TW500723B - Tricyclic pyrido vasopressin agonists - Google Patents

Abstract

The present invention provides compounds of the general formula, wherein W is O or NH, optionally substituted, as well as methods and pharmaceutical compositions utilizing these compounds for the treatment of disorder which may be remedied or alleviated by vasopressin agonist activity, including diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, or temporary delay of urination.

Description

500723 A7 B7 II —1U · Samen · 11 · 1 ir- 1 I——W · * · —WWW—WW ——— M · —WMMW ——————— μμμμμμμμΜ! -1 V. Description of the Invention I )) The present invention 僳 relates to a tertiary compound or a pharmaceutically acceptable salt thereof which can be used as an agent of vasopressin, and a treatment method using the compound and its peony composition Background of the invention Vasopressin (antidiuretic hormone, ADH) ) Is a non-peptide hormone and neurotransmitter, which is synthesized in the nucleus of the hypothalamus and optic bed of the brain, and is sent from the nucleus of the optic bed to the posterior pituitary for storage. When the osmotic receptor of the brain senses an increase in osmotic pressure or the decrease of blood volume or blood pressure by the sensory receptor and volume receptor, it releases vasopressin into the blood, which can activate the Vla receptor in the blood vessel and cause the blood vessel to contract. While increasing blood pressure and vasopressin h receptors in the kidney while retaining water, and reducing the level of electrolytes to expand blood volume (Cervoni and Chan, Diuretic Agents, in Kirfc-Other: Encyclopedia of Chemical Technology, 4th ed., Wiley , Voluaie 8, 3 9 8-4 3 2, 1 9 9 3). Presence of vasopressin in the hypothalamus before 1 8 9 5 (Oliver, Η · and Schaefer, J.

Physiol (London) 18: 277-279, 1895) 〇 du Vigneaud was determined by the M Department Λ only X consumption report printed shirts (please read the precautions on the back before filling this page) and others learned in 1954 Structure of vasopressin and its overall synthesis (du Vigneaud, Gish, and Katsoyannis, J. Air · Chei. S oc. 76: 4751-4752, 1954) 〇The role of vasopressin Vla receptors is by the phospholipid diaphragm muscle Alcohol pathway is mediated. Activated vasopressin vla receptors can cause vascular smooth muscle to contract and increase blood pressure. The role of vasopressin V2 receptors is to increase the amount of intercellular cAMP by activating the adenylyl cyclase system. Activation of vasopressin V 2 receptors by vasopressin or vasopressin-like (peptide or non-peptide) compounds can increase the paper size Applicable to Chinese National Standard (CNS) A4 size (210X297 mm) 500723 A7 B7 V. Description of the invention (Chen Yanbu, ^, in the form of inulis in the form of metamorphosis, S, can be used to produce nKiiMJ animals, but humans are close to c water. Press tl for lack of tube positive. _ 保 »« _ Add p C into blood when water infiltrates, " Concrete urinary fluid Bto blood #Constriction of kidney phase plus urine tension_release. The concentration of leptin increases and decreases by 11 releases and releases pressure, but the disease is concomitant with the thick tube _ will be 1 release, this amount of blood after the brain and tuberculosis, urinary tube without filtration M, 2 ^ water blood_urinary When the low episode is over M, the V2 will shrink and shrink, and the tube will be reduced. W Cheng Su 趿 The brain tube is dense and the kidneys are small? «Overpressure again, the blood method is due to the kidney collection. The renal tube collapses with water urea C. This U blood is due to urinary constriction chromogenic factor, or neutral and sexual C tube concentrating angle. Cheng Zhengshou Releasing blood and infiltrating nl with low harvest phase or being born into kidneys and extremely low-heavy axillary organs (please read the precautions on the back before filling this page) 10 times the volume of urine, and extremely sensitive to vasopressin and vasopressin V 2 agents. Vasopressin and ligament vasopressin (which is the peptide of natural vasopressin) Analogues) in patients with central diabetes insipidus. Vasopressin V 2 acting agents can be used to treat, such as nocturnal urination, nocturia, urinary incontinence, and if necessary, temporarily delay urination ^ Vasopressin can be activated by ν la The device shrinks blood vessels and raises blood pressure. Vasopressin vla receptors have the opposite effect. Vasopressin and vasopressin can release factor VIII and von Wilebrand factor, so it can treat blood loss such as hemophilia Abnormal. Vasopressin and vasopressin-like agents can also release tissue-type plasminogen activator (PA) into the blood, so it can be used in patients with cardiac embolism and other thrombotic disorders to dissolve blood clots (Jackson , La.sopressin and other agents Applicable to China National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention () affecting the renal conservation of water0, in: Goodman's and Gilman ^ The P har and aco 1 ogica 1 Basis of Therapeutic, 9th e d., ed s. Hardman Li Jin bird, Molinoff, Ruddon and Gilman, McGraw-Hill New York * PP 7 15 -7 3 1 9 1996, Let eth ag e η 9 s. 1 Ann He mat ο 1., 69 1 7 3 -180 (1994), Cash, et al • > B rit. J • H ae Lan 玨 t 27; 36 3- 3 6 4, 1 97 4., David, R eg ul at ory P ept ides, 4 5; 3 1 1-3 1 Ί, 1 99 3; Bur gg ra af eta 1 ·, Cl i. S ci. 8 6; 49 7- 50 3 (1 9 9 4) O The following prior art references Angiotensin antagonizes m: M. Mann in geta 1. 9 J. Med. Che m. 9 35, 382 (1 99 2); M. Mann in geta lk J * Med. C he m. , 35 3 8 9 5 (1 9 9 2); HG avr as and B * La mm ek, US patent 50 70 187 (1 99 1); M. Mann in g an d W. Sa • Sawyer, US patent 5 0 5 5 4 48 (1991) F. E. A 1 i * »US Patent 4766108 (1 988) • 'R. R • R uff olo eta 1., Drug Ne ws and Per spective 9 4 (4) 9 2 1 7 (Ma 1991) 0 W i 1 1 ia crude s et al. Reported potential—JL * peptide oxytocin antagonist U Med. Che n. 35 3 9 0 5 I [19 92]], which It shows weak vasopressin antagonist activity on the receptors bound to V i and V 2 o The peptide vasopressin antagonist has the disadvantage of lack of oral activity, and many ifeifenes are not selected because of their partial action activity. Antagonist. Recently, non-peptide vasopressin antagonists have been published. Albright et al., Published in U.S. Patent 55 1 6774 (May 14th, 1996) because of antagonism of vasopressin and oxytocin_; JP 0808146D-A (March 26 This paper standard applies to Chinese national standards (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) Order 500723 A7 B7 V. Description of the invention (4) Day, 1 9 9 6) Tetrahydrobenzidine diazine is published because Vasopressin Antagonism_; Ogaowa et al., WO 9534540-A, published that phenylhydrazone heterocyclic derivatives are vasopressin and oxytocin to antagonize rain; Albright, et al., U.S. Patent 5 5 1 2 5 6 3 " (April 30, 196), published a trisphenazine diheptin derivative as a vasopressin antagonist; and Venkatesan et al. In U.S. Patent No. 5 5 2 1 1 7 3 (May 28, 1 9 6) reported that tricyclic benzodiazepine derivatives were vasopressin and oxytocin antagonists. As described above, ligament vasopressin (budenamine arginine vasopressin) (Huguenin, Boissonnas, Helv · Chim · Aeta, 49,695 (1966)) is an vasopressin agent. This compound is a synthetic peptide with various bioavailability. The intranasal route is poorly tolerated and is 10 to 20 times higher than the intranasal prescription for oral discharge. The compound of the present invention is a non-peptide and has excellent oral bioavailability. It is a lotus-selective vasopressin acting agent and has no V-acting activity to raise blood pressure. In contrast, prior art compounds are vasopressin antagonists (except for parts of W 0 9 5 3 4 5 4 D-A). Summary of the Invention The central sample rate of the Ministry of Economic Affairs and the exclusive cooperation of the private printing industry are related to a novel compound selected from the following formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

(Read the precautions on the back before filling this page)

Z (I) This paper size applies Chinese National Standard (CNS) A4 specification (210% 2 still mm) -6- 500723 A7 B7 V. Description of the invention (where r is W, or NR 6 A and B each Is C or NR 1 is a C s CR 9 7 alkyl group or is selected from the group

R2

\ = (2⑻R

⑻

⑻

(d)

⑻ R4 jn a, cr ① I (I) (Read the precautions on the back before filling in this page)

, 1T (i)

(m) Work only through the central unit of the M section. # 印 繁 or ⑻ ⑻ R2, R3 and Rs are each hydrogen, "-8 straight chain alkyl, C3-7 branch bond alkyl, C 3- 7-ring courtyard group, or Ci-e peroxyfluorenyl group; R 4 is hydrogen, C a-e straight chain alkyl group, C 3-7 branch chain alkyl group, C 3 _ 7 cycloalkyl group, C2 > »7 courtyard Chloroyl, which is substituted by C7 -12 aromatic radical, or fluorenyl substituent, is selected from a group such as (: 2-7 alkylfluorenyl, C3-7_fluorenyl, this paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (k I-? Cycloalkylfluorenyl, aralkylfluorenyl (including 6 alkyl), 7-13 aryl halogenated aryl or hydrogen based Hydrazine 7 BC or alkane bond straight alkane hydrogen hydrogenation for each ¥ and alkane bond straight alkane chain branched alkane cyclin haloalkoxy alkane or hydrazine or yl, alkane 3 »group« Faii C-bond 7 »* Straight 2 C8 hydroxy ,, AL, C sulfonyl or hydrogen halide, alkane as the base bond Z d-Cycloalkyl fluorofluoride * or 3 C, C-alkyl alkane hydroxy chain 8 Divide 1-point C or radical based on the extra-chain points 7 B 1 C ^ Contains »meaning any of the table total of 6 nitrogen C and, or argon *, radicals 8 aryl hydrazones or radicals 0 and straight alkanes such as ring members 6 or 5 ο or SN commercially available zi 9 9 ' 9. ， 9 f 9 0 or 乂 N3 (read the precautions on the back and then fill out this page) After the central part of the M department #. Quasi-only consumer cooperation, the initial printing of the basic meaning is 逑 i J 烷 is directly included as f ： Huahan—10 ding— 6 round R is better,!-· Fan- is better than 11c§ «iio! Fi RR 9 is for hair and one hair: 910z i RRR This T Y5 such as the basic group is closed. Such as

W is the product made by Xuanrong Pharmaceutical. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) and the alkane is low. Ο is A, W medium, 6 of which β

X B A

X or B before form medicine 500723 A7 B7 V. Description of the invention (R6

Z R5 where

R or x >; (k) (Read the precautions on the back before filling in this page), 1T # Μ 部 摞 量 ^ ¾ ΗConsumer cooperation drawing, R3 and Rs are each hydrogen, Ci-e straight 鐽Alkyl, C3-7 fluorenyl, C3-7 cyclofluorenyl, or perfluorofluorenyl; R4 is hydrogen, Ci-8 straight fluorenyl, C3-7 fluorenyl alkyl, C3-7 fluorenyl , C2-7 fluorenyl, optionally substituted C7-I2 aryl, or fluorenyl substituents selected from a group such as C2-7 alkylfluorenyl, C 3-7 alkenyl, C3-7 fluorenyl ((37-12 aralkyl fluorenyl or heteroaralkyl fluorenyl) can be arbitrarily substituted with 1 ~ 2 锢 C 6 alkyl or C b 6 aralkyl fluorenyl; -9-This paper size applies to Chinese national standards (CNS ) Α4 size (210 × 297 mm) MM central «quasi-negative X consumption cooperation Miyin 500723 A7 B7 V. Description of the invention (/) R6 is hydrogen, fluorenyl, Ci-e linear alkyl, or C 3- 7-membered alkyl groups; X and Y are each hydrogen, C-6 straight-chain alkyl groups, C3_7-membered alkyl groups, C3-7 cycloalkyl groups, C2-7 alkane alkyl groups, halogens (containing chlorine, Bromine, fluorine, and iodine), linear or branched alkoxy, hydroxyl, CF3, or C2-8 perfluoroalkyl; Z is hydrogen or Ci-6 straight-bonded alkyl , C3-7 branched chain alkyl, C3_7 cycloalkyl, halogen, C 2-7 alkylchloroalkyl, C 8 hydroxyalkyl, or CH 2 NR 7 R 8; B7 and R8 are each hydrogen, C is straight Alkyl, C3-7 branched-chain alkyl, aryl or aralkyl; or co-expressed with nitrogen to contain any one or more additional pyrene atoms, preferably selected from 5 or 5 of N, S or 0 (preferably N or 0) 6-membered ring, such as -Ο, -Ο, -Ο, -〇-r1 °, -〇, »~ 0,4; s R 8 is C i -6 straight alkyl; Aryl contains, for example, phenyl and naphthyl, each of which may be substituted with one or more substituents selected from hydrogen, halogen, cyano, Ci-8 straight alkyl, c3-7 branched alkyl, Ci-e alkylchloro Cf3 or phenyl, the phenyl substituent may be optionally substituted with one or more substituents selected from hydrogen, halogen, cyano, Ci-6 straight-chain alkyl, C3-7 branched alkyl, or cf3. Aryl is phenyl, biphenyl, and substituted or unsubstituted naphthyl. -10- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling in this Page), 1T 500723 A7 B7 V. Description of the invention (?) (Please read the note on the back first (Please fill in this page for more details) Unless otherwise specified, the above compounds refer to arylfluorenyl, containing benzylfluorenyl and fluorenyl, each of which may be substituted with one or more substituents selected from hydrogen, halogen, cyano, linear alkyl, C3-7 fluorene alkyl, Ci-8 alkanoyl, CF 3 or phenyl, this phenyl substituent can be optionally substituted with one or more substituents selected from fluorene, halogen, cyano, linear alkyl, The preferred alkyl group of Ca-7, or CF3, is benzylfluorenyl, (phenyl) benzylfluorenyl and pharmacofluorenyl, which are substituted or unsubstituted. If there is no special description for the above compound, heteroarylfluorenyl group refers to a 5- or 6-membered heterocyclic ring directly bonded to a carbonyl group, and contains 1 to 2 fluorenes selected from N, 0, or S heteroatoms, such as carbonyl or pyridinecarbonyl. . This heteroaryl group may be individually substituted with one or more substituents selected from the group consisting of hydrogen, hydrogen, cyano, C ^ e linear alkyl, C3-7 alkyl, or CF3. Unless otherwise specified, the aralkyl fluorenyl group refers to a benzylcarbonyl group or a naphthylcarbonyl group containing a C6 alkyl group, and the carbonyl group is directly bonded, in which the alkyl terminal is substituted with an aryl group, and the definition of the aryl group is as above. Unless specified above, aralkyl refers to benzyl or naphthylmethyl containing alkyl (preferably Ci-e alkyl, most preferably C & 3 alkyl), wherein the alkyl terminal is substituted with aryl, And the definition of this aryl group is as above. Unless otherwise specified, the above compounds refer to molybdenum, bromine, fluorine and iodine. Preferred compounds of the present invention contain: [2-chloro-4- (3-methylpyrazol-1-yl) phenyl]-(5 , 11-dihydro-pyridinepyrene [2,3-1)] [1,5] phenylpyridinediazepine-6-yl) -methyl-; [2-chloro-4-(5-methylpyrazole- 1-yl) phenyl]-(5, 1 1 -dihydro-pyridine hydrazone [2,3-b] [l, 5] phenylhydrazine diazepene-6-ylcarbazine, -1 1- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (β) [2-Bromo-4-(3-methylpyridine Bi-1 -yl) phenylbenzene (5 , 1B dihydro-pyridine hydrazone [2,3-b] [], 5] phenylhydrazine diazepine-10-yl) -stilbone; (5, U -dihydro-pyridine hydrazone [2, 3- b] [1,5] phenylhydrazine-6-yl)-(4-fluoro-2-trifluorotolyl) -methanone; (5, Π-dihydro-pyridinehydrazone [2,3- b] [1,5] Benzenediazepine-6-yl)-[4-(3 -methylazole-ί -yl) -2 -trifluorotolylbuprofen |; (5,1 1- Dihydro-pyridine hydrazone [2,3-b] [1,5] Benzene diazepine-6-yl) -f 4-(3 -methylpyrazole-1 -yl) -2 -trifluorotoluene 1-1 salt of methane] and methanesulfonic acid (5,11-dihydro-pyridine hydrazone [2,3-1)] [1,5] phenylhydrazine-6-yl)-f4- (3-methylpyrazol-1-yl)- 1: 1 salt of 2-trifluorotolyl] -methanone and hydrochloride; 4- (3-methylpyrazol-1-yl) -2-trifluoromethyl-benzoic acid methyl ester; 4-(3 -Methyl __- buquidyl) -2 -trifluoromethyl-benzyl acid; (5, Π -dihydro-pyridinepyrene [2,3-b] [1,5] phenylpyrene diazepine-10 -Yl)-[4- (5-methylpyrazol-1-yl) -2 -trifluorotolyl pyridine ring; (5,1 dipyridine-pyridinium [2,3-h] [l, 5] Phenyldiazepine-6-yl)-[2-trifluoromethyl-4- (3-trifluoromethyl-pyrazole-b-yl) -phenyl] -methyl;椋 Leopard's consumption report is privately printed (Please read the precautions on the back before filling this page) (5-methyl-5, 11-dihydro-pyridine hydrazone [2, 3-b] [l, 5 ] Benzyldiazepine-10-yl)-[4- (3-methylpyrazol-1-yl) -2-trifluoromethyl-phenylpropanone; (5,11-dihydro-_ ; 碇 骈 [2,3-1}] [1,5] Benzenediazepine-10-yl)-[2-fluoro-4 (3-methylpyrazol-1-ylphenylphenylbuprofen) Ketone; {2,4-difluorophenyl)-(5,11-dihydro-pyridine hydrazone [2, 3-b] [1,5] benzene-12- (CNS) A4 specification (210X297 mm) 500723 A 7 B7 V. Description of the invention (Η) 骈 Diazepine-10-yl) -methyl ketone; (5,] Benzodipine-pyridine hydrazone [2,3- b] [l, 5] Benzenediazepine-10-ylb [4-fluoro-2- (3-methylpyridin-1-yl) -phenylpropanone; (2 -chloro ~ 4- (3-methylpyrazole-butyl) phenyl)-(5-methyl-5,1 1-dihydro-pyridine hydrazone [2,3-b] U, 5] Benzene diazepine-1 0-kibbyl_; (2-chloro-4-fluorophenyl)-(5-methyl-5,11-dihydro-¾spinamidine [2,3-b] [1,5] benzenepyridine Azepine-10-yl) -a-ring; (5, 卜 dihydro-pyridine [2,3-b] [1,5] benzene azepine diazepine-1 0 -yl) -f 2- Methyl-5- (3-methylpyridin-1-yl) -phenylbupropionone; (5,1 1 -dihydro-pyridinepyrene [2,3 -b] [1,5] benzopyridine Acetane-6-yl) (5-fluoro [4- (3-Third-butyl-azozo-butyl) -2-trifluorotolyl]-(5,11-dihydro-pyridinium [ 2,3-b] [1,5] Phenyldiazepine-1 0 -yl> -methyl-; f 2 -chloro-4-(3-methylpyridyl-phenyl) phenyl]-( 1 1 H HI-4, 1 0 > • Diaz-diphenylhydrazone [ad] cyclohepten-10-yl) methyl_; [2-chloro-4-(3 -trifluoromethylpyridine -1 -yl) phenylphenyl (5,1 1 -dihydro-Bft) pyridine [2,3-b] [l, 5] phenylhydrazine-6-ylbutanyl-1; [2-chloro -4- (1-methyl- -yl) -phenylbenzene (5,11_dihydro via the central standard of the Ministry of Work and Consumers' Cooperation Private Label f (Read the precautions on the back before filling this page) Pyridoxine [2,3-b] [l, 5] Benzenediazepine-10-yl) -methyl-; [2-chloro-4 (bumethyl-3-yl) -phenyl]-(5 -Methyl-5, 1-dihydro-pyridine hydrazone [2,3-b] [l, 5] phenylhydrazine diazepine-10-ylbuproline 6, Π-dihydro-5 hydrazone-pyridine hydrazone [ 2,3-b] [1,5] Benzene diazepine-13- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 V. Description of the invention (^) [2- Chloro-4- (5-methyl2,4-triazol-3-yl) -phenyl]-(5,11-dihydro-Bttpyridine [2,3-b] [l, 5] benzene Diazepine-6-yl) -methanone; f 2-bromo-4- (3-methylBft oxazole-phenyl) phenyl]-(ΙΙΗ-5-Bf -4, 10-diazepine-diphenyl骈 Ud] cyclohepten-10-yl) methyl_; [4-(3 -methylpyridine-1 -yl) -2 -trifluorotolylb (1 1 Η-5 -Nato-4, 10 -di Acryl-diphenylhydrazone [ad] cyclohepten-10-yl) methyl_; [2-fluoro-4-(3 -Methylpyrazole-1 -yl) -2 -trifluorotolyl]-(1 1 Η-5 -Β 琴 4,1 0-diacridyl-diphenyl hydrazone [a · d] fluorene heptene-1 0- And methyl); and [2-chloro-4-(1-methylazol-3-ylbuphenylphenyl (11H-5-?-4, 10-diazepine-diphenylhydrazone [ad] cycloheptene -10-Base) Formamidine |. It has been approved by the Central Department of the Iodine Department and is only compatible with consumer cooperation printing (please read the precautions on the back before filling this page). Those skilled in this art will know that the compounds of the present invention are regarded as R 2, R 3, R 4, R s, R 6, R 7, Rs, X, Y and Z are defined, and can contain more than one asymmetric center to obtain optical isomers and diastereomers. The present invention contains all optical isomers and diastereomers with specific activity ; And racemic isomers and analytical isomers, enantiomerically pure R and S stereoisomers; and other mixtures of R and S stereoisomers and their pharmaceutically acceptable salts. Optical isomers can be obtained purely by standard methods familiar to those skilled in the art. It should be noted that the compounds of the present invention contain all regioisomeric forms and mixtures thereof having specific activity. This regioisomer can be obtained purely by standard methods familiar to the artist. Pharmaceutically acceptable salts contain organic and inorganic acids such as citric acid, lactic acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, hydrochloride, hydrobromide, phosphoric acid, nitric acid, sulfuric acid, formic acid Sulfonic acids, and the like are known to tolerate acids. -14- This paper size applies to Chinese National Standard (CNS) A4 specification (2! 0X297 mm). The sample rate in the Ministry of Economics and Industry is only for consumer cooperation. Private printing f 500723 A 7 B7 5. Description of the invention (A) The invention also provides a method for treating a disease, symptom, or abnormality that requires the activity of a vasopressin-acting agent, including a method for administering an effective amount of the compound of the present invention or a peony composition to humans and animals. Among them, it is necessary to release factor VIII and von Wilebrand factor to the circulation strip, release tissue type cytoplasmin activator (t-PA) into the blood, or affect renal water conservation and urine concentration. This treatment includes, but is not limited to, human diabetes insipidus, nocturnal urination, nocturia, urinary incontinence, or bleeding and clotting disorders. The method here includes a method for facilitating the temporary delay of urination for humans and animals, which can also be referred to as the inability to temporarily delay urination for control or treatment. This method includes the convenience of temporarily delaying the treatment of urination, which differs from nocturnal urination and nocturia. According to the present invention, there is provided a pharmaceutical composition containing a compound of the present invention in combination with a pharmaceutically acceptable carrier ^ In particular, the present invention provides a peony composition containing an effective amount of the compound of the present invention and a pharmaceutically acceptable carrier or excipient. This composition should preferably be administered orally. However, other methods of administration, such as parenteral administration, are also suitable for patients with heart failure. In order to obtain consistency of administration, the composition of the present invention should be used in unit dosage form / appropriate unit dosage containing tablets, capsules, and powder (small bag powder and vial powder. The unit amount can contain 0.1-1 G 0 0 mg of the compound of the present invention and preferably 2 unit doses containing 5-2 5 mg of the compound of the present invention. The compound of the present invention can be administered orally at a dose of 0.0 1-1 fl 0 mg / kg, and preferably 0.1-10 μg / Dosage in kg. This composition can be administered 1 to 6 times a day, preferably 1 to 4 times a day. The composition of the present invention can be formulated with conventional excipients such as fillers, disintegrating agents, binding agents, lubricants, fragrances , Etc. It can be used as required _ 1 5-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 > < 297 mm) (read the precautions on the back before filling this page), 1T __ 500723 A7 B7 V. Description of the invention (^) The method is prescribed as known antihypertensive drugs, diuretics and / 8-blocking agents. The invention also provides a method for preparing the compounds of the invention. Preparation method of the invention

