-propionic acid tert-butyl ester (Example K15). Obtained yellow foam (522 mg) MS (ISN) 671.2 [(MH)·]· Example M52 {5--disorder tetradecyl-1-yl-2-indole-3-(2-carbyl-p ratio-4-yl) -3-indolyl-propylaminomethyl-1·4-trifluoromethyl-phenylindole-amine methyl acid 1,3-tributyl ester The title compound is prepared according to the general procedure from 2-amino- 3-Nitrotetradecyl-1-yl-4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (Example J17) and 3-(2-cyano-pyridin-4-yl) 3-keto-propionic acid tert-butyl ester (Example K3). Obtained pale yellow 123 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1296622 A7 _ B7 V. INSTRUCTIONS (120) &quot; • f Solid (131 mg). MS (ISP) 470 [(M+H)+]; mp 166-167. Example M53 (5--azaindole-1-yl-2-{3-"3-(3-methyl-isoxazol-5-yl)-stupyl 1-3, a certain decylamino group }-4_Trifluoromethyl-phenyl)-amine methyl acid The third-butylated title compound was prepared according to the general procedure from 2-amino-5--nitrotetraindole-1-yl-4 -trifluoromethyl-phenyl)-aminomethyl acid tert-butyl ester (example j17) and 3_[3_(3·methyl-isoxazol-5-yl)-phenyl]-3-one- Base-propionic acid third-butyl ester (Example K4). A pale yellow foam (218 mg) was obtained. MS (ISN) 557.2 [(M-Η)·]; mp. Example M54 (RS)-[5-^^鼠四园-1-yl-2-(3-indolyl-3·{3-"5-(tetrazin-2-yloxymethyl)- [1,2,3]二° sit-1-yl-1-yl}-propylamino)-4-trimethylmethyl-phenyl-1-aminomethyl acid tert-butyl ester title compound According to the general procedure, it is prepared from (2-amino-5--nitrotetradec-1-yltrifluoromethyl-phenyl)-aminomethyl acid tert-butyl ester (example j17) and (RS) Wortone-3-{3-[5-(tetrahydrotetrapyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid - butyl ester (Example K5). Obtained a yellow foam (450 mg). MS (ISN) 657.1 [(M-Η)-]; mp. 76-77T: mp. -(3-pyridin-1-yl-phenyl)-propionylamino 1-4-trifluoromethyl-phenyl-p-methylamino acid tert-butyl ester The title compound is prepared according to the general procedure. From (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (Example J6) (319 mg, 1.0 _-124-_ paper Zhang scale applies Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (121 mmol) and 3-keto-3-(3^ ratio jun-1-yl·benzene ) - third-butyl propionate (Example K16) (286 g, 1.0 Torr). Obtained yellow amorphous material (4 g 5 mg). MS (ISN) 530 [(Μ-Η)Ί - Example Μ 56 ]1:_Dimethylamino-2-[3- 棊-棊-3-(3-"1,2,41-triazol-4-yl-phenylv-propenylamine, ι· 4-trifluoro Methyl-phenyl-b-aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-5-dimethylamino-4-difluoromethyl-phenyl)-amine Tri-butyl methacrylate (example j6) (383 mg, 1.2 Amor) and 3-keto-3-(3·[1,2,4]triazol-4-yl-phenyl)_ Ethyl propionate [CAS-No. 335255-97-5] (259 mg </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 62 ° C. Example M57 15-Methylamino-2-[3-(3-benzo-l-yl-phenyl)-3- keto-propenylamino 1 ice trifluoromethyl-benzene The quinone-aminomethyl acid tert-butyl ester title compound is prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid Third-butyl ester (Example J6) and 6·(3·imidazole+yl-phenyl)-2,2-dimercapto-[1,3]dioxane 4-one (Example L3). Obtained orange oil (238 mg). MS (ISP) 432 [(M+H)+]. Example M58 分 卜 气 -5-5-dimethylamino-2-(3-keto-3-{3-f4-(tetraindole-pyran) -2-A certain gas __ 棊 峻 峻 二 二 二 二 二 二 二 二 1 1 1 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题2-Amino-4-yl-5-di-125- This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) Binding

Line 1296622 A7 B7 V. INSTRUCTION DESCRIPTION (122 Methylamino-phenyl)-Aminomethyl acid tert-butyl ester (Example Jl) (429 mg, 1.5 mmol) and (RS)-3-keto- 3-{3-[4-(tetrahydro-pyran-2-yloxymethylX唆-1-yl]-phenylpropanoic acid tert-butyl ester (Example K17) (601 mg, 1.5 m Mol). Obtained yellow amorphous material (710 mg). MS (ISN) 610 [(MH)·] and 612 [(M+2-H)-]· Example M59 (RSH5-dimethylamino-2 -(3-keto-3-{3-"4-(tetrahydro-pyran-2-yloxymethyl)-exoquinone-1-yl 1-phenyl-propionylamino)-4- Trifluoromethyl-phenyl [amine methyl acid, third, butyl, the title compound is based on the general procedure M · from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) )-Aminomethyl 3-butyrate (Example J6) (479 mg, 1.5 Amol) and (RS)-3-keto-3-{3-[4-(tetrahydro----- - methoxy fluorenyl) _? 比 · · 1-yl]-phenyl}-propionic acid third-butyl ester (Example K17) (601 mg, u mmol;). Obtain pink amorphous substance (641 mg) MS (ISN) 644 [(MH)']. Example M60 (KSH5-dimethylamino-2-(3-{3-"3-methylindole (tetrahydro-基 甲 ) ! ! -5 - - - - - ! ! ! - - - - 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题From (2-amino-5-dimethylamino-4-dimethyl-ethyl)-aminomethyl, di-g-g (segment jg) and (r§)-3-{ 3-[3·methyl-4-(tetrahydro-pyran-2-yloxymethyl)-iso 1r-thin-5-yl]-phenyl-3-keto-propionic acid third-butyl Ester (Example K13). Obtained red oil (424 g) MS (ISN) 626 [(MH)*]. -126· This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1296622 A7 _ B7 V. Inventive Note (123) Example M61 (Μ):·[5·Dimethylamino-2-(3-keto-3-{344-(tetrahydro-pyran-2-yloxy) Methyl group is different! i. succinyl 1-phenylpropionylamino hydrazine-trifluoromethyl-phenyl 1-amine methyl acid tert-butyl ester The title compound is based on the general procedure Μ, from (2- Amino-5-dimethylamino-4-trifluorodecyl-phenyl)-amine methyl acid tert-butyl ester (example J6) with (RS)-3-keto-3-(3-[3-[ 3-(tetrahydro-piperidin-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert-butyl ester (example K18 ). Obtained as a pale yellow solid (145 mg). MS (ISP) 647 [(M+H)+]. Example M62 (RS)-(5-dimethylaminoindole 3-(2-methylthio-imidazol-1-yl)-phenyl 1-3- Ketopropyl-propionylamino hydrazine_4-trifluoromethyl-p-stylamine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from (2-amino-5-dimethylamino) 4- 4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (example j6) (319 mg, 1. 〇 millimol) and 3-[3-(2-methylthio-imidazole) 1-yl)-phenyl]-3-keto-propionic acid tert-butyl ester [CAS-No. 335256-01-4] (432 mg, 1.3 mmol). Obtained pale brown amorphous material ( 493 mg) MS (ISP) 333·2 [(M+H).]. Example M63 (RS)-[5-monomethylamino-2-(3-{3-『2-methyl-4- (tetrahydro-bito-2-yloxymethyl)·gM-pyrazol-3-yl 1-phenylindol-3-one-propionylamino)-4-trifluoromethyl-benzene The title compound of the base V amine methyl acid tert-butyl ester is prepared from (2-amino-5-dimethylamino-4-trifluoromethylphenyl)-amine methyl acid according to the general procedure. Tri-butyl ester (Example J6) and (rs)-3-{3-[2- -127- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description (124) Methyl-4-(tetrahydro-bungan-2-yloxymethyl)-2H-pyrazol-3-yl]-phenyl-3-keto-propionic acid tert-butyl ester (Example K19). A pale red solid (576 mg) was obtained. MS (ISN) 658 [(MH)·]· Example M64 {4-chloro-5-dimethylamino-2-indole-3-one-3 -(3-Π, 2,41 triazole-μ-----v-propylamino-phenylphenyl-aminomethyl-tert-butyl ester, the title compound is prepared according to the general procedure from 2-amine Hydrylchloro-5-dimethylamino-phenyl)-amine methyl acid tert-butyl (example J1) and 3-keto-3-(3-[1,2,4]triazole- 1-Benzyl-phenyl)-propionic acid tert-butyl ester [CAS-No. 335255-88-4]. Obtained as a pale yellow solid (427 mg). MS (ISN) 497 [(Μ-ΗΠ and 499 [(M +2-H)-]· Example M65 {5-Dimethylamino-243-keto-3-(3-indole, 2,41 triazole small-phenyl)-propanylamino group 1-4 -Trifluoromethyl-phenyl Vamine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl) )-Aminomethyl 3-butyrate (Example J6) and 3-keto 3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid Third-But Ester [CAS-number 335255-88-4]. A pale red solid (502 mg) was obtained. MS (ISN) 531 [(MH)&quot;]. Example M66 (2-[3-(3-Cyano-phenyl)-3-keto-propenylamino)1-5-dimethylamino- 4-Trifluoromethyl-phenyl}-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from (2-aminodimethylamino-4-trifluoromethyl-phenyl). -Aminomethyl 3-butyrate (Example J6) (320 mg, 1. 〇-128- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1296622 A7 _________ B7 V. Invention Description (125) 耄Moel) and 3-(2,2-dimethyl-6-keto-6H-[1,3]dioxanthene-based ice-based benzoic acid (peripheral Ll) (275 EK '1.2 Amol). Obtained red viscous oil (196 mg) MS (ISN) 489.1 [(MH)-]· Example M67 Avoid H5-(cyclopropylmethyl-methyl-amino) -2-(3-ketotetrahydro-fluoren-2-yloxymethyl)-[1,2,3]distiminyl 1_phenylindole-propionylamino) ice trifluoromethyl Phenylphenyl 1-aminomethyl acid tert-butyl ester. The title compound was prepared according to the general procedure from [2-amino-5-(cyclopropylmethyl-methyl-amino)-4-tri Fluoromethyl-phenyl]-amine methyl acid, third butyl ester (example J18) (719耄克' 2.0耄莫耳) with (RS)-3-_yl-3-{3-[5-(tetrahydro-bran-2-yloxymethyl)-[1,2,3]triazole 1-yl]-phenyl}-propionic acid tert-butyl ester (example k5) (8 〇 3 mg, 2.0 mmol). A yellow amorphous material (985 mg) was obtained. MS (ISP) 687 [(M+H)+]· Example M68 [2-[3-(2-Cyano-Exo 1:N--4-yl)-3-keto-propionylamino 1 5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl-1-aminemethyl acid tert-butyl ester The title compound was prepared according to the general procedure from [2-amine -5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid, third butyl ester (Example J18) (180 mg, 0.5 mmol) And 3-(2-cyano-pyridin-4-yl)-3-keto-propionic acid tert-butyl ester (Example K3) (123 mg, 〇·〗 mM). A yellow amorphous material (206 mg) was obtained. MS (ISP) 532 [(Μ+Η)+ ]. Example -69 -129- This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Inventions (126) (RS )-{5-Dimethylamino-2-P-keto-yl (3-{242-(tetrahydro-pyran-2-yloxy-Vethyl-1 -2indole-pyrazol-3-yl-V-benzene) ))-propionylamino 1-4-trifluoromethyl-phenyl hydrazine-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from 2-amino-5-dimethyl Amino-4-trifluoro-methyl-phenyl)-amino-mercaptoic acid tert-butyl ester (example j6) (639 mg, 2.0 mmol) and (RS)-3-keto-3- 3-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-exotrizin-3-ylphenyl)-propionic acid tert-butyl ester (example κ2 〇) (829 mg, 2.0 mmol). Obtained pink amorphous material (272 mg). MS (ISN) 658 [(M-Η)&quot;]. Example M70 Cyano-pyridinyl V3-ketone Base-propionylamino 1-5-(cyclopropyl-methyl-amino)-4-trifluoromethane-phenylamine decanoic acid tert-butyl ester The title compound is prepared according to the general procedure. From [2-amino-5-(cyclopropyl-methyl-amino)-4·trifluoromethyl-phenyl]-aminomethyl Acidic third-butyl ester (Example J19) (259 mg '〇·75亳莫耳) and 3-(2-cyano-pyridin-4-yl)-3-keto-propionic acid third-butyl vinegar (example) K3) (192 mg, 〇······························································· Base-5_[3_keto-1 31 triazole-fluorenyl-phenyl)·propylpyrazine J-anthene-1-biphenyl-4-ylindole-amine methyl acid tert-butyl ester The title compound is based on general Procedure, prepared from (5-amino-2-dimethylamino-2'-fluoro-biphenylyl)-amine methyl acid tert-butyl ester (Example J20) (691 mg, 2.0 mmol) ) with 2,2-dimethyl winter (3-[1,2,3]triazol-1-yl-phenyl Hl,3]dioxane ·__130-130- Standard ^ Α 4 specifications _ χ tear public love -- -- 1296622 A7 B7 V, invention description (127 ) &quot; 4- ketone (example L4) (543 mg, 2.0 mmol). Obtained a yellow solid (82 〇 mg) Melting point 125-135 ° C. Example M72 (RS)-{5-Dimethylamino-2-"3-keto-3-(3-{5-Γ2-(tetrahydro-piperidin-1,2) , 3] triazole-l-yl}-phenyl-propionylamino 1-4-trifluoro-j-yl-phenylmethyl The third-butyl ester title compound was prepared from (2-amino-5-dimethylamine-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure (example) J6) and (RS)_3-g synonym 3-(3-{5-[2-(tetrahydro-bran-2-yloxy)-ethyl]-[1,2,3] -1- kibphenyl) propionic acid third-butyr (example K21). Obtained a light red oil (527 mg). MS (ISP) 577 [(M+H)+]. Example M73 (RS)-[5-dimethylamino-2-(3-keto-3-indole3-"5-(tetrahydro-pyran -2-ylylmethylmethyl-Vinyl-1-yl]-phenyl}-propanylamino)-4-trifluoromethyl-phenylamine methyl acid, third butyl ester, title compound According to the general procedure, it is prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (example j6) and (RS)_3_ Keto group·3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-pyrazole small group]-phenyl}-propionic acid ethyl ester (Example K22). 179 mg) MS (ISP) 646 [(M+H)+]. Example M74 {5-Dimethylaminodi-2-indole-3-indenyl (3-"1,2,31 triazole small group -笨)) - propylaminomethyl 1- 4-trifluoromethyl-phenyl}-amine methyl acid, the third-butyl hydrazine title compound is based on the general procedure, from (2-amino-5-di Methylamino-131- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 _B7 _ . V. Description of invention (128) 4-Trifluoro-methyl-phenyl)-amine Tri-butyl methacrylate (Example J6) (639 mg, 2.0 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazole Benzyl-phenyl)-[1,3]dioxantemene-4-one (Example L4) (543 mg, 2.0 mmol). Obsed a red solid (915 mg). MS (ISP) 533.3 [(Μ +Η)+]; melting point 79-81 ° C. Example M75 [2-"3-(2-Nitentyl-Salt-4-yl)-3-indolyl-propylaminoamine-5-( 2,2,2-Tris-ethoxymethyl)-4-trifluoromethyl-phenyl 1-aminemethylhydrazine tert-butyl ester The title compound is prepared according to the general procedure from [2-amino- 5-(2,2,2-trifluoro-ethoxy) ice trifluoromethyl-phenyl]-amine methyl, acid tert-butyl ester (example J21) and 3-(2-cyano-pyridine Ice-based) keto-propionic acid tert-butyl ester (Example K3). Obtained as a pale brown solid (262 mg). MS (ISN) 545·0 [(M-Η)·]; melting point 158 ° C (decomposition Example M76 {2-"3-(3-Alkyl-phenyl)-3-S synthyl-propanylamino 1-4-dimethylamino-5-methyl-phenyl-p-amine The title compound of the third-butyl ester of the acid is prepared from (2-amino-5-dimethylamino-4-methyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure (example) J22) (300 mg, 1.0 mmol) and 3-(3-cyano-phenyl)-3-keto-propionic acid tert-butyl ester (Example Κ 2) (245 G, 1.0 mmol). Obtained a light brown foam (250 mg, 57.). MS (ISP) 437.4 [(Μ+Η)+ ]. ^ Example Μ77 (RS)-[5-Dimethylamino-4-methyl-2-(3-keto-3-{3-『5- (Four gas - shouting-2-yloxy J7-based Hl, 2, 31 triazole small group 1-phenylindole-propionylamino) · stupid amine methyl acid -132- This paper size applies Chinese National Standard (CNS) Α4 Specification (210X 297 mm) 1296622 A7 B7 V. Description of Invention (129) Tri-butyl ester The title compound is prepared according to the general procedure from 2-amino-5-dimethylamino. -4-methyl-phenyl)-amine methyl acid tert-butyl ester (example J22) (265 mg, 1 〇 millimolar) and (RS)-3-keto-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.) Obtained yellow foam (420 mg, 71%). MS (ISP) 593.5 [(M+H)+]. Real-example M78 gas base-2-〖3-(3-night base -Dongji)-3-indolyl-propylaminomethyl]-4-dimethylamino-winteryl-aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure (2- Amino-4-cyano-5-dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example J23) (276 mg, 1·0 mmol) And 3-(3-cyano-phenyl) keto-propionic acid tert-butyl ester (Example Κ 2) (245 mg, 1.0 mmol) afforded a brown foam (290 mg, 65.) MS (ISP) 448.3 [(M+H)+ ]. Example M79 "2-"3-(3-Cyano-phenyl)-3-keto-propionylamine 1-5-Methyl- 4-(Methyl-propyl-amino)-phenyl 1-amine methyl hydrazine tert-butyl ester The title compound was prepared according to the general procedure from [2-aminom-methylmethyl-propylamino) -Phenyl]-aminomethyl acid tert-butyl ester (Example J24) (293 mg, 1.0 mmol) and 3-(3-cyano-phenyl-ketone nasal-propionic acid tert-butyl ester ( Example K2) (245 mg, 1.0 mmol). Obtained light brown oil (170 mg, 37%) MS (ISP) 463.3 [(MH)&quot;]. Example M80-133- _______ This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) Binding

Line 1296622 A7 ____B7 __ V. Description of Invention (130 ) (Minylmethyl-5-(indolyl-propyl-amino)-2-(3-indolyl-3-{3-[5-(tetrachloro)喃 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [2-Amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J24) (293 mg, 1·〇 mmol) ()) with (RS)-3-keto group {3-[5-(tetrahydro-pyran-2-yloxymethyl)&gt; [1,2,3]triazole small group]-phenyl propyl Acid butyl butyl ester (Example K5) (402 mg, 1. 〇 莫 耳). Obtained yellow squirt (350 mg, 569.) MS (ISP) 621.2 [(M+H)+]. M81 (RS)-"5-(ethyl-methyl-amino)- ice methyl-2-(3-keto-3-{3-"5-(tetrahydro-pyran-4-yloxymethyl) MU, 31 triazole small group 1-phenyl V propyl decylamino)-phenyl 1-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5 -(Ethyl-methyl-amino-amino)-4-methyl-phenyl]-amine methyl acid, third-butyl ester (Example J25) (279 mg, 1.0 mmol) and (RS)-3 -keto-3-(3-[5-(tetrahydro-pyran-2-yloxymethyl[1,2,3]triazole)-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1. 〇mole). Obtained a yellow foam (4 </ RTI> </ RTI> </ RTI> </ RTI> 66.) MS (ISP) 607.1 [(M+H)+]. Example M82 (RSH4- Cyano-5.dimethylamino-3-{3·"5-(tetrahydro-pyran-2-yl argonmethyl)-"1,2,31 triazole small group 1-phenyl The title compound is prepared according to the general procedure M, based on the general procedure M, from the amide aminocyanyl-5-di-134- Standard (CNS) A4 specification (210 X 297 public) binding

Line 1296622 A7 B7 V. Description of the Invention (131) Amidino-phenyl)-Aminomethyl 3-butyrate (Example J23) (276 mg, 1.0 mmol) and (RS)-3-keto -3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl]-propionic acid tert-butyl Ester (Example K5) (4〇2 mg, 1·〇 mmol). Obtained a light brown foam (360 mg, 590 /.). MS (ISP) 602.1 [(Μ-ΗΠ. Example Μ83 (RSH4-carbyl-5·(isopropyl-methyl-amino)-2-(3-keto-3){3-Γ5-(four Hydrogen-pyrano-decyloxymethyl Ml, 2,31 triazol-1-yl-p-phenylpropanylamino)-phenyl 1-aminemethyl acid tert-butyl ester The title compound is according to the general procedure. ·, prepared from [2-amino-4-carbyl-5-(isopropyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J26) (300 mg, 〇·% millimolar) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole -1-yl]-phenyl}-propionic acid, third-butyl vinegar (Example Κ5) (383 mg, 0.96 mmol). Obsed pale yellow oil (530 mg, 86 </ s). MS (ISP) 639.2 [ (MH)-]. Example M84 [4-Methyl-2-{343-(3-methyl-isoxazol-5-yl V stupin-3-keto-propenylamine V 5-( Methyl-propyl-amino)-phenyl 1-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from [2-amino-4-methyl-5-(methyl- Propyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J24) (293 mg, 1·〇 mmol) and 3-[3-(3-indolyl-isosaki: Sodium-5-yl)-phenyl]-3-one - Propionic acid tert-butyl ester (Example K4) (301 mg, 1 〇 mmol). Obtained a pale yellow foam (340 mg, 65.) MS (ISP) 519.3 [(MH)-]. 135- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Gutter 1296622 A7 _ B7__·_ V. Description of Invention (132) Example M85 (4-cyano-5-dimethylamino-2-indole 3-"3-(3-methyl-isoxazole-5- ))-phenyl-1-keto-non-nonylamino fluorenyl-phenyl)-amine methyl methic acid tert-butyl ester The title compound is prepared according to the general procedure from 2-amino-4- Disperse-5-diamidino-phenyl)-amine methyl acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and 3-[3-(3-methyl-isoindole) Triazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol) afforded pale brown foam (320 mg, 64%). _ MS (ISP) 504.3 [(M+H)+]. Example M86 (5-(ethyl-methyl-amino)-4-mercapto-2-{3-P-(3-methyl-iso) Oxazol-5-yl V-l-yl l- 3-keto-propionylamino fluorenyl-phenyl)-aminomethyl acid tert-butyl hydrazine The title compound is prepared according to the general procedure from [2-amine 3--5-(ethyl-methyl-amino)-4-methyl-phenyl]-amine methyl acid tert-butyl ester (example J25) (279 mg, 1.0 mmol) and 3-[ 3-(3-methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example K4) (301 mg, 1.00 mmol) Obtained brown foam (390 mg, 77°). MS (ISP) 505.3 [(MH)*]. Example M87 (5-dimethylamino-4-methyl-2-{3-『3-( 3-mercapto-isoxazol-5-yl)·stupyl-1-keto-dipropenylamino-p-phenyl)-amine methyl acid tert-butyl ester The title compound is based on the general procedure. , prepared from (2-amino-5-diamidino-4-methyl-phenyl)-amine methyl acid tert-butyl ester (Example J22) (265 mg, 1. 〇 millimol) and 3-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (-136-I paper scale applicable to Chinese national standard (CNS) ) Α4 size (210 X 297 mm) '~&quot; ' 1296622 A7 ____B7__ V. Description of invention (133) Example K4) (301 mg, ΐ·〇 mmol). Obtained brown foam (33 mg, 67 %) 〇MS (ISP) 491.3 [(M-Η)']. Example M88 (RS)- 4-Alkyl-5_(isobutyl-methyl-amino)-2-(3-indolyl- 3-{3-[5-(four mice- shouting _ g: yloxymethyl Hl, 2,31 triazol-1-yl 1-phenylindole-propenylamino)-phenyl 1- Aminomethyl acid tert-butyl ester The title compound is prepared from [2-amino-4-yl-5-(isobutyl) according to the general private order. -Methylamino)-phenyl]-aminomethyl acid tert-butyl ester (Example J27) (328 mg '1·〇 mmol) and (RS)-3-keto-3-{3- [5-(Tetrahydro-piperidin-2-yloxymethyl)-[1,2,3]triazole small group]-phenylpropionic acid tert-butyl ester (Example Κ5) (401 mg, 1. 〇 莫 )). Obtained a light brown foam (330 mg, 50%). MS (ISP) 655.1 [(M+H)+]. Example M89 (4-carbyl-5-(isobutyl-methyl-amino)-2-{3-丨3-(3-methyl- Isoxazol-5-yl)-benzamine] j-dione-propionylamino-p-phenylamine methyl acid tert-butyl ester-based compound is prepared from [2-amino group according to the general procedure. 4-milyl-5-(isobutyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (example J27) (328 mg, 1·〇 mmol) and 3 -[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol). Light yellow foam (360 mg, 65.) MS (ISP) 555.1 [(M+H)+j. Example M90 (RS)-"4-cyano-2-(3-keto-3-) 345-(tetrahydro-pyran-2-yloxymethyl-137- _ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 B7 V. Description of invention (134) Triazole -1-yl I-jamman-propionylamino)-5-tetrahydropyrrole-1-yl-phenyl 1-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure. (2-Amino-4-cyano-5-tetrahydropyrrole-1-yl-phenyl)-amine methyl acid tert-butyl ester (Example J28) (302 mil , 1.0 mmol) and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole- 1-Phenyl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) afforded pale orange foam (380 mg, 60%). MS (ISP) 630.1 [ (M+H)+]. - Example M91 (4-cyano-2-(3-f343-methyl-isoxazole-5- some V stupyl 1-1-3-keto-propionylamino group 1 -5-tetrahydropyrrole s-phenyl)-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from (2-amino-4-cyano-5-tetrahydropyrrole small group). -Phenyl)-aminomethyl acid tert-butyl ester (Example J28) (302 mg, 1·〇 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)- Phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol) afforded pale brown foam (420 mg, 79.) MS (ISP) 530.2 [ (Μ+Η)+]· Example Μ92 (RS)-丨4-wrapy-5-(methyl-propyl-amino)-2-(3-indolyl tetrad-brown-2· oxime Methyl group)-oxime 1.2,31 triazol-1-yl-1-p-phenylpropanylamino)-phenyl [amino acid tert-butyl ester compound according to the general procedure Μ ' [2-Amino-4-based-5-(methyl-propyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J29) (304 mg, 1·〇 mmol) ()) and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxyindenyl)--138- This paper scale applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1296622 A7 B7_-__ V. Description of Invention (135) [1,2,3]Triazol-1-yl]-phenylpropanoic acid tert-butyl ester (Example K5) ( 401 mg, 1.0 mmol.) Obtained a light red foam (440 mg, 70 ° 0) ° MS (ISP) 630.1 [(M+H)+]. Example M93 [4-Cyano-2-(343-(3-methyl-isoxazole) -5-yl)-styl 1-3-keto-propionylamino}-5-(methyl-propyl-amino V-methyl 1-aminomethyl acid tert-butyl title compound Prepared according to the general procedure from [2-aminopiperidin-5-(methyl-propyl-amino)-phenyl]-amine methyl acid tert-butyl ester (example J29) (304 mg , 1·〇mmol) and 3-[3-(3-indolyl-isoxazol-5-yl)-phenyl] keto-propionic acid tert-butyl ester (Example K4) (301 mg , 1.0 mmol, obtained a pale brown foam (370 mg, 70%). MS (ISP) 532.3 [(M+H)+j. Example M94 (4-cyano-5-diethylamino) 2-(343-(3-Methyl-isoxazol-5-yl)-phenyl1-3-one^: and mercaptoaminophenyl phenyl)-amine methyl acid tert-butyl ester According to the general procedure, it is prepared from (2-amino-4-cyano-5-diethylamino-phenyl)-amine methyl acid tert-butyl ester (Example J30) (304 mg, 1·〇)亳Moel) and 3-[3-(3-methyl-isoxazole-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, ΐ·〇毫默). Obtained a light brown foam (360 gram, 68%.) MS (ISP) 530.2 [(M+H)+]. ^ Example M95 cyano-5-(isopropyl -Methyl-amine _2]3-P-(3-methyl-isoxazol-5-yl V stupid) 士: mercapto-propenylamine hydrazine-stupid V amine methyl acid Tri-Butyl Ester _ -139- i Paper Scale Optimum® g Home Standard (CNS) A4 Specification (21QX297 Public) ' &quot; 1296622 A7 __B7 __-_ V. Description of Invention (136) The title compound is based on the general procedureΜ , prepared from [2-amino-4-cyano-5-(isopropyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J31) (304 mg, 1 · 〇 millimol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl vinegar (example Κ 4) (301 mg , 1.0 mmol.) Obtained light brown foam (380 mg, 71.) MS (ISP) 530.2 [(M-Η)']. Example M96 (RSH4-cyano-5-(isopropyl- Mercapto-amino V2-G-keto-3-ylidene 3-"5-(tetrahydro-pyranyl) 2-yloxymethyl)-oxime 1,2,31-tri. sit-1-yl 1-phenylindole-propionylamino)-phenyl&gt; Aminomethyl acid tert-butyl ester The title compound is based on general Ordered from [2-amino-4-cyano-5-(isopropyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J31) (304 mg , 1.0 millimolar) with (RS)-3-keto-3-{3-[5-(tetrahydro-bran-2-yloxymethyl)·[1,2,3]triazole- 1-Methyl]-phenylpropionic acid tert-butyl ester (Example Κ 5) (401 mg, 1·〇 mmol). Obtained yellow foam (460 mg, 73 〇 /.). MS (ISP) 630.1 [(MH)·]. Example M97 (4-cyano-5-(isobutyl-methyl-amino)-2-indole-f3-(3-methyl-isoxazole- 5-yl)-benzone -3-keto-propionylamino 1-phenylaminomethyl acid tert-butylamine The title compound is prepared according to the general procedure from [2-amino-4- Cyano-5-(isobutyl-methyl-amino)-phenyl]-amine methyl, acid tert-butyl ester (example J32) (318 mg '1.0 mmol) and 3-[3- (3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example K4) (301 mg, 1. 〇m.). Foam (400 mg, 73 °.) -140-I paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot; 1296622 A7 __ B7 V. Description of invention (137) MS (ISP 544.3 [(MH)']. Example M98 (RS)-[4-cyano-5-(isobutyl-methyl-amino)-2-(3-keto-3-13-丨5- (tetrahydro-pyro- -2-yloxymethyl)-, 2, 31. Sodium-1-yl 1 phenyl hydrazine-propyl arylamino V stuccinyl amino acid third-butyl The ester title compound is prepared according to the general procedure from [2-aminopiperidin-5-(isobutyl-methyl-amino)-phenyl]-aminomethyl Third-butyl ester (Example J32) (318 mg, 1·〇 mmol) and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl) Base)-[1,2,3]triazole-based]-phenyl}-propionic acid tert-butyl ester (Example Κ5) (401 mg, 1.0 mmol). Yellow foam (470 m·)克, 730.) MS (ISP) 644.2 [(MH)-]. Example M99 (4-cyano-2-(343-(3-methyl-isoxazol-5-yl)) stupid 1 Keto-propionylamino}-5-hexahydropyridin-1-yl-indole-amine methyl acid-------------- -Cyano-5-hexahydropyridin-1-yl-phenyl)-amine methyl acid tert-butyl ester (Example J33) (316 mg, 1.0 mmol) and 3-[3-(3-A) Isooxazol-5-yl)-phenyl] keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol) afforded a pale brown foam (420 mg, 77%) MS (ISP) 544.2 [(M+H)+]. Example M100 (4-Chloroisobutylamino-2)3-[3-(3-methyl-isosorbed)) 3·-keto-propionylamino group, phenoxy, V-amino acid, third-butyl-free title compound, according to the general procedure, from (2-amino group) Winter Chlorine Iso-141 - __ This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (138) Butylamino-phenyl)-amine methyl acid Third-butyl ester (Example J34) (314 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid Third - Ding Zhi (Example K4) (301 mg, 1.0 mmol). Obtained off-white foam (34 mg, 63°'). MS (ISP) 542.2 [(Μ+Η)+]· Example Μ101 (RS)-[4-Alkyl-5-isobutylamino-2-(3-keto-3-{3-丨5- (tetrahydro-piperidin-2-ylmethyl)-[1,2,31 triazol-1-yl 1-peptidyl-propenylamino)-styl 1-amine methyl acid - The tri-butyl ester title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-amine methyl acid tert-butyl ester according to the general procedure (Example J34). (314 mg, 1.0 mmol) with (RS)-3-keto-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). Obtained red oil (180 mg, 28%). MS (ISP) 640.2 [(M-Η)·]· Example M102 (RS)-[5-(Methyl-propyl-amino)-2彳3-keto-3-{3-"5-( Tetrahydro-n-butan-2-yloxymethyl)-[1,2,31-triazol-1-yl V-benzophenylideneamino-trifluoromethyl-phenyl&gt; Aminomethyl acid-third The title compound of butyl ester is prepared according to the general procedure from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid. Ester (Example j35) (380 mg, 1.09 mmol) with (rS)-3-one gas (tetrahydro-t-butyl-2-yloxymethyl)-[1,2,3]triazole small group ]-Phenyl]-propionic acid tert-butyl ester (Example K5) (439 mg, 1.09 mmol). Obtained red foam (150 mg, 20%). MS (ISP) 675.4 [(MH)· ] · -142- This paper size applies to China National Standard (CNS) A4 specification (210X297 public) binding

Line 1296622 A7 _____ B7 V. Description of the invention (Example M103 Κ3-[3·(3-toxaisoxazole-5-yl)·phenyl 1-3-keto-propenylamine-based 5-( Capsules - aryl-amino-tertylfluoromethyl-phenylaminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(methyl-propyl). 3-Amino)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example J35) (36 mg, 1.04 mmol) and 3-[3-(3 Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (312 mg, 1.04 mmol). Obtained a pale red foam (270 Mg, 45.. _ MS (ISP) 573.2 [(MH)']. Example M104 (RS)-[5-(isobutyl-methyl-amine)-2-(3-keto-3 -{3-"4-(tetrahydro-pyran-2-yloxymethyl)-"1,2,31 triazole small group 1-styl fluorenyl-propyl decylamino) ice trifluoromethyl -Phenyl-1-aminomethyl acid tert-butyl ester The title compound was prepared according to the general procedure from [2-amino-5-(isobutyl-methyl-amino)-4-trifluorodecyl. -Phenyl]-aminomethyl acid tert-butyl ester (Example J36) (370 mg, 1.02 mmol) and (RS)-3-keto-3- 3-[5-(tetrahydro-piperidin-2-yloxymethyl)-[1,2,3]triazole small group]-phenyl}-propionic acid tert-butyl ester (Example K5) ( 411 mg, 1.02 mmol. Obtained as a light brown foam (520 mg, 7.4). MS (ESI) 687.2 [(MH)-]. Example M105 (5-(isobutyl-methyl-amino) -2-{3-P-(3-methyl-isoxazol-5-yl)-phenyl1-3-keto-propionylamino-4-bufluoro-4-phenyl)- Aminomethyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(isobutyl-methyl-amino) glacial trifluoromethyl-phenyl]-amine A Third acid butyl ester (Example J36) (360 -143- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 __ B7 V. Description of invention (140) ^ — mg, 1.0 mmoler) with 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-g-iso-propionic acid tert-butyl ester (Example K4) (302 mg , 1.0 mmol, obtained a pale brown foam (430 mg, 73.) MS (ISP) 587.3 [(MH)*]. Example M106 (RS)-[5-(isopropyl-fluorenyl- Amine-keto--3-{345-(tetrahydro-l-ammon-2-ylhydromethyl)-"1,2,31 triazole Base - 苽 丨 - propyl hydrazino) winter trifluoromethyl - jasmine 1-amino acid tert-butyl ester, the title compound is based on the general procedure 制, from [2-amino-5 -(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example J37) (340 mg, 0.98 mmol) and (rs) 3-keto-3-yl-3-(3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole small group]-phenyl}-propionic acid Tri-butyl ester (Example K5) (393 mg, 〇 98 mmol). Obtained a pale yellow foam (51 mg, 77%). MS (ISP) 673.3 [(Μ-Η)']. Example Ml07 (5-(isopropyl-methyl-amino ν2-η-Γ3-(3-methyl-isoxazol-5-yl)- Phenyl 1-3-keto-propionylamino ruthenium-4-ylidene. Methyl-stupyl V amine methyl acid tert-dibutyl ester The title compound is prepared from [2-amino group according to the general procedure. -5-(Isopropyl-methyl-amino)-4-trifluoromethyl-phenyl&gt; Amino-tert-methyl-tert-butyl ester (Example J37) (350 mg, 1.01 mmol) and 3 -[3-(3-Methyl-iso-[upta]--5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example K4) (304 mg, 1.01 mmol). Obtained a light brown foam (380 mg, 66 〇 /.) MS (ISP) 573.2 [(MH)']. Example Ml08 ______ _144 - ^_ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1296622 A7 __ B7 _._ V. INSTRUCTIONS (141) (RS)-[5-(X-butyl-methyl-amino)-4-methyl-2-(3-indolyl-3 -{3-[5-(tetraz-pyranyl-2-yloxymethyl)-indole, 2,31 triazole small group 1-phenyl-propionylamino)-phenyl 1-amine The tert-butyl ester of the acid is the title compound from [2-amino-5-(isobutyl-methyl-amino) according to the general procedure. Methyl-phenyl]-amine methyl acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and (RS)-3-keto group {3-[5-(tetrahydro-piperidin)喃-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 Torr) Obtained a light yellow bubble (330 mg, 52%). MS (ISP) 635.2 [(M+H)+]. Example M109 (5-(isobutyl-methyl-amino)-4- Methyl-2-{3-丨3-(3-methyl-isoxazol-5-yl)-phenyl 1 _3 keto-propionylamino phenyl)-amine methyl acid -Butyl ester title compound is prepared according to the general procedure from [2-amino-5-(isobutylmethyl-amino)-4-mercapto-phenyl]-amine methyl acid tert-butyl Ester (Example J38) (307 mg, 1·〇 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid - butyl ester (Example Κ 4) (301 mg, L0 mmol). Obtained pale yellow foam (330 mg, 62.) MS (ISP) 535.4 [(M+H)+]. Example Ml 10 (RSH4 -methyl-2-(3-keto-3)345-(tetrahydro-piperidin-2-yloxymethyl Hl, 2,31 triazol-1-yl 1-stupyl-propanyl Amine V5-tetrahydropyrrole -Phenyl 1-amine mercapto acid tert-butyl ester The title compound is prepared according to the general procedure from (2-aminopiperidin-5-tetrahydropyrrol-1-yl-phenyl)-amine methyl Acid tris-butyric acid tert-butyl ester (Example J39) -145- This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (142 ) (292 Mg, 1.0 mmol, and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole Small base]-phenyl]-propionic acid tert-butyl ester (Example K5) (401 mg, 1·〇 mmol). Obtained a pale yellow foam (410 mg, 66%). MS (ISP) 619.3 [(M+H)+]. Example Mill (4-methyl-2-{3-f3-(3-methyl-iso-4 17-s--5-yl)-phenyl 1-3 - copper-propylaminoamino}-5-tetrahydropyrrole small group-stupyl V amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from (2-amino-4-methyl) 3--5-tetrahydropyrrole small-phenyl)-amine methyl acid tert-butyl ester (Example J39) (291 mg, 1·〇 mmol) with 3-[3-(3-methyl- Isoxazol-5: yl)-phenyl] keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol). Obtained light brown foam (330 mg, 640 /.) MS (ISP) 517.3 [(MH)-]. Example M12 (4-carbyl-5-isopropylaminomethyl-2-{3-f3-(3-methyl-isoxazole-5-yl) )-phenyl-1-keto-propionylamine 丨-phenyl)-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from 2-amino-4-chloro 3--5-isopropylamino-phenyl)-amine methyl acid tert-butyl ester (example j4〇) (300 mg, 1.0 mmol) and 3-[3-(3-methyl-iso) Oxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example Κ 4) (301 mg, 1.0 mmol). 169 mg, 32°.). One MS (ISP) 525.2 [(MH)']. Example Ml 13 (RS)-[4-Alkyl-5-isopropylamino-2-(3-keto- 3-丨3-f5-(tetrahydro-pyran-2-yloxy-146- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 _B7_ V. Invention description (143) Steaming ·Methyl)-π,2,3ΐtriazole small group]-phenylv-propenylamine-based benzyl-aminomethyl acid tert-butyl ester The title compound is based on the general procedure Μ, from (2- Amino-4- carbyl-5-isopropylaminophenyl)-amine methyl acid tert-butyl ester (example j4 〇) (3 〇〇 mg, 1. 〇 millimol) and (RS) -3*-酉同基-3-{3-[5-(tetrahydro-a-n-butyloxymethyl)_[ι,2,3]III.sodium-1-yl]-phenyl}- Third-butyl propionate (Example Κ 5) (401 mg, 1. 〇 millimol). Obtained a pale yellow foam (375 mg, 60%). MS (ISP) 625.1 [(MH)·]. Ml 14 (RS)-[4-Alkyl·5·(methylpropyl-amino y2〇g-yl-3-{3-f5-(tetrahydro-furan-2-yloxymethyl) )-Π,2,4~|three. sit-1-yl 1-styl propyl propylamino) phenyl 1 amine methyl acid tert-butyl ester According to the general procedure, from [2-amino-4-carbyl-5-(methyl-propyl-amino)-phenyl]-amine methyl acid, third butyl ester (example J8) (l .〇克, 3.19 毫摩尔) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[l,2,4j III Olefinyl]-phenyl}propionic acid tert-butyl ester (Example K24) (1.28 g, 3.19 mmol). Yellow foam (1.48 g) was obtained. MS (ISP) 641.3 [(M+H)+]· Example Ml 15 §§4·Chloro-5-(isobutyl-methyl-amino)-2-(3-keto- each 丨3-" 5. (tetrahydro-pyranyl-methylmethyl M1, 2,41 triazole small group: N stupyl 1-propenylamino)-phenyl 1-amine methyl acid third-butyl ester The compound was prepared according to the general procedure from [2-amino-4-carbyl-5-(isobutyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (Example J24) ) (l.〇mg____-147-___ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1296622 A7 B7 _____ V. Description of the invention (144), 3.05 millimolar) and (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxy) Methyl)·[1,2,4]disth-1-yl]epi]]-propionic acid third-butyric acid (conventional K24) (1.22 g '3.05 mmol). Obtained a light brown foam (620 mg, 31 °). MS (ISP) 655.1 [(M+H)+]. Example M1 16 (RSH5-(isobutyl-methyl-amino)- ice methyl-2-(3-keto- each {3-『5-( Tetrahydro-bromo-2-yloxymethyl)-[1,2,41 triazole small group 1-phenylindole-propionylamino)-styl 1-amine methyl acid third-butyl Ester _ The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-amine methyl acid tert-butyl ester according to the general procedure. (Example J38) (1.0 g, 3.25 mmol) with (RS)-3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1, 2,4]Triazol small group]-phenyl]propionic acid tert-butyl ester (Example K24) (1.31 g, 3·25 mmol). A pale yellow foam (970 mg, 47°) was obtained. MS (ISP) 635.2 [(M+H)+j. Example Ml 17 {5-(methyl-propyl-amino)-243-keto-3·〇-Π, 2,41 triazole small group- Phenyl V-propionylamino 1-4-trifluoromethyl-phenyl hydrazine-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(A) 3-propyl-amino) 4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) with 3-keto-3- (3-[1,2,4] triazole is small (Phenyl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) afforded pale yellow foam (320 mg, 57°). MS (ISP) 561.4 [(M+ H)+]. Example Ml 18 ___ -148 -___ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1296622 A7

V. Description of invention (145)

{5-(Methylpropyl-amine V243-keto-3-G-[l,2,31 triazol-1-yl-phenylamino 1 glacial trifluoromethyl-phenylindole-amine Methyl acid tert-butyl IL The title compound was prepared according to the general procedure from [2-amino-5-(methyl-propyl-amino-M-trifluoromethyl-phenyl]-amine methyl acid Third-butyl ester (Example J35) (347 mg, 1·〇 mmol) and 3-keto-3-(3-[1,2,3]triazole small-phenyl)-propionic acid - butyl ester (Example Κ 23) (287 mg, 1.0 mmol). Obtained light brown oil (340 mg, 610 〇) 〇MS (ISP) 561.3 [(M+H)+]. - Example Ml 19 {5- Isobutyl-methyl-amino)-2-indol-3-one-3-(3-exo 1: te-1-yl-phenyl)-propenylamino>&gt;4-trifluoromethyl - stupyl hydrazine-amine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(isobutyl-methyl-amino) ice trifluoromethyl-benzene. 3-aminobutyl-amino acid (Example J40) (361 mg, 1.0 mmol) and 3-keto-3-(3-pyrazol-1-yl-phenyl)-propionic acid Tri-butyl ester (Example K16) (286 mg, 1.0 mmol). Obtained as a pale brown foam (500 mg, 87 s.). MS (ISP) 574.2 [(M +Hf]. Example M120 (2-[3-(2-cyano-pyridyl)-based V3-keto-propionylamino-5-(isopropyl-methyl-amino)-4-tri Fluoromethyl-phenyl 1-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from [2-amino-5-(isopropyl-methyl-amino)-4-tri Fluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example J37) (5〇〇爱克' 1.44 Amor) and 3-(2-^基比症-4-yl)-3 - mercapto-propionic acid third · butyl ester (example K3) (355 mg, 1.44 mmol). Obtained light orange oil (67 〇 -149 - This paper scale applies to Chinese National Standard (CNS) Α 4 specifications ( 210X297 public)

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1296622 A7 B7 V. Description of invention (146) grams, 90%). MS (ISP) 518.1 [(M-Η)·]· Example M121 oxy_5·(isobutyl-1 yl-amino)_2_『3.yl_3_(3_『12,41 triazole small group- Phenyl group> propyl decylamino 1-phenyl amide amine dimethyl butyl butyl ester The title compound is prepared according to the general procedure [ from [2_amine chlorophenyl (isobutylmethyl) )-Phenyl]-amine methyl acid third-butyl ester (Example J27) (5 〇〇 mg '1.53 mmol) and 3-keto-3-(3-[1,2,4]triazole Small base-phenyl)-propionic acid tert-butyl ester (Example K25) (438 mg, 丨.53 mmol). Obtained light orange foam (700 mg, 85.) MS (ISP) 539.2 [(Μ-Η)']. Example Μ122 11-((Isobutyl-fluorenyl-amino)-2·"3-keto--3-(3-indole, 2,41-triazol-1-yl) -Phenyl)-propionylamino-M-trifluoromethyl-pyridylamine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(isobutyl) 3-methyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example j36) (361 mg, 1.0 mmol) with 3-keto-3- (3-[l,2,4]Triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol). Pale red foam (490 mg, 85%). MS (ISP) 575.2 [(M+H)+j. Example JV1123 {4-chloro-5-(isobutyl-methyl-amino)-243 -keto-3-(3-"1,2,31-triazol-1-yl-phenyl)-propionylamino-1-phenylindole-amine methyl acid tert-butyl ester General procedure Μ, made from [2-amino-4-chloro-5-(iso--150- this paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) binding

Line 1296622 A7 ______ B7_._ V. Description of the invention (147) Butyl-methyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (Example J27) (328 mg '1·〇 mmol Ear) and 3_keto-3·(3-[1,2,3]triazole-p-phenyl)-propionic acid ternary-butyl hydrazine (Example Κ23) (287 mg, L0 mmol). Obtained orange oil (250 mg, 460/〇). MS (ISP) 539.2 [(Μ·Η)·]. Example Μ124 ί_5-(Isobutyl-methyl-amino ν2·[3-keto-^(^^^^) triazole small-phenyl) _Propylamino 1-4-trifluoromethyl-phenyl-amidamine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(isobutyl- Methyl-amino)-4-trifluorodecyl-phenyl]-amine methyl acid tert-butyl ester (Example J41) (46 mg, 1.27 mmol) and 3-keto-3-( 3-[l,2,3]triazole-p-phenyl)-propionic acid tert-butyl vinegar (example K23) (364 mg, 127 mmol). Obtained a pale brown oil (480 mg, 69 〇/.) MS (ISP) 573.1 [(MH)·]. Example M125 {2-[3-(3-imidazol-1-yl-phenyl)-3-one-propenylamino)- 5-Isobutylamino-t-trifluoromethyl-phenyl-V-amine methyl acid tert-butyl ester The title compound was prepared according to the general procedure from [2-amino-5-(isobutyl-amino) )-4-trifluoromethyl-phenyl]-amine methyl acid, third butyl ester (example J41) (347 mg '1·〇 millimolar) and 3-(3-mi. sit-1-yl -Phenyl)-3-i-iso-propionic acid tert-butyl ester (Example K26) (286 mg, 1. 〇 mmol M. Obtained a pale yellow bubble (43 mg, 77%) MS (ISP) 558.2 [(MH)']. Example M126 -151 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ________B7___ , description of the invention (148) 11-chloro-2-indol-3-(3-methane.-1-yl-phenyl)_3-ketooxime-propylaminomethylamine methyl acid: _ vinegar The title compound was prepared according to the general procedure from (2-amino-4-carbyl·5·isobutylamino-phenyl)amine methyl acid tert-butyl ester (Example J34) (313 mg, 1 〇亳Moel) and 3-(3-imidazolyl-phenyl) keto-propionic acid tert-butyl ester (example phantom 6) (286 mg, 1·〇 mmol). Obtained a pale yellow foam (330 mg, 63 〇/.) MS (ISP) 524.1 [(MH)-]. Example M127 14-Alkyl-5-(isobutyl-amino V2-(3-keto-3-(3) - hydrazine, 2,31 triazol-1-yl squarylamine 1-phenylindole-amine methyl acid, third butyl vinegar, title compound, according to the general procedure, from [2-amino hydrazine base (岂Butyl-amino)phenyl]-amine methyl acid tert-butyl ester (Example J34) (313 mg, 1 〇 mmol) and 3-S homo-yl-3-(3-[1,2, 3] three. sit-1-yl-phenyl)-prop Third - D Cool (solid Example K23) (287 mg, 1 mmol-square). Obtained a light brown foam (22 grams, 420 inches). MS (ISP) 525.1 [(MH)·]. Example M128 {5-_C-isobutyl-amino)-2-"3-keto- each (341,2,31 triazole small-phenyl-~) -4-II says methyl-phenyl}-amine methyl acid, the third-butyl hydrazine title compound is prepared according to the general procedure from [2-amino-5-(isobutyl-amino)-4- Trifluoromethyl-phenyl]-amine methylhydrazine tert-butyl ester (Example J41) (347 mg, 1·〇 mmol) and 3-keto-3-(3-[1,2,3 Triazol-1·yl-phenyl)-propionic acid tert-butyl ester (Example Κ23) (287 mg, 1.0 mmol) afforded pale yellow foam (340 mg, 60°). Zhang scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (149) MS (ISP) 559.2 [(MH)·]. Example M129 lysine-5-( Iso-I-amino-V243-keto-(341,2,41-triazol-1-yl-phenyl)-propan-ylamino]-phenyl-ytamine methyl acid tert-butyl ester Prepared from [2-amino-4-chloro-5-(isobutyl-amino)-phenyl]-amine methyl acid tert-butyl ester according to the general procedure (Example J34) (313 mg , 1.0 mM) and 3-keto-3-(3-[1,2,4]triazol-1-yl-benzene --T-butyl acrylate (Example K25) (287 mg, L0 mmol). Obtained a pale yellow foam (390 mg, 740 〇) 〇MS (ISP) 525.1 [(MH)*]. Example Μ130 Κisobutyl-amino V2-"3-keto-3-(3·'1,2,41-triazol-1-yl-phenyl)-propionylamine 棊]-4-trifluoromethyl -Phenyl-ylumamine methyl acid tert-butyl ester The title compound is prepared according to the general procedure from [2-amino-5-(isobutyl-amino)trifluoromethyl-phenyl]-amine Methyl acid third butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-keto-3-(3-[1,2,4]triazole small-phenyl)-propionic acid Third-butyl vinegar (Example K25) (287 mg, 1.0 mmol). Obtained pale yellow foam (43 mg, 77°). MS (ISP) 559.2 [(M+H)+]. Preparation of N: aryl-1,3-dihydro-benzofbin, 4l diazepine-2-one: {2-[3-aryl-3-keto-propionylamino]- Phenyl-p-butylamino acid tert-butyl ester or {2-[3-(yl)-3-copperyl-propylamino]-phenyl-p-aminomethyl acid: Ding g (1.0 mmol) ) in CH2% (5 ml) [Addition of toluene or hydrazine if necessary, 3•二-153- This paper size is suitable Chinese National Standard (CNS) A4 size (210 X 297 mm)

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缘1296622 A7 B7 V. Description of the invention (15G) methoxybenzene (5-15 mmol) solution or suspension, treated with TFA (0.5-5.0 ml) at 0 ° C, and at 23 Continue to stir at °C until TLC shows complete consumption of the starting material. Treatment Procedure a·· Remove the solvent in the air and treat the residue with a small amount of ether, which is crystallized therein. The solid is stirred with a saturated NaHCO3 solution or a 1 M Na.sub.2 C.sub.3 solution, filtered, washed with H2O and ether or ether / THF / MeOH mixture and dried to give the title compound. The crystals were purified by column chromatography on a hexane/EtOAc or EtOAc/EtOAc. Procedure b: The reaction mixture was diluted with DCM or EtOAc, washed with sat NaH.sub.3 solution or 1M Na.sub.2 C.sub.3, brine, and dried with EtOAc. The solvent is removed in the open space, leaving a material which can be triturated with ether or ether / THF / MeOH to give the title compound or, if necessary, crystallized from 1,4-dioxane, or The alkane / EtOAc or EtOAc /EtOAc. Example 1 3-(7-Gas-8-dimethylamino) ketophenone-4,5-dihydro-3H-benzo "blfl, 41 diazepine-2-yl)benzonitrile Prepared from {4-carbyl-2-[3-(3-cyano-phenyl)-3-keto-propenylamino]-5 by treatment with TFA in CH2Cl2 according to General Procedure -Dimethylamino-phenyl}-aminomethyl acid tert-butyl ester (Example M1). Obtained a yellow solid (85 mg). MS (ISP) 339 [(M+H)+] and 341 [(M +2+H)+];melting point&gt;250°C. Example 2 -154- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ___ B7 V. Description of invention (151) Bucket (3-"1,2,31 triazol-1-yl-phenylindole, 3-dihydrobenzo", "1,41 dioxanthracene title compound according to the general procedure N, via tfA in CH2 Cl2 Medium treatment 'made from {4-chloro-5-dimethylamino-2-oxoyl 3-(3-[1,2,3]triazol-1-yl-phenyl)-propanyl Amino]-phenyl}-amino acid tert-butyl ester (Example Μ 2). Obtained as a pale yellow solid (87 mg). MS (ISP) 381 [(M+H)+] and 383 [(Μ+ 2+Η)+]; melting point 222-225 ° C. Example 3 士 I base _7· dimethyl 羞 「 "3- (5-hydroxyl - "1,2,31 triazole small phenyl 1-U-dihydro-benzo[|blfl, 41 diazepine-2-one standard compound according to the general procedure, via D in FA2 Processed in %, prepared from (RS)-[4-carbyl-5-dimethylamino-2-(3-g-iso-yl){3-[5-(tetrahydro-pyro--2-yloxy) Methyl)-[1,2,3]dis-l-yl]-phenylpropanyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (Example M3). Obtained beige Solid (6 mg) MS (ISP) 411 [(M+H)+] and 413 [(M+2+H)+]; melting point 21 〇-214 ° C. Example 4 iHg--methylamino j, synthyl-7-phenylethynyl-4,5-dihydro-3Η-benzofbin, 41diazepine-2-yl)-benzonitrile, the title compound is based on the general procedure N, via TFA Treated in CH2, from {2-[3-(3-cyano-phenyl) keto)-propionylamino group] dimethylamino-4-phenylethynyl-phenyl} Aminomethyl hydrazine tert-butyl ester (Example M4). Obtained an orange solid (65 mg). MS (ESI) 405 [(M+H)+]; mp 215-216 ° C. Example 5 -155- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)