The compounds of the present invention can be prepared by any of the following methods. Compounds of formula (I) wherein W is 0 or NR6 and R6 is hydrogen can be prepared by the following reaction scheme I. Process I

It has been printed by the central sample rate for consumer cooperation (please read the precautions on the back before filling this page) because of the existence of inorganic osmium such as potassium sulfonate, and non-proton such as dimethylformamide In an inert polar solvent; or an organic hydrazone such as 4-dimethylaminopyridine, or an aprotic inert solvent such as dichloromethane or tetrahydrofuran, at -40 ~ -16- This paper applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) 500723 A7 B7 V. Description of the invention (Through the central sample M 中央 Consumer Cooperative Printing f 50 ° C treatment to properly substituted haloaryl fluorenyl (heteroaryl fluorenyl) _ compound, should be The intermediate awakening derivative (3) can be obtained by the formula (2, J = C0C1) fluoroarylfluorenyl or fluoro (chloro) heteroarylfluorenyl chloride. In addition, the sulfonium compound can also be a mixed anhydride with respect to a carboxylic acid, For example, according to Instnaga et al., Bull. C hem. S oc. J pn. Chlorobenzyl chloride. The mixed anhydride of formula (2) is dissolved in a solvent such as dichloromethane in the presence of an organic base such as 4-dimethylamine pyridine. The intermediate tritiated derivative (3) of reaction scheme I can be obtained by treating pyridine, benzodiazepine, and diazepine (or benzodiazepine) with the formula (1) at a temperature between 0 and the reflux temperature of the solvent. ) The compound is treated in an aprotic inert solvent such as dimethylformamide (or tetrahydrofuran) at room temperature to the temperature just under the reflux temperature. The formula (4, where R1 is a, b, c, d,],! 1, or 0) A suitably substituted heterocyclic pin (potassium or lithium) salt can be obtained as a compound of formula Π), wherein W is 0 or NΗ, and A, B, X, Y, Z, R The definitions of 2, R 3, and R s are as above, R s is hydrogen, and R 1 is a fluorene ring. The above is selected and the lanming is as follows: a., B, e, d, 1, η, Or 〇 group., Q, 〇Ά

(a) (b) R2 (c) (d) (Please read the notes on the back before filling out this page) R2 ① ⑻

(Ny2 Ά N = N N == / H

R2 -17- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (Shi) The intermediate product of formula (3) can be different from the salt of intermediate product of formula (4). The regioisomers of the formula (1) can be separated by chromatography and / or crystallization in reaction scheme I. The preferred formula (2) substituted fluoroarylfluorenyl and fluoro (chloro) heteroarylfluorenyl chloride are commercially available. It can be obtained or known in the literature, or can be prepared according to similar methods of the compounds known in the literature. In Reaction Scheme I, the formula (4, where R1 is selected from the group consisting of a, b, c, d, 1, II, or 0) of a heterocyclic sulfonium ring (potassium or lithium) salt may be -4fl ° C to room temperature under aprotic inert solvents such as dimethylformamide or tetrahydrofuran, such as sodium, potassium or lithium hydride or aurantium chloride to obtain. In addition, look at the formula (1) in Scheme I The compound can be obtained according to the preparation method of Reaction Scheme II. (Read the precautions on the back before filling out this page) .—

, 1T

Process I I

The Central Economic Commission of the Ministry of Economic Affairs and Economic Cooperation

(7) J = COOCH3 (8) J = COOH

-18- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 OX297 mm) 500723 A7 B7 V. Description of the invention () Therefore, formula (5) has appropriately substituted fluoroaryl or fluoro (chloro) heteroaromatic carboxyl The acid can be used in conventional methods, such as in the presence of a catalytic amount of dimethylmethylamine, treated with an alcoholic solvent (methanol) containing chlorammonium chloride or sulfonyl chloride, or in the presence of an acid catalyst such as It is esterified by condensation with methanol at room temperature to the reflux temperature of the solvent. An ester of formula (6) in a polar aprotic inert organic solvent such as dimethylformamide at room temperature to the reflux temperature of the solvent, and an appropriate formula (4, where R 2 is a , b, c, d, 1, n, or 0) substituted fluorene sodium (potassium or lithium) salt reaction to obtain the formula (?) intermediate ester ^ (6) condensation can be obtained in (4) different formulas (7) Regioisomers, which can be separated by chromatography and / or crystallization. Hydrolysis of the intermediate ester of formula (7) with, for example, NaOH-containing methanol (or Na Li in tetrahydrofuran) can provide a carboxylic acid of formula (8). The intermediate carboxylic acid of formula (8) can be converted into a halogenating agent using any of the foregoing methods, and is preferably a chlorine or mixed anhydride of formula (9). The compound of formula (1) in reaction scheme I can be obtained by condensing pyridine, benzene, diazepine (or phenylhydrazine_azepine) with formula (9) according to any of the previous methods, wherein R1 is Is selected from the group a, b, c, d, 1, η, or 0 of the upper ring group. Printed by the central sample of the Ministry of Justice and cooperating with the labor and consumption (read the precautions on the back before filling this page) The appropriate formula (5) in Reaction Scheme II has been substituted with fluoroaryl or fluoro (chloro) fluorenyl aryl carboxyl The acid is commercially available or known in the literature, or can be prepared according to similar methods for compounds known in the literature. In addition, the substituted carboxylic acid of formula (8) in the reverse orbital scheme I I can be prepared according to the reaction scheme I I I. -1 9- This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 500723 A7 B7 V. Description of invention (彳)

Process I I I .R 1 -H (4)

Isolation of hydrolysis R1

HOO (10 Y is not CF 3) (8, R a, b, c, dJ, n, o) The central sample of the M part is accurate and negative. Consumption is reported as f. Formula (10) is fluoroaryl or fluorine (Chloro) heteroaryl is in a polar aprotic inert organic solvent such as dimethylformamide, at room temperature to the reflux temperature of the solvent, with the appropriate formula (4, where R1 is a , B, c, d, 1, hydrazone, or 0 group) substituted heterocyclic sodium (potassium or lithium) salt reaction to obtain the intermediate product of formula (11). Condensing (10) with the intermediate product (4) can obtain regioisomers of formula (U) in different proportions, which can be separated by chromatography and / or crystallization. The intermediate nitrile of formula (11, where Υ is not CF3) is preferably hydrolyzed in the presence of dilute sulfuric acid and at room temperature to 60 ° C. In addition, the hydrolysis of nitrile (Π) can also be carried out in the presence of a strong solvent such as NaOH and an alcohol solvent such as ethanol, and heating in the absence of a phase transfer catalyst such as benzyldimethyltetradecylammonium chloride. The obtained carboxylic acid of formula (8) is converted into the target compound of formula (1) in Reaction Scheme I according to a similar method as described above, wherein R1 is selected from a, b, c, d, 1, ii, or base. The substituted fluoroaryl or fluoro (fluorene) heteroaronitrile of the appropriate formula (10) in Reaction Scheme III is commercially available or known in the literature, or can be prepared according to a similar method for compounds known in the literature. In addition, the formula (8, where R1 is not b or d) in reaction scheme II has been taken. -20- Please read the notes on the back first.

500723 A7 B7 V. Description of the invention The preparation of the (t9) carboxylic acid intermediate can be as shown in Reaction Scheme IV. According to Kartritzky et al., Synthesis, 949 (1989), formula (11, where A and B are C, and R 1 Is selected from the a, c,]., Η, or 0 groups of the above heterocyclic group, but is not the b or d of the above heterocyclic group) treated with dimethylperoxide containing hydrazone peroxo; and then the formula ( 12) Amidoamine should be hydrolyzed by diluting sulfuric acid and sodium nitrite according to the method of Hales et al., Tetrahedron, 51, 7 403 (1 995).

Process IV: Wenyi produces gas sense (12) (1), RV is not b or d> (8, A and B = sulfo R 1 = a, c, e, l, n, t 〇 is not b or d ) The preferred method for preparing the substituted carboxylic acid intermediate of formula (8) in reaction scheme II is shown in reaction scheme V, where R1 is a group selected from the above Ri heterocyclic groups. (Read the precautions on the back before filling this page ) The paper is printed in accordance with the standards of the Ministry of Industry and is only for private consumption. This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 V. Description of the invention (Process VΥΆ (13) J = COOCH3 Ambient Logic-^ one (14) J = COOCH3 ^ V ^ nhnh2 HC1 (15) J = COOCH3 O R3 P (35) hydrolysis

JxV ^ B ^ person 2. Crystal

(7) J = COOCH3 (8) J = COOH

Z (Read the precautions on the back before filling in this page) (9) The brewing part (IW = 0, NH; R ^ a) The central sample rate of the Ministry of Decoration is responsible for the printing of consumer cooperatives. Therefore, the formula U 3) Appropriate substituted aniline diazotization, and then according to the method of Street et al., J. Med. Chei., 36, 1529 (1993), the diazonium salt of formula (1 4) is concentrated in tin (II) chloride. Reduction in hydrochloric acid gives the intermediate well hydrochloride of formula (1 5). (1 5) is condensed in a solvent such as methanol and at room temperature to 10 fl ° C to formula (3 5, where R 2 and R 5 are as defined above, R 3 is hydrogen, and P is dioxal acetal) Aldehyde derivatives such as acetoacetaldehyde dimethyl acetal, or formula (35, where R2 and RS are as defined above, R3 is not hydrogen, and P is 0 or country) -22- This paper size applies Chinese national standards ( CNS) Α4 specification (210X297 mm) 500723 A7 B7 R3

V. Description of the invention (^ Ketone (or ketone derivative), after crystallization, formula (7, where Ri is selected from the above heterocyclic group) can be converted to formula (I, formula according to the above reaction scheme II) In the above, R1 is a heterocyclic group a) selected from the above and ramming is as follows. R6 is not 氲, and R1 僳 is selected from the above heterocyclic groups a, b, c, d, 1, η, or 〇, It can be prepared by alkylation or deuteration of the intermediate product of formula (3, W = NH) according to Reaction Scheme VI. (Read the precautions on the back before filling this page) Consumption cooperation Zhao Yin ^ This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 500723 A7 B7 V. Description of invention (")

Process VI

(Please read the precautions on the back before filling this page) The central sample rate of the sludge department is Λ 鈒, the consumer cooperation is private printing, and the anti-dusting process I Chinese formula <3, W = NH) intermediate compounds such as dimethylformamide An aprotic, inert solvent of amine or tetrahydrofuran, treated at 0-80 ° C with a base such as NaH (or KH) and an alkylating agent such as an alkyl halide (preferably an alkyl chloride (bromine or iodine)) The compound of formula (16, where A, B, X, Y, Z, and R6 are as defined above) is obtained. In addition, the compound of formula (3, W = NH) in reaction scheme I is present in the presence of an amine base such as pyridine or triethylamine In an aprotic inert solvent such as dichloromethane (when -24- this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 500723 A7 B7 V. Description of the invention (4 agent structure dissolve, what is the right word) The acid is not carboxylated or the halogen acid is exposed to carboxyl to lower the temperature in the X chamber, B to ° CA, 40 in formula i, methyl formaldehyde is combined with the alkyl group or the alkyl group to form a compound. 6) The formula in R is as defined in the formula, β is defined as 1 8 in R formula and the formula Z is dissolved in R1 machine. At lower temperatures agent solution to flow back to the room temperature and the white-yl Jing said heteroaryl is selected from d Jing or heteroaryl group is bonded substituting for a given

For and ⑻ R2

The formula is obtained, the base &gt; HR1 or alkoxide, the sodium on the alkane is as defined below. I *-lithium or potassium

A

X white choose B, the basic ring is (please read the notes on the back before filling this page) d base ο or R2

, 1T S 'R2 (d)

, N \ 1/2/7% | 1 R2 pounds, the central sample rate of the Ministry of Consumers, only the consumer cooperatives, India, f, the system is a legal system (I, phase formula and intermediate VI in the alkylation process, the flow VI has been Cheng Cheng should submit a counterfeit essay, which should be relied on externally or Cheng Liu should reciprocate (0) to sell an It-ftT Hehua knows that the paper has been submitted or produced by DEK. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) .— 500723 A7 B7 V. Description of the invention (-0

The central standard of the Ministry of Economic Affairs and Industry Co., Ltd. printed organic solvents at room temperature to the reflux temperature of the solvent and the appropriate formula (4, where R 1 is a, b, c, d, 1 selected from the above heterocyclic groups. , η, or 0 group) The substituted heterocyclic sodium (potassium or lithium) salt can be reacted to obtain an intermediate product of formula (I, where W is NΗ). This intermediate product can be directly alkylated (or ) To obtain the target compound of formula (I, where W is, and R6 is alkyl or fluorenyl). This method can be used to obtain formulas of different proportions (I, where W is NR 6 and R. 6 is alkyl or radical; A, B, X, X, Z, R2, R3, R4 and R5 are as defined above, and R1 is the fluorene ring moiety as defined in Reaction Scheme VI) regioisomers. Regioisomers of formula (I) can be separated by chromatography and / or crystallization. Compounds of formula U) in Reaction Scheme I (wherein A and B are sulphur, R2 is hydrogen, and R1 is a heterocyclyl lotus root heterocyclic g group) can be prepared according to Reaction Scheme V U I. -26- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 V. Description of the invention (&gt; 〇 Submerged vm Υ ^ ςχΒΓ (17) J = COOMc (18) J = COOMe

Line ▲ r4nhnh2 — (36) ’(20) J = COOMe (main) separation

Mii’Ministry of Central Standards and Border Bureau, Shellfish Consumer Cooperatives, India, 11

(23) j = brewing fraction J: COOH (22) This paper size applies to Chinese national standard (CNS &gt; Λ4 specification (210X29 * 7 male 500723 Α7 Β7) V. Description of the invention (&gt; ί〇

(Read the precautions on the back before you fill in this page) I (W = 〇, ΝΗ; Α, Β = 破; RU g) The substituted heteroaromatic carboxylic acid ester will be appropriate, which should be formula (17, where A and B is sulfo) bromide (or iodo) benzyl methyl ester) in the presence of catalysts such as bis (triphenylphosphine) lead (II) chloride and copper (I) iodide, and organic bases such as triethylamine Is a solvent at room temperature to 80 ° C, coupled to A 1 a roi et al., T etrahedr ο η L et, t., 3 4, 6 4 G 3 (1 9 9 3 &gt; Dialkylamine propyne provides a substituted acetylene intermediate product of formula (18). The intermediate product (18) is subjected to any standard gasification method (see A1 bini, Synthesis, 263, (1 99 3)) or _ Alkane (see Murray, Cheme Rev., 1 187 (1989)), the non-proton inert gas such as digas methane passes the central standard of the M part and the consumption cooperation prints common organic solvents and is below room temperature This intermediate N-oxide can be used without any method of Diishin et al. It can be rearranged in vitro to a formula (19) by heating with a hydroxyl solvent such as methanol. This method provides novel By propargylamine ( Or its N-gas), a method for synthesizing enamine ring compounds in a hydroxyl solvent (the final reaction result of alum). This novel method for synthesizing enamines provides another convenient method in the existing method, and the expansion can be converted into The raw material range of the enenone product. Although the precise mechanism for the conversion of propargylamine N-oxide to the enamine round product is not yet 28, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 — ——______________ — --- 5. Description of the invention (&gt; 7) (Read the precautions on the back before filling this page) Clearly, it is similar to two known methods: propargylamine N-gas heat f2, 3 Isigmatropic rearrangement again (Craig et al., Tetrahedron Utt., 4025, (1979); Hallstrora, et al., Tetrahedron 1 "11:., 667, (1980); 1 ^ 111: 11161 ', for, 1! Etc. People, 1 (^ 6 Seoul · Soe. Chew. Coffiroun ·, 9, (1979) and the conversion of specific isomers to enamines I (Liguori et al., Tetrahedron, 44, 1255, 1988). Will (19) Treated with acetic acid which has been substituted with rhenium (36) at room temperature to the temperature of the painting flow, different formulas can be obtained ( 20) and regioisomers of formula (21). The main isomers of formula (20, where R2 is H) can be separated by chromatography and / or crystallization, and then hydrolyzed to obtain the target carboxylic acid of formula (22). The intermediate product (22) can be converted into a hafnium compound according to the previous method, and it is preferably a chlorine (bromine or iodine) of formula (23) or mixed hafnium. This acidification ((2 3)) can be used to further purify the pyridine, phenyl, diazepine (or phenyl _ B yaheptene) according to the aforementioned method to obtain the target compound of formula (I), where W is 0 Or NH, &amp; and 8 are C, X, Y, Z, and R 4 are as defined above, R 2 is hydrogen, and R 1 is a heterocyclic group. After all the central standards, only the consumer cooperatives printed the land 6, like (3