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Line 1296622 A7 _______ Β7 V. Description of the invention (152) Methylaminophenylethynyl-4-G-[l,2,31 triazol-1-yl-phenyl wilting [bin, 41 diazepine - The 2-keto-standard compound was prepared from {5-dimethylamino-2-[3-keto-(3-[1,2,3]triazole by treatment with TFA in CH2Cl2 according to the procedure. -1-yl-phenylidylamino]-4-phenylethynyl-phenyl}-amine methyl acid, third butyl ester (Example M5). Obtained an orange solid (76 mg). ISP) 447 [(M+H)+]; melting point 185-186 ° C. Example 6 t gas-based 7--methylamino-4-"3-(3-methyl-iso-p-jun-5- The title compound is obtained from (4-chloro-5-dimethyl) by treatment with TFA in CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub. Amino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-keto-propionylamino}-phenyl&gt;amine methyl acid Third-butyl ester (Example: Obtained light yellow solid (68 mg). MS (EI) 394 (M+) and 396 [(M+2)+]; mp. 212-215 ° C. Example 7 M?, 3 -difluoro-phenyl)-7-dimethylamino winter [3-(5-hydroxymethyl-indole, 2,31 triarsenic diyl) phenyl]-1,3-dihydro -Benzo[~bl"l,4~|diazepine-2-g with the title compound according to the general procedure N, by treatment with TFA in CH]Cl 'from (RS)-[2- Methylamino-2,3,-difluoro-5-(3-keto-3-{3-[5-(tetrahydro-tham-2-yloxymethyl)-[1,2, 3] III. -1'-yl]-phenyl-propyl-propylamino)-biphenyl-4-yl]-aminomethyl acid tert-butyl ester (Example M7). Obtained a yellow solid (26 mg MS(ISP)489 [(M+H)+]· Example 8 156- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 ____B7 _._ V. Invention description (153) &quot;&quot; 8: ί^_3: difluoro-stupyl)-7-diamido-4-(3-indole, 2,3~ oxatriazole small group-phenyl V1.3-dihydro- Benzo[b~|"l_,41diazepine-2-one" compounds were prepared from {2-diamine-2,3 by treatment with TFA in CH2Cl2 according to the general procedure N. ,·Difluoro_5-[3-keto-(3-[1,2,3]triazol-1-yl-ylyl)-propanylamino]-biphenylyl]-aminomethyl Acid third · vinegar (example Mg). Obtained as a yellow solid (47 mg). MS (ISP) 459 [(M+H)+]; mp 197-199. Example 9 Twist: (2,3-difluoro-pen _1 hydrazine dimethylamine -4-keto-4,5-dihydro-3 沁 丨 丨 131 [~ 〗. 41 diazepine- 2-Based 1-Benzene-titled compound was prepared from {5-[3-(3-cyano-phenyl)-3-keto-propionium by treatment with TFA in CH2Cl2 according to the general procedure 3-Amino] 2 -diaminoamino 2',3'-difluoro-biphenylyl yl}-amine decyl acid tert-butyl ester (Example M9) afforded a pale yellow solid (75 mg) MS (ISP) 417 [(M+H)+]; mp 228-229 ° C. Example 10 decyl-7-dimethylamine _4ϋ2-(3-methyl-isoxazol-5-yl)- Pyridinyl 1-1,3-dihydro-benzo-"bl" 1,41-diazepine-2-one title compound was prepared according to the general procedure N, eluted with TFA in CH2Cl2 from (4- Gas-based 5-dimethylamino-2-{3-[2-(3-methyl-isoxazol-5-ylpyridinyl)-3-one-propionylaminopyridyl) • Aminomethyl acid tert-butyl ester (Example M10). Obtained a yellow solid (hi mg) MS (ISP) 396 [(M+H)+] and 398 [(M+H+2)+]; &gt; 25(TC. Example 11 -157-I paper size applicable towel S national standard (CNS) ΜSpecifications (9) (four) machigong love) 1296622 A7

Jjt 基·7-〖(2-yl-ethyl)-methyl^^ ΐ-4·"3^3•methyl_isoxazole heart}: wilty base--1,3-diphenylene And the title compound of the hydrazinone is prepared according to the general procedure N, from (4-chloro-5-[(2-methoxyethyl) by butyl 1 :8 in 〇% (:12 in f L) _Methyl-amino]ι{Η3·(3•methyl·iso-5azol-5-yl)-phenyl]-3-keto-propionylamino]phenyl)amine methyl acid _ Butyl ester (by example). Obtained as a yellow solid (m.m.). MS (EI) 438 (M+) and 440 [(M+2)+]; Methyl-amino-Im-4·“2-(3-methyl-isoxazol-5-ylindenyl-1)=1-hydrogen-benzoxene 14]diazepine·2·ketone oxime The compound was prepared according to the general procedure from (2-chloro-5-[(2-methoxy-ethyl)-methyl-amino]i{H2_(3; Methyl·xyzol-5-yl)-pyrazin-4-yl]-3-keto-propionylaminophenylphenylamine methyl acid tert-butyl ester (Example M12). Obtained a yellow solid (1〇6 mg) MS (ISP) Φ40 [(M+H)+ ] and 442 [(Μ+Η+2)+ ] ; *Tolerance point 213 ° C. Example 13 g base - 4 points (:) Methyl-"1,2,3" triazole]-yl)_stupyl 1-7-"(2_methylhydro-ethyl)_ 棊-棊-amine 1-1 hydrogen-benzo" The title compound of bl "Ml.sup.2.indol-2-one is prepared according to the general procedure N, by treatment with TFA in ch2 Ci2 from (RSH4-chloro-5-[(2-methoxy-ethyl) _Methyl-amino]keto] 3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)_[u,3]triazole small group]•phenyl}•C Benzylamino)-phenyl]-aminomethyl acid tert-butyl ester (Example Μ 13). Obtained a beige solid (50 mg). MS (ISP) 455 [(Μ+Η)+] and 457 [( Μ+Η+2)+ ]; melting point 185 ° C. 158- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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tjHjA -7-. methoxy-ethion-upper (3-Π, 2,31 三峰ny芊v L3-dihydro-benzo-1, 41 bis-title compound according to the general procedure N, via TFASCH] Processed in %, from {4-carbyl-5-[(2-methoxy-ethyl)-methyl-amino]&gt;2·[3·keto-based winter (3·[1,2,3 Triazol-1-yl-phenyl)-propionylamino] phenyl]aminomethyl acid tert-butyl ester (Example Μ 14) Obtained as a yellow solid (69 mg). MS (ISP) 425 [ (Μ+ΗΠ with 427 [(Μ+Η+2Π; melting point 156. (:. Example 15 soil i7-chloro-8-dimethylamine soil ^ storm-4,5·dihydro_3H_ stupid The title compound of 冽 diazepine-2-yl)pyridine-2-carbonitrile is prepared from {4-carbyl-2-[3-(2) by treatment with TFA in CH2a according to the general procedure N. -Cyano-pyridyl-4-yl)-3-keto-propionylamino]- 5-dimethylamino-phenyl-p-methylamino acid tert-butyl ester (Example M15). Obtained yellow Solid (50 mg) MS (ISP) 340 [(M+H)+] and 342 [(M+2+H)+];, j: 216 ° C. Example 16 m -7--methylamine 4-·3-(2-methyl-2H-p than ternary-3·yl V stupyl 1-1,3-dihydro-benzo-"bl"l,41 diazepine with the same title The compound was prepared according to the general procedure N from (4-carbyl-5-dimethylamines {3-[3-(2-methyl-2H-pyrazole-3-). ))-phenyl] ό-S syn-yl- acetoxyamino]-phenyl)-amine methyl acid ternary-butyl hydrazine (example M16). Obtained as an off-white solid (67 mg). MS (ISP) 394 [(M+H)+ ] and 396 [(M+2+H)+ ]; melting point 225 ° C. -159- This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (156) Example 17 7-Dimethylamine. Benzyl [3-(5-hydroxymethyl-"1,2,3]triazol-1-yl-V-m-8-trifluoro甲. The title compound of 1,3-dihydro-benzo[b~|H,41-diazepine-2-one is prepared according to the general procedure N by treatment with TFA in CH2Cl2 from (RS)- [5-Dimethylamino-2-(3-keto){3-[5-(tetrahydro-pyro--2-yloxymethyl)·[1,2,3]三峻-1- Alkyltrifluoromethyl-phenyl]-aminomethyl-fe-second-butyl-form (Example Ml7) gave an off-white solid (62 mg). MS (ISP) 445 [(M+H)+]: melting point 2HTC. Example 18 Ζι_dimethylamino ice "3-(3-methyl-isoxazoloyl)-phenyl.1-8-trifluoromethyl],3-dihydro-benzofblfl, 41 dioxin The hydrazine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2C12 (5-monomethylamino-2-{3-[3-(3.methyl). 5_yl)-phenyl]-3-g-iso-propionylamino}-4-trifluoromethyl-phenyl)-aminomethyl acid tert-butyl ester (Example M18). Obtained as an off-white solid (28 mg) MS (ISP) 429 [(M+H)+]; mp. 223T: </RTI> Example 19^11^7-dimethylamine hydrazone "3-(4-hydroxymethyl- oxazolungyl) 1 1-1,3-Dihydro-Celi [bl "l,41 dioxabenzene-2-one title compound is prepared from 3-(7-carbyl-8-dimethylamino-4-one) Base _4,5·dihydro-3 hydrazine and [b][l,4] oxazepine-2-yl)-benzene T sulphur amine {from the following 3-(7-gas group) Butyldimethyl ketone ketone 4,5-dihydro-3H·benzo[b][l,4]diazepine I)) benzonitrile (Example 1): hexamethyldifluorene Thiocarbazone (〇55 millimuses, 2.6 millimolar) Add __ -160- paper at 20 ° C in a solution of 1,3-dimethyl-2-imidazolidinone (2.6 ml) Scale for money National Standard (CNS) ΜSpecifications ((10)x 297 public)~ ' 1296622 A7 B7 V. Description of Invention (157) Add sodium methoxide (0.13 g, 2.5 mmol). Stir the mixture for 15 minutes, then form The blue solution is added to 3-(7-chloro-8-dimethylamino-4-keto-4.5-dihydro-3H-benzo[b][l,4]diazepine-2- Benzobenzonitrile (Example 1) (0.34 g, 1 〇 mmol) in a solution of 1,3-dimethyl-2-ipiridine (2 mL). The mixture was taken at 20 ° C Stir for 3 hours, then pour into water. Separate the precipitate by filtration and triturate with acetone to obtain 3·(7-chloro-8•dimethylamino) ketone-4.5-dihydro·3Η-benzo[ b][l,4]diazepine asyl)-phenylhydrazine thiocarboximine (〇35g) as a colour solid with a melting point of 234 ° C. MS (ISP) 373.2 [(M+H)+ ]} (0.71 g, 1.9 m Mo), ι, 3-di-2-acetone (〇·36 g, 2.85 mmol) and sodium bicarbonate (0.24 g ' 2.85 mmol), Heated to 60 ° C in ι,4-dioxane (15 ml) for 48 hours. This clear solution was evaporated in the sputum. The residue was in 1,4-dioxene. The (5 mL) of was added 2N koh (3.8 ml) was' added and the mixture 2〇. Stir under the arm for 1 hour. Water (100 ml) was added and the mixture was stirred for 5 hours. The resulting precipitate was collected by EtOAc (EtOAc m. MS (ISP) 427·2 [(Μ+Η)+]; m.p. (: decomposition example 20 chloro 4·ΐΖ: dimethylamine-based winter P-_(5·dimethylaminomethyl-hydrazine, 2,3 ΐ triazole small group) _phenyl 1-1,3·dihydrogen -Benzene "b][l,4l dioxin-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 (4-carbyl-5-dimethylamino) -2-{3-[3-(5-Dimethylaminomethyl-[1,2,3]trisyl)-phenyl]-3-keto-propenylamine phenyl ) - Amino acid methyl third-butyl ester (Example M19). Obtained a beige solid (34 mg). 161 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 public) Binding

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MS (ISP) 438 [_Η)+] with 440 [(Μ+2+ΗΠ; melting point 145-16 (rc example 21

Dihydro-benzoxanthene, 41ρ1Π,41 diazepine-2-one titled compound was obtained by treatment with TFA according to the general procedure 衣(4-carbyl-5-monoamido-2- 3-[3-(3-decyloxyindenyl-iso-inden-5-yl)-phenyl]-3-keto-propenylamino}}phenyl]-amino acid Ester (Example M20) gave a pale yellow solid (157 mg). MS (ESI) 425 [(M+H)4*] and 427 [(M+2+H)+];,]: 191 °C Example 22·

The title compound of the indole-2-yl)-pyridine-2-carbonitrile is prepared from {2-[3-(2-cyano-pyridyl) based on the general procedure N by treatment with CH2% in hexanes. -3-keto-propionylamino]-5-dimethylglycosyl-4-difluoromethyl-phenyl-p-methylamino acid tert-butyl ester (example Μ 2ι). A yellow solid (158 mg) was obtained. MS (ISP) 374 [(M+H)+]; mp 248. 1 example 23

[b]fl,41 diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH^?? from [2,-fluoro-5-[3- (3-imidazol-1-yl-phenyl)_3 marriage-propionylamino] 2-(2,2,2-difluoro-ethoxy)-biphenylyl yl]-aminomethyl Acidic third-butyl ester (example M22). Obtained as a brown solid (50 mg). -162-

1296622 A7 B7 V. INSTRUCTIONS (159) MS (EI) 494 (M+); mp 208-210X:. Example 24 8: (Fluorobenzoquinone) H7 [3-(3-Methyl-isoxazol-5-yl Vphenyl 1-7·(2,2,2-trifluoro-ethylhydro))- 1, hydrazine-dihydro-benzo-"bl"l,4~|diazepin-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from [2'-fluoro- 5.13-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionylamino}-2-(2,2,2-trifluoro- Ethoxy)-biphenylyl ice-based &gt; Amino acid tert-butyl ester (Example Μ 23). Obtained as a pale-yellow solid (21 mg). MS (ΕΙ) 509 (Μ+); mp 218-220 C. Example 25 • fluorinated phenyl group » (3-[1,2,31 triazole small group-phenyl V7-(2,2,2_trifluoro-ethane gas V1夂 dihydro-benzo-network) The title compound of 1,41 diazepine-2-one was prepared from [2,-fluoro-n--5-[3-keto- each (3-[1] by TFA in CH2Cl2 according to the general procedure N. , 2,3]triazole-based-phenyl)-propionylamino]-2-(2,2,2-trifluoro-ethoxy)-biphenyl]-amino]-amino hydrazino Tributyl vinegar (example M24). Obtained an orange solid (45 mg). MS (EI) 495 (M+). Example 26 Μϋ phenyl)-4-"H5·Methyl-π,2,3ΐ三峻-1-yl-v phenyl i —7m 三气. Ethoxy)-1,3-dihydro-benzo41diazepin-2-one The title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2. )-[2,-Fluoro-5·(3-keto-3-{3 (tetrahydro-I-an-2-yloxymethyl)-[1,2,3]triazole small group] -phenyl}-propionylamino)-2(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example Μ 25 Obtained off-white solid-163- This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (16〇) Body (10 mg) MS (ISP) 526 [ (M+H)+]; m.p. 232-234° C. Example 27 8-Chloro-7-dimethylamino-443-(4-hydroxymethyl-oxazol-2-ylphenyl H, 3- Dihydro-benzopyrene Π1, 41 diazepine-2-one titled compound is prepared according to the general procedure from (2-amino-4-yl-5-dimethylamino-phenyl)-amine A Tri-butyl acrylate (example j2) (n 〇 mg) and (RS)-3-keto-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)- Oxazol-2-yl]-phenyl}-propionic acid tert-butyl ester (Example K11) (270 mg). According to the general procedure N, the obtained material is subjected to removal protection and cyclization by treatment with TFA in CH2C12. Obtained as a pale yellow solid (110 mg). MS (ISP) 411.2 [(M+H)+]; mp 193-195. Example 28 8-Chloro-7-(ethyl-methyl-aminohydroxymethyl-indole, 2,31 triazole small group)-stupid 1-1,3-dihydro-benzo"bin,41 The diazepine-2-one title compound was prepared from (RS)-[4-chloro-5-(ethyl-methyl-amino)- by treatment with TFA in CH.sub.2Cl. 2-(3-keto-3-{3-[5·(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenylpyrene Amino-phenyl]-aminomethyl acid tert-butyl ester (Example Μ 26) (0.5 g, 0.8 mmol). Obtained as an off-white solid (60 mg). MS (ISP) 425.4 [(Μ+Η)+]; melting point 206, °C (decomposition) · Example 29 8-chloro-7-(methyl-propyl-amino)-443-(5-hydroxyl Base-Π, 2,31 triazole small base)- 笨 1 1-1,3-dihydro-benzofblfMl diazepine-2-one 164 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 ________B7 V. INSTRUCTIONS (161) The title compound was prepared according to the general procedure N by treatment with TFA in CH2Cl2 from [RS]-[4-chloro-5-(methyl- Propyl-amino)-2-(3-keto-3-{3-|&gt;(tetrahydro-furan-2-yloxymethyl(4)phanyl)triazole phenyl phenyl decylamine Peptide &gt; Phenyl]-amino acid tert-butyl ester (Example Μ 27) (〇·41 g, 0.64 mmol). Obtained as pale yellow solid (110 mg). MS (ISP) 439.3 [( Μ+Η)+]; melting point 178 ° C (decomposition) · Example 30 g-based 7-(diethyl-amino)-4-(3-(5-methyl--1,2,31 The title compound of the oxazol-1-yl V phenyl 1-hydro-benzo-bf 1,41 diazepine-2-one is prepared according to the general procedure N by treatment with TFA in CH2Cl2. [4-Alkyl-5-(diethyl-amino)-2-(3-keto-3-{3-[5_(tetrahydro] shouting喃-2-yloxymethyl)-[1,2,3]triazole succinyl]-phenyl}-propenylamino)phenyl]-aminomethyl acid tert-butyl ester (example) M28X 0.53 g, 0.827 mmol, obtained as an off-white solid (210 mg). MS (ESI) 439·3 [(M+H)+]: melting point 208 ° C (decomposition) · Example 31 L-chloro-7 -Dimethylamino-4-"3-(3-hydroxymethyl-iso-succinyl-5-ylphenyl-1-lanyl-1-.-di- benzopyrene) 1 oxime, 41 diazepine-2-one title The compound was prepared from (RS)-[4-carbyl-5-dimethylamino-2-(3-keto-3-{3-[] by treatment with TFA in CH2CI? 3-(tetrahydro-indol-2-yloxymethyl)-isoxazol-5-yl]-benzene, yl}-propenylamino)-phenylamine methyl acid tert-butyl ester (Example M29) (81 mg, 0.13 mmol).yield of yellow solid (38 mg). MS (ESI) 411 [(M+H)+] & 413 [(M+2+H)+]; °C. -165- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 _____B7 Five T invention description (162) Example 32 gA.·Base^Triazol-1-yl)- Stupid Base π four gas 呔 呔 uu^ i,3-dihydro-benzo 〖bl『l,41 diazepine-2-one heading The compound was prepared according to the general procedure N by treatment with TFA in Ch2% from (RS)-[4-carbyl-2-(3-keto-3-{3-[5-(tetrahydro-brum)喃-2-yloxymethyl)-[1,2,3]-indolyl-1-yl]-misopropylamino)-5_tetrahydrop-pyrrolidyl-phenyl]- Amino-methyl acid second-butyl ester (conventional example 30). Obtained as a yellow solid (58 mg). MS (ISP) 437 [(Μ+Η)+ ] and 439 [(Μ+2+Η)+ ] ; *Range 193-197°C. Example 33 Ζι-Methylamino-4-[3-(2-methyl-2H-p-pyrazol-3-yl)- phenyl 1-8-trifluoromethyl-1,3-dihydro-benzo Fbl "l,41 diazepine-2-one title compound is prepared according to the general procedure N, by treatment with tfa in ci, (5-dimethylamino-2-{3-[3-(2) -Methyl-2H-p than tern-3-yl)-phenyl]-3-g-iso-propylaminomethyl} glacial trifluoromethyl-phenyl)-amine methyl acid butyl butyl ester (Example M31) (78 mg, 0.14 mmol). m. m. m. - gas-based (cyclopropylmethylammonyl)-4-g-iso--4,5-dihydro-3H-benzofblfMl-a misc #-2-基比咬-2-甲月青The title compound was prepared according to the general procedure from [2-aminocarbazin-5-(cyclopropyl-methyl-amino)-phenyl]-aminemethylhydrazine tert-butyl ester (example; ) 〇 5〇 mg ' 〇 · 5 house Moules) with 3-(2-cyanobite-4-yl)-3-g-iso-propionic acid third · butyl g (example K3X150 mg, 〇· 61 millimoles). According to the general procedure N, the treated material is removed and protected by TFA in CH2%. -166- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) &quot; ---- 1296622 A7 B7 V. Invention description (163) &quot;&quot; Obtained yellow solid (69 mg) MS (ISN) 364.1 [(M-Η)·] with 366 [(Μ+2-ΗΠ; melting point 199-201. (:. Example 35 t-chloro-7-dimethylamine based bucket "3-(4 -hydroxymethyl-3-indolyl-isoxazole-5-yl)-stupidyl 1,3-dihydro-benzo[~bl"l,41diazepine-2-indole with the title compound according to general Procedure N, via treatment with TFA in CH2 C1), from [RS]-[4-chloro-5-dimethylamino-2-(3-{3-[3-methyl-4-(four) Hydrogen-nonyl-2-ethyloxymethyl)-isoxazole-5-yl]-phenyl}-3-yl-propionylamino)phenyl]-aminomethyl acid - Butyl ester (Example M32) gave a yellow solid (60 mg). MS (ESI) 425 [(M+H)+] and 427 [(M+2+H)+]; mp 232-233 ° C. Example 36 8-Chloro-7-(cyclopropyl-methyl-amino)-4-P-(3-methyl-isoxazol-5-yl)-phenyl 1-dihydro-benzoxium, 4ΐ The diaza-U-ketone title compound is prepared according to the general procedure from [2-amino-4-carbyl-5-(cyclopropyl-methyl-amino)phenyl] -Aminomethyl 3-butyrate (example) (156 mg '0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3- Keto-propionic acid tert-butyl ester (Example K4) (170 mg, 〇·56 mmol). The obtained material was deprotected and cyclized according to the general procedure N by treatment with TFA in CH2C12. Obtained as a yellow solid (49 mg). MS (ISP) 421.3 [(M+H)+] and 423 [(M+2+H)+]; mp 195-197. Example 37 8-A gas 4 -7-(cyclopropyl-methyl-amino)_4_"3_(5. hydroxymethyl_[ι·2,3ι三唑_卜基)^, steamed HA dihydro-wild And the title compound of blH,41 diazepine-2-one is based on the general procedure N, via TFA in CH2 Cl2 -167. The paper scale is suitable for the standard (CNS) A4 specification (210 X 297 公爱) ----一1296622 A7 __B7 V. Invention description (164 ) &quot;&quot; &quot; from 'RS> [4- gas-based-5-(cyclopropyl-methyl-amino) K3 -keto-3-(3-[5-(tetrahydro-pyran-2-yloxyindenyl)-[1,2,3]triazol-l-phenylphenylpropanylamino)· Phenyl]-aminomethyl acid tert-butyl ester (Example M33) (200 mg, 0.313 mmol) afforded pale yellow solid (54 mg). MS (ISP) 437.3 [(M+H)+] 439 [(M+2+H)+ ]· ~ \ Example 38 h methylamino-4-, (5-dimethylaminomethyl is _ "1,2,31 triazole small v phenyl 1-8 -Trifluoro!-yl-1,3-dihydro-benzo-"blH,41-dioxan-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2. Methylamino-2-{3-[3-(5-dimethyl-aminomethyl-[ι,2,3]triazol-1-yl)-phenyl] keto-propionyl Amino]-4-trifluoromethyl-phenylamine methyl acid, tert-butyl ester (Example M34) (126 mg, 0.214 mmol) afforded pale yellow solid (23 mg). MS (ISP) 472 [(M 十 H)+ ]; melting point 20 (TC. Example 39 gi gas -7-dimethylamino-4-[3-(5-hydroxymethyl-2-methyl-2H-pyrazole-3) · phenyl) 1,3-dihydro-benzo-"bl" 1,41 diazepine-2-one titled compound is obtained by treatment with TFA in CH7Cl7 according to the general procedure N RS)-[4-Alkyl-5-dimethylamino-2-(3·{3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-2H- Pyrazol-3-yl]-phenyl}-3-mercapto-propionylamino)-phenyl]-aminomethyl acid tert-butyl ester (example Mg5) (278 mg, 0.44 mmol) Obtained as a pale yellow solid (129 mg). MS (ESI) 424 [(M+H)+] and 426 [(M+2+H)+]; mp 184 ° C. Example 40 -168- China National Standard (CNS) A4 Specification (210X 297 mm) 1296622 A7 _ __ B7 V. Description of Invention (165) Red 4:j with the same base-8-tetraki-7-trifluoromethyl-4,5- Hydrogen-3H-^#_网[1 4] diazepine-2-ylpyridin-2-methylpyrene The title compound is based on the general procedure N, Treated with TFA in ch2C12, from {2-[3-(2-cyano-P-pyridyl)yl)-keto-propionylamino]-tetrahydrogen p-ha-1-yl-4- Difluoromethyl-phenyl}-amine methyl acid tert-butyl ester (Example M36). Obtained an orange solid (65 mg). MS (ISP) 400.4 [(M+H)+]; melting point 188 ° C (decomposition) · Example 41 fbO-p-methyl ιΟΑΙί^azole small base)-stupyl 1-7-tetrapyrrole small group The title compound of the tris-capto-I,3-dihydro-benzo-IMMl-diazepine-2-one is prepared according to the general procedure 经由 by treatment with tfa in CH2C12 'from (RS)-[2-(3) -keto-based winter {3-[5-(tetrahydro-pyran-2-yloxyindenyl)-[ι,2,3]diin-1-yl]-phenylpropylpropanylamino) Hydrogen p piroxicamyl trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example M37). Obtained as a pale yellow solid (33 mg). MS (ISP) 471.2 [(M+H)+]; mp. Example 42 Ζι^ methylamino-8-gas j-443-(5-hydroxymethyl-"1·2,31 triazole small group stupid 1-1,3-dihydro-benzo-"bl"l, 41 diazepine-2-S and the title compound were prepared according to the general procedure N, by treatment with TFA in CH.sub.2Cl.sub.2 from (RS)-[5-monomethylamino-4-carbyl-2. -mercapto-3-{3-[5-(tetrachloro-pyranyl-2-yloxymethyl)-[1,2,3]dis-l-yl]-phenyl-bromo-yl-amino • Phenyl]-amino acid tert-butyl ester (Example Μ 38) (375 mg, 0.63 mmol). Obtained a yellow solid (115 mg). MS (ISP) 395 [(Μ+Η)+ ] ; Melting point 75 ° C. -169- The paper scale is suitable for @@家料(CNS) A4 specification (210X297 mm) ' &quot; 1296622 A7 B7 V. Invention description (166 ) Example 43 2: +Methylamine 4-[3-(5-Dimethylaminomethyl-[1,2,3]triazole-1-v vyl 1 perfluoro-1,3-dihydro-benzofbin, 41 II The azaphen-2-one title compound was prepared from (5-dimethylamino-2-{3-[3-(5-didecyl-amine) by treatment with tfa in ch2 Cl2 according to the procedure. Methyl-[12,3]triazole-based)-phenyl]-3-1-iso-propyl-SS-ylamino}-4-fluorophenyl)-amine methyl acid </RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Gemstone-4-[3-(3-methyl-iso-prior-5-yl)-phenylidene-dibenzo-benzo-1,41-diazepine-2-one title compound is based on General procedure N, via treatment with TFA in CH2Cl?, from [RS-[5-dimethylamino-4-fluoro-2-(3-keto){3-[3-(tetrahydro) -piperidin-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propenylamino)-phenylamine methyl acid tert-butyl ester (example M40) (314 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Amino 2-[3-(5-tetrakilylmethyl-oxime-2,31 triazole oxime v winter base 1-1,3-dihydro-benzofb~||~l,41 diaza Grass _2-g is the same as the title compound from 8-oxyldimethylamino-4-[3-(5-hydroxy-methyl·[1,2,j]di.su-1-yl)-benzene ]]-1,3-dihydro-benzo[b][i,4]diazepine-2-one (Example 3) (123 mg, 0.3 mmol) via s〇Ci2 ( 〇〇44 L, 0.6 mmol) in Οί ^ 12 (2 mL) from 23. 〇Return to 15 minutes -170- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public)—------

Binding

Line 1296622 A7 ______ B7 V. Invention description (167_) ~&quot; Clock' then evaporated. The crude vapor was dissolved in DMF (2 mL) and stirred with &lt;RTI ID=0.0&gt;0&gt;&gt; The reaction mixture was taken up in EtOAc (EtOAc)EtOAc. The solvent was removed in the helium to leave a yellow semi-solid which was purified by column chromatography. Obtained a yellow solid (101 mg). MS (ISP) 464 [(M+H)+ ] and 466 [(M+2+H)+ ];,]: Capacity 180-182Ό. Example 46

Zl dimethylamino winter [3-indole methyl-iso-salt-5-yl] phenyl 1 each trifluoromethyl·ι,3·dihydro-stupid) 1Π,41 diazepine The 2-keto-title compound was prepared from (RS)-[5-dimethylamino-2-(3*•keto-3-)3- via TFA in CH?Cl2. [3 (tetrahydro-pyran-2-yloxymethyl)-isoxazole-5-yl]-phenyl}-propenylamino)_4-trifluoromethyl-phenyl]-amine A Third acid butyl acrylate (Example M41) (680 mg, 1.05 mmol). Obtained as a yellow solid (294 mg). MS (ISP) 455 [(M+H)+]; mp. Example 47 7 diammonium-8-fluoromethyl-isoxazole-5-yl)-phenyl 1-1,3-dioxene-fushen "1,41 diterpenoid-2- The title compound of the ketone is prepared according to the general procedure N from (5-dimethylamino-4-fluoro-{3-[3-(3-methyl-isoxazole-5) by treatment with TFA in CH2Cl2. -yl)-phenyl]-3-keto-propionylamino}-phenyl)-aminomethyl acid tert-butyl ester (example M42) (233 mg, 0.47 mmol). Solid (59 mg) MS (ISP) 379 [(M+H)+]; m.p. 124 ° C. 171 - The paper size applies to the Chinese National Standard (CNS) A4 size (210X 297 mm) 1296622 A7 ___wr_._ V. INSTRUCTIONS (168) • ., 丨y Example 48, ', 'HH5--azetidin-1-ylmethyl-"1,2,31-triazol-1-yl)-phenyl 1-8 -Chloro-7-dimethylhydrazine^-1,3-dihydro-benzo[1^1,41-dioxan-2-one title compound is as described in Example 45, via S 〇 C12 ( 3 equivalents) and trimethylene imine (10 equivalents), prepared from 8-chloro-7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]-three Zin-1-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine-2·one 3) (123 mg, 0.3 mmol) afforded a yellow solid (17 mg). MS (ESI) 450 [(M+H)+]: 153 ° C. Example 49 ^1^-7-dimethylamine 4--4-(5-Hydroxymethyl-isoxazol-3-yl)-phenyl 1-1,3-dialdehyde-benzo[~bl"l,41diazepine-2- The title compound of the ketone is prepared according to the general procedure N, by treatment with TFA in CH.sub.2Cl.sub.2 from [RS]-[4-chloro-5-dimethylamino-2-(3-indolyl-3-{3 [5-(tetrahydro-pyro--2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propenylamino)phenyl]-aminomethyl acid - butyl ester (Example Μ 43). Obtained as a yellow solid (in mg) MS (ISP) 411.3 [(Μ+ΗΠ and 413 [(Μ+2+ΗΠ; melting point 211. (:(decomposition)· example 50 H4-[ 3-(5-hydroxymethyl-oxime, 2,31 triazol-1-ylphenyl 1-7-hexahydropyridine·]·葚· U·dihydro-benzo-|~bl “l,41 dinitrogen The title compound of the hetero-y-2-one is prepared according to the general procedure N, by treatment with butyl fa in CH 2 Cl 2 'from (RS)-[4-chloro-2-(3-keto), 3-{3-[ 5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]tris-l-yl]-phenyl-propenylamino)_5_hexahydropyridine+yl-phenyl ]-amine methylation Two - but-purpose g (penetration Example M44). Obtained as a pale yellow solid (99 mg). MS (ISP) 451 ·3 [(Μ+ΗΠ and 453 [(M+2+H)+ ]; melting point 246°C (decomposition)· • 172-

1296622 A7 _ B7 V. INSTRUCTIONS (16^ &quot; Example 51 7-dimethylamine roll-4-[g-(5-hydroxymethyl-isoxazol-3-yl)-phenyl 1-8-three Gas methyl-1,3-dihydro-benzo[b],1,41diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (RS) -[5-Dimethylamino-2-(3-keto- each {3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl Tri-butyl butyl trifluoromethyl-phenyl]-amine methyl acid (Example M45) gave a pale yellow solid (1 〇 3 mg). MS (ISP) 445.3 [(M+H )]]; melting point 241 ° C (decomposition). Example 52 8-Chloro-7-sj7-amino-4-0 pyrazole small group-phenyl VI,3-dihydro-stupid "Qiu 1,41 The title compound of diazepine-2-one is prepared from {4-chloro-5-dimethylamino-2-[3-keto-3- by treatment with TFA in CH.sub.2Cl.sub. (3-pyrazole small-phenyl)-propanylamino]-phenyl-p-methylamino acid tert-butyl ester (Example M46). Obtained as a yellow solid (75 mg). MS (ISP) 380 [ (M+H)+ ] and 382 [(M+2+H)+]; melting point 231-234Ό. Example 53 7-Dimethylamine 棊2-[3-(3-4 Pyrrol-1-ylmethyl-isoxazolylphenyl 1 each trifluoromethyl-1,3-dihydro-benzo-[~1,41-dioxaindole-2-one title compound is according to Example 45 Said, by treatment with s〇Cl2 (3 eq.) and tetrahydroppyrrole (10 eq.), from 7-methylamino-4-[3-(3-methyl-iso-4. Each group)-phenyl]-8-trifluoromethyl-i,3-dihydro-benzo[t,4,2,diazepine (Example 46) (1 Π Φ克 '0.25 mmol) Obtained as a yellow solid (28 mg). MS (ESI) 498 [(M+H)+]; melting point 160 ° C. -173- The paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) --- A7 B7 1296622 V. Description of the invention (1701 Example 54 7_ — methyl-isoxazole·5_yl stupid 1 winter trifluoromethyl], .3: dihydrodi^^^ diazepine The 2-keto-labeled compound was prepared as described in Example 45 by treatment with s〇Cl2 (3 eq.) and EtOAc (10 eq.) from 7-dimethylamine [3-(3-hydroxy) Methyl-isoxazole _5_yl)-phenyl]-8-trifluoromethyl-1,3·dihydro-benzo[b][l,4]diazepine-2-one (Example 46 ) (53 mg, 0.12 mmol). Obtained as a yellow solid (33 mg). MS (ISP) 514 [(M+H)+]; melting point i65 °C. Example 55 bis-indole-blue hydrazinomethyl-isoxazole _5-yl) phenyl hydrazine trifluoromethyl-1,3-dihydro-benzo-~bin, 41 diterpenoid- The 2-keto-title compound was prepared as described in Example 45 from dimethylaminosyl-[3-(3) by treatment with s 〇 〇Cl 2 (3 eq.) and 4 〇 % EtOAc. _ hydroxymethyl · iso '. sit-5-yl)-phenyl] winter trifluoromethyl", 3_ dihydro _ benzo [T (4) diazepine-2-one (Example 46) (53 mg (U2 mmol). Obtained as a pale-yellow solid (21 mg). MS (ISP) 472 [(M+H)+]; melting point MfTC. Example 56 4-(7-fluoro-4-keto- 8-tetrahydropyrrole small group-4,5-dihydro-3H- phenanthrene bbin, 41 dimercapto-2-yl)-pyridin-2-methylidene title compound according to the general procedure N, via TFA Treatment of '2-[3-(2-cyano-P-preo-4-yl)-3-keto-propanylamino]-4-fluoro- 5-tetrahydro in CH2Cl2 Pyrrol-1-yl-phenyl}-amine methyl acid tert-butyl ester (Example M47). Obtained an orange solid (54 mg). -174- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) binding

Line 1296622 A7 B7 V. Description of the invention (171) MS (ISP) 350 [(M+H)+]; melting point 278-279Ό. Example 57 8-Fluoro-4-"3-(3-methyl-isoxazol-5-yl)-phenyl 1-7-tetrahydropyrrole-1-yl-1,3-dihydro-benzo M "l,41 diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (4-fluoro-2--2-3-[3-(3- -isoxazol-5-yl)-phenyl] keto-propionylamino}-5-tetrahydropyrrole-1-yl-phenyl)-amine methyl acid tert-butyl ester (example) Obtained as a brown solid (86 mg). MS (ESI) 405 [(M+H)+]; mp 236 ° C. Example 58- 8-fluoro-4-[3-(5- "1,2,3~|tripa-1-yl)-phenyl 1-7-tetrahydroρpyrrolidyl-1,3-dihydro-benzofbl "l,41 diazepine-2 - the same title compound is prepared according to the general procedure N, by treatment with TFA in CH9Cl2 from (RS)-[4-fluoro-2-(3-keto-3-{3-[5-(four) Hydrogen guar 2 - yloxymethyl)-[1,2,3]di-n-l-yl]-winteryl}-propanylamino)-5-tetrachloro-pyl]-yl- Phenyl]-aminomethyl acid tert-butyl ester (Example M49). An orange solid (72 mg) was obtained. MS (ESI) 421 [(M+H)+]; mp 184-185 ° C. Example 59 4-(8--nitrotetramethylene-7-yl-4-keto-4,5 -Dihydro-3H-benzo-[1,41diazepine-2-yl)-pyridin-2-yl-title compound was obtained from <RTI ID=0.0> --Nitrogen tetrahydrazide small base gas base 2 -[3-(2-cyano·pyridinyl)·3•keto-propanyl-8-amino group]•element}-amine methyl acid third- Ding g (example μ%). Obtained orange solid (66 mg) -175- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public) 1296622 A7 ___ B7 V. Invention description (172 ) &quot ; ^ MS (ISP) 352 [(M+H)+] and 354 [(M+2+H)+]; melting point 276 ° C. Example 60 Methyldiazol-3-yl)-phenyl 1- 7-tetrahydropyrroles, each of trichloromethane 1,3-dihydro-indole and "blfl, 41 diazepine-2-one title compound are treated according to the general procedure N via TFA in CH2Cl2 'Manufactured from (RS)-[2-(3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-iso-g--3-yl]-豕} - - 胺 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ MS (ISP) 471.2 [(M+H)+]; mp. Example 61-Packet 8·-Nitrogen tetramethylene] 2 三氟 酮 基 · 7 7 7 三氟 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并 并The title compound is obtained from {5-nitrotetradecyl-2-[3-(2-cyano-pyridine) according to the general procedure N by treatment with tfa in CH?Cl? Tetyl)-3-keto-propionylamino]-4-trifluoromethyl-phenyl-p-methylamino acid tert-butyl ester (Example M52) Obtained an orange solid (51 mg). (ISN) 384.2 [(M-Η)·]; Capacity 241 ° C. Example 62 t Nitrotetrazole-4-"3 (3-methyl-isoxazol-5-yl)· Stupid 1 Winter Tris-methyl-L1: dihydro-benzo-l~b~|n,41-diazepine-2-one title compound is prepared according to the general procedure ,N, by treatment with TFA in CH2Cl2. -Nitrogen tetramine·丨_yl_2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]· 3-indanyl-propenylamine} Ice III Fluoromethyl-phenylamine methyl acid, third butyl ester (Example Μ 53). A yellow solid (94 mg) was obtained.

1296622 A7 __B7___ V. Description of the invention (173) MS (ISP) 441·3 [(M+H)+ ]; melting point 239 ° C (decomposition) · Example 63 7--azatetraind-1-yl-4-" 3-(5-Hydroxymethyl-"1,2,31-triazol-1-yl)-phenyl 1-8-trifluoromethyl-1,3-dihydro-benzo"blfl,41 diaza The indole-2-one title compound was prepared from (RS)_[5--azaindole-1-yl-2-(3-keto-3-) by treatment with TFA in CH.sub.2Cl. {3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]di-n-yl]-phenyl}-propenylamino)-4- Trifluoromethyl-phenyl]-aminomethyl acid tert-butyl ester (Example M54) obtained as a yellow solid (182 mg). MS (ESI) 457.4 [(M+H)+]; Decomposition) · Example 64 - Bisexyl winter (3-pyrazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-stupid "bl"l,41 diazepine The 2-keto-title compound was prepared according to the general procedure N, eluted with TFA in CH.sub.2Cl.sub.2 from [5-diaminoamine![3-keto-3-(3-pyrazol-1-yl-benzene) Tris-butyl propylaminomethyl-4-phenylmethyl-phenylamine methylate (Example M55) (438 mg, 0.82 mmol). . 238 mg) MS (ISP) 414 [(M + H) +];. Mp 176 ° C Example 65

Zir^.Methylaminotriazol-4-yl-phenyl)-t-trifluoromethyl-1,3-dihydro-benzofblfMldiazepine-2-one title compound is based on the general procedure N Treatment with TFA in CH2Cl2's from {5-monomethylamino-2-[3-S-yl-3-(3-[1,2,4]tris-l-yl-phenyl)- Tri-butyl ester of propylamino-4-pyridylmethyl methacrylate (example m56) -177- This paper scale applies to Chinese National Standard (CMS) A4 specification (210X297 mm) 1296622 A7 __B7 V. Description of invention (174) ~^ (280 mg, 0.526 mmol). Obtained a yellow solid 〇 21 mg). MS (ISP) 415.3 [(M+H)+]; mp 247-250. Example 66 Ζι dimethylamino 4 · (3: • raw; 7 sitting-1-yl-phenylfluoromethyl hydrazine dioxon - jasmine fblfl, 41 diazepine-2-one title compound according to general Procedure N, prepared by treatment with TFA in CH2Cl2 from {5-dimethylamino-2-[3-(3-imidazolyl-phenyl)-3-indolyl-propenylamino]-4 -Trifluoromethyl-phenyl}-aminomethyl acid tert-butyl ester (Example M57). Obsed a yellow solid (132 mg). MS (ESI) 414 [(M+H)+]; °C. Example 67 8-Alkyl-7-dimethylamino-443-(4-methyl-p ratio. Sodium group)·Phenyl]·ι,3·Dihydro-benzo-[叩1 , 41 diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl7 from [RS]-[4-carbyl-5-dimethylamino-2-(3) -mercapto--3-{3-[4-(tetrahydro-pyro--2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propenylamino)-phenyl --Aminomethyl acid ternary-butyl chloroform (Example M58) (642 mg, 1.05 mmol) afforded a yellow solid (365 mg). MS (ESI) 410 [(M+H)+]; °C. Example 68 7-Dimethylamino-4-"3-(4-methyl-P-Butyl)-phenyl]-t-trifluoromethyl _1,3_Dihydro-benzo-fbl "l,41-diazepine-2-one title compound was prepared from (RS)-[5-dimethyl via TFA in CH2Cl9 according to General Procedure N. Amino-2-(3-keto-3-{3-[4-(tetrahydro-pyran-2-yloxy-178-) paper size applicable to China National Standard (CNS) A4 specification (210 X 297 ^ &quot; 1296622 A7 B7 V. DESCRIPTION OF THE INVENTION (175 ) Methylmethyl)-pyrazol-1-yl]-phenyl}-propenylamino)-4-trifluoromethyl-phenyl]-amine A Third-butyl acrylate (Example M58) (590 mg, 0.91 mmol) afforded pale-yellow solid (299 mg) MS (ESI) 444 [(M+H)+]; Dimethylamine based "3-(4-hydroxymethyl_3_methyl-isoxazol-5-yl)-phenyl 1-8-trisole", 1,3, dihydro-benzoic acid The title compound of the hydrazine-2-one is prepared according to the general procedure and N, by treatment with TFA in CH2Cl2 from (RS)-[5-dimethylamino-2-(3-{3-[3- Methyl ice (tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-keto-propionylamino)-4-trifluoromethyl Monophenyl--amino phthalic acid tri-butyl ester (Example M60). Obtained as a pale yellow solid (64 mg). MS (ISP) 459 [(M+H)+]; mp 207-208. Example 70 7-Dimethylamine-based [3-(4-hydroxymethyl-isoxazol-3-yl)-phenyl 1-8-trifluoromethyldihydro-benzofblfl, 41diazepine The 2-keto-title compound was prepared from (RS)-[5-dimethylamino-2-(3.-keto-3-{3-[4] via TFA in CH.sub.2 Cl. -(tetrahydro-pyran-2-yloxymethyl)-iso-4-oxa-3-yl]-phenyl}-propenylamino)trifluoromethyl-phenyl]-aminomethyl acid Third butyl ester (example M61). Obtained as a pale yellow solid (5 mg). MS (ISP) 445 [(M+H)+]; mp. Example 71 7-Dimethylamino-4-|~3-(2-methylthio-isobenzo-1-yl)-phenyl 1 winter trimethylmethyl·υ·dihydro-benzom” 41 diazepine-2-one-179 This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

Line 1296622 V. Inventive Note A7 B7 176) The standard compound is prepared according to the general procedure N, by treatment with TFA in ch2 Cl2 'from 5-(dimethylaminomethylthioimidazolylphenyl) ketone group - Propylaminomethyl}.4-trifluoromethyl-phenyl&gt; Amino acid tert-butyl ester (Example M62) (4d0 mg 〇 78 mM). Obtained a yellow solid (253 mg) MS (ISP) 460 [(M+H)+]; melting point i92 ° C. Example 72 21_Dimethylaminomethyl-2-methyl-2H-pyrazole-3-V-phenyl 1 Trifluoromethyl-1,3-dihydro-benzo[|blfl,4~|dioxan-2-yl as the title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl2. RS)-[5-monomethylamino-2-(3-{3-[2-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-2H-p ratio jun-3 -yl]-phenyl-p-3-S-iso-propionyl-amino)-4-trifluoromethyl phenyl]-aminomethyl acid tert-butyl ester (Example M63). Obtained as a yellow solid ( 272 mg) MS (ISP) 458 [(M+H)+]; mp 243-244 ° C. Example 73 _ _ _ s -7-dimethylamino-4-(3-"1,2 ,41 triazole small group-stupid)-1,3-dihydro-stupid m "l,41 diazepine-2-one The title compound was prepared according to the general procedure N by using TFA in CH? Cl2 from {4-carbyl-5-dimethylamino-2-[3-keto-3-(3-[l,2 , 4] Triazole succinyl-phenyl)-propionylamino]-phenyl}-aminomethyl acid tert-butyl ester (Example M64). Obtained a yellow solid (316 mg)., MS (ISP) 381 [(Μ+ΗΠ with 383 [(M+2+H)+] ·, melting point 239-241. (:. Example 74 7-dimethylamino-4-(3-indole, 2,4] -1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-stupid-180- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1296622 A7 B7 V. Invention Description (177) and "blfl, 41 diazepine-2-indole with the title compound according to the general procedure N, by treatment with TFA in CH2Cl2 'from {5-monomethylamino-2. Keto-3-(3-[1,2,4]tris-l-yl-phenyl)-propsylamino]-4-trifluoromethyl-phenyl-amino-amino acid _ Butyl ester (example </RTI> <RTIgt; </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Trifluoromethyl-4,5-dihydro-3H-benzo[~bin,41diazepine-2-yl)-benzonitrile The title compound was prepared according to the general procedure N from <RTI ID=0.0># </ RTI> </ RTI> </ RTI> <RTIgt; Dimethylamino-4-fluoromethyl-phenyl}-amine methyl acid tert-butyl ester (Example M66) (180 mg, 1.0 mmol). Obtained as a yellow solid (41 mg). MS (ISN) 371 [(M-H)-]; mp 224-227. Example 76 Dimethylamino winter (3-{5-[(2,2,2-trifluoro-ethylamino)-methyl Hi, 2,31 triazole phenyl)-8-trifluoromethyl The title compound of the 1,3-dihydro-p- and "b][l,41 diazepine-2-one is as described in Example 45, via S0C12 (3 eq.) and 2,2,2- Treatment with trifluoroethylamine (10 equivalents) from 7-dimethylamino-4-[3-(5-methyl-[1,2,3]triazole)-phenyl]-8- Trifluoromethyl hydrazine, 3-dihydro-benzo[b][l,4]diazepine-2-one (Example 17) (133 mg, 0.3 mmol) afforded a pale yellow solid (19 Mg) MS (ISP) 526 [(M+H)+]; melting point 168-170 ° C. Example 77 -181 - This paper scale applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1296622

Base) ice [3-(5-exi-yl 41,2,31 triazole phenyl) 1 phenyl 1 sulphate-benzofbin, 4i bis- 2 ketone title compound according to the general procedure Ν 17 VIII in (::% (:19 treatment of 'made from (RS)-[5-(cyclopropylmethyl-methyl-amine substrate (3-mercapto) {3 四 tetrahydro-pyran- 2-yloxymethyl H1,2,3]triazole small group]-phenyl}propenylaminotrifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example M67) 939 mg, 1.37 mmol, obtained as a pale yellow solid (544 mg). MS (ISN) 483 [(M-Η)·]; mp. 212: C. Example 78 - Amino) The title compound of benzyl-4,5-diazaindole HVpyridine-2-carbonitrile is prepared from [2-[3-(2-cyano-pyridine) according to the general procedure N by treatment with butyl octa. 4-yl) keto-propionylamino]_5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid third-butyl Ester (paste M68) (173 g, 〇 33 mmol). Obtained as a yellow solid (8 mg). MS (ISN) 412 [(M-Η)-]; mp 155 ° C. Example 79 社3_( 4_cyclopropylamine roll-mercapto-pyrazole small group V stupyl 1-7-diamine amine -8- The title compound of the di1,3-dihydro-benzo-fblfl,4]diazepin-2-one was as described in Example 45 via EtOAc (3 eq.) and cyclopropylamine (10 eq.) Treatment, prepared from 7' dimethylamino-4-[3-(4-hydroxymethyl-pyrazole.1yl)-phenyl]-8-trifluoromethyl],3-dihydro-benzo[ b][1,4]: azaindole-2-one (Example 68) (133 mg, 〇·3 mmol). Obtained a yellow solid (45 mg). MS (ISP) 483 [(Μ+Η) +]; melting point 135 ° C. -182·

1296622 A7 B7 V. Description of invention (179)

tMM cyclopropylaminomethyl-|~ι.2.η sazole small group)-phenyl 1-7-(cyclopropylmethyl-methazine j-anthyl)-8-trifluoromethyl-1.3-two舒-苽 and "bin, 41 diazepine-2-one title compound was prepared as described in Example 45 by treatment with EtOAc (3 eq.) and cyclopropylamine (10 eq.). Propylmercapto-methyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole)-phenyl]-8-trifluoromethyl-1, 3-dihydro-benzo[b][l,4]

Diazepine-2-one (Example 78) (145 mg, 〇·3 mmol). A yellow solid (97 mg) was obtained. MS (ISP) 524 [(Μ+Η)+]; mp 35-46 Ό. Example 81 Alkyl-4-{3-"2-(2-hydroxy-ethyl)-2Η-pyrazol-3-yl 1-phenyl-win dL3-dihydro-benzofb][l,41 二氤Cichlid-2-one

The title compound was prepared from (RS)-{5-dimethylamino-2-[3-keto-3-(3-{2-[2-] via TFA in CH.sub.2 Cl. (tetrahydro-pyran-2-yloxy)-ethyl]-2Η-pyrazol-3-ylphenyl)-propenylamino]trifluoromethyl·pyridylamine methyl acid Tri-butyl ester (Example Μ 69) (237 mg, 0.36 Torr). Obtained as an off-white solid (48 mg). MS (ISP) 458 [(Μ+Η)+]; melting point 138. (:. Example 82: triazole small group y stupid 1-7-dimethyl hydrazine dihydro benzo-"1,41 diterpene brewing 1 ' The title compound was as described in Example 45, via S0C12 ( 3 equivalents) and succinylamine (10 equivalents), prepared from dimethylamino 1[3_(5-hydroxymethyloxadiazol-1-yl)-phenyl]-t-trifluoromethyldihydro-benzo[ b][1,4]diazepine-183-1296622 A7 B7 V. Inventive Description (180) Ketone (Example 17) (444 mg, 1·〇 mmol). Obtained as a yellow solid (248 mg). 145-148 ° C. Example 83 4_[8_ 遵··13⁄4 shame-amino)_4_酉-yl trifluoromethyl-4,5-dihydro·3Η- benzodiazepine-2-yl 1-Pyridin-2-methylpyrene title compound was prepared from [2-[3-(2-cyano-4-pyridin-4-yl)-3-indole by treatment with TFA in CH.sub.2Cl.sub. Base-propionylamino]-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example M70) (215 g ' 〇·42 mmol. Obtained as a yellow solid (87 mg). MS (ESI) 400.4 [(M+H)+]; mp. 200-205 ° C. Example 84 7-Difluorophenyl) -(3-『1,2,31 triazol-1-yl-phenyl) -1,3-Dihydro-Crafting of "blfl,4] sinensis - oxalate - the same title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from {2-dimethylamino -2,-fluoro-5-[3-keto-3-(3-[1,2,3]triazole-p-phenyl)-propenylamino; μbiphenyl-4-yl }-Aminomethyl 3-butyrate (Example M7 〇) (810 mg, 1.45 mmol) obtained as a yellow solid (61 mg). MS (ISP) 400.4 [(Μ+Η)+]; Melting point 225-230 ° C. Example 85 7_dimethyl-shoes __4·-4-{ΗΗ2-hydroxy-ethyl)-"U, 3l triazol-1-yl 1-styl}-8-three oxime The methyl-1,3-dihydro-benzo-"blH,41 diazepine-2-one title compound was prepared according to the general procedure N via TFA in CH2Cl? from (RS)-{5 -monomethylamino-2-[3-keto-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,2,3] Triazole-l-yl}-phenyl)·propanylamino]4·trifluoromethyl _ -184- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1296622 A7 B7 V. INSTRUCTIONS (181) Phenyl}-aminomethyl acid tert-butyl ester (Example M72). Obtained as a pale yellow solid (179 mg). MS (ISP) 459 [(M+H)+]; mp 172-175. Example 86 2-Dimethylamino-4-[3-(5-hydroxymethyl-carbazoleylphenyl)8-trifluoromethylhydro-benzofbin, 41diazepine-2 The ketone title compound was prepared according to the general procedure N from (RS)-[5-diaminoamino-2-(3-keto){3-[5-(tetrahydrogen) by treatment with TFA in CH2Cl2. -piperidin-2-yloxymethyl)-pyrazole-1.yl]-phenyl}-propenylamino)·4-trifluoromethyl-phenyl]-amine methyl acid third- Butyl ester (Example M73). Obtained as a pale-yellow solid (1 </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -[1,2,31 triazole small-phenyl)-8-trifluoromethyl], 3-dihydro-benzonet, 41 diazepine-2-one title compound according to the general procedure N , by treatment with TFA in CB:) Cl9, from {5-dimethylamino-2-[3-keto-3-(3-[l,2,3]triazole small-phenyl) -Prodecylamino]-4-trifluoromethyl-phenyl}-amine methyl acid tert-butyl ester (Example M74) (905 mg, 1.7 mmol). A yellow solid (566 mg) was obtained. MS (ISN) 413.2 [(M-H)·]; mp. 210-212. Example 88 4-[4-Ketyl-8-(2,2,2-trifluoro-ethoxy]7-trifluoromethyl-4,5-dihydro-3H-benzofb~|『l , 4l diazepine·2·yl-pyridin-2-methylpyrene title compound is prepared according to the general procedure 经由, by treatment with TFA in CH 2 Cl 2 , from [2-[3-(2-cyano) Pyridin-4-yl)-3-keto-propionylamino]-5-(2,2,2- -185- _______________—^ This paper scale applies to China National Standard (CNS) A4 specification (210X297) PCT) 1296622 A7 _ B7 V. Inventive Note (182) &quot; Difluoro-ethoxy)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (Example M75). Yellow solid (100 mg). MS (El) 428.2 (M+);