Take 4 not {according to the formula in the place of X at the temperature of I should be reversed to obtain the solvent soluble acid to the room of B temperature H) where is the nitrogen ring _ I This formula C is the conversion of the material and the intermediate ester In the case of azole compounds, H) is 4 and yl is hydrazone or alkane and alkoxide can be combined. Xi is ο, where 中 is a radical of gigantic as defined above, and 如 is selected from J. Is a B ring and heteroA is

X and basic paper size apply Chinese National Standard (CNS) A4 specification (11¾¾¾7mm) 500723 B7 V. Description of invention (W) mm ii

JM alkyl 12 Ο (t9y J ^ COOCH, νη2νη2 -► (36, R4 = Η)

(24) J = COOCH3 dazzling or brewing_ Base

R4

R (please read the notes on the back page again) (21) J = COOCH3 (Main) (20) J = COOCH3 89) Isolation Hydrolysis γ

5Γ-11 rounds in the center of the immersion department oc_T- Consumption together bamboo shirt print $ (26) J = surface area

(25) J = COOH

• 30_ Wooden paper scales use the Chinese national standard cockroach ((1 ^) 8 4 gauge (^ 0 'dog 297 males) 500723 Μ Β7 V. Description of the invention (#) In the formula (24, where R2 is Η , A and B are C) in an aprotic inert solvent such as dimethylformamide or tetrahydrofuran, and treated at 0-80 ° C with an alkylating agent such as NaH or KH and an alkylating agent such as an alkane window (preferably Alkyl chloride (bromine or iodine)) can be obtained by alkylation in different proportions of the regioisomers of the formula (20) and (21) ^ formula (21) main regioisomers can be separated by chromatography and / or crystallization Then, the target carboxylic acid of formula (2 5) can be obtained by further hydrolysis, and then converted into a halogenating agent according to the foregoing method, preferably chlorine or mixed rhenium. Then, this halogenating agent (2 6) can be used to dilute pyridine of formula (I) Phenylhydrazine ("Yaquinine") (or phenylhydrazine) yields the target compound of formula (I), where W is 0 or NΗ, A and B are C, X, Y, Z, and R4 are as defined above, R. 2 is hydrogen, and R 1 is heterocyclyl, as above, and lanmine is the f group of the following fluorene ring group. (Read the precautions on the back before filling this page)

The target compound of the formula (I), wherein W is 0 or NH, A and B are C, and R1 is the h group of the above-mentioned heterofluorenyl group, which can be prepared according to Reaction Scheme X. The central sample rate of the Ministry of Economic Affairs and Economics is only printed by consumer cooperation. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 500723 A7 B7 5. Description of the invention (knowledge)

Process X

(Please read the precautions on the back before filling in this page.) After the central sample of the Ministry of M and the consumer cooperation cooperation, Layin Fan will replace the appropriate formula (2 7) with malonaldehyde at room temperature to the reflux temperature of the solvent. The intermediate product is acetic acid, and the intermediate product, pyrazole, is oxidized with potassium permanganate in a basic solution at room temperature to the reflux temperature of the solvent to obtain a carboxylic acid intermediate product of formula (2 8). The acid (28 &gt;) is converted into a halide according to the previous method, preferably an atmosphere (bromine or iodine) or a mixed phrase. The halogenating agent (2 9) and the pyridine, benzene, diazepine of formula (I) can be used again. The target compound of formula (I) can be obtained by (or benzodiazepine) reaction, wherein W is 0 or NH, A and B are C, X, Y, Z, and R4 are defined as above, and head R 1 is heterogeneous. The fluorene group is selected as above and the h group of the heterocyclic group is clarified as described above. -32- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7. Print

5. Description of the invention (V

The preferred formula (2?) Malonaldehyde and hydrazone (36) in reaction scheme X are commercially available or known in the literature, or can be prepared according to similar methods for compounds known in the literature, such as Knorr et al., 0 rg. Chem ·, 49, 1 2 8 8 (1 984) ¾ Copploa et al., J. Het. Che® ·, 5 1 (1 9 7 4) 〇 Another preparation reaction scheme X in formula (28) intermediate carboxylic acid (where Y Definition is as above and R.4 is not hydrogen) as shown in Reaction Scheme XI. Process X I

BXr (30) I W R3§ 丨 (31) Coupling (Read the precautions on the back before filling this page) • —gt.

(33) J = COOCH3 (34) J = COOCH3

(28) J = COOH (R4 is not Η) -33 This paper size applies to China National Standard (CNS) A4 (210X297 mm) ^ / 23 A7

The Central Department of Qingyi Department is accurate and only works in consumer cooperatives. Yinfan 1. Description of the invention (々 &gt;) Rotary type (3U organotin reagent based on Farina .A, J.Org.Cheni ·, 59, 5 9 0 5 (1 9 9 4) method in the presence of a catalyst such as tetra (triphenylene) lead (0) ¾ copper (I) iodide, in an aprotic organic solvent such as dimethylformamide, in Coupling reaction with Sti lle at room temperature to 150 ° C and _ when substituted aryl (heteroaryl) _, it is preferred to react with bromine (or iodine) of formula (3 4). The obtained ester of formula (3 2) in alcohol Or lithium hydroxide, hydrolyzed with tetrahydrofuran and room temperature to the solution temperature and NaOH to obtain the anti-plugging formula X in formula (28), intermediate m-carboxylic acid. Reaction scheme XI in formula (3 1) organotin reagent (where R should be fluorenyl) can be prepared according to the method of Martina et al., Synthesis, 8, 613 "1991", the formula (3D) 4-bromoalkane_wow in the presence of gold gull reagent such as n-butyl lithium, such as ether It is an aprotic inert organic solvent, which is obtained by metallizing a trialkyltin compound (preferably tributyltin chloride (or bromine)) at -40 to room temperature. In reaction scheme XI, the preparation of the preferred formula (30) of the substituted alkyl group can be 4-bromo adducted in the presence of a base such as NaH (or KH), in aprotic Organic solvents, alkylated at 0-80 ° C to alkyl (preferably alkyl chloride (bromine or iodine)). In addition, the alkylation of 4-bromopyrazole can also be used in the alkylating agent, And a strong catalyst such as Nao, which is present in phase transfer catalysts such as benzyldimethyltetradecyl ammonium vaporization or benzyltrimethyl chloride (see Jones, Aldrich iinica Acta, 9, 35 (1976)) The preferred formula (3 4) aryl (heteroaryl) iodine in the reaction scheme χ I can be diazotized by the formula (3 3) relative to the substituted aniline, followed by Street et al., J. Med. Chem., 3 6, 1 5 2 9 (1 9 9 3) and Coffen et al., J. Org · Cheeu, 49, -34- This paper size is applicable to China National Standard (CNS) A4 (21 OX297 mm) (read first Read the notes on the back and fill out this page) — ·

1T 500723 A7 B7 V. Description of the invention) 29 6 (1 98 4) is prepared by reacting a relatively diazonium salt with potassium iodide in an acidic matrix. The compound of formula (I) can be prepared by the following method. As shown in Reaction Scheme XI ，, the formula U) pyrimidine benzene benzodiazepine (or benzene 骈 栲 B aheptene) according to any of the foregoing methods has appropriately substituted the acetamidine (fluorenyl) halide, Preferably, the reaction of formula (3 7, J = C 0 C1) acetamidine (heteroarylfluorenyl) chloride can obtain a tritium derivative of formula (3 8). (3 8) According to the method of Li η et al., J. H et. Dialkylammonium dioxane is condensed as shown in the formula (39, wherein the alkyl group is C Η 3) dimethylamidamine dimethyl acetal to obtain the formula (40). The target compound of formula (I) can be obtained by treating (4 D) at room temperature to the reflux temperature of the solvent with acetic acid of the formula (3 6) hydroxylamine or substituted well, wherein W is 0 or Ν, Α, B, X, Υ, Z, R2, and R4 are as defined above, and R 1 is a 雑 璟 group. The custom group is as described above and Lanming's f, g, or j group is as follows. (Please read the notes on the back before filling this page)

, 1T

The Central Ministry of Economic Affairs, China ’s Consumers ’Cooperative Association, f. Reaction Process X, 较佳 The better formula (3?) In the formula (3?) Has been substituted for acetamidine (heteroarsynyl). It is prepared by treating with sulforamidine chloride or aprotic inert solvents such as digasmethane or tetrahydrofuran in the presence of dimethylformamide and 0-40 ° C. -3 5-This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) 500723 A 7 B7 V. Description of the invention (from) (Read the precautions on the back before filling this page) Reaction Process X ϊ I The preferred medium (3 9) dialkylamidinedioxal acetal is commercially available or known in the literature, or can be prepared according to similar methods for compounds known in the literature (see Kantlehner, Chem. Ber ·, 105, 1340 ( 1972) 〇

Process X I I

Another method for preparing the intermediate product of formula (38) in reaction scheme X I I is shown in reaction scheme X I I I. Approved by the Central Government and only printed by consumer cooperatives f -3 6- This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 V. Description of the invention (from process X ΐ ϊ ϊ

ζ HC = C—R9 (53) age__ι Pd / Cu

Br

(Please read the precautions on the back before filling this page) MM Central Samples ^ Only the consumer cooperative seal t will be the formula (1)% pyridinium benzodiazepine (or benzodiazepine) The above method is used to treat the substituted bromoarylfluorenyl (heteroarylfluorenyl) compound, which is preferably a bromoarylfluorenyl (heteroarylfluorenyl) gas of formula (4 2) to obtain a halogenated intermediate product of formula (4 3). . The intermediate product (43) was prepared according to the method of Martinez et al., J. Med. Chem., 52,3491 (1 987) in the presence of, for example, pyridine and bis (triphenyllin) platinum (II) chloride and iodination. Under the copper (I) catalyst, it is coupled to the formula (5 3 in a closed pressure tube at room temperature to 100 ° C in organic tritium such as triethylamine as a solvent and R 9 should be trimethylsilyl or C i-e lower alkyl) mono-substituted acetylene c »the intermediate product of formula (4 4) acetylene according to Reed et al., J. 0 rg. C he ro ·, 5 2, 3 4 9 1 (1 9 8 ?) Method, such as tetrahydrofuran in an aprotic inert solvol saturated with mercury (II) sulfate treatment with 1% sulfuric acid to hydrate to obtain the target compound of formula (38), where W is 0 or NH, A, B, X, Y, -37- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. The invention description (work) and Z are as defined above, and R 9 is hydrogen or C i — elow alkyl. In addition, the compound (44) in which R9 is trimethylsilyl can be treated with diethyl ether solvent such as tetrahydrofuran to fluorinate n-butylamine to obtain compound (4 4) in which R Q is hydrogen. The preferred formula (42) in the reaction scheme XII 1Ϊ can be treated with a substituted formula (41) substituted aryl {heteroaryl) carboxylic acid at room temperature to the reflux temperature with sulfonium chloride, or in the presence of digas methane or Tetrahydrofuran is an aprotic inert solvent. It is prepared by treating with dimethylformamide and 0-40 ° C in the catalyst amount. The acetylene intermediate (5 3) in reaction scheme XIII is commercially available or known in the literature, or can be prepared according to similar methods of known compounds in the literature. Β As shown in reaction scheme XIV, the acetylene intermediate in reaction scheme XII (38) The preparation is mainly based on the method of Kosugi et al., Bull Chew. Soc. Jpn., 60, 7 6 7 (1 9 8 Ή), in the presence of a catalyst amount of bis (triphenyl_) platinum (II) chloride, in For example, aprotic inert organic solvents of toluene and the reaction temperature from room temperature to the reflux temperature of the solvent, Stil] e coupling reaction formula (43) bromine (fluorenyl) compound is shown in (X-alkane vinyl) Alkane is preferably (a -Hi gas vinyl) tributyltin of formula (45).

Process X I V

-38- Private Printing of Central Samples of MM Department

(Read the precautions on the back before you fill in this page.) This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 5. Description of the invention (shirt) Preparation of acetamidine compound (38) Nong Cabri et al., Tetrahedron Le 11 ·, 3 2, 1 7 5 3 (1 9 9 1), a vinyl alkyl ether platinum-catalyst such as ethylene butyl ether was aromaticized with formula (4 3) Intermediate products. The (α-alkanevinyl) trioxane intermediate (45) in the anti-plugging process X IV is commercially available or known in the literature, or can be prepared according to a similar method for compounds known in the literature. Compounds containing one or more heteroatoms can be prepared according to Reaction Scheme XV. (Read the precautions on the back before filling this page) -1¾.

， 1T Printed by the Central Ministry of Economics and Consumers Cooperatives of the Ministry of Economic Affairs -3 9- This paper size applies to the Chinese National Standard (CNS) Α4ίΙ (210X297 mm) A7 B7 V. Description of the invention (々〇

Process XV

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 500723 A7 B7 V. Description of the invention (shirt) The formula (1) pyrimidine benzophenone diazepine (or phenylpyridine Bi azepine) ) Processed according to any of the above methods to appropriately substituted hafnium aryl "heteroaryl" halides, preferably a cyanoaryl (heteroaryl) group of formula (46). An intermediate nitrile of formula (54) can be obtained. The intermediate product (5 4) is treated at room temperature to 50 ° F. The inorganic acid with sulfuric acid can be converted into intermediate amine of formula (47). Treat (47) in an aprotic inert organic solvent such as dichloromethane or tetrahydrofuran at 0 to 8f) ° C with dialkylamine dialkyl acetal, such as formula (39, wherein the alkyl group is CH3) dimethyl The intermediate dimethyl acetal can obtain the intermediate product of formula (4 8). The target compound of formula (I) can be obtained by treating (4 8) at room temperature to the reflux temperature of the solvent with acetic acid of the formula (3 6) hydroxylamine or substituted well, wherein W is 0 or NH, A, BX, Y, Z, R2, and R4 are as defined above, and BR 1 is a fluorene ring group. The above-mentioned heterocyclic group is e, or k, as described above. (Please read the notes on the back before filling this page)

y: y r4 &lt;

The VX process flow in the amine acid should be prepared 1 The other is that the process flow in B and A should be reversed to the sulphur type. The appropriate will be replaced by the sulphur for B and the central sample rate of the laboratories. Human and other water _ method will be 0)) / ΙΛ 9 (V 98 amine (1 醯 49, 9 is es Ke thfil yn sub S A, hydrogen two zk. Huat oxygen rt over Ka sex depends The basic nitrile is based on the aromatic formula as the conversion method (1 any formula 1 *-Bfc, then the method is repeated, and the compound can be used to make any acid using carboxyl to make C decompose the water content 2) Ministry {5 骈 Benzene 骈 腚 UW β is based on \ * / indine acridine Ⅰ benzene or / 1 in acridine diamine 囲 DEK carbon as B and this paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 500723 A7 B7 V. Description of the invention (eg)

(52> J = Brewing part (47 Α, Β = 0 = 硪) (Please read the notes on the back before filling this page) Another method for preparing compounds of formula (I) in reaction scheme XV, where W is 0 or NH and R 1 are selected from the heterocyclic group e or i as above, and R 4 is not hydrogen, as shown in reaction scheme XVII. After the central standard of the M department, only the consumer cooperation private printing f paper The scale is applicable to the Chinese National Standard (CMS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (4 ·

Process XVII (50) J = COOCH3 Τλ R4_H2-► N ~ N weave) 2 -► (39) T (36) (55) J = COOCH, water m (read the precautions on the back before filling this page) 鳑Central Ministry of Economic Affairs and Consumer Cooperatives

(56) J = COOCH3 (57) J = COOH (R1 = e, i and R4 do not edit H)

The intermediate product of formula (5 5) can be obtained by using a dioxane-amine dioxal acetal, such as formula (39, wherein the alkyl group is C H 3) dimethylformamide dimethyl acetal. The intermediate tri-ester of formula (5 6) can be obtained by treating <5 5) with acetic acid having a substituted well of formula (36) from room temperature to the solvent reflux temperature. The ester (5 6) is hydrolyzed with the formula (5 7, wherein R 1 is a heterocyclic group, and the e or i group is selected as above and R 4 is not hydrogen). The carboxylic acid is -43- This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (heart) According to the above method, it will be converted to _ chemical surface, which should be formula (58) chlorine or mixed words. The compound of formula (I) can be obtained by using the compound (58) to convert the formula (1) to 8ft pyridine, benzodiazepine (or benzodiazepine), wherein W is 0 or NH, A, B , X, Y, Z and R 2 are heterocyclic groups. The above are selected from the above and the e and i groups of the following heterocyclic groups are shown, and R 4 is not hydrogen.

Another method for preparing a compound of formula (I) in reaction scheme XV, wherein W is 0 or NH, R1 is a fluorene ring group, and the e or i group of the heterocyclic group is as above, and fluorene 4 is not hydrogen. XVIII. (Read the precautions on the back before you fill in this page.) The central standard of the Ministry of Economics and Economics, cooperation and printing f -44- This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) 500723 A7 B7 V. Description of Invention (〇

Process X V I I

(36, R4 = H) nh2nh2

mumit hydrolysis bell V-R2 N _ j = cooch3

(61) J = COOH

(Please read the precautions on the back before filling out this page) The central sample rate of the Ministry of Economic Affairs and the consumer cooperative, Yin Fan, will process the intermediate formula (5 5) of reaction process XVII at room temperature to the solvent reflux temperature to treat the unsubstituted trap ( 36, wherein R4 is the acetic acid of acetic acid, and intermediate triazole ester of formula (59) can be obtained. At this time, the heterocyclic nitrogen can be alkylated or tritiated according to the previous method to obtain a substituted triazole_ of formula (60). The _ (60) is hydrolyzed with a carboxylic acid of formula (6 1), and then converted into a hydrazone according to the method described above. It is preferably a formula (6 2) chloro or mixed anhydride, so that -4 5-This paper is applicable to China. Standard (CNS) Α4 specification (2 丨 0X297 mm) 500723 A7 B7

N—N · Η V. Description of the invention (M with a chemical agent (6 2) with a chemical formula (1) of pyridine, benzene, benzodiazepine (or azepine such as benzene, β) can obtain formula (I ) The compound of interest, in which W is 0 or N Η, X, Υ, Z, A, B, and R, 2 are defined as above, R 1 is a heterocyclic group, and the e and i groups of the fluorene ring group are selected, and R 4 It is not hydrogen. In addition, the reaction scheme XV is a compound of formula (I), wherein W is 0 or NH, A, B, X, Y, Z and R2 are as defined above, R1 is a heterocyclic group, as defined above and the following heterogeneous The e or i group of a fluorenyl group, and R4 is hydrogen, can be a compound of formula (I) from Reaction Scheme XVIII, wherein R4 is an optionally substituted aralkyl group, preferably p-chlorobenzyl, Nong Buckle, A, J. Chew .Soc. Perki η · T rans · 1, 6 2? (1 8 2) method is prepared using a series of hydrogenolysis or treatment at 0-reflux temperature with a strong acid such as trifluoroacetic acid.