Kg-dimethylamine 棊-7-methyl-4-keto-4,5-dihydro-3H- benzo[~bin,41 diazepine-2-yl)-benzonitrile is the title compound General procedure N, via treatment with TFA in CH2Cl2, from {2-[3-(3-cyano-phenyl)-3-keto-propenyl-amino]-4-dimethylamino -5-Methyl-phenyl-b-aminomethyl acid tert-butyl ester (Example Μ76) (0.22 g, 0.55 mmol). Obtained as a pale yellow solid (114 mg, 59.). MS (ISP) 319.3 [(Μ+Η)+]; mp 257. Example 90 7-Dimethylamino-4-[3-(5-hydroxymethyl-"1,2,31-triazol-1-yl)-phenyl 1-8-methyl-1,3-di-氲-Benzo[bl『l,4l-dioxan-2-one title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (RS)-[5-dimethylamino 2-(3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-benzene Benzyl propylamino)-phenyl-p-methylamino acid tert-butyl ester (Example Μ 77) (0. 42 g, 0.71 mmol) afforded pale yellow solid (200 mg, 720.) MS 391.3 [(Μ+ΗΠ; melting point 19CTC. Example 91 M3-cyanyl phenyl) &gt; 8-:V methylamino-4-3⁄4 synthyl-4,5-dihydro-3H-▲ and "blfl, 41 Dioxanthene-7-carbonitrile The title compound is based on the general procedure N, by using TFA in CH2C12 at __ -186- This paper scale applies the Chinese national standard A4 specification (21〇χ 297 mm) —- 1296622 A7 ____B7 V. INSTRUCTIONS (183) ~ 'LI' from {5-cyano-2-[3-(3-cyano-phenyl)-3-keto-propionylamino]-4 - dimethylamino-phenyl-b-aminomethyl acid tert-butyl ester (example Μ 78) (〇·28 g, 〇·63 mmol) Obtained as a yellow solid (36 mg, 590.) MS (ESI) 328.3 [( Μ-Η)·]; mp 251 ° C. Example 92 3- [7-methyl-(methyl-propyl-amino) )-4-mercapto_4,5-dixin·-3H-benzo[|bin,4&quot;|diazepine-2-yl 1-methane syllabic title compound according to general procedure-order N, Prepared from [2-[3-(3-cyano-phenyl)-3-iso-yl-propenylamino]methyl-4-(methyl-propyl) by treatment with TFA in CH2Cl2 -Amino)-phenyl]-aminomethyl acid tert-butyl ester (Example Μ79) (0.17 g, 0.37 mmol). Obsed as a yellow solid (74 mg, 58 〇.) MS (ISP) 347.4 [(Μ+Η)+]; melting point 195 ° C. Example 93 4- [3-(5-Hydroxymethyl-"1,2,3]triazole small group Vphenyl 1-8-methyl- 7-(曱-propyl-amino-dihydro-benzo-"blfl, 41-diazepine-2-one title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl? RS)-[4-Methyl-5-(methyl-propyl-amino)-2-(3-indolyl-3-{3-[5-(tetrahydro-pyran-2-yloxy) Methyl)-[1,2,3]triazol-1-yl]-phenylpyridinylamino)phenyl]-amino acid tert-butyl ester (Example Μ80) (0·42 g, 0.71 Mole). Obtained as a pale yellow solid (200 mg, 72.). MS (ISP) 419.4 [(Μ+Η)+]; mp 186J. Example 94 7-(Ethyl-indenyl-amino)-4-"3-(5. via methyl-"1,2,31 triazole small group V phenyl each methyl. 1,3-dihydro -Benzene Πρ1Π,41 diazepine-2-one-187· This paper scale applies to Chinese National Standard (CNS) A4 Specification (210X297 mm) 1296622 A7 B7 V. Description of Invention (184) The title compound is based on general Procedure N, by treatment with TFA in CH2Cl2, from (RS)-[5-(ethyl-methyl-amino)-methanol-2-(3-keto-3)3-[5- (tetrahydro-fluoren-2-yloxymethyl)-[1,2,3]triazole small group]-phenylpropanylamino)-phenyl]-amine methyl acid third-butyl Ester (Example Μ 81) (0. 39 g, 0.64 mmol). m. m. 8-Dimethylamino-243-(5-hydroxymethyl-"1,2,31 triazole small group]-phenyl1-4-one hydrogen-3Η-benzo is called [~1,41 diaza The title compound of 萆-7-methylformin is prepared according to the general procedure N··, by treatment with TFA in CH2C12 'from (RS)-[4-indol-5-dimethylamino-2-(3-indole) Base-3-{3-[5·(tetrahydro-pyranyl-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}- Tert-butylamino)-phenyl]-aminomethyl acid tert-butyl ester (Example Μ 82) (0·35 g, 0.58 mmol) afforded a yellow solid (149 mg, 64.) MS. 402.5 [(Μ+Η)+ ]; melting point 234 ° C. Example 96 8-Alkyl-443-(5-hydroxymethyl-oxime, 2,31 triazole small group)-Phenylisopropanol-A The amino-amino)-1,3-dihydro-benzo-fblfMl-diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (RS)-[4- Benzyl-5-(isopropyl-methyl-amino)-2-(3-ketotetrahydro-methylene-2-yloxymethyltriazole)-phenylpyridylamino) _Phenyl]-amino acid tert-butyl ester (Example Μ83) (0·53 g, 0.83 mmol). Obtained as an off-white solid (120 mg, 33.) MS (ISP) 439.5 [(Μ +Η)+ ]; melting point 207 ° C. -188- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

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Line 1296622 A7 B7 V. INSTRUCTION DESCRIPTION (185) Example 97 ^ 棊 丨 丨 methyl-propyl-amine a v 〇 _ trioxo-benzopyrene bl "l, 4l bis-h-indole 2 - ketone title compound system According to the general procedure N, the treatment of 'clothing from [wood methyl-2-{3-[3_(3_曱基_isoalpha))-phenyl) is carried out by using TFA in c]^ci2 Base-propionylamino]-5-(methyl-propyl-amino group &gt; phenyl]-amine methyl acid tert-butyl ester (Example Μ 84 Χ 0.33 g, 〇 · 63 mmol). Obtained as a pale yellow solid (163 mg, 64 〇0) MS (ISP) 403.4 [(Μ+Η)+]; melting point i94 ° C. Example 98 Daddy didimethylamine to ^isoxazole·5_ ·Phenyl]·4•keto group·4,5•diindole_3Η·Benzo[b][l,4]diazepine-7-methyl guanidine The title compound is based on the general procedure N, via TFA Treated in CH2%, prepared from (4-cyano-5-dimethylamino lap#•methyl-isoxazole ice-based)·phenyl]-3-S synthyl-propionylamino benzene Base &gt; Amino acid tert-butyl ester (Example Μ 8:)) (0·31 g '〇·62 mmol). Obtained as a pale yellow solid (171 mg, 72.) MS (ISP) 386 ·3 [(Μ+Η)+]; melting point 248 ° C. Example 99 Z-(Ethyl-methyl-amine-indenyl)-8-methyl-4K3-methyl-isoxazole-5-yl)-stupyl VI.3-dihydro-benzo[b]" l,4~|Diazin-2-S with the title compound is prepared according to the general procedure 彳N, by treatment with TFA in CH2Cl2 (5-(ethyl-methyl-aminomethyl-2) {3_[3&lt;3-methyl-iso-sigma-azolyl)-phenyl]-3-S-iso-propionylamino-p-phenyl-p-butylamino acid tert-butyl ester (Example Μ86) (0·38 g, 0.75 mmol). Obtained a pale yellow solid (16 mg, 55-189- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 public) Binding

Line 1296622 A7 B7 V. Description of the invention (186) 0 〇 ) 〇 MS (ISP) 389.5 [(M+H)+ ]; melting point 198. (: Example 100 methylaminomethylmethyl syl-isoxazole-5-ylphenyl bis-indenyl fluorene fbl "l,41 diazabenzene-2-one tropoline according to the general procedure N, via Treated with TFA in Ch2 % from (5-dimethylamino ice methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3- Ketopropyl-propionylaminophenyl &gt; Amino acid tert-butyl ester (Example M87) (〇··················· MS (ISP) 375.4 [(Μ+Η)+ ]; melting point 204. 〇α Example 101 Shame-based winter "3_(5-existing methyl-"1" triazole small base) · Stupid base 1-7_ (Iso Methyl-amino-amino)-1,3-dihydro-bromo-[b~|"l,41-diazepine-2-one title compound is treated according to the general procedure N via TFA in %' Prepared from (RS)-[4-chloro-5-(isobutylmethyl-amino(9) ketone group ρκ tetrahydro-pyran-2-yloxymethyl H1,2,3]triazole Small phenyl phenyl propylamino) phenyl]-amino acid tert-butyl ester (Example M88) (32 g, 〇·49 mmol). Obs. MS (ISP) 453.4 [(Μ+Η).]; dissolve 2〇rC. Example 102 L-oxy-7-(isobutyl-methyl-amine ν4-[3-(3·甲--isoxazole_5•yl-vphenyl [dibenzo-"bin, The title compound of 41 dioxin-2-one is prepared according to the general procedure N by treatment with TFA in CH2Cl? (4-carbyl-5-(isobutyl-methyl-amino)-2. ·{3-[3-(3-Methyl-isoxazole- ____ -190- This paper scale applies to Chinese National Standard (CNS) A4 Specification (210X297 mm) 1296622 A7 _________B7 V. Invention Description (187) 5- ))-phenyl]-3-keto-propionylamino}}-phenyl-aminomethyl acid tert-butyl ester (Example Μ89) (0·35 g, 0.63 mmol). Solid (114 mg, 41 〇/〇) 〇MS (ISP) 437.4 [(M+H)+]; mp 194 ° C. Example 103 2-[3-(5-hydroxymethyl-[1,2,3 Triazol-1·yl)_styl 1_4-keto-tetrahydropyrrole-based 4,5-dihydro-3H-benzo is called 1,1,diazepine-7-methyl-title compound According to the general procedure and N, by treatment with TFA in CH2Cl2, 'made from (RS)-[4. cyano-2-(3-keto-3-{3-[5-(tetrahydro-pyro--2) -yloxymethyl)-[1,2,3]triazole-1_yl]-phenyl}-propenylamino)_5·four Small-yl-pyrrol-phenyl] - carbamic acid tert - butyl ester (Example Μ90) (0 · 37 g, 0.59 mmol). Obtained a yellow solid (140 mg, 56. / 〇). MS (ISP) 428.5 [(Μ+Η)+]; mp 241 °C. Example 104 methyl-isoxazol-5-ylphenylanthracene-one 氪pyrrole small group-4,5-dihydro-3H-benzofbl "l,41 diazepine-7-carbonitrile according to general Procedure N, prepared by treatment with TFA in CH2Cl2 from (4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-g Homo-propionylaminodiphenyl 5-tetrahydrofolate b each small-phenyl)-amine methyl acid tert-butyl ester (Example M9i) (〇.41 g, 〇·77 mmol). Obtained as a yellow solid (90 mg, 28%). MS (ESI) 412·3 [(M+H)+]; mp 267 ° C. Example 105 bis [3-(5-permethyl-[1, 2,3]二峻小基)-Phenyl ι-g·(Methyl-propyl-gum)·4-ketoindole dihydro-3Η-benzo”bl”l,4l diazepine π生-191- This paper size applies to China's g standard (CNS) A4 specification (210X 297 metric tons)' '&quot; 1296622 A7 ______ B7 V. Description of invention (188) The title compound is based on the general procedure N, via TFA Processed in C% %, prepared from (RS)-[4-cyano-5-(methyl-propyl-amino group&gt;2-(3-mercapto-3-{3-[5-(tetrahydro) -piperidin-2-yloxymethyl)-[ι,2,3]triazole+yl]-phenylpyridylamino>&gt;phenyl]-amine methyl acid - butyl ester (Example Μ 92) (〇··········································· Example 106 Methyl-iso-i-Jun-5-yl)·Phenyl&gt; 8-(Methyl-propyl-amino)-free ketone Some-4 5_ s hydrogen-3H-benzo- </ br> The azaindole-7-carbonitrile title compound was prepared from [4-cyano-2-{3-indole-3-methyl-isoxazole-5 by treatment with tfA in CH2Cl2 according to the procedure -yl)-phenyl]-3.keto-propyl-arylamino}-5-(methyl-propyl-amino group&gt;phenyl&gt; amine methyl acid tert-butyl ester (example M93) (0.36 g, 〇·········································································· 2. "3-(3-Methyl-isoxazol-5-yl)-phenyl H-keto-4,5-dihydro-3H-benzofbl "l,41 diazepine-7- The title compound was prepared according to the general procedure N by treatment with TFA in CH2Cl2 from (4-cyano-5-diethylamino) {3-indole (3-methylisoxazole-5-yl) )-Phenyl]-3-keto-propionylamino 1-phenyl)-aminomethyl acid tert-butyl ester (example M9 4) (0.35 g, 0·66 mmol). Obtained a tan solid (2〇9 mg, 77%). MS (ISP) 414.4 [(Μ+Η)+]: Melting point 191. (:. Example 108 8-(isopropyl-methyl-amino)-243-(3-methyl-isoxazol-5-yl)-phenyl1-4-one--192- This paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Invention description (189) 4,5-Dihydro-3H-stupid and "bl"l,41 diazepine-7 - A time-title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (4-cyano-5-(isopropyl-methyl-amino)-2-{3-[3- (3-Methyl-iso-quot; oxazol-5-yl)-phenyl]-3,yl-propionylamino}-phenyl)-amine methyl acid tert-butyl ester (Example Μ 95) 0·37 g, 0.70 mmol; obtained a yellow solid (219 mg, 76 0 〇) 〇 MS (ISP) 414.4 [(M+H)+]; melting point 197 ° C. 5-hydroxymethyl 41,2,31 triazol-1-yl)-phenyl 1 each (mercaptopropyl-methyl-amino) mercapto-4,5-dihydro-3H-benzopyrene) 1Π,41二i.Hybromo-7-carbonitrile the title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (RS)-[4-cyano-5-(isopropyl-methyl) --amino)_2_(3·keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole small group]- Phenylpropanylamino)-phenyl]-aminomethyl acid tert-butyl ester (Example M96 X 0.45 g, 0.71 mmol). Obsed as a yellow solid (236 mg, 77.) MS (ISP) 430.5 [(M+H)+]; melting point 206 ° C. Example 110 Μisobutyl methyl-amino)-2-[3-(3-methyl-isoxazol-5-yl)- Phenyl H-keto-furo-5-dihydro-3 fluorene-benzofbin, 41 diazepine-7-methan-title compound was prepared according to the general procedure N by using TFA in CH2Cl2. -Cyano-5-(isobutyl-methyl, yl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-ί Base-propionylamino}-phenyl)-amine methyl acid tert-butyl ester (Example Μ97) (0·39 g, 0.71 mmol). Obtained a yellow solid (230 mg, 75-193-ben The paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm)

Binding

Line 1296622 A7 B7 V. INSTRUCTIONS (190) MS (ISP) 428.5 [(M+H)+]; melting point i7〇°C. Example 111 g±3-(5· via phenyl 1 each (isobutyl.methyl-amino M-nicin-4,5-dihydro-3H-stupid and blfi, 4 diazepine) The 箪-7-methyl guanidine standard compound was prepared according to the general procedure N, by treatment with TFA in % (made from (RS)-[4-cyano-5-(isobutyl-methyl-amino group&gt; 2-(3-g-iso-yl-3-{3-[5-(tetrahydro-pyran-2-yloxymethylhh]]triazole+yl]-phenylpropenylamino)·phenyl ]-Aminomethyl-tert-butyl ester (Example M98) (〇46 g, 〇·71 mmol). Obtained as a yellow solid (180 mg, 57.'.) MS (ISP) 444.4 [(Μ +Η)+]; melting point 199 ° C. Example 112 methyl-isoindole-5-yl)-stupyl-4-keto-8-hexahydropyridin-1-yl-4.5-dihydro-3Η -Benzene "bl|~l,41 diazepine-7-methine title compound was prepared according to the general procedure N by treatment with TFA in CH2Cl2 (4-cyano-2-{3- [3-(3-Methyl-isoxazol-5-yl)phenyl]-3-keto-propionylamino}-5-hexahydropyridin-1-yl-phenyl)-aminomethyl Acidic third-butyl ester (Example Μ 99) (0.41 g, 〇·75 mmol) obtained as a yellow solid (226 mg, 70%) MS (ISP) 426.4 [(Μ+Η) + ]; melting point 246 ° C. Example 113 ^ gas-based 7-isobutylamino-4-"3-(3-methyl-isoxazole-5-phenyl 1-1,3-dioxin) - 芡 and fbl "l,41 diazepine-2-one title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (4-carbyl-5-isobutylamino-2 -{3·[3·(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionylamino}-phenyl)-amine methyl acid third-butyl Ester (Example Ml〇〇) -194- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 _____ B7 V. Invention Description (191)~&quot;One&quot; (0.34 g' 0.63 mmol. Obtained as a yellow solid (216 mg, 81%). MS (ESI) 423·3 [(M+H)+]; melting point 249 ° C. Example 114 Building Base-4·[3·( 5-triazole-1-V-phenyl 1-7-isobutylamino-U-dihydro-benzo[b][l,41diazepine-2-one title compound according to the general procedure N, via treatment with TFA in CH2Cl2 'made from (RS)-[4-carbyl-5-isobutylamino-2-(3-keto- each {3-[5-(tetrahydro- shouting喃-2-yloxyindenyl)_[丨,2,3]triazole small group]•Phenylpropanyl-amino group&gt;Phenyl&gt; Amine methyl acid Third-butyl ester (example Μ1〇1) (〇·17 g, 0.27 mmol). Obtained as a yellow solid (41 mg, 35%). MS (ISP) 439.4 [(Μ+Η)+]; m.p. 2M. Example 115 Methyltriazole small group v benzene methyl-propyl-amino group each three rabbit methyl-1,3-dihydro-benzodiazepine-2-one title compound according to the general procedure N By treatment with TFA in CH2Cl2 'from (RS)-[5-(methyl-propyl-amino).2·(3·keto-3-{3-[5-(tetrahydro 4) ··2-yloxymethyl)-[1,2,3]triazole small group]-phenyl}-propenylamino group&gt;4-trifluoromethyl-phenyl]-amine methyl acid The third-butyl ester (Example Μ1〇2) (〇·15 g, 〇·22 mmol) obtained an off-white solid (31 mg, 30 〇〇). MS (ISP) 473·2 [(Μ+Η) +]; melting point 230 ° C. Example 116 m-methyl-iso-[indenyl]-yl)-phenyl 1-7-(indolyl-propyl-amino)-8-trifluorodecyl datum 3-dihydro- Benzo-fbin, 41-diaza:-2-one The title compound is based on the general procedure N, via tfa in CH2Cl2 ______ -195- This paper scale applies to the Sg family standard (CNS) Μ specification (21 〇χ297 公公) -- 1296622 A7 B7 V. Description of Invention (192 ), from [2-{3-[3-(3-indolyl-isoxazol-5-yl)-phenyl]-3 • Ketopropyl-propionylamino}-5-(methyl-propyl-amino)-4-trifluoromethyl-benzene Aminobutyric acid methyl third-butyl ester (conventional Μ103) (0·26 g, 〇·45 mmol). Obtained as a pale yellow solid (127 mg, 61 EtOAc). MS (ISP) 457.4 [(Μ+Η)+]; mp 193. Example 117 1±3-(5-side-formamidine.-[1,2,3]tris-s-l-yl)-phenyl]_7_(isobutyl-methyl-amine from S-fluoromethyl-1 , 3-dihydro-benzo is called "1,4:|dioxan-2-one title compound according to the general procedure N, by treatment with tfa in CH2Cl2 'from (RS)-[5-( Isobutyl-methyl-amino)1(3-keto-3-{3-indole(tetrahydrotetram-2-yloxyindenyl)-[1,2,3]triazole-1- ]]-phenylpyridinylamino)-4-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example Μ1〇4) (0·51 g, 〇·74 mmol) Obtained as an off-white solid ( 169 mg, 470.) MS (ESI) 487.3 [( Μ Η Η)+]; mp. 230 ° C. Example 118 Ζι (isobutyl-methyl-amino)-4-f3- (3-methyl-isoxazol-5-yl)-phenyl 1-8-trifluoro-yl-I,3-dihydro-benzo- (1) diazepine-2-one title compound is based on General procedure N, via treatment with TFA in CH2Cl2 'N-(well butyl-methyl-amino)-2-{3-[3-(3-methyl-iso-sigma. Sit- 5-yl)-phenyl]-3-keto-propionylamino} glacial trifluoromethyl-phenyl)-amine methyl acid ternary-butyr S (example Μ 105) (0. 42 g, 0.71 mTorr Obtained a yellow solid (161 g, 48 〇 / 〇) MS (ISP) 471.2 [(M+H)+]; melting point 195 ° C. Example 119 - 196 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210X297 mm) binding

1296622 A7 ________B7 V. Description of invention (193) &quot; ^^ III. Sitting -1-yl-VI-based 1-7-(isopropyl- 曱一_ _ neck and "blfl, 41 diazepine-2-one'-based compound according to the general procedure N, via TFA in C% % Treatment, prepared from (RS)-[5_(isopropyl-methyl-amino) 1 (3-ketoyl {3-[5-(tetrahydro-pyran-2-yloxymethyl)^ 3] triazole + phenyl phenyl fluorenyl-amino) 4 - trifluoromethyl-phenyl]-amine methyl acid third butyl ester (example m106) (0 50 g, 0·74 亳Obtained as an off-white solid (156 mg, 450.) MS (ESI) 473.3 [( Μ+Η)+]; melting point 234 ° C. Example 120 Methyl-isoxazole-5-yl V 1-8-三^^ base: 1,3·dihydro-benzo-"bl"l,4~|diazepin-2-one title compound is treated according to the general procedure N by TFA in CH2 CL 'Manufactured from (5-(isopropyl-methyl-amino)-2-{3-[3·(3-methylisoxazole i-based), phenyl]-3-keto-propionium Amino-amino-trifluoromethyl-phenyl)amine methyl acid, third, butyl ester (Example Μ 107) (0·37 g, 〇·64 mmol). Obtained a yellow solid (74 g, 250 〇) MS (ISP) 457·4 [(Μ+ΗΠ; melting point 199 ° C. Example 121 gl oxy; (methyl-amine V4-[3-(5-tetrahydropyrroleylmethyl allyl-1-yl)-phenyl]^3-dihydro-stupidyl "1,41 diazepine-2" ketone title compound is based on The method described in Example 45 was carried out by reacting with di-sulfurized sulfite in dichloromethane, followed by tetrahydropyrrole in DMF to treat the corresponding chloride from 8-alkyl (methyl-propyl- Amino) winter [3 hydroxymethyl-[1,2,3]tris-l-yl)-phenylindole, 3-dihydro-benzo[b][l,4]diazepine- 2-ketone (real______-197- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1296622 A7 B7 V. Invention description (194) Example 29) (220 mg, 0·50 Obtained yellow foam (63 gram, 26 ° 〇) ° MS (ISP) 492.3 [(M+H)+]. Example 122 4-"5--nitrogen tetrahydrazide丨-丨1 31 triazole·1-yl)-phenylchloro-7-(mercapto-propyl-amino)-1,3-dihydro-benzo[&quot;bin,4]diazepine The title compound was treated according to the method described in Example 45, by reacting with sulfinium dichloride in dichloromethane, and the corresponding hydrazine was treated with trimethyleneimine in DMF. 'system 8-Alkyl-7-(methyl-propyl-amino)-4-^3-(5^monomethyl-[1,2,3]triazol-1-yl)-phenyl]-1 , 3-dihydro-benzo[b][l,4]diazepines (Example 29) (118 mg, 0·27 mmol). Obtained a pale yellow solid (65 g, 50 〇.). MS (ISP) 478.3 [(Μ+Η)+]; mp 169. (:. Example 123 8-chloro-4-[3-(5-diethylaminomethyl-indole, 2,31 triazole-1·yl V-methyl-l-7-(methyl-propyl-) Amino)-1,3-dihydro-benzo-fbin, 41-diazepine-2-indole with the title compound according to the method described in Example 45, with di-sulphurized sulphur in dichloromethane The reaction is followed by treatment of the corresponding vapor with diethylamine in DMF from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1, 2,3] Trisin-1-yl)-phenyl]-1,3-dihydrobenzo[b][l,4]diazepine-2-one (Example 29) (219 mg, 0.50 Obtained as a pale yellow solid (123 mg, 5 </ s). MS (ESI) 494.3 [(M+H)+]; mp 151: C. Example 124 oxy-4-(3-{5 - [(isopropyl-methyl-amino)-methyltriazole·丨·kibphenyl): Z-(methyl-propyl-amino)-1,3-dihydro-benzofblfM 〗 diazepine-2-one-198- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) binding

Line 1296622 A7 B7 V. INSTRUCTION DESCRIPTION (195) The title compound was subjected to the method described in Example 45, via dichlorination

The sub-mer is reacted in a chloroformin, followed by treatment of the corresponding chloride with N-isopropyl-methylamine in DMF from 8-chloro-7-(methyl-propyl-amino)- 4-[3-(5-Hydroxymethyl-[1,2,3]diazoleyl)-phenyl-H-dihydro-benzo[[丨丨...diazepine·2-ketone] ) (219 Aike, 〇·5〇m). Obtained as a pale yellow solid (129 mg, 520 MSm MS (ISP) 494.3 [(Μ+Η)+]; melting point i48 ° C. 实-例125 羞基_7-( 异包羞:^基-胺基V4_"3-(5-tetrahydropyrrol-1-ylmethyl pep!. small base hydrogen-benzofbin, 41 diazepine-2-one title compound according to the method described in Example 45, via Sulphur dichloride SS is reacted in di-methane, followed by treatment of the corresponding chloride with tetrahydropyrrole in DMF, from 8-gas-based ice [3-(5-hydroxymethyl-[1,2,3] Triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)phosphonium diamine-benzo[b][1,4]diazepine-2·§同(example 96) (219 mg, 〇·5 mM). Obtained as a pale yellow solid (157 mg, 64 〇). MS (ISP) 492·3 [(Μ+ΗΠ; melting point 172. 〇. Example 126 8- Chlorocap _7_(isobutyl-methyl-amino hydrazine "3-(5-tetrahydropyrrole small methyl-flUL)-1,3-dihydro- And blfl, 41 diazepine-2-g with the title compound was reacted according to the method described in Example 45, with thionyl chloride in dichloromethane, followed by tetrahydropyrrole in DMF. Handling the corresponding chloride 8-Chloro-4-[3-(5-hydroxymethyl-indole, 2,3]triazole)-phenyl]-7-(isobutyl-methyl-aminodihydro-benzo [b][l,4]diazepine-2-g is the same (real-199- this paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 1296622 A7 ____B7 V. Invention description ( 196 ) ~ Example 101) (226 mg, 〇 _5 〇亳 Mo). Obtained as a pale yellow solid (163 mg, 640 / 〇) MS (ISP) 506.3 [(M+H)+]; melting point i90° C. Example 127 Oxy-indole dimethylaminomethyl hydrazine, 2,31 triazole small group)-stupyl 1-7-(isopropyl-methyl-amino H,3-dihydro-stupid "b" "l,41 diazepine-2-one title compound was reacted according to the method described in Example 45 by reaction with thionyl chloride in dichloromethane, followed by dimethylamine in DMF. Treatment of the corresponding chloride from 8-oxyl-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl](isopropyl-methyl -amino)-1,3-dihydro-benzo[bHl,4]diazepin-2-one (Example 99) (219 mg, 〇·5 〇 mmol). 143 mg, 61 〇.) MS (ISP) 566·3 [(M+H)+]; mp 225 ° C. Example 1 28 4-[3-(5:Methylaminomethyl-"丨,2,31 triazole small group)_Stupyl 1-7_(isomeric hydrazine-amino)-l,3-dihydro- Benzo[b~|fl,41diazepine-2-one "4 compound was reacted with di-halogenated hydrazine in di-methane, followed by dimethylamine according to the method described in Example 45. Treatment of the corresponding chloride in DMF's from 8-oxyl-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7- Butyl-methyl-amino)-1,3-dihydro-benzo[b][i,4]diazepine 4 ketone (Example 101) (226 mg, 〇.5 〇 millimol). Obtained as a light brown solid (134 mg, 56 〇〇) 〇, MS (ESI) 480.5 [(M+H)+]; Example 129 Nitrogen tetra-π,2,3]5 azole small group)-Phenyl 1-8·Gayl-200- This paper scale is applicable to SS standard (CNS) A4 specification (21GX297 public)&quot;&quot ;&quot;' 1296622 A7 ___ B7__._ V. Description of the invention (197) No-綦-methyl-amino)-1,3-di-j-benzo is called 1,1,diazepine-2-one The title compound was prepared according to the method described in Example 45 by reacting with sulfinium dichloride in dichloromethane, followed by treatment of the corresponding gas with trimethyleneimine in DMF. 3-(5-hydroxymethyl^2,3]triazole)-phenyl]-7-(isopropyl-methyl-aminodihydrobenzo[b][1,4]diazepine 2, ketone (Example 99) (219 mg, 〇·5 〇 mmol). Obtained a pale brown solid (1 〇 2 mg, 430 〇) 〇 MS (ISP) 478.3 [(M+H)+]; Capacitance i77 ° C. Example 130 - Nitrogen tetrakisylmethyl-π, 2,31 triazole small group) -Phenyl 1-8-chloro·7_(isobutyl dimethyl-amino)_1, 3-Dinitro-benzo-f,41-diazepine-2-one titled compound was reacted according to the method described in Example 45, with a sulphurous sulph A The imine is treated with the corresponding gasification in DMF, and is prepared from 8·gas-based 4-p-(5-hydroxymethyl-[1,2,3]triazole small group&gt;.phenyl]_7-(isobutyl) -Methyl-aminodihydro-benzo[b][l,4]diazepine-2.one (Example 101) (220 mg, 〇·49 mmol). Mg, 520 〇) 〇 MS (ISP) 492.3 [(M+H)+]; mp 191 ° C. </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -1,3-dihydro-benzo-"1,41-diazepine-2-one title compound is according to the method described in Example 45, via with sulfurous acid dichloride Ss was reacted in dichloromethane, followed by treatment of the colloidal gasification with methylamine in DMF from 8-chloro-7-(methyl-propyl-amino)-4_[3-(5·hydroxyl)基屮, _____-201 - This paper scale applies 0g home standard (CNS) Α4〗 Α (210X297 public) --- 1296622 A7 "-_____B7 . __ V. Invention description (198) San Jun-1- Base)-phenyl]],3_dihydro-benzo[b][1,4]: azepine 1 ketone (example Μ) (230 EK '〇·52 mmol). Obtained a pale yellow solid (122 mg, 52 〇/〇). MS (ISP) 452.4 [(M+H)+]; dissolved Point 185 ° C. Example 132 1:11-(5-Hydroxymethyl-[1,2,31 triazole small group)-stupyl 1-7-(isobutyl-fluorenyl-amino group) each ^-1,3-two Hydrogen-benzofbin, 41 bisfr齄茧^ lion title compound was prepared according to the general procedure N, by treatment with TFA in CH2C12 'from (RS)-[5-(isobutyl-methyl-amino) 4 -mercapto-2-(3-keto-3-{3-[5-(tetrahydro-4-pyran-2-yloxyindenyl)-[152,3]triazole]-yl]-phenyl} -Propylamino)-phenyl]-aminomethyl acid tert-butyl ester (Example Μ 108) (0.33 g, 0.52 mmol). Obtained as a pale brown solid (188 mg, 790 /.). MS (ISP) 431.4 [(M-Η)·]; mp 198. Example 133 hydroxymethyl 41,2,31 triazol-1-yl)-phenyl-m-methyl-7·tetrahydropyrrole small group · 1,3-dihydro-benzofbl|~l,41 dinitrogen The pyridin-2-one title compound was prepared according to the general procedure N by treatment with TFA in CH.sub.2Cl.sub.2 from &lt;&quot;&gt; 5-(tetrahydro-fluoren-2-yloxymethyl)-[1,2,3]dioxin-1-yl]-mungyl}-propanylamino)·5·tetrachlorophenol Ratio ρ-yl-phenyl]-aminomethyl acid tert-butyl ester (Example Μ 110) (0.41 g, 〇·66 mmol). Obtained as a pale yellow solid (239 mg, 86.). MS (ISP) 417·3 [(Μ+Η)+]; m.p. 202: C. Example 134 7-(Isobutyl-methyl-amino)-8-methyl-4-"3-(3-methyl-iso$α-s--5-yl)-phenyl 1_1,3-di Hydrogen-benzofb] "l,41 diazepine-2-indole-202 - This paper scale is suitable for SS standard (CNS) A4 specification (210 X 297 mm) ~ ' 1296622 . A7 _______ B7 V. INSTRUCTIONS (199)^ &quot;&quot; The title compound is prepared according to the general procedure N by treatment with TFA in CH2Cl2 from (5-(isobutyl-methyl-amino)-4-methyl -2-{3-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-keto-propenylamino]-phenyl&gt; Aminomethyl acid · Butyl ester (example M109) (0.33 g, 〇 · 62 mmol). Obtained as a pale brown solid (136 mg, 53 〇 / 〇) 〇 MS (ISP) 417.3 [(Μ+Η)+]; melting point 187° C. Example 135 tmethyl-4-[3-(3-methyl-isoxazol-5-ylphenyl 1-7-tetrahydropyrrole small dihydro-benzo-bl "l, 41 dinitrogen The hydrazine-2-one title compound was prepared according to the general procedure N from (4-methylmethyl-isoxazol-5-yl)-phenyl]-3-one by treatment with TFA in CH2Cl2 -propenylamino]-5-tetrahydropyrrole small-phenyl)-amine methyl acid tert-butyl ester example

Ml 11) (0.33 g, 0.64 mmol). Obtained as an off-white solid (223 mg, EtOAc). MS (ISP) 401.5 [(M+H)+]; mp. Example 136: _: (5-dimethylaminomethyl-[丨, 2,31 triazole small group]-phenyl-7-(isobutyl)-trifluoromethyl-1,3 - dihydro-stupid and squeezing 1,41 diazepine-2-one the title compound was reacted according to the method described in Example 45, with sulfinium dichloride in di-methane, followed by dimethyl The amine is treated with the corresponding chloride in DMF from 4-[3-(5-hydroxymethyl-[1,2,3]triazole)-phenyl]-7-(isobutyl-methyl- Amino) Winter Trifluoromethyl], 3_Dihydro-benzo[b][l,4]diazepine 1 (Example 117) (300 mg, 〇·62 mmol). Obtained as a light brown solid (11 mg, 350 g). 203 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 B7 V. Description of invention (200) MS (ISP) 514.3 [(M+H)+]; melting point 182. Hey. Example 137: Isobutyl-methyl-amino)butanyl-2-"3-(5-tetrahydropyrrolidinylmethyl@jun-1-yl)-phenyl1-4,5-diindole -3Η-Benzene blfl, 41 diazepine-7-carbonitrile the title compound was reacted with disulfide ruthenium chloride in dichloromethane according to the method described in Example 45, followed by tetrahydropyrrole The corresponding chloride is treated in dmf from 2-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)phenyl](isobutyl-methyl-amino) 4-Mercapto-4,5-dihydro-3H-benzo[b][l,4]diazepine-7-carbonitrile (Example 111) (200 mg, 0.45 mmol). Obtained as a pale yellow solid (14 〇m, 630 〇) 〇 MS (ISP) 497.3 [(M+H)+]; melting point 174 °C. Example 138 21 (_. ruthenyl-methyl-amino group &gt; 4-[3-(5-tetrahydro?-pyridin-1-ylmethyl 41,2,31 triazole-1. cap&gt; benzene The 1-8-trifluoromethyl-1,3-dihydro-stupidium "bin, 41 diazepine-2-one" compound was subjected to the method described in Example 45, via a gasification system Thiopurine is reacted in dichloromethane, followed by treatment of the corresponding vapor with tetrahydropyrrole in DMF from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl) Phenyl]-7·(isobutyl-methyl-amino)-8-trifluoromethyl-i,3-dihydro-benzo[b][l,4]diazepine-2· '(Example 117) (300 mg, 〇·62 mmol). Obtained a light orange foam (8 mg, 24%) MS (ISP) 540.5 [(M+H)+]. Isobutyl-methyl-amino)-8-methyl-443-(5-tetrahydropyrroleylmethyl-1-yl)-phenyl 1-1,3-dihydro-benzodiazepine Chowder_2·ketone-204 - This paper scale is suitable for Sg home standard (CNS) Α4 specification (210 X 297 public) "quot; ' &quot; - Binding

1296622 A7 _____B7 __._ V. Description of the invention (2Q1) ^ A title compound was reacted with disulfide ruthenium in a gas-fired gas according to the method described in Example 45, followed by tetrahydro-p-Bilo Treatment of the corresponding chloride in DMF from 4-indole (5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amine Benzo)-8-methyl-i,3-dihydro-benzo[b][l,4]diazepine-2-one (Example 132) (200 mg, 〇 46 亳 Mo). Obtained as a pale yellow solid (50 mg, 22 σ 〇) 〇 MS (ISP) 486.4 [(M+H)+]; dissolved, 177 °C. Example-Based 140-Methyl-amino-isobutyl-methyl-aminomethyl H1.2.31 Triterpene-1-ylphenyl-4-V-4-one a-4,5-dihydro-3H·benzo "bl" 1,41 diazepine-7-carbonitrile title compound was reacted according to the method described in Example 45 with di-sulphurized sulphur in dichloromethane, followed by N-isobutyl _ Methylamine treats the corresponding gasification in dmf from 2-[3-(5-hydroxymethyl-[1,2,3]triazole small)-phenyl]-8-(isobutyl-methyl -Amino group xg is the same as -4,5-dihydro-3H-benzo[t(4)diazepine-7-carbonitrile (Example 111) (220 mg, 〇·5 〇 millimol). Yellow solid (100 mg, 39%) MS (ESI) 513.4 [(M+H)+]; mp.

Li butyl butyl-methyl-amino)-4-G-{5-f(isopropyl-methyl-amino)-methyl my three. Sodium succinyl phenyl-V8-trifluoromethyl-1,3-dihydro-benzo-"bin, 41-diazepine-2- title compound was obtained according to the method described in Example 45, via dichlorination The sulfite ss is reacted in di-methane, followed by N-isopropyl-methylamine in DMF to treat the corresponding gasification from 4-[3-(5-hydroxymethyl-[H3]triazole-丨·Base> phenyl] _____ · 205 - I paper scale applicable to China g standard (CNS) A4 specification (21〇&gt;&lt;297 public recovery) '~一1296622 A7 _———____B7 V. Description of invention (202 Isobutyl decyl-amino) chlorotrifluoromethyl-U-dihydro-benzo[b][l,4]diazepin-2-one (Example 117) (26 〇 mg, 〇· Obtained as a light brown solid (70 mg, 24%). MS (ESI) 542.3 [(Μ+Η)+]; mp 157 ° C. Example 142 MAdbLH Cyclopentylaminomethyl -Π·2,31 triazole small group V phenyl 1-7-(isopropyl acylate)·1,3-di 1 -benzo-"bl"L41 diazepane 茧-2-xitong" 4 compound system According to the method described in Example 45-, by reacting with thionylene dichloride in dichloromethane, followed by treating the corresponding chloride with cyclopentylamine in DMF 'from 8-chloro-4 -[3-(5-Methyl-[1,2,3]triazol-1-yl)-phenyl]-7-(methyl-amino-amino)-1,3-dihydro -Benzo[b][i,4]diazepineone (Example 96) (220 mg, 〇.5 〇 millimol). Obtained as a pale yellow solid (17 mg, 67.). MS (ISP) 506.3 [(M+H)+]: mp. Example 143 propylmethyl-amino V methyl 1-indole, 2,31 triazole small group 笨 辟 辟 1 base) each methyl],3-dihydro-benzofblH, 41 diazepine-2 - Ketone title compound was reacted according to the method described in Example 45, by reacting with thionous chloride in dioxane, followed by treatment of the corresponding vapor with cyclopropylmethylamine in DMF, from 4_[3 Hydroxymethyl is also a cleavage of oxazolyl)-phenyl]·7·( butyl butyl-methyl-amino)_8-methyl-oxime, 3·dihydro-benzo-[1,4] Azagen-2-one (Example 132) (250 mg, 0.58 mmol,). Obtained as a pale yellow solid (5 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (: Example 144 -206- This paper scale applies to the S® standard (CNS) A4 specification (210X297 public) '' 1296622 A7 _________B7_.__ V. Invention description (&quot; Lu-Chloro II ^-Methyl-amino fluorene-oxime hexahydropyridinylmethyl-^)] succinyl) dihydro-benzofblfl, 41 diazepine-2-one title compound according to Example 45 The method described is carried out by reacting with thionerne dichloride in di-methane, followed by treatment of the corresponding gas with hexahydropyridine in DMF, from 8-gas base [3-(5-hydroxymethyl) ^2,3]triazole+yl)phenyl]-7-(isobutyl-methyl-amino)+3-dichloro-benzodiazepine (Example 101) (220 mg, 〇.49 millimoles). Obtained as a light brown solid (25 mg, 990 〇) 〇 MS (ISP) 520.3 [(M+H)+]. Example 145 8-1. Volume -4-{3-[l:L-isopropylamino-methyl)-, 2,31 triazole small group 1-phenylindole-7-(isopropyl. Methyl-shy)-1,3-dihydro-benzo-fbl "l,41 diazepine-2-one labeled compound according to the method described in Example 45, via sulfuric acid disulfide SI Reaction in monochloromethane, followed by treatment of the corresponding chloride with isopropylamine in dmf, starting from 8-oxyl-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1 -yl)-phenyl]-7-(isopropyl-methyl-amino)], 3-dihydro-benzo[b][l,4]diazepin-2-one (Example 96) (220 mg, 〇 50 mmol). Obtained as a pale yellow solid (16 mg, 67 〇.) MS (ISP) 480·3 [(Μ+Η)+]; melting point 208 ° C. Example 146 8dioxy-7-(iso^4_-methyl-amino)-4-"3-(5-{"(2-methoxy-ethyl)-methyl-amine-yl"-methyl }-[1,2oxazolyl-1-yl)-phenyl ι_ι,3-dihydro-benzo is 丨, 41 diazepine-2-indole the title compound according to the method described in Example 45, By reacting with thionerne dichloride in di-methane, followed by Ν-(2-methoxyethyl)methylamine at -207- this paper scale applies to China Home Standard (CNS) Α4 Specifications (210 X 297 mm) stapling

1296622 A7 ___ B7 V. INSTRUCTIONS (204) — Treatment of the corresponding chloride in DMF from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]Sanwa-1 Base)-winteryl-7-(th-propyl-methyl-amino)-1,3-dihydrobenzo[b][l,4]diazepine-2-S (Example 96) (220 mg, 0.50 mmol). Obtained as a pale yellow solid (120 mg, 47°). MS (ISP) 510·4 [(M+H)+]; mp. Example 147 oxy-4-(3-{5-[(cyclopropylmethyl-amino)-methyltri.]Elecylhydrazinyl-phenylk7_-(isopropyl-methyl-aminopurine, 3-Dihydro-benzodiazepine asparagine The title compound was reacted according to the method described in Example 45, with sulfinium dichloride in di-methane, followed by amine methyl-cyclopropane The corresponding gasification is treated in dmf from 8-chloro-4-[3-(5-hydroxymethyl-[nonclear]triazol-1-yl)-phenyl]-7-(isopropyl- Methyl-amino)-indole, 3-dihydro-benzo-[1,4]diazepine-2-one (Example 96) (220 mg, 〇·5〇 mmol). Solid (15 mg, 61%) MS (ESI) 592.2 [(M+H)+]; mp 151X: </RTI> 148 g _7_(isopropyl-methyl-amino) _4·(3) 5-"(isopropyl-a-volume-amino)-methylhydrazine 1,2,3]trim.-1-yl}-phenyl)-1,3.dihydro-benzopyrene, 4] Dioxime, although the title compound of the ketone was treated according to the method described in Example 45, by reacting with thionyl chloride in the dichloromethane, followed by treatment of the corresponding chloride with hydrazine-isopropylmethylamine. From 8-gas group, 4-[3-(5-methyl-[1,2,3]3 Benzyl-1-yl)·phenyl]-7-(isopropyl-methyl-aminodi-argon-benzo[b][1,4]diazepine-2-one (Example 96) 220 mg, 〇.5 〇 millimolar). Obtained a pale yellow solid 〇 2 〇 mg, 490 〇). -208- Jade paper scale suitable for g s standard (CNS) A4 specification (21GX297 public) — -- 1296622 A7 ____ B7__._ V. INSTRUCTIONS (205) r MS (ISP) 494.3 [(M+H)+]; melting point 180 ° C. Example 149 L-chloro- ice (3-(5-"(isobutyl) -methyl-aminomethyl 31 triazole quinone-phenyl) bis 7-(isopropyl-fluorenyl-amino VL3-dihydro-benzo[bl"l,41 diazepine-2 The ketone title compound was prepared according to the method described in Example 45 by reacting with di-sulphurized sulphur in dichloromethane, followed by treatment of the corresponding chloride with N-isobutylmethylamine in DMF. Buck [3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-indolyl-amino) 4,3-dihydrobenzene And [b][l,4] diazepine-2-one (Example 96) (220 mg, 〇.5 〇 millimol). Obtained a pale yellow solid 〇 9 mg, 75α 〇) 〇MS (ISP 508.4 [(Μ+Η)+]; melting point 182 ° C. Example 150 Μ3·(5-diamylamine Methyl-hydrazine, 2,31 triazole small group)-phenyl 1-7-(isopropyl-methyl-n-di-trifluoromethyl-1,3-dihydro-benzo-bin, 41 The alkaloid-2-one title compound was prepared according to the method described in Example 45 by reacting with thionous sulphide SS in di-methane, followed by dimethylamine in DMF. -[3-(5-hydroxymethyl-[1,2,3]triazole small)·phenyl]isopropyl-methyl-amino)-8-trifluoromethyl-1,3-di Hydrogen-benzo[b][1,4]: azainone (Bell 119) (200 mg, 0.42 mmol). Obtained as an off-white solid (10) mg, 380 〇) 〇 MS (ISP) 500.4 [(M+H)+]; Example 151 7: (Lilyl-methyl-aminotetrahydropyrrole-1:ylmethyl·丨12^2a) Tea._棊]I-trifluoromethyl-1,3-dihydro-benzo -209- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- 1296622 A7 ______ B7 V. Invention description (2〇6]~' - 铋l The system was reacted with dithionium dichloride in dichloromethane according to the method described in Example 45, followed by treatment of the phase iC vapor with tetrahydropyrrole in DMF, from 4-[3_(5- Hydroxymethyl_[ι,2,3]triazoleyl)phenyl](isopropyl-methyl-amino)-8-trifluoromethyl],3-dihydro-benzo[b][ 1,4]diazepine 2-ketone (Bei 119) (200 g, 〇42 mmol). Obtained a pale brown solid (14 mg, 63 〇/〇) 〇MS (ISP) 526.2 [( M+H)+]; melting point i75°c. Real-example 152 K propyl-li __4^^}^(3-{5-"(isopropyl-decyl-amine-v-methyl 1-丨1.2.31 三·小基卜签曱基·1,3-dihydro-benzofbin,41diazepine-2-one title compound was subjected to gasification according to the method described in Example 45 Thionine is reacted in dichloromethane followed by N-isopropylmethylamine in dmf Treatment of the corresponding gasification from winter [3-(5-hydroxymethylindole) triazole small group)-phenyl] 7-(propylidene-methyl-aminotrifluoromethyl-hydrazine , 3_Dihydrobenzo[b-,4]diazepine-2-indole (Example 119) (220 mg, EtOAc 47 mmol) afforded pale yellow solid (110 mg, 45.) MS (ISP) 528.4 [(M+H)+]; melting point i82 ° C. Example 153 cyclopropyl i-amino-amino)-methyl [oxime, 2,3] triazole small group μphenyl) -7-(Iso-yl-methyl-amine fluorofluoromethyl-U-diaza-stupidium "bin, 41 diazepine-2-one'-per compound is according to the method described in Example 45, The reaction is carried out by reacting with di-sulfurized sulfite in dichloromethane, followed by treatment of the corresponding vapor with d-mf with aminomethyl-cyclopropane, from 4-[3-(5-hydroxymethyl-[1, 2,3]triazole small group)-phenyl]-H isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][l,4] Diazo _ -210- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1296622 A7 ______B7 _ ___ V. Invention description (207 ) 萆-2-_ (Cheng 119) (210 mg , 0.44 millimoles). Obtained a light brown solid (Π 0 mg, 47. . ). MS (ISP) 526.2 [(M+H)+];:): Capacity point i52 °C. Example ig4 .8 dinonylcyclopropylamino oxazolidine)-phenylmethyl-feyl)-l,3-dihydro-benzo-buydiazepine-2-one title compound according to Example 45 The method described in the above, by reacting with dichlorosulfuric acid in di-methane, followed by treatment of the corresponding chloride with cyclopropylamine in DMF, from 8-chloro-based winter [3-(5-light armor) -[1,2,3]triazol-1-yl)phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][l,4 Diazetidin (Example 96) (220 mg, 〇·5 〇 mmol). Obtained as a pale yellow solid (40 mg, 17 Μ 0 MS (ISP) 478.4 [(Μ+Η)+]; °C. Example 155 4 bis {3-[5-(isopropylamino-methylindole, 3i triazole small group 1-phenylindole isopropyl-trifluoromethyl hydrazine-stupid) Blfl, 4 l diazepine-2-one title compound was treated according to the procedure described in Example 45, by reacting with sulphur disulfide SS in di-methane, followed by isopropylamine in DMF. Prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazole)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl Base-1,3-dihydrobenzo[b][l,4]diazepine 2-ketone (Example 119) (236 mg, 0.50 mmol) obtained as a pale yellow solid (1 mg, 390 〇) 〇 MS (ISP) 514.4 [(M+H)+]; Example 156 -211 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (208) 8: Monochloro-based-4-{3-[5-( Isobutylamino-indenyl Π, 2,31 triazol-1-yl 1-bumpy-7-fluorenyl-methyl-amine 1,3-1,3-diox-benzofblfl, 41 diazepine-2-one title compound was treated according to the method described in Example 45, by reacting with thionyl chloride in dichloromethane, followed by isobutylamine in DMF. Produced from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole)-phenyl]-7-(isopropyl-methyl-amino)-1, 3-Dihydro-benzo[b][l,4]diazepineone (Example 96) (220 mg, 〇 50 mmol) afforded a pale yellow solid (16 mg, 65 0 / 〇 〇MS (ISP) 494.4 [(Μ+Η)+]; melting point 182 ° C. Example 157 4-13: (5-cyclopropylamine 0 Γ·1,2,31 triazole small group)_phenyl group&gt; 7-(isopropyl-hydrazino)-trifluoromethyl-I,3·2 The hydrogen-stuppy 1,41 diazepine-2-one title compound was reacted in a di-methane with two gasified sulphur, followed by cyclopropylamine in dmf according to the procedure described in Example 45. Medium treatment. Corresponding chloride, prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazole small)-phenyl](isopropyl-methyl-amino) winter three Fluoromethyl-i,3-dihydro-benzo[b][l,4]diazepine-2-one (Example 119) (236 mg, 〇.50 mmol). Obtained as a pale yellow solid (7 〇m, 270 〇) 〇 MS (ISP) 512.4 [(M+H)+]; melting point 178 °C. Example 158 MU. 曱-曱-Amino-mercapto-443-(5-tetrahydropyrrole small group A ^£[^三·!1_±.·棊)_Benzic > 1,3-dihydrogen - 茇 and "1,41 diazepine-2-one title compound was reacted according to the method described in Example 45, with thionium dichloride in dioxane, followed by tetrahydropyrrole in DMF Medium treatment ____-212- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) &quot;&quot;~~

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Line 1296622 A7 ___ B7 V. Description of the invention (209) — ~^ Corresponding chloride, prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazole small group &gt; phenyl]- 7_(Isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][l,4]diazepine-2-one (Example 132) (180 mg , 0.42 mmol, obtained as an off-white solid 〇〇 6 mg, 52 〇 / 〇) 〇 MS (ISP) 486.5 [(M+H)"; melting point 164 ° C. Example 159 ΙιίΆ cyclopropylaminomethyl-fl, 2,41三峻小基)-Phenyl 1-7-(isobutyl-methyl-amino-based cardiomethyldihydro-benzo CblfMl diazepine-2-one title compound according to Example 45 The method is prepared by reacting with thionylene dichloride in dichloromethane, followed by treating the corresponding chloride with d-propyl in cyclopropylamine, from 4-[3-(5-hydroxymethyl-[1 , 2,3]triazole small group)-phenyl]_7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][l,4] Diazepine-2-one (Example 132) (180 mg, 〇·42 mmol) obtained as a pale yellow solid (108 mg, 550 〇) MS (ISP) 472·4 [(M+H)+ ] melting point 114 ° C. Example 160 8-chloro-7-isopropylamino-4-pyrene Η3-Methyl-isoxazol-5-yl)-phenyl 1-1,3-dihydro-benzo-benzo-1,41-diazepine-2-one title compound is based on the general procedure N, TFA was treated in CH2Cl2 from (4·5-isopropylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]- 3-keto-propionylamino}Phenyl): Amino-tert-butyl 3-butyrate (Example M12) (0·16 g, 0·31 mmol). Mg, 93. 〇) MS (ISP) 409.4 [(Μ+Η)+ ]; melting point 225 ° C. Example 161 - 213 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1296622 A7 B7 V. INSTRUCTIONS (21Q ) ^棊-4-[3·(5-Hydroxymethyl-"1,2,31 Sanjun small phenyl 1-7-isopropylamino-1,3- Di-j-benzo (~b~|"l,41-diazepine-2-one title compound was prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (RS)-[4- -5-isopropylamino-2-(3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazole Small base]-phenylpropenylamino)phenyl] Aminomethyl-tert-butyl ester (Example M13) (0.37 g, 0.60 mmol). Obtained as a pale yellow solid (209 mg, 82.). MS (ISP) 425.4 [(M+H)+]; mp. Example 162 8-Chloro-7-(methyl-propyl-amino)-443-(5-hydroxymethyl 41,2,41 triazole small moth] -1,3·dihydro-benzo Fblfl, 41 diazepine-2-one title compound was prepared from (RS)-[4-chloro-5-(methyl-propyl-amino) by treatment with TFA in CH2C12 according to General procedure )-2-(3-keto-3-{3-[5-(tetrahydro-n-butan-2-yloxymethyl)-[1,2,4]tri-1-yl]-benzene Benzyl-p-propylamino)-phenyl]-amine methyl acid tert-butyl ester (Example M14) (1. 47 g, 2.29 mmol) afforded pale yellow solid (1.0 g, 99. MS (ISP) 439.5 [(M+H)+]; m.p. </RTI> </RTI> </RTI> </RTI> <RTI ID=0.0> The title compound of phenyl 1-7-(isobutyl-methyl-l-H,3-dihydro-benzodiazepine-2-one is based on the general procedure ,N, via TFA in CH2Cl2 Medium treatment, prepared from (RS)-[4-carbyl-5·(isobutyl-methyl-amino)-2-(3-ketotetrahydro-l-butan-2-yloxymethyl) -[1,2,4]triazol-1-yl]-phenyl}-propionylaminophenyl]-amine methyl acid tert-butyl ester (example M15) (0.61 g, 0.93 mmol) Ear) -214- This paper size is applicable National Standard (CNS) A4 Specification (210X 297 mm) 1296622 A7 B7 V. Description of Invention (211) Obtained a light brown solid (290 mg, 690.) MS (ISP) 453.5 [(Μ+Η)+] 195 ° C. tiH 164 chloro-7-(propyl-amino) oxime 3-(5-tetrahydro-p-l-bu-methyl-triman-1-yl)-phenyl]^, 3-Dihydro-benzoxazin-2-one title compound was reacted according to the procedure described in Example 45, with thionyl chloride in dichloromethane, followed by tetrahydropyrrole in DMF The corresponding chloride is treated in the form of 8-methyl-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl·[1,2,4]di-1- Phenyl]-phenyl]-i,3-dihydro-benzene-[b][l,4]diazepin-2-one (Example 162) (220 mg, 〇.5 〇 millimol). Light yellow solid (114 mg, 46 σ 〇) 〇 MS (ISP) 492.3 [(Μ+Η)+]; mp 183 ° C. Example 165 8-chloro-7-(isobutyl-methyl-amino) Ice [3-(5-tetrahydrofuran-1-ylmethyl 9^j triazol-1-yl) phenyl 1-1,3-dihydro-benzoindole, 41 diazepine The 2-keto-title compound was subjected to gasification according to the method described in Example 45. Thiopurine is reacted in methylene chloride, followed by treatment of the corresponding chloride in dmf with tetrahydro-p-ha, from 8-chloro-4-[3-(5-hydroxymethyl-[1,2, 4] Triazole small group &gt; phenylene] isobutyl-methyl-amino)-1,3-dihydrobenzo[b][M]diazepine (Example 163) (200 mg, 0.44 Millions of ears). Obtained as a pale yellow solid (99 mg, 44.). MS (ISP) 506.4 [(M+H)+]; Example 166 8-Chloro-4-[3_:(^dif-aminomethyl 41,2,41-triazole xiao, -^JJL^^^-amino-amino)-1,3-dihydro- Stupid and called, 41 diazepine-2-S with -215- binding

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1296622 A7 ___ B7 V. INSTRUCTION DESCRIPTION (212) The title compound was reacted with thionyl chloride in dichloromethane according to the procedure described in Example 45, followed by dimethylamine in DMF. , from [8-methylmethyl-propyl-amino) 4-[3·(5-methyl-[ι,2,4]triazol-1-yl)-phenylindole, 3 - Dihydro-benzo[b][1,4]diazepine-2-one (Example 162) (220 pg '〇.5〇 mmol). A pale yellow solid (93 g, 54 〇 σ 〇) was obtained. MS (ISP) 466·4 [(Μ+Η)+]; melting point 170 °C. -Example 167 a gas propylaminomethyl _π, 2, servatriazole small group) _ 笨 > 7_(methyl propyl)_1, 3: dihydro-stupid and fbin, 41 diazepine The 2-keto-title compound was prepared according to the method described in Example 45 by reacting with di-sulphurized sulfinium in di-methane, followed by treatment of the corresponding chloride with cyclopropylamine in DMF. -7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl_[丨,2,4]triazole small)-phenyl H,3-dihydro-benzene And [b][l,4] diazepine-2-one (actual example 162) (220 gram, 〇·5 〇 millimolar). Obtained as a pale yellow solid (95 mg, 4 〇 0 〇). MS (ISP) 478.4 [(M+H)+]; mp. Example 168 4-[3-(5-Light methyl-oxime, 2,4]triazole small)-phenyl 1-7-(isobutyl-methyl-amino ν8·methyldihydro-stupid It is also called "1,41 diazepine-2-one according to the general procedure N, by treatment with T^A in CH2Cl2, from (RS)-[5-(isobutyl-methyl-amino) Methyl-2-(3-keto-3-{3-[5-(tetrahydro-pyroxan-2-yloxymethyl)-[1,2,4]trident-1-yl] -Phenyl}-propylamino) phenyl]-amino acid tert-butyl ester (Example Ml 16) (0.96 g, 1.51 mmol). Obtained light brown - 216 China National Standard (CNS) A4 Specification (210X 297 mm) 1296622 A7 ______ B7 V. Description of Invention (213) &quot; — Solid (480 mg, 73〇/.) MS (ISP) 433·6 [(Μ+ ΗΠ; melting point 191. (:. Example 169