YV Η.Ν—Ν e (R4 = H) i (R4 = H) The compound of formula (I) is preferably prepared, wherein R1 contains 4 heteroatoms, W is 0 or NH, and MR4 is hydrogen. The preparation method is as follows: XIX.

Process X I X (Please read the notes on the back before filling in this page) ^ ... via the central sample rate ΛΜ Η consumer cooperation 4i 印 t

NaN3, NH4C1 DMF X-ceP &quot;

This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 500723 A7 B7 V. Description of the invention (W) The intermediate product of formula (5 4) nitrile in reaction scheme XV is used as dimethylformamide An aprotic inert organic solvent, treated at room temperature to the solvent reflux temperature, and treated with sodium hydrazine and ammonium chloride to obtain the target compound of formula (I), wherein W is 0 or Ν, Α, Βχ, Y, and Z are as defined above, R1 is a heterocyclic group as described above and the m group of the following heterocyclic group is shown, and R4 is hydrogen.

R1 =, S NN m (R4 = H) compounds of formula (I), wherein R1 is a heterocyclic group selected from e, f, g, h, i, .1, or k, W is NR6 and R6 is not hydrogen, The preparation method can be obtained by alkylating or deuterating reaction schemes VIII, IX, X, XII, and XV as shown in reaction scheme XX).

Process XX (Read the notes on the back before filling in this page)

Printed by the central sample rate of the Ministry of Industry and Technology

1 (from process Vlli) I (W = NΗ; A, B = sulphur; R 1 = g) (W = NR 6; A, B = sulphur; R1 = g) or U from process IX) (W = ΝΗ , · Α, B = carbon; R 1 = f) (W = NR. 6; A, B = carbon; R 1 = f) -47- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) 500723 A7 B7 V. Description of the invention (4) or OR (from process X) (W = ΝΗ; A, B = sulphur; R 1 = h) (W = NR6; A, B = carbon; R 1 = h ) Or U from Process XII) (W = NH; A, B = C or N, R 1 = f, g, j) (W = NR6; A, B = C or N; R 1 = f, g, j) OR OR 从 (from process XV) (W = NH; A, B = C or N, R. 1 = e, i, 1? &gt; (W = NR 6; A, B = C or N; R 1 = e, i, k) Compounds of formula (I, W = NH) in reaction schemes VIII, IX, X, XII and XV in an aprotic inert solvent such as dimethylformamide or tetrahydrofuran, at 0-8D ° Compounds of formula (I) can be obtained by alkylation with a base such as NaH (or KH) and an alkylating agent such as an alkane halide (bran or iodine), where W is NR6. R6 is Alkyl, A, B, and R1 are defined as in Reaction Scheme XX and explained below. In addition, reaction schemes VIII, IX, X, XII XV Chinese formula (I, printed in accordance with the central standard of Part M and printed as a secret seal f (please read the notes on the back before filling out this page) W = Ν Η) compounds can exist in the presence of Trialkylamine base of triethylamine, in an aprotic solvent such as dichloromethane (when pyridine is used, no solvent is used), at-40 ° C to room temperature _ Or carboxylic anhydride can be obtained compounds of formula (T, where W = NR 6 and R 6 is fluorenyl, A, B, and R 1 are defined as shown in reaction scheme XX) as shown below. Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of invention (47)

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 500723 A7 B7 V. Description of the invention (will)

R6

Μ hydrolysis

Re

NaN3, NH4CI DMF 〇2 〇 if Λ 丨) (Cafe 2 ^^ Thief 0 $ &quot; | 2) R4NHNH2 (36) (or NH20H) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-50- (Please read the back first (Notes to fill out this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 500723 A7 B7 V. Description of invention (rush)

After the central sample rate of the sacrum, only the consumer cooperation private printing ¾ apply the reaction scheme XV in the formula (5 4, W = Ν 腈) nitrile compound in an aprotic solvent such as dimethylformamide or tetrahydrofuran, at 0-8 Treatment at 0 ° C with a base such as NaH (or KH) and an alkylation such as alkane (preferably an alkyl chloride (bromide or iodine)) can be obtained by alkylation with formula (6 3, W is NR 6 and R 6 Is alkyl) alkylated nitrile. (5 4) can be stored in amines such as pyridine or trialkylamine in triethylamine, in aprotic solvents such as dichloromethane (no solvents are used when pyridine is used), at -4 G ° C Compounds of formula (6 3, W is NR 6 and R 6 is fluorenyl) can be obtained by hydration with carboxylic acid or carboxylic acid at room temperature. By a similar method to the above-mentioned (54, W = NH) compound, the formula (47, ¥ 411) _amine compound in reaction scheme XV can be alkylated or deuterated to obtain the formula (64, W-NR 6 MR 6 = alkyl Or fluorenyl) alkylated or tritiated intermediates. XXI intermediate nitrile (6 3) and amidine (6 4) can be converted into compounds of formula (I) in a similar manner, where W = NR6 and R6 is alkyl or fluorenyl, R1 is optional as shown in the reaction scheme XIX heterocyclyl in group, or converted to a compound of formula (I), where W = N R. 6 and R 6 is alkyl or fluorenyl, R 6 is optional as shown in Reaction Scheme XV and the following heterocycles are identified The base is e, I, or k. -51- (Please read the notes on the back before filling this page) ίΜ 'order The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ uu / 23 A7 B7 V. Description of the invention (

N-N • Ν, or Ν R4 R4〆 (e) ⑴ R〆 ㈨ (m) Only the X consumer cooperatives print the X through the central unit rate of the M part. The target compound of the present invention can be tested for its biological activity according to the following method. In normal sobriety, the effect of vasopressin V 2 in water-negative rats normalizes male or female blood pressure and body weight of Sprague-DaWley ® (Charles River Laboratories, Inc., Kingston, 350-500 g). , NY) was supplied with a quasi-r0 () ent diet (Purina Rodent Lab · Chow 50 (Π) and water. On the day of the test, the rats were placed in a metabolic cage with facilities for separating feces and urine and urine collection Container. The test compound or reference material is administered in a dose of 10 mg / kg and the carrier used for the 10 mg / kg volume is 2 (U DMS0 at 2.5% pre-boiled corn flour. After 30 minutes, use the needle. Inject 30 «ig / fcg water to the stomach. During the test, no water or food was given to the rats. Urine was collected 4 hours after the administration of the test compound. Urine volume was measured after 4 hours. Fiske On-Ten 0sBiffleter (Fiske Associates (Norwood, Μ, 02062) or advanced CRYOMATIC oseiOHieter, model 3 C 2 (A dvanced I nstrunt, N orw od, MA) to measure urine permeability. Ionization using Beckman SYNCHRON EL -ISE Electrolyte strip analyzer Dedicated electrode measurement of Na +, K + and C1- The urine permeability should be increased in proportion. In the screening test, two rats were used for each compound. If the urine volume difference between the two rats was greater than 50%, the third rat was used. The results are listed in Table I below. 52 -This paper ruler> 1 applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this page) Order 500723 by the central sample rate of Part M and print on the consumer cooperative society fi A7 B7 V. Description of Invention (rr) Table 1

Example U 1 U decreases) θ Difference in urine permeability b Mouse type c 1 80 272 CD 2 61 288 CD 3 85 346 CD 4 87 339 CD 6 25 103 CD 7 69 283 CD 8 72 298 CD 9 59 372 CD 10 63 276 CD: 11 71 375 CD I: 12 -2 101 CD 13 6 106 CD 14 83 (1 mg / kg) 321 CD! 15 98 (1 mg / kg) only Yodo 1363 CD 16 41 142 CD 17 72 262 CD 18 76 234 CD 20 10 89 CD 24 86 615 CD At a dose of 10 mg / kg, the percentage decrease in urine output relative to the control group is used at a dose of lfl mg / kg, compared to the difference in the permeability of the control group. Mouse type: Sprague-Dawley (CD) -53- This paper size is applicable to Chinese National Standard (CNS) A4 (2 丨 0X 297 mm) (Read the precautions on the back before filling this page)

The Ministry of Economic Affairs's central government is responsible for the printing of cooperation shirts. 500723 A7 ____________ B7 ________________________ --------------- '-V. Description of the invention (η) The following examples can be used for _ Ming It does not limit the scope of the invention. Example "... ^ ^ ® 4 ^ ^ PJ; L Wow-1-a) Gaihua 1-(5—i-Ll · —ft — all over L2Stf zi» Y Tang Yin-6-based "JL disorder-Step A · 6,1 i -dihydro_ 5 H -pyridine hydrazone [2, 3-b] U, 5] phenyl hydrazine-5-one hydrochloric acid 1:〗 Salt will be 1,2- Cyclohexanone (52g, 480 «〇1) and nicotinic acid (76§, 482 ffi ffi 〇1) under reflux under nitrogen for 2.5 hours. Generated after heating Precipitation. The reaction temperature was carefully poured into ice-cold dichloromethane (100ffil) under vigorous stirring. The semi-solid was collected, washed with dichloromethane and dried in vacuo to obtain 98e9g (83; 〇title compound, which may Purified for use in the next step. Step B. fi, U-Dihydro-pyridine [2,3-b] [l, 5] Benzenediazepine diborane dimethylsulfide complex (358 | 1) Under nitrogen, add from syringe to step A-6,] [1,2] -dihydro-5H __pyridinium [2,3-b] [1,5] phenylhydrazine-5-one with Hydrochloric acid 1: 1 salt of dioxane (230181). Ultrasonic vibration overnight at room temperature and vacuum drying. The edge color residue was treated with cold 2N HC1 and ether. The cooling water layer was 5fl5KNaO H was converted to pH 9 and then brewed with ethyl acetate. The organic layer was dried under anhydrous potassium sulfonate and evaporated to obtain a red picture (2 4 · 3 5 g, 6 1 · 4%). The crude product was milled. Diethyl ether was used for purification. The paintings were collected, washed and dried under vacuum. Combined different mother liquors, the mixture (18.5 g) was subjected to flash chromatography (silicon_Merck-60, dissolved in 20% ethyl acetate in hexane) Additional homogeneous material (yellow solid, 1 1 g) can be obtained by TLC. -5 4-This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page )

JUU723 A7 One B7 ~ ______________________ — One, five, description of the invention (to) Step C.2-Chloro-4-fluorobenzyl chloride (Please read the precautions on the back before filling this page) Will contain a few drops of dimethylformamidine Amine and 2-chloro-4-fluorobenzyl acid (1 3 · 6 1 g, 7 8 111 Μ) in methylene chloride (8 5 ffi 1) were added dropwise to a solution of oxadiazine in dioxane under nitrogen. (1 · 2 equivalents). When gas generation ceases, reflux for another 25 minutes and air dry. This crude_chlorine was used directly in the next step. Step D · (2-Chloro-4-fluorophenylb [5,1b dihydrocyclo [2,3 ~ b] ίΐ, 5〗 Benzohydrazine-6-yl) methanone will contain a step 6,1 1 -dihydro-5 Η -pyridine hydrazone [2,3-b] Π, 5] Benzodiazepine (12.8 g, 65 ΒΠΒ01) dimethylformamide (12〇8 | 1) Under nitrogen, add potassium sulfonate U 3 · 7 6 g, 1 4 3 ffi ® ο 1). Cool and add dropwise the crude 2-chloro-4-fluorobenzylamine ammonia (78ηιβο1 &gt; dimethylformamide (50) in step C. Stir at room temperature for 75 minutes, dilute with water and dichloromethane Rhenium extraction. The organic extract was dried under magnesium sulfate and dried under vacuum. The crude product was obtained from the column "silicon_ Merck-60, hexane-ethyl acetate: 95: 5 ~ 80: 20) to obtain the pure title compound U4 .25g, 62X) and some impurities (2.7g). This pure product is a white crystalline solid, which can be used directly in the next step ^ NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H; CONCH2), 6.52 (m, 1H), Ministry of Economic Affairs Central sample rate 趵 Consumer Cooperatives India 6.71-6.79 (m, 2H), 6.98-7.16 (2 m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H ), 9.53 (s, 1H, NH) MS (El, m / z): 353/355 [M] &quot;, 196-step E · [2-chloro-4- (3-methylBftazolyl) phenyl ]-(5,11-monohydrogen 4 than hydrazone [2,3-»)] [1,5] benzenehydrazone diheptin-6-yl) shen_NaH (60% oil, 1.88, 45.19 μm βϊ〇1) was washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (1 3 0 »1). -55- at 0 ° C ^ Paper size is suitable for Chinese National Standard (CNS) A4 size ^ 210x297 mm) 500723 A7 B7 .....-.-............... .. 1 丨 丨 丨 丨 丨 丨 丨 丨 '1 1_ 丨 丨 · Ι ___ 丨 丨 -............... ... 丨 丨 丨 丨 丨 丨 丨 丨 丨 _ 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 ............ ............................................ ........................ 丨 丨 · 丨 丨 丨 丨 — Five 'invention description (Hugh) Add blunt 3-methylpyrazole (3.71 g, 4 5 · 19 9 and ο 1}. When the gas stops forming, remove the ice bath and stir at room temperature. Add once in step D (2_ (please Read the precautions on the back before filling out this page) 氡 -4-Fluorophenyl)-(5,11-dihydro-pyridine2 [2,3-1)] [1,5] Benzene diazepine- 6-based) formazan (8.111, 22.59 »1» 〇1), placed in an oil bath (preheated to 130 ° C) for 2 hours. After cooling, the layers were partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and dried under vacuum. Dissolved in dioxane and adsorbed to i ^ Merck-6fl column. The hexane-ethyl acetate (95: 5 ~ 3: 2) was used for the dissociation to obtain the target compound and a part of the compound containing the target compound and its higher polarity, the 5-methylpyrazole regioisomer in Example 2. The title compound (6.4 g, 6 8 χ) was obtained as a white solid by crystallization from hexane-ethanol supersonic salt, melted at 207 ° C. NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3H), 4.14 and 5.45 (dd, 2H, CONCH2), 6.32 (m, 1H, pyrazole CH), 6.51 (m, 1H), 6.74-6.79 ( 2m, 2H), 6.98 (m, 1H), 7.25 (m, 2H), 7.58-7.70 (mm, 3H), 8.11 (m, 1H), 8.38 (m, 1H, pyrazole CH), 9.55 (s, iH , NH) MS (El, m / z): 415/417 [M] +; (+ FAB, m / z): 416/418 [M-hH] + Calculated value for elemental analysis: C23H18C1N50: C 66.43; H 4.36 N 16.84. Measured value: C 66.11; H 4.42; N 16.64 m2 [2-i-4 二 ί_5. 二 里 __- 卜 华) Cangmou 1- (5,11-two 1 two 1! &Amp;-痖 1 Sampling rate in the crotch and the slave labor cooperative cooperative Yin Fan will obtain the 3-methyl and 5-methylpyrazole plaque domain isomers (0.543g) obtained in step E of Example 1 by the column (silicone Merek -60, dissolve with toluene-ethyl acetate: 9 0. · 10, and then toluene-ethyl acetate-acetonitrile 9 0 · · 10: 5), fl.327g example can be obtained by etheric-hexane sonication 3-Methyl isomers in 1 and amorphous solids of the title compound of O.lOSg. -56- The size of this paper is China State Standard (CNS) A4 (21 × 297 mm) 500723 A7 B7 — ——— …. —— One _______ ..... One ............... ........................................ . -.....—— _— 5. Description of the invention (if) NMR (DMSO-d6, 400 MHz): δ 2.27 (s, 3H), 4.16 and 5.45 (dd, 2H, CONCH2), 6.25 (m , 1H), 6.54 (m, 1H, pyrazole CH), 6.79 (m, 2H), 7.01 (m, 1H), 7.26 (m, 1H), 7.40-7.54 (mm, 3H), 7.61 (m, 1H) , 8.11 (m, 1H, pyrazole CH), 9.56 (s, 1H, NH) MS [El, m / z]: 415/417 [M] +, 219/221, 196 cases] [2dibromodi4: (3-methylffi; beer-1-yl) cage- (5 · -digas-pyridine hydrazone 12, ΛζΜΙΙ Step A · 2-bromo-4-fluorobenzyl chloride will contain a few drops of dimethylformamide Amine and 2-bromo-4-fluorobenzic acid (6.87g, 31.37 μl) in dichloromethane (7fl «il) were added dropwise to a 2M solution of dichloromethane in dichloromethane (1.16 equivalents) under nitrogen. . When gas generation ceased, reflux for another 25 minutes and dried under vacuum. This crude osmium chloride was used directly in the next step. Step B. [2-Bromo-4-fluorophenylb (5, [b] dihydro-pyridinium [2,3-b] U, 5] b [phenyl] diazepine-6-yl) The central part of the rate is negative and π eliminates the cooperation. (Please read the precautions on the back before filling out this page.) Example 1 Step B-6, 11-dihydro-5H-pyridine [2,3- b] [1,5] Phenyldiazepine (5.15 g, 26.1 Bi hi ο 1) dimethylformamide (70)) Under nitrogen, potassium sulfonate (7.95 g, 57 · 51ιηηο1). Cool and add dropwise dimethylformamide of the crude 2-bromo-4-fluorophosphonium chloride (31 · 37βι®ο1) in step A at room temperature, stir for 75 minutes, dilute with water and extract with dichloromethane . The organic extract was dried under sulphuric acid and dried under vacuum to obtain a brown solid foam. The crude was dissolved in dichloromethane and attached to a silica Merck-60 spin column. Dissolve in hexane-ethyl acetate (95: 5 ~ 7 5: 2 5) to obtain the pure title compound (6.18g, 59.5%) and some impurities (1.2gh by milling with hexane to obtain a white solid foam, It can be directly used in the next step-57- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7__ 5. Description of the invention (Mu) NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.53 (m, 1H), 6.74-6.79 (m, 2H), 6.98-7.16 (2 m, 3H), 7.25 (m, 1H), 7.40-7.50 (broad s, 1H), 7.59 (m, 1H), 8.1 (m, 1H), 9.54 (s, 1H, NH) MS (El, m / z): 397/399 [M] +, 196 Step C · [2 -Bromo-4-(3-methylpyrazole-1 -yl) phenylbenzene (5,1 1 -dihydro-8 | 1; pyridine [2,3-1)] [1,5] phenylhydrazine Heptane-6-yl) formaldehyde_ NaH (6 (in U oil, 1.2 g, 30 · 15κΐϋ〇1) was washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (1) 0 ® 1). Add pure 3-methylpyrazine (2 · 4 7 g, 3 · · 1 5 BI ro ο 1) dropwise at 0 ° C. When the gas generation stops, remove the ice bath and stir at room temperature Add the 2-bromo-4-fluorophenylbenzene in step 8 all at once. (5,1 dihydro-pyridine hydrazine [2,3-1)] [1,5] phenylhydrazine diazepine-R-yl) methyl- (6 g, 1 8 · 0 7 m and ο 1 ). Placed in an oil bath (preheated to 130. 0 &gt; 40 minutes, cooled and partitioned between water and ethyl acetate. The organic mash was dried under sodium sulfate and dried under vacuum. Soluble in dichloromethane And adsorbed to silicon_ »01 ^} 1-6〇 column &lt;) dissociated with hexane-ethyl acetate (95: 5 ~ 75: 25) to obtain the target compound (3.8 8 g) with lower polarity and 3- and 5-methylpyrazole regioisomeric mixtures (o.eeog). The title compound (3.5g, 51%) was obtained from hexane-ethanol supersonic crystallization, melting point 2D8- 2 0 9T: (decomposition) 。 Printed by the M industry with the sample determination rate in the M department (please read the notes on the back before filling this page) NMR (DMSO-d6, 400 ΜΗζ): δ 2.21 (s, 3H), 4.15 and 5.44 (dd, 2H, CONCH2), 6.31 (m, 1H, pyrazole CH), 6.52 (m, 1H), 6.77-6.80 (2m, 2H), 6.99 (m, 1H), 7.25 (m, 1H), 7.59- 7.63 (2 m, 2H), 7.88 (m, 1H), 8.11 (m, 1H), 8.37 (s, 1H, pyrazole CH), 9.55 (s, 1H, NH) MS (+ EI, m / z): 459/461 [MT, 265/263 Calculated by Elemental Analysis ·· C23H18B rN50 ·· C 60.01, H 3.94, N 15.21. Measured value: C 59.92, H 4.05, N 15.01-5 8-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Invention Explanation (μ)

Example JL (5 .1 1 -digas-pyridine 骈 2 · 3-b 1 f 1 JO cap straight two JIJSI two 1 two ^ _1 two r 4- (3- φ _-1-yl) -2- Trimethylamine Step A · 2-trifluoromethyl-4-fluorobenzyl chloride will contain a few drops of dimethylmethylamine and 2-trifluoromethyl · 4-fluorobenzoic acid (16.85g, 8ίη »ιηο1) Dichloromethane (150βι1) was added dropwise with chloramphenicol (8.5 m), 9 ∼ 4 m κι ο 1) under nitrogen. When the gas ceased to form, then refluxed for 10 minutes and dried under vacuum. This crude 粗Chlorine can be used directly in the next step. Step B (5,〗 Dihydro-Bft pyridine 骈 f 2,3-b] [1,5] Benzene diazepine-6-yl)-(4-fluoro -2-Trifluorotolyl benzophenone will contain 6 of Example 1, Step B, Benzodihydro-5 Η-1¾ pyridine 骈 [2,3-b] [1,5] Phenyldiazepine (lfK6g, 53.8 fli «iol) dimethylformamide U25ml) Under nitrogen, potassium carbonate (22.4g, 162ι» ηιο1) was added. Cool and dropwise add crude 2-trifluoromethyl-4-fluorobenzylphosphonium chloride in step A (81MIB01) dimethylformamide (25rol). Stir for 2 hours at room temperature, dilute with water and climb with dichloromethane. Dry the organic extract under magnesium sulfate and dry under vacuum. The crude material was dissolved in dichloromethane and purified by flash chromatography (Silica Merck-8 fl, hexane-ethyl acetate (8 0 ·· 20)) to obtain the pure title compound (6.9 g, The final sample rate &gt;P; M-X · consumer cooperation ii. (Read the precautions on the back before filling this page) 3 3.1%), crystallized by hexane-ethanol supersonic oscillation, melting point 1 8 3-1 8 5 ° C. NMR (DMSO-d6, 400 MHz) δ 4.16 and 5.43 (dd, 2 H, CONCH2), 6.56 (m, 1H), 6.64 (m, 1H), 6.79 (m, 1H), 7.02 (m, 1H), 7.26-7.40 (m, 3H), 7.58-7.65 (ra, 2H), 8.12 (m, 1H), 9.59 (s, 1H, NH) MS (El, m / z ): 387 [M] + Calculated value for elemental analysis: C20H13F4N3O: C 62.02, H 3.38, N 10.85. Measured value: C 62.06, H 3.22, N 10.67 -59- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 500723 A7 B7__ V. Description of the invention (Η) Step C · (5,1 1 -diaza-pyridine hydrazone [2,3-b] [1,5] benzene benzodiazepine (please read the back first) For the matters needing attention, please fill in this page again.) Because of the 6-yl 4- (3-methylpyridin-1-yl) -2 -trifluorotolyl-butanyl chloride, NaH (60% in oil, 0.83g, 20 · 8 Coarse mol) to Alkoxy wash 1, dried under nitrogen and suspended in dry dimethylformamide (6 square m 1). Add 3-A-sleep (0 · 9 and 1,1 · 2 m m ο 1) at one time. When gas generation ceases, the ore is stirred at room temperature. In step B, (5,1 1 -dihydro-pyridinepyrene [2, 3 -M [1,5] phenylbenzodiazepine-6-yl &gt;-> 4-fluoro-2 -trifluoro Tolyl benzoate (3.6g, 9 · 3ϊηηι1), placed in an oil bath (preheated to 130eC) 3 () minutes, after cooling, the layers were separated between water and ethyl acetate. The organic layer was dried under sodium sulfate and dried under vacuum Dissolved in dichloromethane and adsorbed on silica_Merck-60 column. Dissolved in 25% ethyl acetate in hexane to obtain 3.3 g (7.99) of target compound foam. The title compound can be obtained by phononic crystallization, with a melting point of 212-214 ° C. An example can be obtained by re-dissolving 30% ethyl acetate in hexane (5 higher polarity 5 -methyl-regioisomers c NMR (DMSO-d6 , 400 MHz): δ 2.23 (s, 3H, CH3), 4.17 and 5.45 (dd, 2H, CONCH2), 6.35 (m, 1H, pyrazole CH), 6.54 (m, 1H), 6.68 (m, 1H), 6.80 (m, 1H), 7.00 (m, 1H), 7.29 (m, 1H), 7.60 (m, 1H), 7.85 (m, 1H), 8.04 (m, 1H), 8.13 (m, 1H), 8.46 (m, 1H, pyrazole CH), 9.61 (s, 1H, NH) MS (El, m / z): 449 [M] + Calculated value for elemental analysis: C24H18F3N50: C 64.14, H 4.04, N 15.58. Found: C 64.01, H 4.01, N 15.45 Example—5 ([1 丄 1: 二 羞 —: ^^^^^ _ if 12,1-b1LIH -6-¾) -ίΑζίΙζΜ ^ Step A · 4-Fluoro-2-trifluoromethylbenzoic acid methyl ester -6 0 _ This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 V. Description of the invention (Clever) It will contain a few drops of dimethylmethoxamine and 4-fluoro-2 -trifluoro Toluic acid (25.6 g, 123 mm ο 1) in dichloromethane (250 m 1) was added dropwise human chlorchloride (129,5 niffi〇l) under tritium gas. When the gas stopped generating, Reflux for another 15 minutes. Add methanol (50®) to the cooling number. Stir for 2 hours, concentrate and separate the layers in dichloromethane and water. Wash the organic layer with a saturated sodium bisulfate solution, dry under sodium sulfate and dry under vacuum. 〖8. Dg (65. 9%) golden oil of the extreme compound. NMR (DMSO-d6, 400 MHz): δ 3.85 (s, 3H), 7.67 (m, 1H), 7.80 (m, 1H), 7.95 (m, 1H) MS (El, m / z): 222 (M ] + Acidify the aqueous layer with 2N HC1, and collect white solids by filtering! N5g (29.3%) of 4-fluoro-2 -trifluoroformyl benzyl acid. Step B * 4-(3 -Methylpyrazole-Bulkyl)-2 -trifluoromethyl benzyl acid _ 决 the sample rate in the full part and only the consumer cooperation private printing f (read the precautions on the back before filling This page) NaH (6 (U oil, 3.85 g, 96.3 μ · ο1) was washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (150 m 1). At room temperature Add dimethylformamide (5 (111)) (7 · 7 5 m], 9 6 · 3 «ο 1) dropwise. Stir until the gas ceases to form, add dropwise to step A 4-Fluoro-2-trifluoromethylbenzoic acid methyl_ (17. ", 80.11» 1〇]) dimethylmethylamine "5 (I · I). After stirring at room temperature for 3Q minutes, add The saturated ammonium chloride solution was reacted with fh and extracted with ethyl acetate. The organic layer was dried under sulfuric acid pin and dried under vacuum. It was dissolved in dichloromethane and hexane (1: 1) and adsorbed to silicon_Merck- 60 column. Dissolve in dichloromethane-hexane (1: 1 to 4: 1) to obtain the title compound as a white solid (13.6 g, 59.7%), melting point 5 9 -6 1 ° C 〇-6 1-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 5 Description of the invention (b ',) NMR (DMSO-d6, 400 MHz): δ 2.28 (s, 3H), 3.86 (s, 3H, C02CH3), 6.43 (m, 1H, pyrazole CH), 7.97 (m, 1H ), 8.18 (m, 1H), 8.23 (m, 1H), 8.62 (m, 1H, pyrazole CH) MS (El, m / z): 284 [M] + Calculated value for elemental analysis: C13HuF3N202: C 54.93, Η 3.90, N 9.86. Measured values: C 54.80, Η 3.73 N9.81 Ester formic acid. Lower acid methyl, fluoromethylene trigas 2 three)-2 base hemp I \ / 1 base I I0 $ 7 ~ / V 甲 _ I 4 3 {Medium I Β 4 Step C Step includes step V of alcohol methyl) / 1 ο m ID 2 4 Add TMX and acetic acid titled acid to get ethyl can be dried and steamed 19 Condensed 2-concentrated 19 and dried at the same point but melted cold acid, sulfur content will be added in 90 laminar flow machine will add C 〇 layer 4g 1) points. 1 ο 1: 1 0 C (3ΪΒΗ 物 8.1.N Combined solid color white // °° C (Please read the precautions on the back before filling this page) The central sample rate of the net department and only the consumer cooperative printing NMR (DMSO-d6, 400 MHz): δ 2.28 (s, 3H), 6.42 (m, lHt pyrazole CH), 7.95 (m, 1H), 8.14 (m, 1H), 8.20 (m, 1H), 8.61 (m, 1H, pyrazole CH), 13.4-13.7 (broad s, 1H; C00H) MS (+ FAB, m / z): 271 [M + H] + Calculated value of charge analysis: C12H9F3N202: C 53.34, H 3.36, N 10.37. Found: C 53.35, H 3.29, N 10.21 Step 1) (5 1,1 dihydro-Bft pyridine [2,3-b] [1,5] phenylhydrazine diazepine-6-yl) -f4- (3-methylpyridin-1-yl) -2-tris The fluorotolyl benzoate will be 4- (3-methylpyridine ... buyl) -2-trifluoroformylbenzoic acid (l.lg, 4, 1 hi ο 1) and triethylamine (0.5 7 m 1,4 · 1 Bi ο 1 &gt; of dichloromethane (2 0 ra 1) was added with 1,3,5-trifluorobenzyl hydrazone gas (0.63111), 4.0.110.01). After stirring for 5.5 hours, 6,1 1 -dihydro-5 hydrazone-pyridine hydrazine [2,3-b] [1, 5] phenylbenzenediazepine (0 · 6 7 g, 3 · 4 «11 ο 1) and 4 -dimethylamine pyrimidine (0, 4 2 g, 3.4 · mw ο 1). After stirring for 18 hours, it was poured into a saturated sodium disulfonate solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness. 62- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 ....... 丨 .................... ................. Read ......... 111 | · Ν · ...... .................................. _ V. Description of the invention () Dissolve in two Chloromethane is attached to the silica_M e 1, ck-6 fl column by column dissolution with ethyl acetate-ethyl acetate "8: 2 ~ 13) to obtain the title compound foam (〇 ^ 9g, 58-2 mmol). It is crystallized from hexane-ethanol supersonic salt and has a melting point of 212-214Ό. This compound is the same as the compound of Example 4. Example-Nong (5.1 1 -dihydro-m pyridine 骈 2 · 3-b 1 Π, 5 1 phenyl hydrazone Ⅱ 庚 -heptane-in-dihydrazone ~ Li--. -S- cover-poor-L : Li Shiyi and 『a Lihuang ~ Liane_ &amp; 1 丄 3acetic acid. Ethyl-ester-soluble..combined-withdrawal ― According to Example 4, the title foamy compound (0.35 g, 8% ), Crystallized by ethanol-hexane supersonic, melting point 2 3 8-2 4 (TC. NMR (DMSO-d6, 400 MHz): δ 2.29 (s, 3H), 4.19 and 5.46 (dd, 2H, CONCH2) , 6.28 (m, 1H, pyrazole CH), 6.57 (m, 1H), 6.71 (m, 1H), 6.80 (m, 1H), 7.02 (m, 1H), 7.29 (m, 1H), 7.58-7.67 ( m, 4H), 7.81 (m, lH), 8.13 (m, 1H), 9.63 (s, 1H, NH) MS (+ FAB, m / z): 450 [M + H] + Elemental analysis calculated value: C24H18F3N50 + a〇9 CH2C12 + 0.13 C4H802: C 63.09, H 4.13, N 14.95 · Measured value: C 63.39, Η 4 · 23, N 14.89

Example L (1 "1, 22, 2 and 2 emerald straight L—L2 _. ^ The central standard of the Ministry of Manchuria is only printed by the consumer cooperatives (please read the precautions on the back before filling out this page) [2: 三 《—s Benzyl-4- (3-trifluoromethyl-im · mim di Shen—see NaH (fifl% oil, 0.17 g, 4.25 μβιο1) was washed with hexane, dried under nitrogen and suspended in anhydrous dimethyl Formamidine (10m 1). Add 3-trifluoromethyprazole (0.34 g, 2.5 in B1 ο 1) in one portion. Stir at room temperature after gas generation stops. Add in one portion Example 4, in step B, (5, 11-dihydro-pyridine hydrazine [2,3-bH], 5] phenylhydrazine-6-kib (4-fluoro-2-trifluoromethyl-6 3 -This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (h) Phenylmethanone (0.75g, 〖, 94 errent 〇1), put in oil bath (Preheated to 130 ° C) overnight. After cooling, the layers were separated between water and ethyl acetate. The organic layer was dried under sodium sulfate and dried under vacuum. Crystallization from ethanol gave the title compound (0.57 g, 5 7 3 SO doped white solid, melting point 1 2 7-1 2 9 ° C. NMR (DMS0-d6, 400 ΜΗζ): δ 4.19 and 5.46 (dd, 2H, CONCH2), 6.54 (m, 1H), 6.70 (in, 1H), 6.80 (m, 1H), 7.02 (m, 1H), 7.07 (m, 1H, pyrazole CH), 7.29 (m, 1H), 7.61 (m, 1H), 8.00 (m, 1H), 8.05-8.16 (m, 2H), 8.84 (m, 1H, pyrazole CH), 9.63 (s, 1H, NH ) MS (El, m / z): 503 [M] + Calculated value for elemental analysis: C24Hl5F6N50: C 57.26, H 3.00, N 13.91. Found: C 57.07, H 2.97, N 13.58 fli: JLCL: cover)-" 4- (3-methyl 1 ^ beer-1-yl) -2-trifluorotolyl 1-formamidine will be f) aH ((50% oil, 0.12g, 3.0ml »ιοο1) was washed in his own hospital, Dried under nitrogen and suspended in anhydrous dimethylformamide (2 0 re 1). Human pure 3-methylpyridine (0 · 〖3ϊβ1) was added dropwise at room temperature. Printed by Zhuanyi only consumer cooperatives (please read the precautions on the back before filling this page) y Stop the lh generation, and add it once in step B of Example 4 (5, 1 1 -Dihydro-Bft Price® 骈 f 2, 3-b Η5] benzodiazepine-6-kib (4-fluoro-2 -trifluorotolylbuphenone (0.52 g, 1.34fflino 1). Place in an oil bath (preheat to 1 30 ° C) for 30 minutes. After cooling, NaH (60% oil, 0.08 g, 2.0 ηιο1, washed with hexane) and methyl iodide (0.25 ml, 4.0 «〇1) were added. After «mixing for 15 minutes, the layers were partitioned between water and ethyl acetate. The organic layer was dried under sodium sulfate and evaporated to dryness. Dissolved in dichloromethane and attached to a silica Merck-60 column. The title compound (0.28g, 45.1g) can be obtained by dissolving in 20% ethyl acetate in hexane. -64- This paper size applies the Chinese National Standard (CNS) A4 specification (2) ox297 mm. Yield &gt; PJI II Consumer Co., Ltd. Yinfan 500723 A7 B7 V. Description of the invention) A white solid can be obtained by crystallization from ethanol-hexane supersonic oscillation, melting point 188-1 90 ° C NMR (DMSOd6, 400 MHz): δ 2.23 (s, 3H, CCH3), 3.55 (s, 3H, NCH3), 4.37-4.43 (broad s, 1H, CONCH2), 5.71-5.76 (broad s, 1H, CONCH2), 6.35 (m, 1H, pyrazole CH), 6.89-6.93 (m, 3H), 7.19-7.24 (m, 2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.90 (m, 1H), 8.06 (m, 1H), 8.24 (m, 1H), 8.48 (m, 1H, pyrazole CH) MS (EI, m / z): 463 [M] + Calculated value for elemental analysis: C25H2 () F3N50 ·· C 64.79, H 4.35, N 15.11 · Measured Value: C 64.55, H 4.29, N 15.04 Example. 9 (Γ &gt; · 1 Ί-two gas-畦 骈 畦 骈 "2 · 3-b 1 f 1 · 5 1 cage 骈 diazepine -1 0-even" -Γ 2-g-4-(1- PH: post-1 -some) -cage 1-methyl_ 0. 1 9 Hydrate step A. 2,4-difluoro-benzylhydrazone will contain several drops of two Methylformamide and 2,4-difluoro-benzyl (3.6 g, 22.8 dichloromethane (40ml) was added dropwise chlorchloride (2.4 ancestral 1, 27Jimo1U when the gas was stopped! H generation, then refluxed for 15 minutes and dried under vacuum ^ this crude _Chlorine can be used directly in the next step. Step B (2,4-difluorophenyl)-(5, Π-dihydro-pyridine hydrazone [2,3-b] f 1,5] phenylhydrazine Heptane-1 0 -yl) -formyl will contain 6 in step 1 of Example 1, 1 dihydro-5H-Bttidine 骈 2,3-b] [1,5] · 0 g, 15 · 2 m Bi ο 1) dimethylformamide (3 5 er 1) Under nitrogen, add potassium sulfonate (6.3 g, 45 · 6βιβ »ο1), and then add 2 in step A Dimethylformamide (15wil), crude, 4-difluoro-benzylhydrazone (22.81 «111〇1). Stir at room temperature for 20 minutes, wash with water and stir to collect solids by filtration. Dissolved in chloroform and washed with N N a. 0 Η and brine. Put the organic layer on sulfur _ 6 5-This paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

500723 A7 — _ B7 ___ 5. Description of the invention (b) _ Dry under sodium and vacuum dry. The crude was dissolved in dichloromethane and attached to a silica Merck-60 column. Dissolve in 20% ethyl acetate in hexane to obtain 泡沫 g of compound (2.6g, 51%) as a white foam, and then crystallize by Kojima-ethanol ultrasonic vibration. Melting point] 6 1-1 6 3 ° C. NMR (DMSO-d6, 400 MHz): δ 4.12-5.46 (dd, 2H, CONCH2), 6.52 (m, 1H), 6.67 (m, 1H), 6.76 (m, 1H), 6.98-7.07 (m, 3H ), 7.26 (m, 1H), 7.35 (m, 1H), 7.57 (m, 1H), 8.10 (m, 1H), 9.56 (s. 1H, NH) MS (El, m / z): 337 (M ] + Calculated value for elemental analysis: C19H13F2N30 ·· C 67.65; Η 3.88; N 12.46 · Measured value: C 67.30; H · 3.98; N 12.10 Step C (5, U -Dihydro-pyridine hydrazone [2,3 -t)] [1.5] Benzene diazepene-10 -yl)-[2 -fluoro-4-(3-methylpyridin-1_yl-p-phenylphenylpropionate β-19 hydrate M Central standard ^ ¾ printed by Industrial Consumer Cooperative (please read the precautions on the back before filling this page) NaH (60% oil, n.48g, washed with hexane, dried under nitrogen and suspended in anhydrous dimethyl ether Methylformamide (60 M 1). Add pure 3-methylpyridine (0.48 ffi 1, fi η »1 〇1). Hold the ore and stir until the gas stops generating. Add in step B (2 at a time) , 4-difluorophenylbenzene (5, 1 dihydrogen «骈 t2,3-b〗 [l, 5] Benzodiazepine-10-ylbuprofen (2g, 5.9_01) .Place in oil bath (preheated to 13 (TC) for 60 minutes, after cooling in water and ethyl acetate The layers were separated. The organic layer was dried over sodium sulfate and evaporated to dryness. It was dissolved in dichloromethane and attached to a 5 ^ _Merek-60 column. It was dissolved in hexane-ethyl acetate (9 .. Bu 1: 1). The title compound and Example 10 were obtained with higher polar fluoro regioisomers. The foam of the obtained title compound (0.30 g, 12 · 7) was crystallized from hexane-ethanol-supersonic vibration, melting point 122- 125 ° C. -66 ^ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 cm) 500723 A7 B7 V. Description of the invention (br) NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3Η , CH3), 4.13 and 5.48 (dd, 2H, CONCH2), 6.32 (m, 1H, pyrazole CH), 6.51 (m, 1H), 6.70 (m, 1H), 6.77 (m, 1H), 7.01 ( m, 1H), 7.27 (m, 1H), 7.35 (m, 1H), 7.41 (m, 1H), 7.53-7.59 (m, 2H), 8.10 (m, 1H), 8.35 (m, 1H, pyrazole CH ), 9.57 (s, 1H, NH) MS (El, m / z): 399 [M] + Calculated value for elemental analysis: C23H18FN50 + O ″ 9 H20 ·· C 68 ·: 57, H 4.60, N 17.38 · Real Found: C 68.53, H 4.68, N 17.56

Inverted 1JL, 1,2,3,2,2,2,3: Li 2 1 2 Poor—LHU—imi According to the method of Example 9, the title compound and its 2-fluoro regioisomer can be obtained by preparative Η PLC (water silica_column, Dissolve in hexane-ethyl acetate (5 5: 4 5), flow rate: 50 / min, detect at 2 5 4 η η »to obtain pure title compound foam (fl.25g, 10.6%), and then Crystallized from hexane-ethanol-supersonic oscillation, melting point 1 80-18 1 ° C 〇MS (El, m / z): 399 [M] + Calculated value of elemental analysis ·· C23H18FN50 + 0.20 C2H60: C 68.78, H 4.74, N 17.14. Measured values: C 68.67, H 4.76, N 16.97 M.11. "2-氤 -4- (3 -Shen gH; _ -1-some)-¾ (5 -Shen—JLzl.丄 Covered by the Central Standard Date and printed by the MX Consumer Cooperative (please read the precautions on the back before filling this page) Step A (2-chloro-4-fluorophenyl)-(5_methyl-5, 1b Dihydropyridine [2, 3-b] [1,5] Phenyldiazepine-10-ylmethanone NaH (6fl% oil, 0.76g, 19.0ΐ8Ηΐο1) was washed once with hexane, Dried under nitrogen and suspended in anhydrous dimethylformamide (1 0 ® 1). At 0 ° C, it was added dropwise to the step D of Example 1 (2-chloro-4-fluorophenylbubble (5,1bub) Gd-Py-6 7- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). Central sample rate of the Ministry of Economic Affairs and Industry Cooperatives Co., Ltd. Yinfan 500723 A7 B7_ 5. Description of the invention (W) Meng 骈 1: 2,3 ~ b ] 〖L, 5] Benzamidine diazepine-6-yl) methanone (6.12g, 7.3 in in 〇]) dimethylformamide (50 〇). The gas stops generating and moves backward Remove the ice bath and stir at room temperature. Add methyl iodide (2.5lg, 1 7 · ί 1 m ο 1) to the yellow solution in one portion, and stir for 1 hour. Between 2 (U sodium chloride and methylene chloride) The layers were separated. The organic layer was dried under magnesium sulfate and evaporated to dryness. It was dissolved in dichloromethane and adsorbed on silica. Mercury 60 column ^ dissociated with hexane-ethyl acetate (95: 5-85: 15) to obtain The title compound was obtained as white crystals of the title compound (4.55 g, 72%), melting point 222-223 Ό. NMR (DMSO-d6, 400 MHz): δ 3.46 (s, 3H, NCH3), 4.37 and 5.67 (2 broad m , 2H, C0NCH2), 6.87-6.97 (m, 2H), 7.06-7.14 (m, 2H), 7.20-7.32 (m, 3H), 7.36 (ra, 1HX 7.60 (ra, 1H), 8.21 (m, 1H ) MS (El, m / z): 367/369 [M] +; (+ FAB, m / z): 368/370 [M + H] + Elemental analysis calculated value: C2QH15C1FN30 : C 65.31, H 4.11, N 11.42. Actual traceability: C 65.04, H 4.14, N, 11.27 Step B (2-Gas-4- (3-methylpyrazol-1-yl) -phenylbenzene (5- Methyl-5, dihydro-pyridine hydrazine [2,3-1)] [1,5] phenylhydrazine diazepine-10-yl) -formaldehyde NaH (60% in oil, () (264 g, 6.6 minol), washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (8 Bi 1). Add pure 3-methylamine dropwise at 0 ° C and sleep (0 · 5 4 1 g, 6 · 6 m ro ο 1). Remove the ice bath and stop stirring at room temperature after the gas has ceased to form. Add in step A (2-Chloro-4-fluorophenylb- (5-methyl-5,1b-dihydro-pyridine) [2,3-1 &gt;] [1,5] Phenyldiazepine-kibbam_ (1.2〗 1,3 · 3μ_ο1). Place in oil bath (preheat to 1 3 G ° C) 3 ( I points, after cooling, at 20% sodium gaseous and dimethane-6 8 _ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

500723 A7 B7 5. Description of the invention (h) The organic layer is dried under sulfuric acid IS and evaporated to dryness. Soluble in dichloromethane and adsorbed to the silica_Merc k-6 60 column. Dissolve in hexane-ethyl acetate (9 5: 5 7 0: 30) to obtain the title compound with lower polarity (0.936 g, 66%).

And 3-and 5 -methazol regioisomers (0.22 g). The title compound was obtained as a white solid by crystallization from hexane-ethanol supersonic salt. Melting point 2 1 8-2 1 9 ° C (Decomposition U NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3H, pyrazole C- CH3), 3.49 (s, 3H, NCH3), 4.39 and 5.69 (broad dd, 2H, CONCH2), 6.32 (mt 1H, pyrazole CH), 6.88-6.94 (mm, 2H), 7.10 (m, 1H), 7.18 -7.24 (m, 1H), 7.26-7.30 (mm, 2H), 7.59-7.65 (mm, 2H), 7.77 (m, 1H), 8.22 (m, 1H), 8.38 (s, 1H, pyrazole CH) MS (El, m / z): 429/431 [M] +, 219,195 Calculated value for elemental analysis: C24H20ClN5O ·· C 67 · 05, Η 4 · 69, N 16.29. * Measured value: C 67.26, H 4.69, N 16.15 Example—1.2-^ "2. 3-b 1 Π, 5 1 Benzene, diphenyl, diyl hydrazone-L2. Erigai 2 5 2 3 3 2 1 Step A 5 -Fluoro-2 -methylbenzyl_chlorine Central Ministry of Economic Affairs Biaomuer only consumer cooperatives printed f (Please read the precautions on the back before filling out this page) will contain a few drops of dimethylformamide and 5-fluoro-2-benzyl acid (2.31g, 15.0 in in o Dichloromethane (30 m J) of U was added dropwise with human oxalate chloride (1.16 m 1, 18.3 mm) under nitrogen. When the gas stopped generating, refluxed for another 10 minutes and dried under vacuum. Crude Chlorine can be used directly in the next step. Step B (5,1 1 -Dihydro-% pyridinium 丨 2,3 -b] [1,5] Phenylhydrazine B-heptan-6-yl)-(5 -Fluoro-2-tolylbuprofen will contain β, 1budihydro-5H-pyridine cake [nbHU] -6 9- Step 9 of this example.- This paper size applies Chinese National Standard (CNS) A4 specifications (2丨 0X297mm) 500723 Printed by the Central Government of the Ministry of Economic Affairs ^ Only printed by X Consumer Cooperatives A7 B7 V. Description of the Invention U /) Dogwood diazepine (2.08, 10.1! 111 «〇]) dimethyl Formamidine (151〇1) Under nitrogen, potassium sulfonate (4.1 g, 29.7 g) was added dropwise. The crude 5-fluoro-2-methylbenzylhydrazone (15 mmol) in step A was added dropwise. ) Dimethylformamide was stirred at room temperature for 15 minutes, diluted with water and mixed to obtain a national body by filtration, dissolved in chloroform, and washed with 1 N Na, 0 Η and brine. The organic layer was dried under a sulfuric acid pin and dried under vacuum to obtain a purple oil. The crude material was dissolved in chloromethane # and adsorbed onto a silica_Merck-6o column. The title compound (1.88g, 55.8%) was obtained by dissolving 20% ethyl acetate in hexane, and then crystallized by ethanol-hexane supersonic vibration, and the melting point was 138-140 ° C. NMR (DMSO-d6, 400 MHz): δ 1.95 (s, 3Η, CH3), 4.11 and 5.46 (dd, 2H, CONCH2); 6.53 (m, 1H), 6.75-6.80 (m, 2H), 6.81-7.06 (m, 4H), 7.24 (m, 1H), 7.60 (m, 1H), 8.11 (m, 1H), 9.57 (s, 1H, NH) MS (El, m / z): 333 (M) + element Analytical calculated value: C20H16FN3O: C 72 · 06, Η 4.84, N 12 · 6 (λ Found: C 71.88, Η 4.78, Ν 12.67 Step C (5,〗 氲 氲-pyridine 骈 2, 3-b] [1,5] Phenyldiazepine-1 0-kib [2-methyl-5-(3-methylpyridine-1 -yl) -phenyl] -methanone will be N a Η "6 0 % Oil, 0.25 g, 6.25 m ο 1) washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (100® 1). Add once at room temperature Pure 3-methylated, azole (0 · 2 8 in 1, 3 · 5 m Βΐ ο 1). Stir continuously until the gas ceases to form. Add in step B (5, 11-dihydro-pyridinium [2, 3- »)〗 [1,5] Phenyldiazepine-6-kib (5-fluoro-2-tolyl) -methyl ring I (0 · 7 5 g, 1 · 9 4 in m ο 1 ). Heat to reflux for 26 hours. After cooling, separate between water and ethyl acetate. Dry the organic layer over sodium sulfate. It was evaporated to dryness and dissolved in dichloromethane and adsorbed to the silica_Merck-6D column. The dissolution was based on hexane-70- this paper ruler ^^ Applicable to China National Standard (CNS) A4 size (2 丨 0X297 mm) (Read the notes on the back and fill out this page)

500723 A7 ________B7 V. Description of the invention (ϋ) Alkane-ethyl acetate {8: 2-7: 3) The title compound was obtained as a pale yellow foam (0.55 g, 5〗 · 5%). Oscillating crystal, melting point 2 η 9-2 1 0 ° C 0 NMR (DMSO-d6, 400 MHz): δ 1.94 (s, 3Η, CH3), 2.23 (s, 3H, pyrazole CH3), 4.13 and 5.49 (dd , 2H, CONCH2), 6.28 (m, 1H, pyrazole CH), 6.50 (m, 1H), 6.78 (m, 2H), 6.97 (m, 1H), 7.07 (m, 1H), 7.24 (m, 1H) , 7.51 (m, 1H), 7.62 (m, 1H), 8.11 (m, 1H, pyrazole CH), 8.19 (m, 1H), 9.60 (s, 1H, NH) MS (El, m / z): 395 [M] + · Calculated value for elemental analysis: C24H21N50: C 72 · 89, H 5.35, N 17.71 · Measured value: C 72 · 57, Η 5.49, N 17.46 Example 丄 3 Γ 4-(3 _ 三 丁丁Tender favor -1 -base}-2 -three bells_cage 1-(5 · 1 1 -secondary: Pinnon earns-[2 "second upper]. · 丄 1 丄 51 盖 —_ 二 Ac_ W- 10-Based on the central sample rate of the M part, only printed by the consumer's cooperation (read the notes on the back and then fill in this page) NaH (60% in oil, 0.12g, 3.0hiwo1) Wash with alkane, dry under nitrogen and suspend in anhydrous dimethylformamide (1 β m 1). At room temperature, add 3-tertiary butyrazole (0.20 g, 1.6 m Μ ο 1) at a time, hold the ore and stir until the gas stops ih generation. Add step 4 of Example 4 once ((5,1,4-dihydro-Bft, pyridine, f2,3-b) [1,5] phenylhydrazine-6-yl)-(4-fluoro-2-trifluorotolyl-methyl-methyl- ( 0 · 50 g, 1 · 3 〇]). Place in an oil bath (preheated to 130 ° C) for 30 minutes and heat to reflux for 5 hours. After cooling, separate between water and ethyl acetate. Organic干燥 Dried under sodium sulfate and evaporated to dryness. Dissolved in dichloromethane and attached to a silica gel rek-6G column. Dissolve in 25% ethyl acetate in hexane to obtain the title compound as a foam (fl .23g, 36%), crystallized from hexane-ethanol, melting point 1 36-1 4 (TC. -7 1- This paper size applies Chinese National Standard (CNS) A4 # A (210X297 mm) 500723 A7 B7__ 5. Description of the invention (π) NMR (DMSO-d6, 400 MHz): δ 1.26 (s, 9H, C (CH3) 3), 4.17 and 5.45 (dd, 2H, CONCH2), 6.47 (m, 1H, pyrazole CH), 6.54 (m, 1H), 6.68 (m, 1H), 6.80 (m, 1H), 7.00 (m, 1H), 7.28 (m, 1H), 7.60 (m, 1H), 7.87 (m, 1H), 8.04 (m, 1H), 8.13 (m, 1Ή), 8.47 (m, 1H, pyrazole CH) , 9.62 (s, 1H, NH) MS (EI, m / z): 491 [M] + Calculated value for elemental analysis: C27H24F3N50: C 65.98, H 4.92, N 14.25. Found: C 65.75, H 4.92, N 13.95

Example 1 JL LL di-fir ..... 佥 ..M Ui 己 —embers ^ _L: J. The salt will contain (5,〗 1-dihydro-pyridine hydrazone [2,3-b] in Step 4 of Example 4 [1,5] Phenyldiazepine-6-yl)-[4-(3-methylpyrazole-1 -yl) -2 -trifluorotolyl] -methyl H (0.5 1g, l.iSmmol) Dichloromethane (lflffll) was added with methanesulfonic acid (n. 0 7 4 wil, l. Hmiaol U and stirred at room temperature overnight, hexane was added and the solid was collected by filtration to obtain the title salt as a white solid (fl.54 g, 87 · 6%), melting point 256-257. 0. MS (+ FAB, m / z): 450 [Μ + ΗΤ Through the central part of the M Department «rates only labor and consumer cooperation shirt printing f (Please read the precautions on the back before filling (This page) Elemental analysis calculation value: C24H18F3N50 + CH403S + 0.15 C6H14: C 55.70, Η 4.35, Ν 12.54 · Found: C 55.37, Η 4.48, N 12.45 Examples "i (m- 二 氪-比" Postscript… [1, —3, 2. Spit with m 脞 M.〇 _ ,. 11 St. Clory I—zhi.::1 salt— -72- &gt; paper size applies Chinese national standard "CNS &gt; Α4 Specifications (210x297 cm) &quot; 500723 A7 — B7___ V. Description of the invention (W) (Please read the precautions on the back before filling this page)

Add (5,1 1 -dihydro-commanded hydrazone [2,3-b] [1,5] phenylbenzenediazepine-6-yl)-[2-trifluoromethyl 4- (3-Metriazol-butyl) phenylbutyrate (0.55 g, 1.22 ιπο1) in dichloromethane (10 ml) was added to 1N HC1 in ether (1.22 WI1). Stir for 1 hour and filter the solid to give the title salt as an amorphous white solid (0.5 g, 84.1%). MS (El, m / z): 449 [M] + Calculated value for elemental analysis: C24H18F3N50 + 1.04 HC1 + 0.10 CH2C12: C 58.38, H 191, N 14.12 · Measured values: C 58.23, H 4.07, N 14.03 Examples —1.6. Azadiphenylhydrazone [a, d] cycloheptene-1 0-yl) -methanone Step A 6 H-pyridinium 丨 2,3-b] M, 5] Benzodiazepine due to nitrogen Lithium aluminum hydride (0.258g, 6.877ι »! Ϊ́ιο1) was added to 6Η-eridine 骈 [2,3-b] [1,5] phenylhydrazine- (0 · 6 3) in portions with stirring. 6 g, 3 mrool) of 25 ral tetrahydrofuran. Heat under reflux for 3 hours, then add 0.3ml of water, 0. 3ηι] 1N NaOH, 0. 9ιη1 water and 3.8g of sulfuric acid pin to decompose excessive lithium aluminum hydride. The solid was collected by filtration and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to obtain a crude product (0.45 g), which was purified by flash chromatography (silicon-Merck-6fl, dichloromethane-ethyl acetate (19: 1)). 〇The yellow compound of the title compound was obtained. Solid (0 · 1 g, 1 U). NMR (DMSO ~ d6, 400 MHz): δ 4.32 (d, 2H, CH2N), 6.09 (t, 1H, NH), 6.56 (t, 1H), 6.62 (d, 1H), 6.82 (t, 1H), 7.00 (d, 1H), 7.18 (m, 1H), 7.79 (d, 1H), 8.165 (m 1H): MS (El, m / z): 198 [M] + Step B [2-chloro-4- Fluorophenylbenzene U 1H-5-4,10-Diazodiphenyl-73- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 __ 5. Description of the invention (&gt;) _ U, d] Heptene-ίο -yl)-methyl ketone (read the precautions on the back before filling in this page) Put 2-chloro-4-fluorobenzoic acid (0.37g, 2.12mffl〇 in the absence of water). l) and chlorammonium chloride (0.30 m), 2.3 m μ ο 1) of 1 〇 1 methylene chloride and the catalyst amount of dimethyl methyl amine are stirred at room temperature until the gas stops generating . Adding crude chloro chloride to 6H-pyridine hydrazone f 2,3-h in step A] [1,5] Benzodiazepine (0.45 g, 2 n 1 2 hi w 〇1 ) And triethylamine (0.35 ffi], 2.5 m ffi ο 1) in a dichloromethane machine-mixed solution [51]. Stir at room temperature overnight, add water and dry under sodium sulfate. The solvent-free surface can be evaporated to give a crude solid compound, which can be used directly in the next step. NMR (DMSO-d6, 400 MHz): δ 5.1 (broad, 2H, CH2N), 6.9-7.5 (m, 8H), 7.92 (d, 1H), 8.22 (m, 1H) MS (El, m / z) : 354 [M] +, 319, 198, 157 Step C · [2 -Chloro-4-(3-methylpyrazole M -yl) phenylbenzene (1 1 -4,1 η -diazodiphenylhydrazone 〖 a, d) Heptene-1 0-yl) methanone

Under nitrogen, 3-methylpyridine (0.16 1 Bi 1, 2 · 0 I »ro 〇]) was added to KH (0.08g, 2.flBiiB01) washed with hexane in class 5 anhydrous 1 Dimethylformamide β was stirred at room temperature until gas evolution ceased. Add the sample containing step [2 P through the central sample rate of the M section and only cooperate with the consumer to print the fluorinated phenylbenzene (Η Η-5 H-4, 1 0-diazodiphenyl 骈 U, d). -10-yl) -methyl surface (0.79 g, 2,14 minol) in 10 ml of dimethylmethylamine. Heat for 1. 3 β ° C 3.5 hours, and then cool in ethyl acetate and water _ water_ after cooling. The organic layer was washed with water, dried under a sulfuric acid pin and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel Merc-6-60, dichloromethane-ethyl acetate U 9: 1 ~ 9: 1)). The title compound was obtained as a white solid (0.18 g, 21%), with a melting point of 2 2 0-2 2 ° C. -7 4-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 500723 A7 B7 V. Description of the invention (μ) NMR (DMSO-d6, 400 MHz): δ 2.218 (s, 3Η, CH3) , 5.106 (broad 2H, C ^ N), 6.325 (d, 1H), 6.927 (t, 1H), 7.03 (d, 1H), 7.21 (m, 2H), 7.27 (d, 1H), 7.44 (m, 1H), 7.67 (d, 1H), 7.70 (s, 1H), 7.88, (d, 1H), 8.24 (m, 1H), 8.397 (d, 1H). MS (El, m / z): 416 [ M] +, 219 mLi .. (!: _ H. Fluorine-Li · 11 挫 —: 丄: Nongi: Gai- Jishang Lili_L2, l Eru will be NaH (60% oil, 0.195g) to It was washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (10 ml). 3-Trifluoromethane (0.336 g) was added dropwise at 0 ° C. Gas generation stopped Then, the temperature was returned to room temperature. (2-chloro-4-fluorophenyl)-(5,1,4-dihydro-pyridinium [2, 3-b] [1, 5] benzene骈 Diazepine-6-yl &gt; formazan (0 · 7 8 7 g, 2 · 2 3 mraol) and placed in an oil bath (preheated to 130 ° C) for 4.5 hours. After cooling, saturated chlorination Sodium and ethyl acetate were decanted. The organic layer was dried under sulfuric acid IS and evaporated to dryness. It was dissolved in dichloromethane and decanted. Attach to silica Merck-60 column. Dissolve in hexane-ethyl acetate (95: 5-3: 2) to obtain the title compound (fl. 7 2 7 g, fi 9 «), and sonicate with hexane-ethanol Crystallized to obtain a white solid, melting point 〖8 3 _ 1 8 5 ° C 〇 It is printed by the Consumer Cooperative Society at the central sample rate of Department M (read the precautions on the back before filling this page) NMR (DMSO-d6, (400 MHz): δ 4.16 and 5.45 (dd, 2H, CONCH2), 6.52 (m, 1H), 6.78 (m, 2H), 7.01 (m, 2H), 7.04 (m, 1H, pymzole CH), 7.26 (m, 1H), 7.61 (m, 1H), 7.74-7.84 (2m, 2H), 8.12 (m, 1H), 8.74 (m, 1H, pyrazole CH), 9.58 (s, 1H, NH) MS (El , m / z): 469/471 [M \\ 273/275, 196 Calculated value for elemental analysis: C23H15aF3N50: C 58.80, H 3.22, N, 14.91. Found: C 58.67, H 3.14, N 14.83 -7 5 -This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 —-------------------__ 5. Description of invention (%) Example — 18 [2: Chlorine: 4: 2 11 Shame ... Base —) di d'LI: 2 — 1: 骈 12 ″ 1 士. 士.;. Geng „Tong.-1 〇-Base)-Step A * 2-chloro-4 ~ (3-dimethylamine propyne μ-yl) formyl benzate The ester was methyl 4-bromo-2-chlorobenzylate (2.5 5 13. g,] 0 1 m ffl ο 1), dimethylamine-2 -propyne (1 6 m), 1 5 0 hi ra ο 1), bis (triphenylphosphine) platinum chloride (U) (1.0 g) and copper iodide (I) (0.15 g) in 10.01 triethylamine were heated to 60 ° C for 2 hours. The reaction was cooled, filtered through Solka floe and washed with ethyl acetate. Layered in ethyl acetate and dilute sodium sulfide. D The organic layer was washed with water and brine, dried under sodium sulfate ^ filtered through a Merck-6 silicon silicon pestle, and concentrated in vacuo to obtain the orange oil of the title compound. (23.8g, 95%), which can be used directly in the next step. NMR (DMSO-d6, 300 MHz): δ 2.25 (s, 6H, NCH3), 3.475 (s, 2H, CCH2N), 3.84 (s, 3H, OCH3), 7.5 (dd, 1H), 7.62 (s, 1H ), 7 · 8 (d, 1H) · Step Re e 2 -Chloro-4-(3 -dimethylamine-2 -propene-1 -yl) benzyl methyl ester under nitrogen 6 g, 9 3 m in ο 1), at -1 0. 〇The following was added dropwise to methylene chloride (23.5 g, 93.4 »ιιπο1) methylene chloride (2 0 0 bi1 &gt; Stir the solution. Add the determinant ^ β 工 消 贽 Cooperative Press printed in the M section (read the precautions on the back before filling in this page) After stirring, stir for 30 minutes at a lower temperature and filter it. Dichloromethane-methanol (9: 1, v / v) aluminum column (400 g, Brockmarr activity I). Intermediate N-oxide was isolated from the upper bar. Dichloromethane was removed from room temperature. Low temperature evaporation carefully replace with methanol and be careful not to evaporate it. Heat to 6n ° C «night, #vacuum dry. By flash chromatography (^^ 1 ^ 11-60 silica column, hexane-ethyl acetate (1)) 1 2 · 1 g can be obtained. Milled with ether-76- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 500723 A7 B7__ 5. Description of the invention (W) can The pure title compound was obtained as an orange solid (β · 15 g, 4 8). NMR (DMSO-d6, 300 MHz): δ 2.98 (s, 3H, NCH3), 3.2 (s, 3H, NCH3), 3.83 ( s, 3H, 〇CH3), 5.85 (d, 1H, vinyl H), 7.75-8.0 (m, 4H, vinyl H + ArH). Φ Step C · 2-Chloro-4-(1 H -pyridin-3 -yl) benzyl methyl ester will be the 2-gas-4- (3-dimethylamine-2-propene) in step B 1-yl) methyl benzate (6,13g, 22.9imol) and glacial acetic acid 15® 1 without water trap (1.44ml, 45 · 8βιβιο1) were heated to 90 ° C for 3fl minutes. Concentrated in vacuo and dissolved in ethyl acetate and water The layers were separated. The organic layer was washed with water and brine, and dried under sodium sulfate. The solvent was evaporated, and the residue was triturated with ethyl acetate-hexane to obtain the title compound as an orange solid (5.11 g, 94%). NMR (DMSO-d6, 300 MHz): δ 3.85 (s, 3H, OCH3), 6.9 (d, 1H), 7.9 (m, 3H), 8.0 (d, 1H), 13.15 (broad, 1H, NH). Step 1) · 2-Chloro-4-(1 -methyl-1 H -nizole-3 -yl) methyl benzyl methylate, only the central government standard of the Ministry of Economic Affairs, and only eliminate the printing of cooperatives (please read the note on the back first) Please fill in this page again.) Under nitrogen, place 2-chloro-4 M 1H-pyridin-3-yl) benzoic acid methyl _ (5,0g, 21.2 «〇1) anhydrous dimethylformamide 50μ1 under nitrogen. Add dropwise to a solution of 5 ml stirring solution of anhydrous dimethylformamide in NaH (fl. 51 g, 21.2 mol) washed with hexane. After stirring at room temperature for 30 minutes, methyl iodide (2.7 ml, 42.2 mmol) was added and stirred at room temperature overnight. Pour into water and extract with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. 4.8 g of orange oil was obtained by distilling off the solvent, and 2.9 g (55%) of sodium bicarbonate was obtained by flash chromatography on a 061 ^ 1 ^ 60 silica column, hexane_ethyl acetate ((4: 1)). Pyro-regioisomers NMR (DMSO-d6, 300 MHz): δ 3.84 (s, 3H, CH3), 3.9 (s, 3H CH3), 6.875 (d, 1H), 7 · 8 (d, 1H), 7.85 (s, 2H), 7.95 (s, 1H), -77- This paper size applies the Chinese National Standard (CNS) A4 * t grid (210X297 mm) Only X Consumption Cooperating Printing 500723 A7 B7 V. Description of the Invention (%) Step E · 2-Chloro-4-U-methyl-azol-3-yl) benzoic acid 1-Methyl-1H-pyrazol-3-yl) benzoic acid methyl ester (2.9 g, 11.6 ιβιπο1) and 5 magnetic 1 2 · 5N NaOH in methanol 20 crude 1 were stirred at room temperature overnight. Add 2.0ml »1 2.5H NaOH and heat gently for 30 minutes. Concentrated in vacuo, diluted with water and acidified with 2 N H C]. The precipitate was collected by filtration and dried to obtain 2.55 g (93 S0 of the title compound. NMR (DMSO-d6, 300 MHz): 6 3.9 (s, 3H, NCH3), 6.85 (d, 1H), 7.82 (m, 3H), 7.95 (s, 1H), 13.3 (broad, 1H, COOH). Step F · [2-Chloro-4- (1-methyl-1-H_oxazole-3_yl) -phenyltriphenyl (5, 1 Dihydro-Bitpyridine [2,3-b] [1,5] Phenyldiazepine-1 octyl-1 -methyl)-methyl chloride 2-Chloro-4-(1- Methyl M Η -pyrazole-3 -yl) benzyl acid (2 .: U, 8.88ιηιο1) and triethylamine (1. 3ιβ1, 9 · 2βι · ο1) of 75μβ] digas methane treatment with 2,4 , 6-Trichlorobenzylphosphonium chloride (1.48βΠ, 9.2ηιβιο1) and stirred at room temperature for 2 hours. Add 6, 1 dihydro-5Η-pyridine [2, 3-1] in step B of Example 1 [1,5] Phenyldiazepine (1.748, 8.918 »101) and stirred] for 8 hours. Wash with saturated sodium bisulfate solution and brine in this order. After drying under sodium sulfate, it was concentrated and attached to the silicone Merck-60. Dissolve in ethyl acetate-hexane (4: 3-2: 1) to obtain the pure title compound slurry, and then crystallize from ethyl acetate. This white solid (0.78 g, 235ϋ yield based on recovered raw material) has a melting point of 196-197 ° C. NMR (DMSO-d6, 400 Mhz): δ 3.831 (s, 3H, NCH3), 4.13 (d, 1H), 5.43 (d, 1H), 6.497 (t, 1H), 6.71 (d, 1H), 6.76 ( m, 2H), 6.97 (t, 1H), 7.24 (d, 1H), 7.6 (m, 3H), 7.705 (d, 1H), 8.10 (dd, 1H), 9.544 (s, 1H, NH) .MS (El, m / z): 415/417 [M] +, 219/221 Calculated value for elemental analysis: C23H18C1N50: C 66.42, Η 4.36, N 16.84. Found: C 66.20, H 4.49, N 16.59.- 7 8-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 ^ 1) I (Please read the precautions on the back before filling this page)

500723 A7 B7 V. Description of the invention (W) Chaos 1SL 12 Second 氲: IL 腚 — 骈 — 『2 · 3-b 1 Μ · 5 1 Cage 骈 二 虏 1¾-1 0-基）-申 _ Yu Wushui will Example} 2-Chloro-4-(1-methyl-1 fluorene-Sftazole-3 -yl) benzyl acid (1.9 g, 8e0ffinto]), oxadichloride ((κ? 9ιη1, 9 · 0ηιβιο1) and dichloromethane containing 20 ml of dimethylformamide with catalyst content and stirred at room temperature for 1 hour. The solvent was distilled off, and solid chloroform was dissolved in 5m of dimethylformamide and directly Add 1,1 dihydro-5H-pyridine hydrazone [2,3-b] [l, 5] phenylhydrazine (1 · 5 9 g, 8 · 0 5 m ro ο 1) and potassium sulfonate (1.25 g, 9 · 0 mmol). After stirring at room temperature for 2 hours, the layers were separated in ethyl acetate and water. The organic tincture was washed with water and brine, and then dried under sulfuric acid. Dry and concentrate. A slurry can be obtained by flash chromatography (Merck-fi 0 silica column, ethyl acetate-hexane (4: 3 ~ 2: 1)), and white solid U.8g, 61 can be obtained by crystallization from ether. % Yield is based on recovered raw materials), melting point 196-197 ° C. A higher melting point can be obtained by recrystallization from ethanol-ether, and the melting point is 202 ° C according to the difference scanner. MS (+ FAB, m / z): 416/418 (M + Η) + · Calculated value for elemental analysis: C23H18C1N50: C ^ .42, Η 4.36, Ν 16.84. Found: C 66.20, Η 4.42, Ν 16.80. · Consumption cooperation private printing f by the central sample rate of the sludge department (please read the precautions on the back before filling this page) Example _.2 Li L2: 氲: if base-1 H -1¾ _-3 -base) Phenylbenzene (5-methyl-5. 11: dihydrodiII abdominal diarrhea "2) Example 19 [2-chloro-4-U-methylpyridin-3-yl) -phenyl)- (5, U -dihydro-piperidine 骈 〖2,3-b] 〖1,5】 Phenyldiazepine-1 0 -yl) -methyl face | (0 · 3 8 2 g, 0 · 9 2 ra m ο 1) of 10 m 1 tetrahydrofuran dropwise addition -79- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7 V. Description of the invention (w) to hexane that has been washed NaH (fl.fl25g, 1.02μβιο1) tetrahydrofuran gas was stopped and methyl iodide (IfflU) was added and stirred for 2 hours. The layers were separated in ethyl acetate and water. The organic layer was washed with brine and dried under sodium sulfate. The solvent was removed and the title compound (Merck-60 silica column, dichloromethane-ethyl acetate (2: 1)) was obtained. 0.18g, 47%). Crystallized from diethyl ether to give a pale yellow solid (0.16 g), melting point 2 49-250 ° C. NMR (DMSO-d6, 400 MHz): δ 3.491 (s, 3H NCH3), 3.835 (s, 3H, NCH3), 4.18 (broad, 1H), 5.7 (broad, 1H), 6.497 (t, 1H), 6.72 (d, 1H), 6.88 (m, 2H), 7.08 (d , 1H), 7.19 (m, 2H), 7.25 (d, 1H), 7.6 (m, 2H), 7.69 (d, 1H), 7.71 (d, 1H), 8.215 (dd, 1H ) · MS (El, m / z): 429/431 [M] +, 219/221. M 21 「2 -BinU 3 -Shen · _Β»; _-1 -some) Cage 1-(5 · 1 1 -Diargon-HH; Printed at the central sample rate of M and printed by a consumer cooperative (please read the precautions on the back before filling this page) Step A 2-Chloro-4-(3-methyl -Phenyl) methyl benzate Add 3 -methylpyridine in one portion to a stirred solution of KH (0.4 2 4 g, 10. 6 81 mol) 5 ffi] dimethylformamide which has been washed with hexane under water. Sleep (0. 8 5 ffi 1, 〖0.6 «nnolU gas stop! After the formation of h, add 2-chloro-4-fluorobenzyl formazan (2.flg, 10.6βΐΒΐο) Λ and heat to 13fl ° C for 15 minutes. After cooling, separate the layers between ethyl acetate and saline. The organic layer was washed with water and brine, and dried under sulfuric acid. The solvent was distilled off to obtain 2.2 g of butter containing 3-methyl and 5-methylpyrene regioisomers. In addition, it is known from NM that approximately 20% of the acid is obtained from the hydrolysis of the ester. A white solid (1-1.5 5 g, 56%). 1 80 ~ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 500723

A B7 V. Description of the invention (π) NMR (DMSO-d6, 400 MHz): δ 2.264 (s, 3Η, CCH3), 3.845 (s, 3H, OCH3), 6.40 (d, 1H), 7.865 (dd, 1H ), 7.93 (d, 1H), 8.00 (s, 1H), 8.535 (d, 1H). MS (EI, m / z): 250/252 [M] '219 Step B 2 -Chloro- 4- (3 -Methyl-exposed f-1--1-yl) benzoic acid will be methyl 2-chloro-4- (3-methyl H-% pyridinyl) benzate (1 · 4 2 I?, 5 · 6 w ο 1) and tetrafran (20 il) containing 6 ffl 1 1 M lithium hydroxide were stirred at room temperature overnight. The layers were separated in ethyl acetate and 1N HC1. The organic tincture was washed with water and brine, and dried under sodium sulfate. Evaporation of the solvent gave the title compound U * 〇5 g, 78%), melting point 192-193 ° C c NMR (DMSO-d6, 400 MHz): δ 2.268 (s, 3H, CCH3), 6.40 (d, 1H), 7.84 (dd, 1H), 7.92 (d, 1H), 8.00 (s, 1H), 8.53 (d, 1H), 13.32 (broad, 1H, COOH). MS (El, m / z ): 236/238 [M] +, 219 Calculated value for elemental analysis: CUH9C1N202: C, 55.83, H 3.83, N 11.84. Found: C 55.79, H 3.98, N 11.73 Step C [2 -Chloro-4 -(3-methylpyrazole-1 -yl) phenyl]-(5,1 1 -dihydro-pyridinepyrene | 2,3 -b Η1,5] phenylpyridine-6 _ The central sample rate of the Ministry of Economics and Industry is only printed by the Consumer Cooperative Cooperative (please read the precautions on the back before filling this page). Example 5 step I) method, using the chlorine B-4-(3 -methyl- 1 fluorene-preferred -1 -yl) phosphonic acid ((I · 9 7 1 g, 4 · 1 in ο 1), triethylamine (0 · 5 7 m 1, 4 elfflffi〇U, 1, 3, 5 'three Chlorobenzyl chloride (0.63β1,4 · (ΐΗ »M〇1), Example 1 6,1 1 -dihydropyridine hydrazone [2,3-h] [1,5] phenylhydrazine in step B (Fl.6 7g, 3.4 η * ηιο1) and 4-dimethylamine pyridine (0.42g, 3.4βιβιο1) in dichloromethane (2 fl in 1) The same compound as in Example 1 can be obtained. M12— BU 氡 -4- (5 -methyldi 11 dibenzidine-zodihydrazone: AiJIJLMJe— Example 2 Step A method, Example 2 1 in 3 -The isomers of methyl Pftazole are composed of step-8 1-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 500723 A7 B7___ V. Description of the invention (P) Analysis (Merck-6 0 Silicon_ Column, dichloromethane) to isolate the title compound as a white solid (0.20 g, NMR (DMSO-d6, 400 Mhz): δ 2.425 (s, 3H, CCH3), 3.875 (s, 3H, 〇CH3) , 6.33 (s, 1H), 7.65 (m, 2H), 7.79 (s, 1H), 7.95 (d, 1H). MS (El, m / z): 250/252 [M] +, 219. m 21 (2 ~ Argon-4 -fluorobenzene-i ^ ^ 骈 2 l heptane will contain the case 〖6,11-dihydro-51! -Benzene 骈 in step 8 [13] 嗽 旋 骈 [2,3-6] fl , 4 丨 Diazepine (fl.lg, 0.51ιη · ο1) tetrahydrofuran when dimethylamine (O.lflg, i.55mmol) and 2-chloro-4-fluorobenzyl chloride (fl.lrol, 0.76n (ffl01). After stirring at room temperature overnight, it was evaporated to dryness and the layers were separated in saturated ammonium chloride solution and dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give the title compound, which was the same as step D in Example 1. Example „2 _4._ L2 Dichloride-Secondary-Ethyl-Glycol-Ethyl-Ethylene-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethyl-Ethylene The sequel to the methyl terephthalate M is determined and the consumption is reported to be printed only (please read the precautions on the back before filling this page). The methyl 2-chloro_4-cyanobenzate (12.4g, 6 3 · 4ΐϋϊηο1) and potassium sulfonate 9.4 · ιβο1) dimethylarylene ill (40rol) was added dropwise with cooling 30% hydrogenated hydrogen (7.8 m 1). After warming to room temperature, stir overnight. Water was added to react for 1 h and the precipitate was collected by filtration. Dissolved in dichloromethane and adsorbed to the silica_Merck-fi0 column. Dissolve in dichloromethane-methanol (98: 2 ~ 9 fl · · 10) to obtain the title compound as a white solid (Ug, 7U), melting point: 154-156 ° C. -8 2 _ This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). The central sample has been filled and printed by the Industrial and Commercial Cooperatives. 500723 A7 B7___ 5. Description of the invention () NMR (DMSO-d6, 400 MHz): δ 3.87 (s, 3Η), 7.67 (s, 1H, NH), 7.86-7.91 (m, 2H), 8.00-8.01 (m, 1H), 8.20 (s, 1H, NH) MS (El, m / z): 213 [M] +

Anal. CalcM for C9HgClN03: C 50.60, H 3.77, N 6.56. Found: C 50.36, H 3.66, N 6.44 Step B 2 -Chloro-N-(1 -dimethylamine ethylene) -methyl terephthalate In step A, methyl 2-chloro-p-gfeate (0.02 g, 4 · 8ηιιο1) and N, N-dimethylacetamidodimethylacetal (3.5ml, 23e9mmol) were heated to 90 ° under nitrogen. C 3 0 points. Cooling and evaporating the solvent in vacuo gave a palm oil which was used directly in the next step. NMR (DMS0-d6, 400 MHz): δ 2.29 (s, 3H), 3.14 (s, 3H), 3.16 (s, 3H), 3.87 (s, 3H), 7.83-7.85 (m, 1H), 8.00- 8.06 (m, 2H) MS (El, m / z): 282 [M] + Step C. 2 -Chloro-4-(5 -methyl-1 H-[1,2,4] triazole-boxy ) Methyl benzylate. Anhydrous hydrazine (0.30 in], 9.6 mm ο 1) was added from a syringe under nitrogen to glacial acetic acid (6. 8 m ο 1) under nitrogen. (6 ffl 1). Heat to 90 ° C for 30 minutes, cool and concentrate in vacuo to obtain a light brown solid. Dissolved in methanol and neutralized with saturated sodium bisulfate solution. Extract with dichloromethane and ethyl acetate, extract the combined solution and dry under sulfuric acid. The solvent was distilled off to obtain a solid, and the title compound was mixed with a white solid (0.81 g, 6U) to obtain the title compound, and the melting point was 9 6-198 ° C. NMR (DMSO-d6, 400 MHz): δ 2.41 (s, 3H), 3.86 (s, 3H), 7.90-8.05 (m, 3H), 13.94 (s, 1H) MS (El, m / z): 251 [M] + Calculated value of element analysis: C 52.50, H 4.01, N, 16.70. Measured value: C 52.68, H 3.83, N 16.50 -8 3 _ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ) &quot; &quot; (Please read the notes on the back before filling this page)

Central sample rate of the drop section M ΗConsumer cooperatives 5007 A7 ____ B7 V. Description of the invention (g &gt;) Step I) · 2-chloro-4-[1 _ (4-methoxybenzyl) -5 -methyl -1 Η-[1,2,4] Tris-3-yl 1-benzyl acid methyl ester with methylene chloride 0 · 03 solvate NaH (60% oil, 0 · 3g, 7 · 5 «〇1 ) Wash with hexane and suspend in anhydrous dimethylformamide (20 ffi 1) under nitrogen. Add the triazole intermediate product 5nm 1) from step C and stir for 1 hour. After stirring for 3 hours, p-methyl benzyl chloride ((K 7 5 «! 1.5, 5mmo 1) was added, and water was added to stop the reaction. The extract was extracted with ethyl acetate, and the combined extracts were dried under anhydrous sodium sulfate and concentrated in vacuo. c Dissolved in dichloromethane and attached to a silica gel Merck-60 column. Dissolve 3% ethyl acetate in dichloromethane to obtain the title compound (1.23 g, 6 (5 6 · U) white solid, melting point 1 0 2-1 0 4 ° C. NMR (DMSOd6, 400 ΜΗζ): δ 2.48 (s, 3H), 3/72 (s, 3H), 3.86 (s, 3H), 5.35 (s, 2Η), 6.90-6.92 (m, 2Η), 7.23-7.25 (m, 2H), 7.89-8.02 (m, 3H) MS (El, m / z): 371 [M] + Calculated value for elemental analysis: C19H18C1N303 + 0.03 CH2C12: C 61.05, H 4.86, N 11.22. Actual value: C 60.83, H 4.96, N, 11.18 Step F: · 2-chloro-4-U ~ (4-methoxybenzyl) -5 -methyl-] H -[1,2,4] Tris-1,3-yl] benzyl acid and ethyl acetate 0. 1 hydrate 0. 0 4 solvate the step D ester intermediate (1.6 g, 4 · 3ηιβιο1) in methanol (15b »1) was treated under nitrogen at 2 · 5 NN a 0 · (3 · 5 in 1,8 · 8» ι]). It was refluxed for 2 hours, cooled and concentrated in vacuo. _ And water layered. The water layer was acidified with 1 NHC 1. The precipitate was collected by filtration to obtain the title compound (1 · 2 5 g, 8 1 · 2 X) as a white solid with a melting point of 1 5 4-1 5 6 ° C. NMR (DMSO-d6, 400 MHz): δ 2.47 (s, 3H), 3.72 (s, 3H), 534 (s, 2H), 6.90-6.93 (m, 2H), 7.23-7.25 (m, 2H), 7.87-7.99 (m, 3H), 13.40 (s, 1H) MS (EI, m / z): 357 [M] + -84- This paper size applies to China National Standard (CNS) A4 (210X297 cm) ( (Read the notes on the back before filling in this page)

500723 A7 B7 V. Description of the invention (shirt) Elementary analysis calculation: C18H16C1N303 + 0.10 H20 + 0.04 C4H802 ·· C 60.07, Η 4.59, N 11.57. Actual traceability: C 59.75, Η 4.41, N 11.43 Step F · 2-chloro-4 M 1-(4-methoxybenzyl) -5 -methyl-1 hydrazone-[1,2,4] triazol-3-yl] benzylhydrazone chloride Step I? Acid Ug, 2 8 mmol) and a few drops of dimethylformamide in dichloromethane were added dropwise with chloramphenicol (0. 3βι1, 3 · 4ηιβιο1) under nitrogen. When the gas stopped, I: generated, refluxed for 15 minutes and dried under vacuum to obtain the title compound, which was used directly in the next step. Step G. [2 -Chloro-4 -f ((4-methoxybenzyl) -5 -methyl-1 fluorene-[1, 2, 4] triazol-3-yl] phenyl]-(5, 11-Dihydro-1% pyridinium [2,3-1)] [1,5] Benzodiazepine-6-yl) -methyl_ 0 · 06 Rate ^ ¾ ΗConsumer Cooperative Seal 54 (Please read the precautions on the back before filling this page) will contain Example 1, step B-6,1 bu dipyridine 骈 [2,3-b] [l, 5] benzene 骈Diazepine (0.55g, 2.8βιβιο1 &gt; dimethylformamide (lOffll), potassium sulfonate (0.39 g, 2. 8 m hi 〇]) was added under nitrogen. Added dropwise to step F Chlorine crude (2.8 wibio)) dimethylformamide (lOffil), stirred at room temperature for 90 minutes, diluted with water and extracted with ethyl acetate. The extracts were combined and washed with IN NaOH, and sulfuric acid It was dried under sodium and evaporated to dryness. It was dissolved in dichloromethane and adsorbed to a silica column. Dissolution was carried out with ethyl acetate · hexane (1: U to obtain impurities of lower polarity. Re-dissolution was 2% Methanol-dichloromethane gave the title compound (0.57 g, 38S!) As a white solid with a melting point of 218-2 21 ° C 0 NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 3H), 3.71(s, 3H), 4.14 and 5.44 (dd, 2H), 5.29 (s, 2H), 6.49 (m, 1H), 6.74-6.80 (m, 2H), 6.88-6.99 (m, 3H), 7.18-7.26 (m, 4H), 7.60 (m, 1H), 7.65-7.75 (m, 2H, ArH), 8.11 (m, 1H), 9.55 (s, 1H) MS (ESI, m / z): 537 [M- hH] + Calculated value for elemental analysis: C3〇H25CK) 2 + 0.06 CH2C12: C 66.60, H 4.67, N 15.50. Measured value: C 66.24, H 4.85, N 15.23 -8 5 ~ This paper uses Chinese national standards ( CNS) A4 specification (21 OX297 mm j 漭 Central sample rate 漭 ΗConsumer cooperative printing f 500723 A7 B7 V. Description of the invention (舛) Step H · [2 -Chloro-4-(5 -methyl-1 -Hydrazone-[1,2,4] triazol-3-yl) -phenyl (5, 11-dihydro-pyridine hydrazone [2, 3-b] [1,5] phenylhydrazine diazepine- 6-based) -formaldehyde_ The trifluoroacetic acid (15 ro I) in the step (5 triazole intermediate (0.5 4 g, 1 · 0 mm ο 1)) was heated under reflux under nitrogen for 7 days. Cool and evaporate the trifluoroacetic acid in vacuo. Dissolved in water and neutralized with saturated disulfonic acid pin solution. Take ethyl acetate, dry under sodium sulfate and concentrate in vacuo to obtain a pale yellow solid. It was dissolved in ethyl acetate-methanol and adsorbed on a silica_Merc-6-60 column. The title compound (0.23 g, 54.fi%) was obtained by dissolving ethyl acetate from 1001 ethyl acetate to 5% methanol to obtain a white solid, m.p.> 2 70 ° C. NMR (DMSO-d6, 400 MHz): δ 2.36 (s, 3H), 4.15 and 5.45 (dd, 2H, CONCH2), 6.50 (m, 1H), 6.75-6.80 (m, 2H), 6.98 (m, 1H ), 7.19-7.27 (m, 2H), 7.60 (m, 1H), 7.70-7.79 (m, 2H), 8.11 (m, 1H), 9.54 (s, 1H), 13.78 (s, 1H) MS (+ FAB, m / z): 417 [M + ΗΓ calculated by elemental analysis: C22H17C1N60: C 63.39, H 4.11, N 20.16. Found: C 63.14, H 4.13, N, 19.90 M2 ... 5 [2 dibromodi i di 丄 3 dual-use _ 舭 -1-radical) stupid 1-η 1 η-5-g 咢 4,1 ο-dirr

Mlf ......... [..sl ..ι xl ... U-shock ..... ·] ._ 0)! 5. 8S ..._ Example lf &gt; The method was carried out by reacting 6 H-pyridine hydrazone f 2,3-h] [1,5] phenylhydrazine in step A of Example 16 with A 2 -bromo-4 -fluorobenzylhydrazone in step 3 of Example 3. The (2 -bromo-4 -fluorophenyl)-(1 1 Η-5--4 ,,] 0-di Τ diphenyl 骈 〖a, d] cyclohepten-10-yl &gt; -methanone intermediate The title compound can be obtained by reacting with the 3-methylpyrazole pin salt according to the method of Step 16 of Example 16. Examples 26 -86- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the note on the back first) Please fill in this page for further information) -1® ^. Ordered by the Central Samples and printed only by the Consumer Cooperatives Co., Ltd. 500723 A7 B7 V. Description of the invention (f) [A: (J -1 azole-2 1 diyl) One cover-ridge "basket-1 cover _ 丄 丄: 11 丄 11 2 5_two 11_two 4,11 two Ξ; 1 ... 2 M ... M, Example 1 2-chloro analogue method in β, From Example 16 step A, 6 Η-pyridine 骈 f 2, 3-h〗 [1,5] phenyl hydrazine diazepine because of the reaction of 2-trifluoromethyl-4 -fluorobenzylhydrazone in step 4 of Example A. The title compound is obtained. {4-Fluoro-2-trifluorotolyl) Stomach-4,] 0-diffylaphenylbenzene [a, d] cycloheptyl-10-yl) -a_intermediate product 3 -Pyridine sodium salt was reacted according to the method in Step 6 of Example 16 to obtain the title compound. Example 21— "2-Hydroxy-4- (3-methyl-1--1-yl) phenyl 1- (1111-5 -_- 4,10-two ..... a .., ... dJ cycloheptyl_-10-yl), imitating the 2-atom analogue method in Example 1 fi, from Example 1 6H-exposure in step A 6 ί 2, 3-h 丨 [1,5] Phenyldiazepine and the 2,4-difluorobenzyl chloride in Step A of Example 9 to obtain the title compound. (2, 4-difluorophenyl) -(11 H-5-Bqin-4, i 0 -diazodiphenyl hydrazone U, (Πcycloheptene_ 1 0 -yl) -methanone intermediate product tree 3 -pyridinium salt according to Example 1 6 steps The title compound can be obtained by the reaction in method C. Μ 28 12 dichloro… τ Α ζΛ Ι ζ m ^ —) phenylbenzene (11 Η-5 di Pi-4 1Q ~ [a. S .. d ^ The pyrazole analog method was carried out from 2-chloro-4-(1 -methyl-1 hydrazone-3 -yl) benzamidine chloride in Example 19 with 6 hydrazone -pyridine hydrazone in Step A of Example 1 [2 ， 3-b] f 1,5] Benzene diazepine can obtain the title compound. -87- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back first) (Fill in this page again)

, 1T

Claims (1)

500723 500723, the scope of application for patent X is hydrogen, or cv6 linear alkyl; Y is halogen, Ci-6 straight alkyl, or CP6 perfluoroalkyl; Z is hydrogen; or a pharmaceutically acceptable salt thereof. 2. The compound according to item 1 of the scope of patent application, which has the formula: R6 Where R1 is a group selected from R2, R3 and R5 are each hydrogen, a linear alkyl group, a C3_7 branched alkyl group, or (^ _6 perfluoroalkyl group; -2- 500723 VI. Application scope of patent R4 is hydrogen, or CK6 straight-chain alkyl; R6 is hydrogen, or CY6 straight-chain alkyl; X is chlorine or C! _ 6 straight-bonded courtyard; Y is halogen '1.6 straight Alkyl, or C16 perfluoroalkyl; Z is hydrogen; or a pharmaceutically acceptable salt thereof. 3. The compound according to item 1 of the scope of patent application, which is [2-chloro-4- (3-methylazol-phenyl) phenyl]-(5,11-dihydro-pyridinepyrene [2,3- b] [l, 5] phenylhydrazine-6-yl) -methanone. 4. The compound according to item 1 of the scope of patent application, which is [2-chloro-4- (5-methylpyrazole-phenyl) phenyl]-(5,11-dihydro-pyridinium [2,3- 1)] [1,5] Benzenediazepine-6-yl) -methanone. 5. The compound according to item 1 of the scope of patent application, which is [2-bromo-4- (3-methylpyrazol-1-yl) phenyl]-(5,11_dihydro-pyridinefluorene [2,3讣] π, 5] phenylhydrazinediazine-10-yl) -methanone. 6. The compound according to item 1 of the scope of patent application, which is (5,11-dihydro-pyridinepyrene [2,3 讣] [1,5] phenylhydrazine_6-yl) _ (renfluoro_ 2_ trifluorotolyl benzophenone. 7. The compound according to item 1 of the scope of patent application, which is (5,11-dihydro-pyridinepyrene [2,3-1 ^ [1,5] benzene骈 Diheptin_6_yl)-[4_ (3-methylpyrazol ^ yl) _2_trifluorotolyl] -methanone. 8 · As the compound in the first item of the patent application, which is (5,11 -Dihydro-pyridinehydrazone [2,3-1 ^ [1,5] phenylhydrazone diheptin-6-yl)-[4- (3-methylpyrazol-1-yl) -2-trifluorotolyl 1: 1 salt of methanone and methanesulfonic acid. 500723 The compound in the scope of patent application a, as in the scope of the first item in the scope of patent application, which is (5, ιι-dihydro-pyridinepyrene [2,3-b] [ 1,5] Benzamidine diheptin-6-yl)-[4- (3-methylpyridin-1-yl) -2-trifluorotolyl] -methanone and the hydrochloride 1: 1 salt. 10. The compound according to item 1 of the scope of patent application, which is 4- (3-methylpyrazol-1-yl) -2-trifluoromethyl-benzoic acid methyl ester. 11. According to item 1 of the scope of patent application Compound, which is 4- (3-methylpyrazol-1-yl) -2-trifluoromethyl-benzic acid or a pharmaceutically acceptable salt thereof or an ester thereof. The compound according to the first item of the invention is (5,11-dihydro-pyridinepyrene [2,3-b] [l, 5] phenylpyrene diheptin-10-yl M4- (5-methylpyrazole- 1-yl) -2-trifluorotolyl] -methanone. Ia The compound according to item 1 of the scope of patent application, which is (5,11-dihydro-pyridinepyrene [2,3-bni, 5] phenylhydrazone Diheptene-6-yl M2-trifluoromethyl-4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -methanone. 14. Compounds as claimed in item 1 of the scope of patent application , Which is (5-methyl-5,11-dihydro-pyridinepyrene [2,3-b] [l, 5] phenylpyridinediazepine-10-yl)-[4- (3-methylpyridine Azol-1-yl) -2-trifluoromethyl-phenyl] -methanone. 15. The compound according to item 1 of the scope of patent application, which is (5,11-dihydro-pyridylhydrazone [2,3- 1) a few 1,5] phenylhydrazone diheptan-10-yl)-[2-fluoro-4- (3-methylpyrazol-1-yl) -phenyl] -methanone. The compound according to item 1, which is (2,4-difluorophenyl)-(5,11-dihydro-pyridine hydrazone [2,3-1 ^ [1,5] phenylhydrazine diazepine-10- 17) The compound according to item 1 of the scope of application for a patent, which is (5,11-dihydro-pyridoxine [2,3-b] [l, 5] phenylhydradinine-10- )-[4-fluoro-2- (3-methylpyrazole-1- -4- 500723 6. Scope of application for patents) -Phenyl] -formamidine. 18 • The compound according to item 1 of the scope of patent application, which is [2-chloro_4_ (3_methylpyrazole_1-yl) phenyl]-(5-methyl-5,11-dihydro_pyridine) [2,3_1)] [1,5] Phenyldiazepine-10-yl) -methanone. 19. The compound according to item 1 of the scope of patent application, which is (2-chloro_4-fluorophenylb (5-methyl-5,11-monohydro-pyridine [2,3-1)] [ 1,5] phenylhydrazine (10_yl) -methanone. 20 · The compound according to item 丨 in the scope of patent application, which is (5, π_dihydro_pyridinium [2,3-bni, 5] phenylhydrazine_ι〇_yl) _ [2_methyl _5_ (3-methylala_boxy) -phenyl] -methanone. 21. The compound according to item 1 of the scope of patent application, which is (5,11-dihydro_pyridinepyrene [2,3-bni, 5] phenylpyridinediheptene_6_yl)-(5-fluoro-2 -Tolyl) -methanone. 2Z The compound according to item 1 of the scope of patent application, which is [4- (3-third-butyl-pyrazol-1-yl) -2-trifluorotolyl]-(5, u-dihydro_pyridine) [2,3-b] [1,5] Phenyldiazepine-l-benzyl ketone. 23. The compound according to item 1 of the scope of patent application, which is [2-chloro-4- (3- Trifluoromethazol-l-yl) phenylphenyl (5,11_dihydro_pyridinium [2,3 讣] [1,5] phenylhydrazine-6-yl) -methanone. 2i For example, the compound of item 1 in the scope of the 5R patent is' [2-chloro_4- (1-methyl_1H-pyrazol-3-yl) -phenyl]-(5,1,1-dihydro-pyridine) [2,3-b] [l, 5] Benzenediazepine-10-yl) -methanone. 2 &amp; As the compound in the scope of patent application item 1, it is [2-chloro_4_ (1_ Methyl_azol-3-yl) · phenyl]-(Hydroxymethyl_5, u_dihydro-pyridinium [2,3_bni, 5] phenylbenzodiazepine-1〇_yl) _methyl Ketone 500723 6. The compound in the scope of application for patent 26 such as the item in the scope of application for patent 1, which is 6,11-dihydro-5H-pyridinium [2,3-bni, 5] phenylhydrazine diazepine-5- 27. The compound according to item 丨 in the scope of patent application, which is [2-chloro-4- (5-methyl-111- [1,2,4-triazol-3-yl) -phenyl]- (5, 11- Hydrogen - pyridin-parallel [2,3-1); | [1,5] benzo diazepine-6-yl) - methanone. 2S · —A pharmaceutical composition for treating abnormalities that can be cured or relieved by the action of mammalian vasopressin, including a pharmaceutically effective amount of a compound such as the first item of the scope of patent application or a pharmaceutically acceptable salt thereof as an active ingredient, As well as combining or combining pharmaceutical acceptable carriers. It is said that, for example, the pharmaceutical composition with 28 items of patent application, wherein abnormalities that are cured or relieved by the action of vasopressin include diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence 'bleeding and coagulation abnormality, or temporary delay in urination.