Zlf. propyl-propyl-amino) + (3-"1,2,4" triazole small-phenyl) winter trifluoromethyl-1.3-dihydro-benzofblf 1,41 diazepine The 2-keto-title compound was prepared from {5-(methyl-propyl-amino group &gt;2.[3. ke to ##]triazole according to the general procedure N by treatment with TFA in CH2Cl2. ]_yl-phenyl)-propyl-arylamino]-4-trifluoromethyl 'phenyl-p-methylamino acid third-butyl ester (example Μ117) (0·31 g, 〇·55 mmol) ). Obtained as a pale yellow solid (192 mg, 78 / /). MS (ISP) 443.4 [(Μ+Η)+]; mp 185 °. Example 170 ?: (-Methyl-propyl-amino)-4-(3-"U,31 triazol-1-yl-phenyl)-t-trifluoromethyldihydro-benzofbl "l,41 Diazepine-2-indole the title compound is prepared according to the general procedure N, by treatment with TFA in CH2Cl2 from (5-(methyl-propyl-amino). [1,2,3]triazole]-yl-phenyl)-propylaminoamino]-4-trifluoromethyl-phenyl-p-methylamino acid, third butyl ester (example M18) (0.33 Grams, 0.59 millimoles). Obtained a pale yellow solid 〇 15 mg, 44 0 〇). MS (ISP) 443.4 [(M+H)+]; mp. Example 171 Ζι [熹 butyl-methyl-amino)-4-(3^bizozol-1-yl-phenyl)-8-trifluoromethyl-U-tri--benzo[1,41 The diazepine-2-S is the same as the title compound according to the general procedure N, via TFA in CH2 Cl2 -217 - this paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 public) ' -- 1296622 A7 ____B7 V. INSTRUCTIONS (214) 'Manufactured from {5-(X-butyl-methyl-amino)&gt;2-[3-g-iso-yl-3-(3-p-biten-1-yl- Phenyl)-propionylamino H-trifluoromethyl-phenyl-p-methyl acid, third, butyl ester (example Mli9) (〇·49 g '0.85 耄mol). Obtained pale yellow/solid ( 324 mg, 83 〇/〇) MS (ISP) 454.4 [(Μ-Η)-]; melting point 182 ° C. Example 172 ϋ8··(isopropyl-methyl-amino)·4·keto Fluoromethyl-4,5-dihydro-3H-oxime [b~||~l,41 diazepine-2-yl p-precipitate-2-carbonitrile title compound according to the general procedure N, via TFA is treated in CH2Cl2 from [2-[3-(2-cyano-pyridin-4-yl)-3-keto-propenylamino]-5-(isopropyl-methyl-amine M-trifluoromethyl-phenyl]-amine methyl acid tert-butyl ester (example M120) (0.67 g, 1.29 Obtained as a pale-yellow solid (21 mg, 41 0 / s). MS (ISP) 400.3 [(Μ-Η)·]; melting point i89 ° C. Example 173 8-Chloro-7- (Iso Butyl-methyl-amino)-4-(3-indole, 2,41 triazole small-phenyl)-U-dihydro-benzo-bl "l,41 diazepine-2-one The title compound was prepared according to the general procedure N from EtOAc (m.p. , 4] triazole small-phenyl)-propionylamino]-phenyl}-amine methyl acid tert-butyl ester (Example Μ121) (0·76 g, 1.41 mmol). Orange solid (53 〇 mg, 89 〇 ), MS (ISP) 423.4 [(M10H)+]; mp 213T: </RTI> 174 7-(isobutyl-methyl-amino)-4-( 3-『1,2,41Triazol-1-yl-phenyl)-8-trifluoromethyl- •218- The paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1296622 A7

Lg-dihydro-benzo"bin,41diazepine-2-one was prepared according to the general procedure N by treatment with TFA in CH2% from {5•(isobutyl-mercapto-amino)- 2-[3-keto-HH1,2,4]triazole-based-phenyl)-propionylamino-H-trifluoromethyl-phenyl-p-methylamino acid tert-butyl ester 22% by weight, 〇·87 mmol. Obtained as a pale brown solid (35 mg, 88%) MS (ISP) 457·5 [(m+H)+]; mp 198 ° C. Example 175 g基-7-(iso)[^1^_-amino-based ice (3-, 2, 31, Sanjun-K-based, stupid, M.3-di-anthracene and [bl]l,41 diazepine The 2-keto-title compound is prepared according to the general procedure N, by treatment with TFA in C12 from [4-carbyl (isobutyl-methyl-amino)·2_[3. [1,2,3]III. Sodium phenyl-phenyl)-propionylamino] phenyl phenylamino acid tert-butyl ester (example Μ123) (0.17 g, 〇·31 mmol) Obtained as a pale-yellow solid (1 mg, 750). MS (ESI) 423.5 [(Μ+Η)+]; mp 85 ° C. Example 176 K butyl-methyl 4-amino) 4-(341,2,31 triazole-p-phenyl)-8-trifluoromethyl-title compound according to the general procedure N, Treated by TFA in CH2Cl2 from {5-(isobutyl-methyl-amino)·2-[3-keto-3-(3-[l,2,3]triazole -Phenyl)-propionylamino]-4-trifluoromethyl/phenyl}-amine methyl acid tert-butyl ester (Example M124) (0.44 g, 〇·77 mmol). Brown solid (170 mg, 490 〇) MS (ISP) 457.5 [(M+H)+ ]; melting point 202 ° C. -219- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT)

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Line 1296622 A7 B7 V. INSTRUCTIONS (216) EXAMPLE 177 Alkylaminotrifluoromethyl_u_dihydrobenzoylfbl "l,41diazepine^2^-* ' 4 compounds according to the general procedure N Prepared from {2-[3-(3-imidazolyl-phenyl)-butanyl-propionylamino]-5-isobutylamino-4-difluoro via TFA in CH2Cl2 Methyl phenyl-p-aminomethyl acid tert-butyl ester (Example Mu) (0.43 g '0.77 亳 Moel). Obtained as a pale yellow solid (26 </ RTI> mg, %). MS (ISP) 442.4 [( M+H)+ ];,]: Capacity 221 ° C. Example 178 gllk·yl 4-pyrimidin-7-isobutylamine Some-i,3-dihydro-benzo is called “1,41 dinitrogen The hydrazin-2-one title compound was prepared according to the general procedure N, from <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; Propionylamino]-5-isobutylamino-phenylumamine methyl acid tert-butyl ester (example Μ126χ〇·33 g, 0.63 mmol). Obtained as a pale yellow solid (24 mg, 94 〇 /.). MS (ISP) 408·4 [(Μ+Η)+]; melting point 212Ό. Example 179 8: qitai isobutandiamine)-4-(3-[L2,31 triazole small group-stupid)-1,3-dihydro-benzo is called "1,41 diazepine" -2-S and the title compound are prepared according to the general procedure N, by treatment with TFA in CH.sub.2Cl.sub.2 from [4-carbo-5-(isobutyl-amine, yl)-2-indolyl-3- (3-[l,2,3]triazole small-phenyl)-propionylamino]-phenyl-p-methylamino acid tert-butyl ester (Example M127) (0.22 g, 0.42 m Moer). Obtained a pale yellow solid (9 mg, 53 〇.) MS (ISP) 407.3 [(Μ-Η)·]; melting point 249 ° C. -220- This paper scale applies to Chinese national standards (CNS A4 size (210X297 mm) 1296622 A7 B7 V. Description of invention (217) Example 180

Zi isobutyl-amino)-4-(3-"1,2,31 triazole small-phenyl)-8-trifluoromethyl-1,3-dixindo is called |~1,41 Diazepine-2. The title compound was prepared according to the general procedure N from <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; [1,2,3]triazole-based-phenyl)-propionylamino]-4-trifluoromethyl-phenyl-p-methylamino acid tert-butyl ester (Example Μ 128) (0·34克, 〇······················································ -(isobutyl-amino)-4-(3-indole, 2,41 triazol-1-yl-phenyl)-1,3-dihydro-mosa-"bl"l,41 diazepine The 2-keto-title compound was prepared from [4-carbyl-5-(isobutyl-amino)-2-[3-keto-3- by treatment with TFA in CH.sub.2Cl.sub.2. (3-[l,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl L-amine methyl acid tert-butyl ester (example M129) (0.39 g, 0.74 m Obtained as a pale orange solid (270 mg, 89 EtOAc). MS (ESI) 407.3 [(MH)-]; mp 222 ° C. Example 182 7-(isobutyl-amino)-4- (341,2 , 41 triazole azo-phenyl)-8-trifluoromethyl-13-diqi-benzofbin, 41 diazepine-2-one titled compound according to the general procedure N, via TFA in CH2Cl2 Medium treatment, prepared from {5-(isobutyl-amino)-2-indolyl-3-(3-[l,2,4]triazol-1-yl-phenyl)-propenylamine Triethyl--4-trifluoromethyl-phenyl}-amine methyl acid tert-butyl ester (Example M130) (0.43 g, 0.77 mmol) afforded pale brown solid (270 mg, 61 -221 - Paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (218 MS (ISP) 441.3 [(Μ·Η)Ί; melting point 191eC. Example 183 8-gas base-7 -(ethyl-methyl-amino)-4-f3-(4-methyl-disc-2-yl)-unyl-1,3·dihydro-benzo-blfl,41 dinitrogen The heteroquinone-2-one title compound is prepared according to the general procedure from [2-amino-bromochloro-5-(ethyl-methyl-amino)phenyl]-amine methyl acid tert-butyl ester. (0.15 g) (Example J7) with 3-indolyl-3-[3-[4-(tetrahydro-t-ammon-2-yloxymethyl)-indole-Shen-2-yl]-benzene Base]-propionic acid tert-butyl ester (0.23 g) (Example Κ 27). The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure. Obtained as a yellow solid (0.14 g). MS (ISN) 439.2 [(M-Fir); mp 136-137 ° C 〇 Example 184 gas-based -4- </ "> 3- (4-dihydromethyl- pyrazol-2-yl)-phenyl 1-7 -(Methyl-propyl-amine a V 1,3-dihydro-stupidated "1,41 diazepine-2-one title compound is prepared according to the general procedure from [2-amino-based ice gas 3--5-(methyl-propyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (0.16 g) (example J8) and 3-keto group [3-[4-(four Hydrogen--pyran-2-yloxyindenyl)-thiazolyl-yl]-phenyl]-propionic acid tert-butyl ester (〇·23 g) (example K27). According to the general procedure N, via TFA Treatment in 03⁄4%, the material obtained was deprotected and cyclized to give a yellow solid (0.10 g), MS (ISN) 453.2 [(MH)-]; melting point 211-213 〇C 〇 Example 185 g: oxy -4-[3-(4-Dihydromethyla-s-indol-2-yl)-phenylindole 7-(isopropyl-methyl-amine-222- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1296622 A7 B7 V. Description of invention (219) }J,3-dihydro-benzofbiri, 4 diazepine-2-one compound is prepared according to the general procedure. From [2-amino-4-yl-5-(methyl-methyl-amino) -Phenyl]-aminomethyl acid tert-butyl ester (0.17 g) (Example J26) with 3-keto-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl) - thiazol-2-yl]-phenyl l-propionic acid tert-butyl ester (Example Κ 27) (〇 23 g). According to the general procedure N, the obtained material was obtained by treatment with TFA in CH 2 Cl 2 Removal of protection and cyclization afforded a pale brown solid (0.05 g). MS (ESI) 455.2 [(M+H)+]; mp 193-195 ° C. Example 186 8 · chloro---- 4-hydroxyl Pyrazol-2-ylphenyl 1-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo-bin, 41-diazepine-2-one title compound is based on general Procedure, prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-amine methyl acid tert-butyl ester (0.23 g) (example J27) And 3-keto-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester ( 〇·32 g) (Example K27). The obtained material was deprotected and cyclized by treatment with TFA in CH2C12 according to General procedure N. Obtained a yellow solid (0.06 g). MS (ISP) 469.1 [(M +H)+]; melting point 135-136 ° C. Example 187 8-chloro-7-(ethyl -Methyl-amino)-4-|~3-(4-A-methyl-azazol-2-yl)-phenyl 1-1,3-dihydro-benzo is called "1,41 diaza The indole-2-one title compound was prepared according to the general procedure from [2-amino-4-carbyl-5-(ethyl-methyl-amino)-phenyl]-amine methyl acid third- Butyl ester (0.15 g) (Example J7) and 3·keto-3-[3-[4-(tetrahydro-tham-2-yloxymethyl)-oxazol-2-yl]-phenyl ]-propionic acid-223- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1296622 A7 ____B7 V. INSTRUCTIONS (220) Second-butyl ester (0.22 g) (Example ΚΙ 1). The obtained material is removed for protection and cyclization according to the general procedure n by treating in t2 in CH2 C12. Obtained as a yellow solid (0.10 g). MS (ISN) 423.1 [(MH; T]; m.p. 165-166 ° C. Example 188 g of di-carbyl s[[(( _ hydroxymethyl)] Methyl-propyl-aminodihydro-benzofbl "l,41 diazepine-2-one title compound is prepared according to the general procedure, from [2-amino-4.chloro-5 -(Methyl-propyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (〇16 g X Example J8) with &gt; keto-3-[3-[4-(tetrahydrogen) - 喊 -2--2-yloxymethyl)-carbazole-2-yl]-phenyl]-propionic acid second-butyl ester (0.22 g) (Example ΚΙ 1). According to the general procedure n, via TFA Treated in CH2%, the obtained material was removed for protection and cyclization. A yellow solid (0.10 g) was obtained. MS (ISP) 437.2 [(M-Η)·]; melting point 166-167 ° C. Example 189 H-based "3-(4-Hydroxymethyl)-oxazol-2-yl)-phenyl-7-f-propyl-methyl-amino)-1,3-dihydro-benzofblfl, 41 The azaindole-2-one title compound is prepared according to the general procedure from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-amine methyl acid. Third-butyl ester (〇17 g) (Example J26) with 3-keto-3-[3-[4-(tetrahydro-peak-2-yloxymethyl)_ Triazol-]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11J). The obtained material was removed for protection and cyclization by treatment with TFA in CH.sub.2 Cl. Obtained a yellow solid (0. 05 g) MS (ISP) 439·3 [(Μ+Η)+]; melting point 143-145 ° C. • 224- This paper scale is suitable for S @家标准(CNS) A4 specification (21G X 297 public) " 1296622 A7 B7 V. Description of the invention (221 ) Example 190 8-Chloro-4-(3-(4-methyl-norsen-2-yl)-benzene 1]_7· (Isobutyl-methyl-amino-based v 1,3-dihydro- accompaniment "blfl.41 diazepine-2-one title compound is prepared according to the general procedure, from [2_amino chlorophenyl] -5-(Isobutyl-methyl-amino)-phenyl]-aminomethyl acid tert-butyl ester (0.23 g) (Example J27) with 3-keto-3-[3-[4- (Tetrahydro-bromo-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.11 g) (example K11). According to the general procedure The obtained material was deprotected and cyclized by treatment with TFA in CH.sub.2Cl.sub.2. Example 191 8-Chloro-7-dimethylamino-4-"3-(4-methylaminomethyl-P-n-n-yl-2-yl)-phenyldihydro-benzo-"bl"l, 41 diazepine-2-one a) 8-alkyl_4-f3-(4-chloromethyl-.sep-p-yl-2-yl)-phenyl&quot;[-7-dimethylmoonan _1,3-dihydro-benzofbl "l,41 diazepine-2-one will be 8-chloro-7-dimethylamino-4-[3-(4- 甲基 methyl- far Σ-yl-2-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine-2-one (0.38 g) (Example 19) and dichloride A mixture of sulfonium (0.1 ml) in CH2Cl2, EtOAc (m.) Brown solid, MS (ISP) 445.1 [(M+H)+]., b) 8-Alkyl-7-dimethylglycolyl-4·"3-(4-Methylphenanthylmethyl-p p sits on _2_yl)-phenyldihydro-benzo-"blfl,41-diazepine-2-one to 8-oxyl-4-[3-(4-chloromethyl-, prazole- 2-Base&gt;Phenyl]1 dimethylamino-u--225- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1129662 A7 B7 V. Invention description (222) II Hydrogen-benzene a mixture of [b][l,4]diazepine-2-one (89 mg) and KI (3 mg) in EtOAc (EtOAc)EtOAc. Η2 Ο (25 ml) was added, and the pH 値 of the mixture was set to 11 by the addition of 2N NaOH. The precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as a solvent. Aqueous 20% aq. MeOH (10 mL) EtOAc (EtOAc m.j. Example 192 8-Chloro-7-dimethylamino-4-"3-(4-homofolin-4-ylmethyl-oxazol-2-yl)-phenyl 1-1,3-di Hydrogen-benzo-old "1,41-diazepine-2-one will be 8-chloro-4-[3-(4-chloromethyl-.s.sodium-2-yl)-phenyl]- 7-Dimethylamino-1,3·dihydro-benzo[b][l,4]diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) a mixture of EtOH (0.5 mL) was stirred at 60 ° C for 3 hours. H20 (25 mL) was added to the cooled solution and the precipitate was collected by filtration. Purification by chromatography on silica gel using AcOEt / acetone (1: 1) as eluent. The product was combined with 20. 〇 Aqueous MeOH (20 mL) was stirred together. The title compound (55 mg) was obtained as a yellow powder. MS (ISP) 496.2 [(M+H)+]; mp 138: 143. Example 193 8-Chloro-7-dimethylamine-based "3-(2-hydroxymethyl-thiazol-4-yl)-phenyl H,3-dihydro-benzo-benzo-1,41-diaza Indole-2-one-226 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Description of invention (223) a) 4-(3-Bromoethenyl) Phenyl)-8-carbyl-7-dimethylamino-1,3-dihydro-benzo"blfl,41 diazepine-2-one 3-keto-3-[3-(2 -Bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (2.34 g) (example K28) and (2-aminobutyryl-5-dimethyl A solution of the amino-phenyl)-amine methyl acid tert-butyl ester (Example J2) (1.57 g) in toluene (16 mL), heated to 100 ° C for 5 hours. The crude product was purified by chromatography on silica gel using CH2Cl2/AcOEt (1: 20) as the solvent. The purified material (2.4 g) in CH2 C12/TFA (1:1,30 ml) Stir at 20 ° C for 15 minutes, then evaporate. Dissolve the residual oil in AcOEt, and wash the solution in HCl and brine, dehydrate dried and evaporated. /Et2 0 crystallizes to give 4-(3-bromoethenyl-phenyl) each gas group-7-dimethylamino-1,3-dihydro-benzo[b][l,4] Azagen-2-one, a pale brown solid. b) m -7-dimethylamino winter|~3-(2-light methyl-p----------- Dihydro-benzopyrene, 41 diazepine-2 ketone 4-(3-bromoethenyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydrogen -Benzo[b][l,4]diazepin-2-one (0.22 g) with 2-(tris-butylcarbonyloxy)oxyethinamide (0.11 g) in Et〇H ( The mixture was heated at 8 ° C for 5 hours. This solution was diluted with AcOEt, washed with saturated NaHC03 solution and brine, dried and evaporated. The residue was taken from Me? The mixture was stirred for 20 min at 2 ° C with a mixture of 15N EtOAc (EtOAc) (EtOAc). ), as a yellow powder. MS (ISP) 427.3 [(M+H)+]; melting point 176-178 ° C. -227· This paper scale is suitable for S @家标准(CNS) A4 specification (210 X 297 public) Love) ' 1296622 A7 B7 V. Description of invention (224 Example 194 4·[3-(2-Aminomethyl plug). -4-yl)-phenyl 1-8-carbyl-7-dimethylamino-1,3-dii-benzo-"bl"l,41-diazepine-2-one

4-(3-Bromoethenyl-phenyl)-8-ylyl-7-dimethylamino-i,3-dihydro-benzo[b][l,4]azaindole- A mixture of 2-S and (0.73 g) (Example 193a) and sulphur (13 g) in hexanes HF (10 mL) was heated to 60 ° C for 15 minutes. The mixture was diluted with AcOEt and washed with a saturated NaHC solution and brine. The organic layer was dried <RTI ID=0.0></RTI> to EtOAc. MS (ISN) 410.2 [(M-H)·]; mp 247-248. Example 195 8-Alkyl-7-monomethylamino-4-f3-(2-ethylamino-?-plug-p--4-yl)-stupyl/μ! 3-diox-stupid and "bl" l,41 diazepine-2-one will be 4-(3'bromoethyl-phenyl)-8-chlorodimethylamino],3-dihydro-benzo[b][l, 4] Mixture of diazepine-2-one (130 mg X Example 193a) with N_ethyl-thiourea (31 g) in THF (3 mL) was heated at 6 (rc for 15 min. The mixture was diluted with AcOEt and washed with aq. sat. NaHC.sub.3 and brine. The organic layer was dried and evaporated and evaporated, and the residue was purified on silica gel eluting with AcOEt/hexane (1: 丨) as solvent. The title compound (24 mg) was obtained as a yellow solid. MS (ESI) 440·3 [(M+H)+]; mp 12} 123 ° C. Example 196 N -{4-[3-(7-Chloro-8-dimethylamino ketone-4.5-dihetero-2-yl)-phenyl 1-P-Setr-S-yl---- 228- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1296622 A7 ____B7 V. Invention description (225 ) &quot; ^ 4-(3-Bromoethenyl-phenyl)_8- Chlorine; dimethylamino], 3•two a mixture of benzo[b][l,4]diazepin-2-one (130 mg) (Example 193a) and N-methylmercapto-thiourea (35 mg) in THF (3 mL) The mixture was heated at 6 °C for 1 hour. The mixture was diluted with AcOEt and washed with saturated NaHC03 solution and brine. The organic layer was dried and evaporated, and the residue was purified by chromatography. AcOEt/Me〇H (20:1) was used as the dissolving agent. The purified product was crystallized from acetone to give the title compound (22 mg) as a yellow solid. MS (ISP) 454.2 [(M+H)+] ;,]: Capacity 221 ° C · Decomposition example 197 ^1_ gas-based 7-dimethylamino-4-{3-『2-(pyridin-4-ylaminopyrazole) 1-phenyl 1,3-Dihydro-benzo-fblH, 41-diazepine-2-one 4-(3-bromoethenyl-phenyl)-8-chloro-7-dimethylamino-i, 3-Dihydro-benzo[b][l,4]diazepine-2-S (130 mg) (Example 193a) and 1-(4-ρ ratio)-2-thiourea (46) The mixture was stirred in THF (3 mL) and heated at 60 ° C. for 45 min. The mixture was diluted with AcOEt and washed with saturated NaHC03 and brine. Drying and evaporation, EtOAc m. MS (ISP) 489. 2 [(M+H)+]; mp. 231-234. Example 198 8-Chloro-4-"3-(2-methyl"oxazol-4-yl)-phenylmethyl-1-propyl-amino H,3-diindole-benzo[Ml,41 Azaindole-2-one, standard 4 compound is prepared according to the general procedure from [2-amino-4-yl-5-(indolyl-propyl-amino)phenyl]-aminomethyl Acidic third-butyl ester (〇16g) (example J8) and 3-indolyl-3-[3·(2-methyl-(yt-4-yl)-phenyl]-propionic acid third- Butyl ester (0.17 g) (Real-229- This paper scale applies to SS standard (CNS) Α4 specification (21G X 297 public) 1 ^ 1296622 A7 B7 V. Invention description (226) Example K29). According to the general procedure n, the obtained substance and mass are removed and protected and cyclized by treatment with TFA in CH2Cl2. Obtained as a yellow solid (0.07 g). MS (ISP) 423.2 [(M+H)+]; mp 163-164. Example 199 Hepta[3-(4-hydroxymethyl-thiazolyl)-phenyl 1-8-methyl-7-(methyl-propyl-amine hydrazin-7-hydrogen-benzo[1,41 The title compound of diazepousonone is prepared according to the general procedure from [2-amino-4-methyl-5-(indolyl-propyl-amino)-phenyl]-amine methyl acid. -Butyl ester (〇·21g) (Example J24) and 3-keto-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]- Phenyl]-propionic acid tert-butyl ester (Example Κ27) (0·31 g). The obtained material was subjected to deprotection and cyclization by treatment with TFA in CH2C12 according to the general procedure. 0·09 g) MS (ISP) 435.3 [(Μ+Η)+]; melting point 222-224 ° C. Example 200 4- "3-(4-hydroxymethyl-oxazol-2-yl)- stupid Base 1 mercapto-7-(methyl-propyl-amino)-1 succinyl-benzofbin, 41 diazepine-2-one title compound is prepared according to the general procedure [ from [2- Amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-amine methyl acid tert-butyl ester (0.21 g) (example J24) and homo--3-[3 -[4·(tetrachloro-pyran-2-yloxymethyl)-...-2-yl]-epi]-propionic acid tert-butyl ester ( Example K11) (0.31 g). EtOAc m. H)+ ]; Melting point 200-202°C. Example 201 -230- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) Binding

1296622 A7 B7 ____ V. INSTRUCTIONS (227) 7-Dimethylamine-based "3-(4-hydroxymethyl-carbazole-2-) VI-1-8-trifluoroindole dihydro-benzofblfl, 41 diazepine-2-one the title compound was prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid. -butyl ester (〇·ΐ6g) (example J6) and 3-keto-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]- Phenyl]-propionic acid tert-butyl ester (Example Κ27) (0.23 g). The obtained material was deprotected and cyclized by treatment with TFA in CH2% according to the general procedure. (0.12 g) - MS (ISP) 461.2 [(M+H)+]; mp 198-199 ° C. Example 202 7-dimethylamino-4-"3-(4-hydroxymethyl-carbazole) 2-ylphenyl 1-8-trifluoromethyl-1,3-dihydro-benzo-"blH,41 diazepine-2-one title compound is prepared according to the general procedure from (2-amine 3--5-dimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester (〇16 g) (example j6) and 3·keto-3-[3- [4-(tetrahydro-bran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid third- Ester (0.22 g) (Example ΚΙ 1). The obtained material was deprotected and cyclized by treatment with TFA in 03⁄4 〇 2 according to General procedure N. Obtained a yellow solid (0.11 g). 445.0 [(Μ+Η)+]; melting point 197] 98 ° C. Example 203 Soil 11: (4-light oxime oxazol-2-yl)-phenyl 1-7-(methyl-propyl- Amino)-8-trifluoromethyl iLj-dihydro-benzo-blfMl diazepine-2-one title compound is prepared according to the general procedure M from [2-amino i (methyl-propyl-) Amino)-4-difluoromethyl-phenyl]-amine methyl acid third-butyl ester (〇17g) (example J35) ____-231 - This paper scales the appropriate SS standard (CNS) A4 specifications (21GX297 public) - 1296622 A7 B7 V. Description of the invention (228) with 3-keto-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazole-2 -Phenyl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g). The obtained material was deprotected and cyclized by treatment with TFA in CH2C12 according to General procedure N. Solid (0.06 g) MS (ISP) 489.2 [(M+H)+]; mp 177 </RTI> </RTI> <RTIgt; </RTI> CTC. Example 204 2: dimethylamino-443-(5-hydroxymethyl-indole, 3, 41 -oxadiazole -2-yl)-phenyl 1-8-tricarbyl-I,3·dihydro-benzo[~bin,41diazepine-2-one title compound is prepared according to the general procedure, (2- Amino-5-dimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester (〇·ΐ6 g) (example J6) and 3-keto-3- 3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]pyrazol-2-yl]-phenylpropionic acid tert-butyl ester (0.23 g) (Example Κ 30). According to the general procedure, the obtained material is removed and protected and cyclized by treatment with TFA in Ct^Cl2. Obtained as an off-white solid (0.06 g). MS (ISP) 462.1 [(M+H)+]; mp 242-246. Example 205 厶dimethylamino-4]3-"5-(2-hydroxy-ethyl)-"1,3,41 oxadiazol-2-yl 1-phenyl^8-trioxymethyl-1 , 3-dihydro-mosa-"bl"l,41-diazepine-2-one title compound is prepared according to the general procedure from 2-amino-5-dimethylamino-4-trifluoromethyl Benzyl-phenyl)-aminomethyl acid tert-butyl ester (〇·ΐ6g) (example J6) and Hongzhi Tongji·3-(3-{5-[2-(tetrahydro-pyran-2-) -yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl]-phenyl)-propionic acid tert-butyl ester (0.22 g) (Example Κ 31). The procedure is to remove the protection and cyclization of the obtained material by treatment with TFA in ¢:3⁄43⁄4. Obtain an off-white solid (〇.〇6g). _ - 232 - This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm)

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1296622 V. INSTRUCTIONS (229) MS (ISN) 474·2 [(M-H)·]; melting point 234-237 °C. Example 206

Zi II...Methyl hydroxymethyl-[1,3,4]oxadiazole trifluoromethyl-1,3-dihydro-benzofblH,41 diazet-2-one The title compound was prepared according to the general procedure from (2-aminosamine dimethylamine 4-trimethylmethyl-phenyl)-amine carbamic acid tert-butyl ester (1.44 g) (Example J6) And 3 = synonym-3-{3-〇(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]σ number II. Sit-2-kid]-benz! Tert-butyl propionate (2.17 g) (Example Κ 32). According to the general procedure ν, the obtained material was deprotected and cyclized by treatment with CH.sub.2 (.sub.2) to afford an off-white solid (0.88 g). MS (ISP) 463.2 [(Μ+ΝΗ4)+]. Example 207 1--dimethylamino-4-{3-"5·(2-hydroxy-ethyl Hl,3,41 oxadiazol-2-yl 1-bumpy n-dimethyl-1,3-di The hydrogen-benzo-"blfl,41-diazepine-2-one title compound was prepared according to the general procedure from (2-amino-5-diguanamine- 4·trifluoro-methyl-phenyl). -Aminomethyl acid third butyl ester (〇16 g) (example j6) and 3•keto-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)· Ethyl]-[1,3,4]oxadiazol-2-ylphenyl)-propionic acid tert-butyl ester (0,23 g) (example K33). According to the general procedure N, via TFA Treatment with CH2Cl2 gave deprotection and cyclization of the obtained material to give an off-white solid (0.88 g). MS (ISP) 460.2 [(M+H)+]; melting point 237JC Decomposition Example 208 dimethylamino-4 -Π-呤 斗 基 -phenyl) each trifluoromethyl-1,3-dihydro-benzopyrene/Π二氤杂茗-2-酉同___ -233-___ __ This paper size applies to China National Standard (CNS) A4 Regulation (210X 297 mm) ' ' 1296622 A7 B7 V. INSTRUCTIONS (23〇) &quot; ~^ The title compound is prepared according to the general procedure from 2-amino-5-dimethylamino-4-difluoro -Methyl-phenyl)-aminomethyl acid tert-butyl ester (96 mg) (Example J6) and &gt; (3-oxazolidine-phenyl) keto-propionic acid tert-butyl ester (1 〇 3 mg) (Example K34). The obtained material was deprotected and cyclized by treatment with TFA in CH2C12 according to the procedure </ RTI> </ RTI> A yellow solid (5 mM) was obtained. MS (ISP) 415.2 [ (M+H)+]; m.p. 218-219° C. Example 209 g. Grid-connected "1,41 diazepine-2-one title compound was prepared according to the general procedure from 2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl) Aminomethyl acid, third butyl ester (% mg) (example J6) and 3-keto-3-(3-pyrazol-4-yl-phenyl)-propionic acid, third-butyl ester (1〇9 mg) (Example K35). The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the procedure of procedure N.克) MS (ISP) 431.2 [(M+H)+]; melting point 200 ° C decomposition example 210 Ζ 士 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲-Trifluoromethyl-1,3-dioxin-benzopyrene, 41 diazepine-2-one The title compound was prepared according to the general procedure from (2-amino-5-dimethylamino-4 -Trifluoro-methyl-phenyl)-amine methyl acid, third butyl ester (〇16 g X example J6) and 3-[3-〇methyl-methylazole yl) phenyl]·3· § Isopropyl propionate third butyl ester (〇 18 g X instance K29). The resulting material is deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure ν. Obtained a yellow solid (〇 4 g). MS (ISP) 429.3 [(M+H)+]; mp. _ · 234 - This paper scale is suitable for @@家料(CNS) A4 specification (210 X 297 public) 犹~_ 1296622 A7 _________B7____ V. Description of invention (231) Example 211 ^Methylamino-4-f3_( 5-Ai oxime _4_V methoxy 1-8-trifluoromethyl-1,3-dihydro-labeled [b][l,41 diazepine-2· The title compound is based on General procedure Μ, from (2-amino-5-dimethylamino-4-trifluoro-methylphenyl)-amine methyl acid, third butyl ester (〇 16 g X example J6) and 3 · [3 · (5-methyl) No. 4-yl)-phenyl]_3_g, homo-propionic acid, tert-butyl ester (〇18 g) (example K36). According to the general procedure n, via tfa Treatment with CH2Cl2 gave deprotection and cyclization of the obtained material. A yellow solid (yield 13 g) was obtained. MS (ISP) 429.3 [(M+H)+]; melting point 238-239 ° C. 212 Ζ dimethylamino-M3-(2-methyl-5-propyl azole-4-yl)-phenyl 1-8-trifluoromethyl-jj-dihydro-benzodiazepine-2 - Ketone title compound is prepared according to the general procedure from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester (8 mg ) (Example J6) with 3-[3-(2-methyl-5-propyl-sodium azole-4- Base)-phenyl]-3·decyl··propionic acid tert-butyl ester (103 克 X 例 K37). According to the general procedure N, the obtained material is treated by TFA in CH]Cl2 Removal of protection and cyclization afforded a pale-yellow solid (20 mg). MS (ESI) 471.2 [(M+H)+]; mp 211-212 ° C. Example 213 7-dimethylamino-4. (5-Methyl-thiazol-4-yl)-Moody, each trifluoromethyl-1,3-dioxin-benzo is called "1,41 diazepine-2-one title compound according to the general procedure Μ, produced from (2-aminodimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester (0.16 g) (example brother) and 3-[3- _ _-235-_____ This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1296622 A7 ____B7 , __ V. Description of invention (232 ) (5-methyl oxazol-4-yl) -Phenyl]-3-keto-propionic acid tert-butyl ester ((9 g) (Example K38). According to the general procedure N, the obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2. Obtained as a yellow solid (yield: 6g). MS (ESI) 445.2 [(M+H)+]; mp 214-215 ° C. Example 214 7-diaminoamine-4- 〖3 -(2,5-Dimethylethazole-4-yl Vphenyl 1-8-trifluoromethyl-1,3-dihydro-benzopyrene, 41 diazepine-2-one title compound According to the general procedure, it was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-amine methyl acid tert-butyl ester (48 mg) (example J6) and 3-[3-(2,5-Methyl-thiazol-4-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (5 mg) (Example Κ 39). The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure. Obtained as a yellow solid (38 mg). MS (ISP) 459.2 [(Μ+Η)+]; mp 208-209. Example 215 Dimethylamino hydrazine 3-(2-hydroxymethyl-pyrazol-4-yl)-phenyl 1-8-trifluoromethylhydro-benzofbin, 41 diazepine-2-one (3-bromoethionyl-phenyl)-7-dimethylamino-8-trismethyl-1,3-1,3-p-benzofblfl, 41-dioxan-2-one (2 -amino-5-dimethylamino-4-trifluoromethyl phenyl)-amine methyl acid third-butyl vinegar (example J6) (0.32 g) and 3-keto-3-[3- (2-Bromodimethoxyethyl)-phenyl]-propionic acid tert-butyl ester (0.43 g) (real, K28) in toluene (3 mL), heated to 100 ° C 2 hours. The solvent was evaporated in the sputum and the crude product was purified by chromatography on silica gel using &lt;RTI ID=0.0&gt;&gt; Purified material (0.57 g) in CH2 C12/TFA (1: 1,7 liters) __ -236- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 A7 _________ B7 ___ V. The solution of the invention (233) was stirred at 20 ° C for 15 minutes and then evaporated. The residual oil was dissolved in AcOEt, and the solution was washed with 1N HCl and brine, dried, dried and evaporated to give crude 4-(3-bromoethyl-phenyl-phenyl)-7-dimethylamino Trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine-2-one (0.22 g), light brown solid b) 7 didimethylamino-4- 『3-(2-Hydroxymethyl-thiazolyl)-V-yl 1 each trifluoro-methyl-1,3-hydroxy-benzo-bin, 41-diazepine-2-one will 4-(3 -bromoethenyl-phenyldimethylamino-trifluoromethyl-l53-dihydro-benzo[b][l,4]diazepin-2-one (0.40 g) and 2-( A mixture of tert-butylcarbonyloxy) thioacetamide (0.21 g) in EtOH (5 mL) was heated at 80 ° C for 0.5 hours. This solution was diluted with AcOEt to sat. The solution was washed with brine, dried over EtOAc EtOAc EtOAcjjjjjjjjjjjj The precipitated product was purified by chromatography on silica gel using EtOAc (EtOAc) eluting MS (ISP) 461.1 [(M+H)+]. Example 216 7-dimethylamino-4-f3-(2-hydroxymethyl-5-methyl-indazole ice-based)-phenyl 1-8 - Tris-methyl-1,3-dihydro-benzo-[1,41-diazepine-2-one title compound is prepared according to the general procedure from 2-amino-5-dimethylamino -4-trifluoro-methyl-phenyl)-amine methyl acid, third butyl ester (0.16 g) (example J6) and 3-keto-3-{3-[5-methyl-2-( Tert-butyl ester of tetrahydro-piperidin-2-yloxyindolyl)-pyrazol-4-yl]-phenyl}-propionic acid (0.26 g) (example K4 〇). According to the general procedure N, via __-237- _____ This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1296622 A7 ____ B7 V. Invention description (234 ) ' TFA is treated in CH2 C12 to remove the obtained material Protection and cyclization. Obtained as a pale-yellow solid (0.11 g). MS (ESI) 475·2 [(M+H)+]; melting point 19 (M 93 ° C. Example 217 7-II.. more. Aminohydroxyl -5-propyloxazol-4-yl)-phenyl 1-8-trifluoromethane _ -1,3_dihydro-benzo[~bl〖l,4l diazepine-2-anthracene The title compound was prepared according to the general procedure from 2-amino-5-dimethylamino-4. Mercapto-phenyl)-amine mercapto acid-third-butyl ester (79 mg X example J6) with 3-indolyl-3-{3-|&gt; propyl-2-(tetrahydro-pyran 2-Benzyloxymethyl)-indazol-4-yl]-phenyl]propionic acid tert-butyl ester (138 mg) (example K41). The obtained material was removed for protection and cyclization according to the general procedure N by treatment with TFA in CH2C12. Obtained as a yellow solid (45 mg). MS (ISP) 503.2 [(M+H)+]; mp. 112-114. Example 218 7-Dimethylamino-443-(5-hydroxymethyl-2-methyl-pyrazole, a stupid trifluoromethyl-1,3-dihydro-benzone, "1,41 two gas The hydrazine-2-one title compound is prepared from (2-amino-5-dimethylamino-4-trifluoro-methyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure. (0.16 g) (Example J6) with 3-keto-3-{3-[2-methyl-5-(tetrahydro-t-butan-2-yloxymethyl)-. ]-Phenyl}-propionic acid tert-butyl ester (〇·26 g) (Example K42). The obtained material was subjected to deprotection and cyclization by treatment with TFA in CH 2 Cl 2 according to General procedure N. Yellow solid (0.11 g) MS (ISN) 473.0 [(Μ·Η)·]; melting point 226-227〇C. Example 219 -238- ___ This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) 1296622 A7 B7 V. Description of the Invention (235) h Dimethylamino-4-"3-(5-hydroxyindolyl-oxazol-4-yl)-phenyl 1-8-trifluoro ^Dihydro-benzo-fblfl, 41-diazepine-2-one title compound is prepared according to the general procedure from (2-aminodiamminyl-4-tetrafluoro-methyl-phenyl)- Aminomethyl 3-butyrate (0·16 g) Example J6) with 3·酉 synyl-3-{[5-(tetrahydrofuran-2-yloxymethyl)septen-4-yl]-phenyl}-propionic acid second-butyl ester ( 0.25 g) (Example K43). The obtained material was deprotected and cyclized by treatment with TFA in CH.sub.2. MH)·]. Example 220 Soil (3-{5-[~(cyclopropylmethyl-amino)-methyl p-saprazole-4-yl 1-phenyl V7-dimethylamino] [Trifluoro Methyl-1,3-dihydro-benzo-blfl, 41-diazepine

7-Dimethylamino-4-[3-(5-demethyl-methyl-trtr-4-yl)-phenyl]-trifluoromethyl-1,3-1,3-hydro-ben-[b] a mixture of [l,4]diazepine-2-one (Example 219) (65 mg) and dimethyl sulfoxide (0.015 mL) in CH.sub.2Cl.sub.2 (0.3 mL). Drop 1 hour. The heterogeneous mixture was allowed to evaporate in the sputum and the residue was suspended in EtOH (0.5 mL). Aminomethyl-cyclopropane (〇 12 ml) and KI (3 mg) were added, and the mixture was stirred at 80 ° C for 5 hours. The mixture was allowed to evaporate in the sputum and the residue was purified by chromatography on silica gel using AcOEt/Me sH (50:1) as solvent. The resulting product was stirred with aq. EtOAc (EtOAc) (EtOAc) (EtOAc) ), as an off-white solid. MS (ISP) 514.3 [(M+H)+]; 157-158 °C. -239- This paper scale is suitable for @@家标准(CNS) A4 specification (21GX297 public) &quot; binding

Line 1296622 A7 B7 V. Invention Description (236) Example 221 -7 22! - 释基斗IH2-isopropyl-1H-imidazolium)-benzene ι·κ-trifluoromethyl_13_ dihydro-benzo[blfl,41 diazepine-2-one title compound is based on general Procedure M, prepared from (2_Aminos dimethylamino-4-difluoro-methyl-phenyl)-amine methyl acid tert-butyl ester (〇 13 g) (example brother) and 3_[3_ ( 2-Dimethyl-3H-mio-4-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (0.20 g) (example K44). The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure n. Obtained an off-white solid (〇1 g). MS (ISP) 456.4 [(M+H)+]; melting point 150 ° C decomposition Example 222

Id»Methyldi-[,3,4]thiadiazole-2-ylphenyl 1-7-(methyl-propyl-amine a Vi 1 -fluoromethyl-1,3-dihydro-stupid "blfl, 4" diazepine-2-one title compound is prepared according to the general procedure from [2-amino-5-(methyl-propyl-amino)-4-difluoromethyl-benzene. Aminomethyl acid, the third amino acid, and the 3-keto-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[ 1,3,4]pyrazol-2-yl]-phenyl-propionic acid tert-butyl ester (0.23 g) (example K30). According to the general procedure N, by treatment with TFA in CH2 (3⁄4) The obtained material was deprotected and cyclized to give a yellow solid ( 0.02 g). MS (ESI) 490.2 [(M+H)+]; mp 193-194 ° C. Example 223 t-oxy-7-dimethylamine Base 4-{345-(2.hydroxy-ethylHl,3,41-pyrimidin-2-yl)^-&gt;1,3-dihydro-stupid "printed 1,41 diazepine- The 2-keto title compound was prepared according to the general procedure from (2-aminopiperidin-5-dimethylamino-phenyl)-amine methyl acid tert-butyl ester (Example J1). 15) Same as the crude -240 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) l296622 — ------- V. Description of the invention (237) A7 B7 -3-(3-{5-[2-(tetrahydro-σ-exan-2-yloxy)-ethyl]-[1 , 3, servant di-salt-2-yl}-phenyl)-propionic acid tert-butyl ester (0.24 g·) (Example Κ 30). According to the general procedure Ν, obtained by treatment with TFA in Ch 2 C 12 Material removal protection and cyclization of hydrazine afforded a yellow solid (0.10 g). MS (ISN) 440.2 [(M-Η)·]; melting point 198-20 CTC. Example I The following composition tablets were prepared in the conventional manner. Powdered lactose white corn powder powder polyvinyl tetrahydropyrrolidone Na methyl starch sodium stearate tablets weight 1 g / tablet 100 95 35 8 10 2 250 Example II The following composition of the tablet is made by the conventional method Ingredients: Active Ingredient Powdered Lactose White Corn Starch Polyethylene Azide? Nitrogen Ratio p Each Nacarboxymethyl Starch Magnesium Stearate ~ Tablet Weight / Tablet 200 100 64 12 20 4 400 ____- 241 -__- --------------- This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1296622 A7 B7 V. Invention description (238) Example III The following composition is made Capsule: mg/capsule live Ingredient 50 Crystalline Lactose 60 Microcrystalline Cellulose 34 Talc 5 Magnesium Stearate 1 Capsule Filling Weight - 150 Active ingredients with appropriate particle size, crystalline lactose and microcrystalline cellulose, uniformly mixed with each other, sieved , -, then mix talc with magnesium stearate. The final mixture is filled into hard gelatin capsules of appropriate size. -242- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Claims (2)

Patent application No. 1296622105209 Replacement of Chinese patent application scope (May 96) VI. Application for patent scope Post compound Wherein X is a single bond or an acetylene diyl group; wherein if X is a single bond, R1 is cyano, halogen, Ci-C7 焼"-based fluoro-CrCy alkyl, or phenyl, which is one or two Halogen substituted; if X is acetylene diyl, then R1 is phenyl which is unsubstituted; R2 is -NR'R", fluoro-C7 alkoxy, or tetrahydrop is 17 to -1-yl or hexa Hydrogen leaf -1--1-yl, the ring is optionally substituted by R"; R' is hydrogen, q-C7 alkyl, c3-c6-cycloalkyl, or 2-CVC7 alkoxy CrC7 alkyl; Rn is hydrogen, 77151-960430.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X 297 metric tons) A8 B8 C8 D8 1296622 Patent application Fanyuan-C7 burning base, C3 -Cg -3⁄4 burning base, gas -Ci -C? burning base, 2-CrC7 alkoxyalkyl, or pyridyl; Y is _CH=; R3 is an optionally substituted five-membered aromatic heterocyclic ring selected from pyrazolyl, oxazolyl, isnzazolyl, Imidazolyl, 2H-pyrazolyl, sulphate, succinyl, [1,2,4]di-[beta]-based, [l,3,4]p-dithiol, [ι,3,4] A oxazolyl, pyrazolyl and 1 Η-imidazolyl group; η is 0, 1, 2, 3 or 4; and a pharmaceutically acceptable addition salt thereof. 2. According to the patent application, the compound of item 1, wherein X is a single bond. 3. A compound according to item 2 of the patent application, wherein Ri is trigasto. 4. A compound according to claim 1 of the patent application, the compound being selected from the group consisting of: 7-diamidino-4-[3-(3-methyl-isoxazole-5-yl) Phenyl]trifluoromethyl _ 1,3-dihydro-benzo[b][l,4]diazepin-2-one, 7-dimethylamino-4-[3-(2- Mercapto-2H-pyrazole-3-yl)phenyl]trifluoromethyl1,3-dihydro-bromo[b][l,4]diazepin-2-one, 7-diindole Amino-4-(3-indolyl-1-yl-phenyl)-8-trifluoromethyldihydro-benzo[b][l,4]diazepin-2-one, 4-[ 3-(3-Methyl-isoxazol-5-yl) phenylmethyl-propyl-amino group each 77751-960430.DOC -2· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ' -----— 1296622 ABCD fluoromethyl-1,3_dihydro-benzo[b][i,4]diazepine-2-one, K-isobutyl-decylamino)_4-[3_(3-methyl _isoxazolidine)·phenyl]I trifluoromethyl-U-dihydrobenzo[b][1,4]diazepineone, anthracenyl-mercapto-amino group ;4-[3_(3_methyl-isoxazyl)-phenyl]_8-trifluoromethyl-I,3-dihydro-benzo[b][1,4]diazepine Ketone, 7-(isobutyl-methylamino)_4-(3·{5_[(isopropyl-methyl-amino)-methyl]_[1,2,3]dis-sodium-1- Phenylphenyl)trifluoromethyl_13 dihydrobenzo[b][i,4]diazepine·2-class, Ηisopropyl-methyl-amino)-4-[3-( 5-tetrahydropyrrole + fluorenyl-based hydrazine three-seat 1 yl)-stupyl]difluoroindolyl-1,3-dihydro-benzo-(1)4]diazepine 2-7-(methyl -propyl-amino 3]triazole small group -phenyl) each tris-methyl-1,3-dihydrobenzo[b][l,4]diazepine-2-one, 7- (isobutyl-methyl-amino)_4-(3-[1,2,3]triazol+ylphenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][ 1,4]diazepine-2-ketone, 4_(3_imidazol-1-yl-phenyl)-7(isobutylamino)trifluoromethyl_u_dihydro-benzo[b][ l, 4] two Azaindene-2-one, 7-dimethylamine-based [3-(4-hydroxymethyl-pyrazolyl)-phenyl]j-trifluoromethyl_1,3-dihydro-benzo[ b][l,4]diazepine; ketone, 7·dimethylamino ice [3-(4-hydroxymethyl-oxazol-2-yl)phenyl]_8-trifluoromethyl-I, 3-dihydro-benzo[b][l,4]diazepaconone, 4-[3-(4-hydroxymethyl-pyrazol-2-yl)-phenyl&gt;7_(methyl -propyl-amino)trifluoromethyl-1,3-dihydro-benzo[b][l,4]diazepine, and 4-[3-(5-hydroxymethyl-[1 ,3,4]thiadiazol-2-ylphenyl]_7•(methyl-propylamineamine 77151-960430.DOC -3- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public 羡) ---------- A8 B8 C8 D8 1296622 VI. The scope of the patent application base) each trifluoromethyl-1,3_dihydro-benzene and [Μ]diazepine-2-one. 5. The compound according to item 2 of the patent application, wherein the compound 1 is a chlorine group. 6. The compound according to item 5 of the scope of the patent application is selected from the group consisting of: 8-gas group-7 -isobutylamine-based [3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3_di-nitro-benzo[b][l,4]diazepine 2-ketone, 8- -7-(methyl-propyl-amino)-4-[3-(5-tetraheptene-p-mentalylmethyl-[1,2,3]triazol-1-yl)-phenyl ]-Μ-dihydro-benzo[b][1,4]diazepine-2-one, 8-chloro-7-(isopropyl-indolyl-amino)_4-|&gt; 5-tetrahydro-p-l-l-ylindenyl_[1,2,31triazol-1-yl)-phenyl]_ι,3_dihydro-abido[b][l,4]diazepine Heterofluorenone, 8-chloro-7-(isobutyl, methyl-amino)-4-[3-(5-tetrahydrop-rho-_1_ylmethyl_[1,2,3]二°坐_1_基)_本基]-i,3-two mouse-benzo[b][l,4]diazepine-2-class, 8-chlorobase [3-(5_ Dimethylaminoindolyl-[1,2,3]triazoleyl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][l , 4] diazepine-2-one, this|&gt;(5_-azatetrakisylmethyl-[1,2,3]triazol-1-yl)-phenyl]·8-chloro _ 7-(isopropyl-methylamino)-indole, 3-dihydro-benzo[b][l,4]diazepine, 4·[3-(5--azatetraindole) -[1,2,3]triazol-1-yl)phenyl]-8-chloro, 7-(isobutyl-methylamino)-1,3_dibenzo[b] [l,4·]diazepine-2-indole, 8-carbyl-7-(isobutylguanidino-amino)-4-[3·(5-hexahydrop Biting 1 -ylmethyl[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][l,4]diazepine, 8-chloro -7-(isopropyl-decyl-amino)-4·(3-{5_[(isopropyl-indenyl)-methylhydrazine 1,2,3]triazol-1-yl }-phenyl)-1&gt;dihydro-benzo[b][l,4]dioxan-2-yl, 8-carbyl-4-(3-{5-[(isobutyl-) Methyl-amino)-methyl H1,2,3]trityl 77151-960430.DOC -4- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1296622 }--phenyl&gt;7-(isopropyl-methyl-amino)&gt;l53_dihydro-benzo[b][14]diazepine-2-indole, plant 8-chloroiso Propylamine base [3_(3_methyl_isoxazole_5•yl)_phenyl]&lt;&amp; dihydro-benzo[b][l,4]diazepine-2·one , 8_Chloro-7-(isobutyl-methyl-amino)&gt;4_(3-[1,2,3]triazole-丨-yl·stupyl) 1,3-dihydro-benzo [b][1,4]diazepine, soil 8-gas-4(3-imidazolyl-phenyl)-7-isobutylamino-3_dihydrobenz[b] [l,4]diazepine_2-g is the same," 8-alkyl-7-(ethyl-mercapto-amino group&gt;4_[3-(4-hydroxymethyl-carbazole_2_ Base)·stupyl]·1,3-dihydro-benzo[b][l,4]diazepine-2-one, 8_glycol_4-[3-(4-hydroxymethyl- Sodium·2-yl)-phenyl]_7-(methyl-propionyl)-1,3-dihydro-benzo[b][l,4]diazepine-2-indole, 8.·Vetyl-4-[3-(4-hydroxyindolyl-farazolyl)-phenyl]_7&lt;isopropyl·methyl Aamino)_1,3-diamino-benzo[b][l , 4] diazepine-2·one, 8-chloro-4·[3-(4.hydroxymethyl-indenyl-2-yl)-phenyl]-7-(isobutyl-methylamine -1,3-dihydro-benzo[b][l,4]diazepine-2-one 8-Chloro-7-(ethyl-indolyl-amino)-4-[3-(4-methyl-methyl)-phenyl]-1,3-dihydro-benzo[b] [l,4]diazepine-2-one, 8-chloro-4·[3-(4-hydroxymethyl]oxazol-2-yl)-phenyl]-7-(methyl·propyl Amino-amino)-1,3-dihydro-benzo[b][l,4]diazepin-2-one, 8-chloro-4-[3-(4-hydroxyindenyl-oxime) Azolungyl&gt;phenyl]^(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][l,4]diazepin-2-one, and 8- Chloro-4-[3-(4-methyl-methyl-2-yl)-phenyl]-7-(isobutylmethylammonyl: M,3-dihydro-benzo[b][l , 4] diazepine-2-one. 77151-960430.DOC _5- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot;' -- Binding # A8 B8 C8 D8 1296622 VI. Patent Application Range 7. The compound according to item 2 of the patent application, wherein R1 is a cyano group. 8. A compound according to item 7 of the patent application, which is selected from the group consisting of: 8_diethylamino winter [3-(3-indolyl-isoxazol-5-yl)- Phenyl]_4-keto-4,5-dihydro-3H-benzo[b][l,4]diazepine-7-carbonitrile with 2-indole (3·methyl·iso$嗤-5-yl)-phenyl]-4-keto-8-hexahydrop-pyridyl-1_yl-4,5-dihydro-3H-benzo[b][l,4]diazepine -7-phthalonitrile. 9. A compound according to claim 1 wherein R3 is an optionally substituted five member aromatic heterocycle selected from the group consisting of pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 2H-pyrazole Base, [1,2,3]triazolyl, [1,2,4]tris-sulphate, [1,3,4]thiadiazolyl and [1,3,4]oxadiazolyl. 10. A compound according to claim 9 of the patent application, the compound being selected from the group consisting of: 7-methylamino-8-phenylethyl carbyl-4-(3-[1,2,3 Tris-π-l-yl-phenyl)q,3-dihydro-benzo[b][l,4]diazepine-2-one, 8-oxofluorophenyl)-4-(3- [1,2,3]triazol-1-yl-phenyl)-7-(2,2,2-trifluoroethoxy)-1,3-dihydro-benzo[b][l,4 Diazepam-2-one, 7·(ethyl-indolyl-amino)-8-methyl-4-[3-(3-methyl-isoxazole-5-yl)-phenyl ]-1,3-Dihydro-benzo[b][l,4]diazepine-2-one, 7-dimethylamino-8-methylcycle [3-(3-methyl-iso) Oxazol-5-yl)-phenyl]-i,3-dihydro-benzo[b][l,4]diazepine-2-one, 7-(isobutyl-methyl-amino )-8-曱 base bucket [3_(3_mercapto-isoxazole_5_yl]&gt; phenyl]-1,3-dihydro-benzo[b][l,4]diazepine- 2-ketone, 7-(isobutyl-fluorenyl-amino)methyl·4-[3-(5-tetrahydropyrroleinyl)_ 77151-960430.DOC -6- This paper size is applicable to China Standard (CNS) Α4 size (210 X 297 mm) A8 B8 C8 D8 1296622 VI. Patent application scope [1, 2, 3] triazole small group) - phenyl]- 1,3-Dihydro-benzo[b][l,4]diazepine·2_, and 4-(3-{5_[(cyclopropylindenyl-amino)-methyl]- [1,2,3]III. Sodium phenylene) 7-(isobutyl-methyl-amino)_8-methyl-1,3-dihydro-benzo-like arsenazo _ 2 a ketone. A medicinal composition for the treatment or prevention of an acute and/or chronic neurological condition, comprising one or more compounds according to any one of claims 1 to 1 and pharmaceutically acceptable 12. The pharmaceutical composition according to claim 11, wherein the acute and/or chronic neurological condition comprises psychosis, schizophrenia, Alzheimer's disease, cognitive condition, and memory deficiency. 13. A method of preparing a compound of formula I according to claim 1 of the scope of the patent application, the method comprising a) a compound of formula II Reacts with a compound of formula IV or IVa 77151-960430.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1296622 Wherein R is a -C7 alkyl group, which is a hydrazine compound The receiver performs the function of protecting the base and the cyclization to obtain the compound of the formula R3 wherein R1, R2, R3, X and γ are as defined above, and if necessary, converts the obtained compound into a pharmaceutically acceptable acid addition salt. 14. The method of claim i, wherein the ruler is an ethyl or a butyl group. 15. A compound according to any one of the claims of the invention, which is made according to the method of claim 3 or by an equivalent method. The compound according to any one of claims 1 to 1 which is for the treatment or prevention of acute and/or chronic neurological disorders. 17_—one or more compounds and/or one or more pharmaceutically acceptable acid addition salts thereof according to the scope of patent application No. 771 to 519 430. DOC δ This paper scale applies to China Standard (CNS) Α4 Specification (210 X 297 DON) 1296622 - C8 D8 VI. Use of the patent application for the treatment or prevention of acute and/or chronic neurological disorders. 18. The use according to claim 17, wherein the acute and/or chronic neurological condition comprises psychosis, schizophrenia, Alzheimer's disease, cognitive condition and memory deficiency. 77151-960430.DOC -9- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm)