TW565560B - Tricyclic 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

565560 A7 B7 V. Description of the Invention (/) The present invention relates to a tricyclic compound or a pharmaceutically acceptable salt thereof that can be used as an agent of vasopressin, and a method for treating the compound and a pharmaceutical composition thereof. BACKGROUND OF THE INVENTION (Antidiuretic hormone, ADH) is a non-brachydermal hormone and neurotransmitter, which is synthesized in the nucleus of the naked bed of the hypothalamus of the brain, and is sent to the posterior pituitary gland by the pituitary gland from the nucleus of the optic bed. When the osmotic receptor of the brain senses an increase in osmotic pressure or decreases in blood volume or blood pressure by the gravity sensor and volume receptor, it releases vasopressin into the blood, which can activate the VI a receptor in the blood vessel and make the blood vessel Constriction increases blood pressure and vasopressin V2 receptors in the kidney while retaining water, and reduces the level of electrolytes to expand blood volume (Cervoni and Chan, Diuretic Agents, in Kirk-Othaer: Encyclopedia of Chemical Technology, 4th ed., Wiley, Volume 8, 398-4 3 2, 1993) The presence of vasopressin in the inferior colliculus was known before 1 8 9 5 (Oliver, J. and Schaefer, J. Physiol (London) 18: 277-279, 1895). dll Vigneaud et al. in 1954 learned the structure of vasopressin and its overall synthesis (du Vigneaud, Gish, and Katsoyannis, J. Am. Che®. S oc. 7 6: 4 7 5 1-4 7 5 2, 1 9 5 4) 〇 Printed by the Central Ministry of Economic Affairs and the Consumers' Cooperative (please read the precautions on the back before filling out this page) The role of vasopressin vla receptors is mediated by the phospholipids inositol pathway. 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 adenylate cyclase system. Activation of vasopressin V 2 receptors by vasopressin or vasopressin-like (peptone or non-peptide) compounds can increase the water permeability in the renal collecting tube and can absorb a large amount of water again. Therefore, the paper size can be formed and interpreted. The Chinese paper standard (CNS) A4 (210X297 mm) is applicable. 565560 The central gradient of the Ministry of Economic Affairs and the printing of A7 by the Ordnance and Consumer Cooperatives. 5. Description of the invention (x) Concentrated urine, thus reducing Urine output and increase urine permeability. Vasopressin plays a very important role in conserving water by concentrating urine in the kidney collection tube. The renal collection tube is relatively impermeable to water when there is no vasopressin. Therefore, the hypotonic fluid after the glomerular filtration passes through the tubing,

Henle loop, and after distal recanalization and release with diluted urine. However, during dehydration, volume reduction, or blood loss, the brain releases vasopressin, which activates the vasopressin V2 receptor in the renal collection tube, making the collection tube highly permeable to water, so it can be collected again. Water releases concentrated urine. In human or animal center or neurodiabetes insipidus, the synthesis of vasopressin in the brain is defective, so little or no vasologin is produced, but the vasopressin receptor in the kidney is normal. Because the urine cannot be concentrated, this patient produces 10 times the volume of urine compared to normal people, and it is extremely sensitive to vasopressin and vasopressin V2 agents. Vasopressin and ligament vasopressin (which is natural Angiotensin peptide analogs) in patients with central diabetes insipidus. Angiotensin V2 agents can be used for treatments such as nocturnal urination, nocturia, urinary incontinence, and, if necessary, temporarily delaying urination. Vasopressin can increase blood pressure by contracting blood vessels by activating vla receptors. Vasopressin Vla receptor acting agents have the opposite effect. Vasopressin and vasopressin-acting agents can release factor VI11 and von wilebrand factor, so they can treat blood loss disorders such as hemophilia. Vasopressin and vasopressin-like agents can also release the group plasminogen activator (t ~ PA) into the blood, so it can be used in patients with cardiac congestion and other thrombotic disorders to dissolve Iftl · Block (Jackson, H Vasopressin and other agents affecting the renal conservation of water ", in: This paper size applies to the Chinese national standard (CNS > A4 specification (2i0x297 mm)) (Please read the precautions on the back before filling in this page)

1T 565560 A7 B7 V. Description of the invention (々)

Goodman / s and Gilman's The Pharmacological Basis of Therapeutic, 9th ed., Eds. Hardman L i in bird, Molinoff, Ruddon and Gilman, McGraw-Hill New York, pp 7 1 5-7 3 1, 1 9 9 6, L ethagen, S., Ann He »ato 1., 69; 1 7 3 -180 (1994), Cash, eta 1., Brit. J. Haematol. 27; 3 6 3-3 6 4, 1 974., David, Regulatory Peptides, 45; 3 1 1-3 1 7, 1 993; Burggraaf, eta 1., C 1 i. S c i. 86; 4 9 7-5 0 3 (1 9 9 4) Technical reference: Peptide vasopressin antagonist: M. Manning eta 1., J. Med. C hem., 35, 3 8 2 (1 9 9 2); M. Manning eta] k J. Med. C he ro., 35, 3 8 9 5 (1 9 9 2); H. Gavras and B. Lai Bfflek, US Patent 5070187 (1991); M. Manning and W. Sawyer, US Patent 5055448 (1 9 9 1) F · E · A 1 i, U.S. Patent 476 fi 1 0 8 (1 9 8 8); R. R. R υ ffo 1 oe t. A 1., Drug News and Perspective, 4 (4 ), 217, (May 1991). Williams et al. Reported a potential hexapeptide oxytocin antagonist [J. Med. Chem., 35, 3905 (1992)], which was printed only by the Consumer Cooperative through the Central Department of the Ministry of Education (please read the back first) Note: Please fill in this page again) The combination of V i and V 2 receptors shows weak vasopressin antagonistic activity. The shortcomings of peptide vasopressin antagonists are the lack of U-activity, and many peptides are not selective antagonists because they have only partial active activity. Recently, non-peptide vasopressin antagonists have been published. Albright et al. Published U.S. Patent 5 5 1 6 7 7 4 (May 5th, 1 996) for tricyclic diazepine because of vasopressin and oxytocin antagonists; JP 08081460-A (March On the 26th, 〖9 9 6) Tetrahydrophenylarsine diazepine was published because of vasopressin antagonist; This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 565560 A7 B7 V. Description of the invention (4 4 er 53 anti-9 agonist wosu and wasuao pressure ο add tube 1 blood 55 for the benefit of the country of birth of the United States Yanmeihuan in the hybrid 骈 and other benzene ht lg nu. Γ b tube 7 blood 11 tj 2 is 5 5 phytobiotic derivatives acridine sa sa ring te tri ka ρκn containing e wa-v) den 6 9 *, 9 s 1 agent, anti-Japanese antagonist 3 prime monthly pressure 4 Π (Lili Zhuanchun · Yu Human blood is biologically derived, i.e. acridine benzene * ring three C vehicle published anti > 96 hormone 19 production, fatigue and 2 elementary monthly pressure (5 plus elementary pressure plus Π, with ni 0 toughness U 8, U method (H square) on the fan _ such as adding tube

ο B-based amine deaerating A acid · amine imine ch is compounded into this compound ο agent is used as a plain pressure plus blood tube is not good resistance to the end of the path A variety of sexually-friendly products can be used for oral health, good quality, high quality, high-peptide formula, non-endogenous ingredients, non-functional ingredients, and clear-cut formulas, and urinary night treatment with ploidy pressure and tubes for blood. La is combined and i ririy / i agent 〇0 uses 丨 -Tech A) as υβ- ο V2 first 54 elements, 3 pressure 95 plus anti wo tube relative to blood. Partial pressure of blood in addition to selective lifting. Selective agents have no resistance to the inconvenience of the glutamate salt Jie Xu Xu total hair Rongming The drug system ----------- (Please read first (Notes on the back then fill out this page)

, 1T The Central Ministry of Economic Affairs, the Ministry of Economic Affairs, the Consumer Cooperatives, India

Z The paper size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 565560 A7 B7 5. Description of the invention (Γ) In the formula: C 2-7 alkyl alcohol group or selected from the following groups W Is 0, or NR6 A and B are each C or HR 1 is -C = C-R 9

Q (b)

(i) r2

(f)

N R2

YV (d) K N—N R4 R〆 (g)

< v n = n R2 (Please read the notes on the back before filling this page) Order " R2 'R2 (j)

V 〆 (m) (n) (k)

(D ginseng-printed by the Central Ministry of Trade and Industry and Consumer Cooperatives and printed R2, R3 and each of hydrogen, Ci-6 straight chain alkyl, c3-7 sub-chain alkyl, C3-7 alkyl, or perfluoro Alkyl; ϋ4 is 氪, Ci-e straight chain alkyl, C3_7 split chain alkyl, C3_7 cycloalkyl, C2_7 alkylchloroalkyl, any substituted C7_12 aralkyl, or fluorenyl substituents selected from a group such as (: 2_7 alkylalkyl, C3_7 alkylfluorenyl, C3-7 cycloalkylfluorenyl, aralkylfluorenyl (containing Ci-6 alkyl), Cm arylfluorenyl or heteroaralkylfluorenyl; this paper is applicable to China Standard (CNS) A4 specification (210X297 mm) 565560 A7B7 V. Description of the invention (knowledge) The central government rate of the Ministry of Commerce only eliminates the cooperative policy R6 is hydrogen, C2-6 fluorenyl, Ci_6 linear alkyl, Or C3-7 technical chain alkyl; X and Y are each hydrogen, Ci-6 straight chain alkyl, C3_7 technical chain alkyl, C3-7 ring courtyard, C2-7 courtyard courtyard, Cl_8 straight or branched chain alkyl chloride, hydroxyl, CF3, or c2-e perfluoroalkyl; Z is hydrogen or (^ -6 straight-chain alkyl, C3-7 technical chain alkyl, C3-7 ring Alkyl, halogen, C2-7 alkane alkyl, or Ci-e hydroxyalkyl, or CH 2 NR 7 R 8; R7 and R8 Each is 氲, a straight-chain alkyl group, a C3_7 branched-chain alkyl group, an aryl group, or an aralkyl group; or co-expressed with nitrogen as containing any one or more additional heteroatoms, preferably selected from 5 or 6 members of N, S or 0 璟, Such as: _nCk -Ο. -Ο3, _ν01 (), _CN, or -〇; R9 is fluorene, a silane-containing group or Cl-e lower alkyl group; and R 1Q is c η-6 linear alkyl group The scope of the present invention includes the above-mentioned subgroups of compounds, in which W is 0, Α, Β, X, Υ, Z, and Ri-R1. The definition is as above; W is NR6, A, Β, X, Υ, Z, and R1-RiQ The definition is as above. The preferred compounds of the present invention or their pharmaceutically acceptable salts, esters or prodrugs are as follows: (Please read the precautions on the back before filling this page)

、 1T This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) 565560 A7 B7 V. Description of invention (9 in the formula

Z kA〆 (Read the precautions on the back before filling in this page) R 1 is c 2 -7 alkylfluorenyl or selected from the following

(b) R2

XV2N—, ⑹ R4YYR2

Order -N (i)

R2 Central government of the Ministry of Economic Affairs and the Consumer Goods Cooperatives R2, R3 and R5 are each hydrogen, Ci-6 straight chain alkyl, C3-7 technical chain alkyl, C3_7 cycloalkyl, or Ci-e perfluoro Alkyl; R4 is hydrogen, Cu straight alkyl, C3-7 technical chain alkyl, C3-7 cycloalkyl, C 2-7 alkoxyalkyl, optionally substituted C 7-12 aralkyl, or fluorenyl Substituents are selected from a group such as: (2_7 alkyl ethynyl, (: 3_7 alkenyl, C > 7 cycloalkyl fluorenyl, C7_12 aralkyl fluorenyl or heteroaralkyl fluorenyl), which can be arbitrarily selected in accordance with Chinese national standards. (CNS) A4 specification (210X297 mm) 565560 A7B7 V. Description of the invention (ί Substituted with 1 ~ 2-6Ci-6 alkyl or Ci_6 aralkylfluorenyl; R 6 is hydrogen, C 2-6 fluorenyl, C Bu 6 straight-chain alkyl, or C 3-7 alkyl; X and Y are each hydrogen, straight alkyl, C ^ 7 alkyl, C% 7 cycloalkyl, (: 2-7 alkyl Oxyalkyl, halides (containing atmosphere, bromine, fluorine, and iodine), Ci-6 straight-chain or split-chain alkanyl, hydroxyl, CF3, or * ^ C2-6 perfluorinyl; Z is hydrogen or Cbs straight chain alkyl, C3_7 branched chain alkyl, C3-7 ring courtyard, ® prime, C2-7 courtyard courtyard, C1-8 classroom courtyard, or C Η 2 NR7 R 8; R 7 and R 8 are each hydrogen, C! — E straight chain alkyl, C 3-7 split chain alkyl, aryl or aralkyl; Atom, preferably selected from 5 or 6-membered rings of N, S or 0 (preferably N or 0), such as -Ο, -Ο, -ν (3, -NCXRl0, (Read the precautions on the back before filling in this Page)-·

, 1T 0 is NQ chain N, straight 9N or 0, and alkane is passed through the central standard of the Ministry of Commerce, and M Η consumer cooperatives printed base C #, and base cyanobenzene, if the element contains a ® group, the aromatic hydrogen refers to the pseudo-selection BenQ said that generations should not be treated as if there is nothing to replace them with each other.-Substitute ΓΓ: C to take, the phenyl phenyl group is 0, and the alkynyl chain branch is arbitrarily 6 1-benzene C is, the aryl cyano is better, and the element is better. 0 9 benzene hydrogen or CF from 3, substituted with alkane on β--1, substituted with C_, substituted with alkyl, straight phenyl or naphthalene, substituted with unsubstituted or substituted by -7 3 and this paper size apply Chinese National Standard (CNS) A4 specification (210X297 mm) Central Standard of the Ministry of Economic Affairs and printed by Consumer Goods and Consumer Cooperatives «565560 A7 B7 V. Description of Invention (9). The above compounds, unless otherwise specified, are pseudo-aryl fluorenyl groups, fluorenyl groups and naphthyl fluorenyl groups, each of which may be substituted with one or more substituents selected from hydrogen, hydrogen, cyano, Ci-β straight bond group, Ca- 7-point bond base, Ci-6 base radical, CF 3 or phenyl, this phenyl substituent can be optionally substituted with one or more substituents selected from hydrogen, halogen, cyano, C 1-6 linear alkyl, C 3 -7 technical chain alkyl, or CF3. Preferred arylfluorenyl groups are benzylfluorenyl, (phenyl) benzylfluorenyl and naphthylfluorenyl, which are substituted or unsubstituted. Unless specified above, heteroarylfluorenyl refers to a 5 or 6-membered fluorene ring directly bonded to a carbonyl group, and contains 1 to 2 heteroatoms selected from N, 0, or S, such as a carbonyl or pyrimidine carbonyl . This heteroaryl group may be individually substituted with one or more substituents selected from the group consisting of hydrogen, hydrogen, cyano, C ^ 6 linear alkyl, C3_7 branched alkyl, or CF3. Unless otherwise specified, the aralkylamidino group refers to a benzylcarbonyl group or a stilbenecarbonyl group containing a C i -e alkyl group, and the carbonyl group is directly bonded, wherein the alkyl terminal is substituted with an aryl group, and the definition of the aryl group is as above. Unless otherwise specified, aralkyl fluorene refers to benzyl or naphthylmethyl containing an alkyl group (preferably a Ci-e alkyl group, most preferably an alkyl group) in which the alkyl terminal is substituted with an aryl group, and this Aryl is as defined above. Unless otherwise specified, the above compounds refer to gas, bromine, fluorine and iodine. The preferred compound of the present invention contains: [2-Gas- 4- (3-methylpyrazol-1-yl) benzyl]-(5, 11-dihydro-pyridinium [2,34] [1,5] benzene骈 Diazepine-6-yl) -methyl_; [2-Chloro-4- (5-methylpyridinyl-phenyl) phenylphenyl (5, 11-dihydro-pyridine} -1 1-This paper Dimensions are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (read the precautions on the back before filling this page)

, 1T 565560 A7 B7 V. Description of the invention (^) ^ 丨 2,3-b 1 [1,5] Phenyldiazepine-6-yl) -methanone; [2 -Bromo-4-(3- Mepyridine-1 -yl) phenylphenyl (5,1 1 -dihydro-pyridinium) 2, 3-b 1 [1,5] phenylpyridine diazepine-1 0 -yl) -methanone ; \ (5,11-Dihydro-E-xylene [2,3-1 > 1 〖1,5] Benzene dihydrazine-6-yl)-(4-fluoro-2-trifluorotolyl ) -Methanone; (5,1 1 -dihydro-Bft _ 骈 丨 2,3-b] [1,5] Benzene di-B-yacene-6-yl) r.-[4- (3- Methyl Bftazol-1-yl) -2 -trifluorotolyl benzophenone; (5,11-dihydro-pyridinium [2, 3-b] [l, 5] phenylhydrazine-6- )-[4- (3-methylpyrazol-1-yl) -2 -trifluorotolyl] -methanone and methanesulfonic acid 1: 1 salt; (5,1 dihydro-pyridine 骈 2 , 3-1) 1 [1,5] Benzenediazepine-6-yl) -f 4-(3 -methylpyrazole-1 -yl) -2 -trifluorotolylbucarpine | with salt 1: 1 salt of the acid salt; 4- (3-methyl Bftazole-butyl) -2-trifluoromethyl-benzoic acid methyl ester; 4- (3-methylpyrazol-1-yl) -2-tri Fluoromethyl-benzoic acid; (5,1 1 -dihydro-pyridine hydrazone [2,3-b] [1,5] phenylhydrazine diazepine-1 0 -Yl)-丨 4-(5 -methylpyrazole-butyl) -2 -trifluorotolyl] -methanone; (5, 卜 dihydro-Bit pyridine [2,3-b 1 [1, 5] Phenyldiazepine-6-yl) (Please read the precautions on the back before filling out this page),?! The central government of the Ministry of Economics and Economics, only the consumer cooperatives printed with ketones * 5 f methyl ) -Fluorofluorenyl tri_0- · methylpyridine 7 Fluoroprazole one one-one * ίU one diyl 1 guan _ — _ 11 1J tb .A bis-IW3 itt2 hydrodifluoromethylfluorotrione heptane Methyl acryl]-]-diyl fluorenyl phenyl blyl group 3 1, 2 2 oxazopyridinylpyridine 3-phenyl] pentyl 5, phenyl ainyl diphenyl group _ A paper size applicable to Chinese national standards (CNS) A Sugiyama (210 × 297 mm) 565560 A7 B7 V. Description of the invention (U) f (2, 4-difluorophenyl)-(5,1 1-digas-Bft pyridine [2,3 -b] 〖1, 5】 Benzyldiazepine-1-10-yl) -methyl_; (5,1 didiazine-pyridinepyridine [2,3-b 1 [1,5] benzenepyridine Azepine-1 0-, yl)-[4-fluoro-2- (3-methylSftazol-1-yl) -phenylpropanyl; (2 -gas- 4- (3-methylpyrazole- 1-yl) phenyl)-(5-methyl-5, 11-dihydro-pyridine hydrazone [2 , 3-1)] [1,5] Benzenediazepine-10-yl) -methyl_; ′ (2-Ga-4-fluorophenyl)-(5-methyl-5, 11- Dihydro-pyridine hydrazone [2, 3-b] [1,5] Benzene diazepine-10-yl) -methyl_; (5,1 dioxane-pyridine hydrazine〗 2,3) ] [1,5] Phenyldiazepine-10-yl) -ί 2-methyl-5 (3-methylpyrazole-butyl) -phenyl] -formamidine |; (5, 1 1- Dipyridine-pyridinepyrene [2,3-b] [1,5] Benzene diazepine-6-yl)-(5-fluoro-2-tolyl) -methanone; (Read the note on the back first (Please fill in this page again)

, 1T group 11-azole ftt I butyltris-tribenzyl fluorotrioxine »ft I hydrodiene I azepine _ methylbenzene \-/ radical oxazoline 1 methylphenyl phenyl P-5-H 1 Dibenzobenzenediene i ΤΣΠ ^ cyclic ketone methyl V) / base meridian rate is negative, τ consumer cooperatives India policy 1 ketone — 3 — 1-1 ί (.—_. ^ '3 (lb- -ft 4-4 2 4 ㈣ 13 11--I 22, 氱 骈 氲. *-I 啶 2 di n ift azole ptt_ S * 5, methyl 1 group 1 methyl m I hydrogen di-1 ·,, 1 Ketones (5methylsynthesis 1/1 / phenylbenzene 6-λ / _ gene * soap 1-acridinium I τπ ^ -3 acridazole, 5 pyrimidine [1 | ~ UH ^ H b J Indyl T-Heptylbenzene 10 Benzene •.-, Diyl :: Benzene. Diphenyl hydrogen; ketone methyl 5 I (\ / one group — dimethyl hydrogen dicake pyridine due to τπ ^ aziridine This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention () m; 丨 2-chloro- 4- (5-methyl-1H_ [1, 2, 4-three Azole-3-ylbuphenyl]-(5, 11-difluoren-pyridinium [2,3-b] [l, 5] phenylhydrazine-6-yl) -methanone;,-丨 2-Bromo -4-(3 -methylpyrazole-1 -yl) phenylbenzene (1 1 Η-5-Mo-4, 1 0 -diazine-diphenylfluorene Ud] cyclohepten-10-yl) formamidine 1 [4- (3-Methylpyrazol-1-yl) _2-trifluorotolylbull (llHUf -4, ί 10-diazepine_diphenylfluorene] cyclohepten-10-yl) methanone; [ 2 -fluoro- 4- (3-methylpyrazol-1-yl) -2 -trifluorotolylb (11H-5-B bend-4,1 0 -diazine-diphenylhydrazone [a · d] ring Heptene-1 0 -yl) acyclic 1; and f 2 -aero-4-(1 -methyl-1 fluorene-imidazol-3 -yl) -phenyl]-(1 1 Η-5-P 咢-4,1 0 -diazine-diphenylhydrazone fa · d] cycloheptene-1 0 -yl) methyl. Those skilled in the art will know that the compounds of the present invention are R 2, R 3, R 4, R 5 , R6, R7, R8, 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 specific activities (This page) The central government of Yiyi and one 5-consumer cooperative printed polymer have Yi Yi, different tolerances and different arts, salt knows that the acid has been dissolved in the structure-containing milk salt. S, I, and other compounds, and acid domains and conformation R can be converted The other substances indicate this c citrate propionate its structure. Things such as sulphuric acid and isomeric pure acid and acid; learn to get the second machine, •, material light requires it without enoic acid structure 0 C and method and butyl thiocyanate isomorphic salt formula. The pure substance is quasi-acceptable. The structure of the acid is different from the acid nitrate and the S drug. The substance and the preparation method are known to contain the butyric acid structure R, the square salt of the cooked salt, the phosphorus is pure, and the quasi one is the acid. The chemical map of the standard is Yung Shih salt, which is mixed with this medicinal acid. Among them, the knowledge is determined by the production, brominated acid, cooked, special hydrogen, and the paper size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 565560 A7 B7 V. Description of the invention (4) According to the present invention, there is also provided a method for treating diseases, symptoms or abnormalities that require the activity of an vasopressin agent, comprising administering an effective amount of the compound of the present invention or its peony composition to humans and animals. Method. The treatment method of the present invention includes diseases, symptoms or abnormalities in which factor VI II and von Wilebr and factor need to be released into the circulation strip, tissue type cytosinogen activator (t-PA) is released into the blood, or the kidney water is preserved. And urine concentration. This treatment includes, but is not limited to, human diabetes insipidus, nocturnal urination, nocturia, urinary incontinence, or bleeding and clotting disorders. According to the present invention there is provided a peony composition comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition comprising an effective amount of a 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. For consistency of administration, the composition of the present invention is preferably used in a unit dosage form. Appropriate unit doses include lozenges, capsules, and powders (small bag powder and vial powder). This unit dose may contain 0 "-0 0 0 0 g g of the compound of the present invention, preferably 2-50 mg. Preferred unit doses contain 5-25 mg of a compound of the invention. The compound of the present invention can be administered orally at a dose of 0.00 mg / kg, preferably at a dose of 0.1-10 mg / 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, and the like. It can be prescribed according to conventional methods such as known antihypertensive agents, diuretics and blockers. The invention also provides methods for preparing the compounds of the invention. The method of the present invention -15 ~ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before reading and writing this page)

'IT ··· 565560 A7 B7 V. Description of the invention (M) The compound of the present invention can also be prepared by any of the following methods. Compounds of formula (I) wherein W is 0 or NR 6 and R 6 is hydrogen can be prepared by the following reaction scheme I. (Please read the notes on the back before filling this page)

Order

Process I

Through the central sample of jujube, the goods and workers cooperate with each other. Therefore, the formula (η-pyridine, benzene, benzodiazepine (or benzodiazepine)) in the presence of inorganic salts such as potassium sulfonate, Methylformamide in an aprotic, polar solvent; or in organic fluorene such as 4-dimethylamine pyridine, in an aprotic solvent such as dimethylmethane or tetramethylfuran, and treated at -40 ~ 50 ° C With the appropriate substituted haloaryl (heteroarylene) halide, preferably -1 6- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention (A) The formula (2, J = C0C1) fluoroarsino or fluoro (gas) heteroarsino can be used to obtain the intermediate tritiated derivative (3). In addition, the tritide can also be a mixed anhydride with respect to a carboxylic acid, such as Inanaga et al., Bull Chem. Soc. J pn., 52, 1989 (1979), treated the acid with an aprotic organic solvent such as dichloromethane, and treated it with 2,4,6-three gases. Benzene tritium gas. The mixed anhydride of formula (2) is dissolved in a solvent such as digas methane in the presence of organic tritium such as 4-dimethylaminopyridine at a temperature of 0 to the reflux temperature of the solvent. The intermediate treatment of formula (1) with pyridinium benzophenone diheptin (or phenylheptane) can obtain the intermediate tritiated derivative (3) of reaction scheme I. The compound of formula (3) can be treated as Amine (or tetrahydrofuran) is an aprotic inert solvent, and is treated at room temperature to the reflux temperature of the solvent. Formula (4, where R1 is a, b, c, d, 1, η, or A suitable substituted heterocyclic sodium (potassium or lithium) salt to obtain a compound of formula (1), wherein W is 0 or NH, and A, B, X, Y, Z, R2, R3, and R5 are as defined above, R6 is hydrogen, and R1 is a heterocyclic ring. The a, h, c, d, 1, n, or 0 group of the heteropyridyl group is as described above. (Read the precautions on the back before filling in this. Page) clothing.

, 1T

This paper size applies to China National Standard (CNS) A4 (21 OX 297 mm)

F (CI) J = COOH (5)

F (CI) J = COOCH3 (6) Esterification 565560 A7 B7 V. Description of the invention (rb Condensation of intermediate product of formula (3) with salt of intermediate product of formula (4) can obtain regioisomers of formula (1) in different proportions It can be separated by chromatography and / or crystallization. In Reaction Scheme I, the preferred formula (2) substituted fluoroarylfluorenyl and fluoro (fluorene) heteroarylfluorenyl are commercially available or known in the literature, or may be It is prepared according to similar methods of known compounds in the literature. In Reaction Scheme I, formula (4, where R1 is a, b, c, d, 1, τι, or 0) heterocyclic sodium selected from the above heterocyclic group The (potassium or lithium) salt can be obtained by treating at -4 ° C to room temperature with an aprotic inert solvent such as dimethylformamide or tetrahydrofuran, such as sodium, potassium or lithium hydride or aurethane gas. In addition, the compound of formula U) in reaction scheme I can be obtained according to the preparation method of reaction scheme II.

Rl-H (4) --► Examination 2. Separation of regioisomers (please read the notes on the back before filling out this page) Central sample rate of Ministry of Economic Affairs and M Industrial Consumer Co., Ltd. Print Fan R1 (7) J = COOCH3 hydrolysis

(8) J = COOH

(IW = 0, NH; R1: a, b, c, d, l, n, o: -18 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 565560 A7 B7 V. Description of the invention ( π) Therefore, formula (5) is suitably substituted with fluoroaryl or fluoro (gas) heteroaromatic carboxylic acid, which can be treated by conventional methods, such as the presence of a catalytic amount of dimethylformamide, and treatment with grass gas or sulfonium Esterification with an alcoholic solvent (methanol) of gas; or esterification with methanol in the presence of an acid catalyst such as p-toluenesulfonic acid and condensation at room temperature to the reflux temperature of the solvent. Ester of formula (6) A polar aprotic organic solvent of methylformamide at room temperature to the reflux temperature of the solvent, with an appropriate formula (4, where R 1 is a, b, c, d, 1, η selected from the above heterocyclic groups) , Or 0 group) reaction of a substituted heterocyclic sodium (potassium or lithium) salt to obtain an intermediate ester of formula (7). (6) Condensation to (4) can obtain regioisomers of formula (7) in different proportions, which can be obtained by Chromatography and / or crystallization. Hydrolyze the intermediate ester of formula (7) to NaOH-containing methanol (or NaLi in tetrahydrofuran) to obtain the carboxylic acid of formula (8). The intermediate carboxylic acid of formula (8) can be used as The foregoing method is converted into a halogenating agent, preferably formula (9) hydrazone or mixed anhydride. According to the foregoing method, pyridine, phenylhydrazone, and diheptin (or heptane such as phenylhydrazone B) are condensed according to the formula ( 9) The intermediate halogenating agent can obtain a compound of formula (1) in Reaction Scheme I, wherein R1 is a group selected from a, b, c, d, 1, η, or ο of the above heterocyclic group.工 工 工 合 相 印 f (Please read the notes on the back before filling out this page) The appropriate formula (5) in Reaction Scheme II has substituted fluoroaryl or fluoro (chloro) heteroarylcarboxylic acid is commercially available or It is known in the literature, or can be prepared according to similar methods of compounds known in the literature. In addition, the substituted carboxylic acid of formula (8) in reaction scheme II can be prepared according to the reaction scheme UI. -9 9- This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of invention (Process 111

1. R Η (4) F (CI)

Hydrolyzed R1

(Please read the notes on the back before filling out this page) Separation ^ R1 (10 Y is not CFs) (8, R ^ a ^ b ^ l ^ o) Put the formula (10) fluoroaryl or fluoro (氱) A heteroaromatic nitrile, such as dimethylformamide, is a polar aprotic inert organic solvent, at room temperature to the reflux temperature of the solvent, with the appropriate formula (4, where R1 is a, b, c, d, 1, n, or 0 group) reaction of a substituted heterocyclic sodium (potassium or lithium) salt to obtain an intermediate product of formula (11). Condensing (1 0) with intermediate product (4) can obtain regioisomers of formula (U) in different proportions, which can be separated by chromatography and / or crystallization. The middle point of formula (11, where Υ is not C F 3) is suitable for the presence of dilute sulfuric acid and hydrolysis at room temperature to 60 ° C. In addition, the hydrolysis of nitrile (1 1) can also be performed in the presence of a strong solvent such as Na 0 Η in an alcohol solvent such as ethanol, and in the absence of a phase transfer catalyst such as benzyldimethyltetradecyl ammonium gasification. get on. The central government of the Ministry of Economic Affairs and the Industrial and Commercial Cooperative Co., Ltd. have converted the obtained carboxylic acid of formula (8) into the compound of objective formula (1) in reaction scheme I according to a similar method as described above, wherein R1 is a selected from the heterocyclic group of the upper ring, b, c, d, 1, n, or 0 groups. 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. -2 0 ~ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention (β)

In addition, the reaction scheme II in the formula "8, where R1 is not b or d) the preparation of the substituted carboxylic acid intermediate can be as shown in reaction scheme IV, Nong Kartritzfcy et al., Synthesis, 949 (1989) A and B are C, and R 1 is a, c, 1, τι, or 0 group selected from the above-mentioned heterocyclic group, but not b or d) of the above fluorenyl group Dimethyla-5 genus; then the amidine of formula (12) should be hydrolyzed by diluting sulfuric acid and sodium nitrite according to the method of Hales et al., Tetrahedron, 51, 7 4 0 3 (1 9 9 5). Process IV H2N ^ V ^ Hydrolysis (Please read the precautions on the back before filling this page) R1

HOO (12)

(11, R 1 is not b or d > (8, A and B = sulfo R 1 = a, c, e, l, n 0 is not b or d) in Scheme II, substituted carboxylic acid of formula (8) The preferred method for preparing the intermediate product is shown in Reaction Scheme V, where R1 is a group selected from the above-mentioned R1 heterocyclic group. 1T is intercalated in the extinction part * ?: The rate of MX consumer cooperation is printed. (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention (/) Process V AhΆη2 (13) J = COOCH3 Diazotization reduction (14) J = COOCH, 0 R3 P (35) nhnh2 HC1 2 .Crystal (15) J = COOCH3

(8) J = COOH (Please read the notes on the back before filling this page) (7) J = C〇OCH3

The central part of the Ministry of Economics and Industry has co-ordinated the private consumption z (9) J = cool part a W = 0, NH; R ^ a) Therefore, formula (13) is appropriately substituted with aniline and recyanated, then Street et al., J. Med · Che ··, 36, 1 529 (1993). The intermediate trap of formula (15) can be obtained by reducing the diazonium salt of formula (14) in concentrated hydrochloric acid of tin (II). Hydrochloride. (15) in a solvent such as methanol and room temperature to 100. The following condensation is defined by the formula (35, where R2 and RS are as defined above, R3 is hydrogen, and P is a dialkyl acetal) aldehyde derivative such as acetoacetaldehyde dimethyl acetal, or formula (35, where R2 and R5 is defined as above, R3 is not hydrogen, and P is 0 or a ketone) or ketone (or _ derivative). After crystallization, formula (7, where R1 is selected from the heterocyclic group as above) can be obtained.逑 The reaction scheme II is transformed into the formula (I, where Ri -22- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7

(Please read the notes on the back before filling out this page) • —.

, 1T 4

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention (") The intermediate compound of formula (3, W = NH >) in reaction scheme I such as dimethylformamide or Tetrahydrofuran is an aprotic inert solvent. It is treated at 0-80 ° C with a base such as NaH (or KH) and an alkylating agent such as alkane (preferably an alkyl chloride (bromide or iodine)). 6, where A,. B, X, Y, Z, and R 6 are as defined above). In addition, the compound of formula (3, W = N Η) in reaction scheme I in the presence of an amine base such as pyridine or triethylamine In an aprotic solvent such as dichloromethane (no solvent is used when using pyridine), the structure can be obtained by hydration with a carboxylic acid halide or carboxylic acid anhydride at -40 ° C to room temperature (16, formula Where A, B, X, Y, Z, and R6 are as defined above). Compound of formula U6, where R6 is an alkyl or fluorenyl moiety) in an aprotic organic solvent such as dimethylformamide, in Treated at room temperature to the reflux temperature of the solvent with an appropriate formula (4, where R1 is a, c, d, 1, n, or 0 group selected from the above heterocyclic group) substituted sodium (potassium) Compound lithium) salts of formula (I), wherein W is NR6, and R6 is alkyl or acyl; A, B, X, (Read precautions and then fill the back side of this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm). Printed by the Central Ministry of Economic Affairs and the Ministry of Labor and Consumer Cooperatives. $ 1 565560 A7 B7. 5. Description of the invention (") Alkylation and acetating agents in reaction process VI It 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 compound of formula (I) in Reaction Scheme VI can also be prepared according to Reaction Scheme VII.

Process V I I

R6 = alkyl or fluorenyl residue) The fluoroaryl or fluoro (gas) heteroaryl intermediate (where W is NH) of formula (3) in Reaction Scheme I will be polar aprotic such as dimethylformamide Inert organic solvent, at room temperature to the reflux temperature of the solvent, with substituted formula (4, where R1 is a, b, c, d, 1, n, or 0 group selected from the above-mentioned heterofluorenyl groups) The reaction of (potassium or lithium) salt can obtain the intermediate product of formula (I, where W is NH). This intermediate product can be directly alkylated (or tritiated) according to the previous method without isolation to obtain formula (I, where W is NR6, and R6 is alkyl or fluorenyl) The compound of interest. The formula can be obtained in different proportions (I, where W is NR 6 -2 5-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page )

1T Printed by the Central Ministry of Economic Affairs and printed by the Consumer Cooperative 565560 A7 B7 V. Description of Invention (W), heading R6 is alkyl or fluorenyl; A, B, X, Y, Z, R2, R3, R4 And R 5 are as defined above, and R 1 is a heteromeric moiety as defined in Reaction Scheme VI) regioisomers. Regioisomers of formula (I) can be separated by chromatography and / or crystallization. Compounds of formula (I) in Reaction Scheme I [wherein A and B are sulphur, R 2 is hydrogen, and R 1 is a heterocyclic group selected from the above-mentioned heterocyclic groups. Ring g group] can be prepared according to the reaction scheme VITI. This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

565560 A7 B7 Employee Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

565560 A7 B7 V. Description of the invention (^)

I (W = 0, NH; A, B = broken; R1: g) will be appropriately substituted heteroaromatic carboxylic acid ester, preferably bromo (or iodine) benzyl of formula (17, where A and B are sulfonic) Esters), in the presence of catalysts such as bis (triphenylene) osmium platinum (TI) and copper (I) iodide, in organic solvents such as triethylamine as a solvent, and at room temperature to 80 ° C, Coupling to dialkylamine propyne to obtain formula U 8) has been carried out in accordance with the method of Alami et al., Tetrahedron Le 11 ,, 3 4, 6 4 (1 3 (1 9 9 3)). The intermediate product U 8) is prepared according to any standard chlorination method (see A 1 b i n i, Synthesis, 263, (1 99 3)) or with a di Hi alkane (see Murray,

Chem. Rev., 1 187 (1989)), Yu Ru'er, the non-proton inert gas of methane passes through the central part of the Ministry of Shanghai ^-^-and only the consumer cooperation deduction of dreams (please read the notes on the back before filling this page) Organic solvents and their oxides at room temperature. This intermediate N-gas can be rearranged in vitro to an enone of formula (19) by heating it with a hydroxyl solvent such as methanol without using any method of Du Shi et al. Without separation. This method provides a novel method for synthesizing an enaminone compound from propargylamine (or its M-gas) in a hydroxy solvent (which affects the final reaction result). This novel method of synthesizing enones provides another convenient method in existing methods and expands the range of raw materials that can be converted to enones products. Although the precise mechanism for conversion of propargylamine N-oxide to enketone is not yet -28- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 gong) 565560 A7 —_____________ B7_ V. Description of the invention (W) (Please read the notes on the back before filling this page.) Clearly, it is similar to two known methods: the heat of propargylamine N-oxide f2,3] sigmatropic rearrangement (Craig et al., Tetrahedron Lett, 4025 , (1979); Hallstroffl, et al., Tetrahedron Lett ·, 667, (198 0); Khuthier, AH et al., J. C he m. Soc · Chem ·

Coffiiniin, 9, (1,979) and the conversion of specific isoxazole to enamone (Liguori et al., Tetrahedron, 44, 1255, 1988). U9) can be treated at room temperature to reflux temperature with substituted hydrazine (36) acetic acid to obtain regioisomers of formula (20) and formula (21) in different proportions. The main isomer 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 (2 2). The intermediate product (2 2) can be converted into a halide according to the aforementioned method, and is preferably a formula (2 3) _chlorine (bromine or iodine) or a mixed anhydride. The amidine (2 3) can be used again to purify the pyridine, phenyl, and diheptin (or benzopyrene) by formula (I) to obtain the target compound of formula (I), wherein W is 0 or NH. , A and B are C, X, Y, Z, and R4 are as defined above, R2 is hydrogen, and R1 is a heterocyclic group. As described above, the g group of the heterocyclic group is as follows.

N—N is printed by R 中央 (g) in the center of the Ministry of Economic Affairs and the Job-seeking Consumer Cooperatives. Similarly, (〖9) is treated at room temperature to the temperature of solvent reflux to treat unsubstituted wells (3 R, where R 4 The acetic acid of ii) can be obtained as the intermediate product of pyridoxine in the reaction scheme IX in the formula (2, R2 and R4 is ii). This heterocyclic nitrogen (24) can be alkylated or tritiated to obtain an intermediate product, which can be converted into the target compound of formula (1), wherein W is 0 or NΗ, A and B are C, X, Y, Z, and R4 is defined as above, R2 is hydrogen, and R1 is a heterocyclic group. The basic paper size of the heterocyclic group f above is applicable to the Chinese National Standard (CNS) A4 specification. [Depends on] 97 public and 1 565560 A7 B7 ---- ---------__-............................................ ...... ry V. Description of the invention (W)

Flooding IX

ο (36, R4 = Η)

(24) J = COOCH3 W j = COOCH3 Alkylated or Rattanized_ Base

Separate

(20) J = COOCH3 pair) (Please read the notes on the back before filling this page) Hydrolysis

N (25) J = COOH (26) J _ chemical part

• 30 · This paper size is applicable to the Chinese standard S (埤) (CNS) Λ4 specification (210X 297 mm) 565560 A7 B7 V. Description of the invention (W) The formula (24, where R2 is H, A and B are C) In an aprotic inert solvent such as dimethylformamide or tetrahydrofuran, treated at Q-80 ° C with a base such as NaH or KH and an alkylating agent such as alkane (preferably alkyl chloride (bromine or iodine) ) Regioisomers of formulae (20) and (21) can be obtained by alkylation in different proportions. The main regioisomers of formula (2 1) can be separated by chromatography and / or crystallization, and then hydrolyzed to obtain the target carboxylic acid of formula (25), and then converted to a halogenating agent according to the aforementioned method, preferably tritium gas or mixed anhydride. Then using this halogenating agent (2 6) to pyridine pyridine, benzophenone diheptin (or benzopyrene) to obtain the target compound of formula (I), where W is 0 or NH, A and B The definitions for C, X, Y, Z, and R4 are as above, R2 is hydrogen, and R1 is a heterocyclic group. The above-mentioned heterocyclic group is the f group. (Please read the notes on the back before filling this page)

The target compound of formula (I), wherein W is 0 or NH, A and B are C, and R is a heterocyclic group. The h group of the above heterocyclic group can be selected according to Reaction Scheme X. ^ Guide to only consumer cooperatives printed and printed paper size applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) 565560 A7 B7 V. Description of the invention (~

Process X

(Please read the notes on the back before filling in this page) (1) (I Α, Β = sulphur; R1: h) (2 9) J = the localized jujube of the Ministry of Economic Affairs and the Ministry of Decoration, and only printed by X Consumer Cooperatives ^ The substituted malondialdehyde of the appropriate formula (27) is treated with acetic acid at room temperature to the reflux temperature of the solvent, and the intermediate product, pyrazole, is vaporized at the aging solution and at the temperature to the reflux temperature of the solvent to potassium permanganate. An intermediate of a carboxylic acid of formula (2 8) is obtained. The acid (28) is converted into a hafnium compound according to the previous hafnium method, preferably a hafnium (bromine or iodine) or a mixed anhydride. The compound of formula (I) can be obtained by using the amidine (29) and pyridine, phenylhydrazine (or phenylhydrazine) to obtain the target compound of formula (I), wherein W is 0 or NH, A and B is C, X, Υ, Z, and R4 are as defined above, and R1 is the h group of the heterocyclic group as described above and the following heterocyclic group is defined. 32- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 Α7 Β7 V. Description of the invention (> /

The preferred formula (27) malonaldehyde and trap (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., J. 0 rg. Chem., 49, 1 2 8 8 (1984) and Copploa et al., J. Het. Chem., 51 (1974). The intermediate carboxylic acid of formula (28) in another preparation reaction scheme X (wherein Y is as defined above and R 4 is not argon) is shown in reaction scheme XI.

Process X I

(30) .W, NH2 (33) J = COOCH3 (Please read the notes on the back before filling this page) R3S 丨 (31) R4 (34) j = COOCH3 coupling

Hydrolysis (32) J = COOCH3 (28) J = COOH (R4 is not Η) -3 3- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 56556〇 Women's Workers' Consumption Cooperation, Printing and Printing A7 B7 V. Description of the Invention (Heart) The organotin reagent of formula (31) is based on Farina et al., J. 〇rg · C hem ·, 59, 5 9 0 5 (1 9 9 4 ) Method, in the presence of a catalyst such as tetra fork (triphenylphosphine) platinum (0) and copper (I) iodide, in an aprotic inert organic solvent such as dimethylformamide, at room temperature to 15fl The coupling reaction with Stille at ° C and the appropriate B-substituted aryl (heteroaryl) should preferably be a bromine (or iodine) reaction of formula (34). The intermediate (carboxylic acid) of formula (28) in reaction scheme X can be obtained by hydrolyzing the obtained ester of formula (32) in alcohol or lithium hydride with tetrahydrofuran and room temperature to the solvent reflux temperature to obtain NaO. The preparation of the organotin reagent of formula (31) (where R is preferably an alkyl group) in reaction scheme XI can be carried out according to the method of Martina et al., Synthesis, 8, 613 (1991). Azole in the presence of gold gull reagents such as n-butyllithium, aprotic inert organic solvents such as diethyl ether, and trialkyltin halide (preferably atmospheric (or bromine) tributyltin) gold tincture at -40 to room temperature Derived. In reaction scheme XI, the preparation of the formula (30> preferably N-alkyl substituted pyrazole) can be used in the presence of 4-bromopyrazole in the presence of NaH (or KH), such as dimethylformamide or tetrafuran. An aprotic organic solvent, alkylated with an alkyl halide (preferably an alkyl chloride (bromo or iodine)) at ° C. In addition, the 4-bromopyridine chemical can also be used in an alkylating agent such as NaOH. The strong test is performed under the phase transfer catalyst (such as Jones, Aldrichimica Acta, 9, 35 (1976)) such as benzyl tetradecyl ammonium ammonium or benzyltrimethylammonium chloride. The best formula (3 4) aryl (heteroaryl) iodine can be diazotized from the substituted aniline by formula (3 3), and then according to Street et al., J. Med. Cheei., 36, 1 5 29 (1 99 3) And Coffen et al., J. Org. Chem., 49, -34- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 搛-丨 (Please read the precautions on the back before filling this page) -Order 565560 A7 B7 V. Description of the invention (W) 2 9 6 (1 9 8 4) The method is prepared by reacting a relatively heavy sulfonium salt in an acidic matrix with potassium iodide. The compound of formula (I) can be prepared according to the following method As shown in Reaction Scheme XII, pyridine, phenylhydrazone, or diphenylheptane (or phenylhydrazone) according to formula (I) according to any of the foregoing methods and appropriately substituted acetamidine (heteroarylfluorenyl), preferably The formula (37, J = C0C1) acetone aryl (heteroarylfluorenyl) chloride can be converted to a tritium derivative of formula (3 8). (3 8) according to L i η et al., J. H et · The method of C hem ·, 3 4 5 (1 9 7 7) is treated in an aprotic organic solvent such as dichloromethane at a temperature of 0 to the reflux temperature of the solvent, and the dialkylhydrazine dioxane is fumed as shown in formula (39, wherein the alkane The group is CH3) dimethylformamide dimethyl acetal to obtain a ketene of the formula (40). The (40) is treated at room temperature to the solvent reflux temperature with a hydroxylamine of the formula (36) or substituted acetic acid The target compound of formula (I) can be obtained, wherein W is 0 or NH, A, B, X, Y, Z, R2 and R4 are as defined above, and HR 1 is a heterocyclic group. f, g or j basis (Please read the notes on the back before filling this page)

According to the step-part central rate and only-T consumer cooperative, the Indian reaction scheme XII, the better formula (3 7) has replaced the acetamidine (heteroarylamyl). The ammonia can be from the relative carboxylic acid at room temperature to the solvent reflux temperature. It is prepared by the following treatment with sulfonium gas, or in the presence of aprotic inert solvents such as dichloromethane or tetrahydrofuran, the catalyst amount of dimethylformamide and 0-40 ° C. The preferred formula (3 9) dialkylammonium dioxal acetal in Reaction Scheme XII is commercially available-3-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 565560 A7 B7 V. Description of the invention (Μ)

Available or known in the literature, or can be prepared according to similar methods for compounds known in the literature (see Kant Lehner, Chem. Ber ·, 105, 1 3 40 (1972). Scheme X I I

Courtyard Tomb (Total 2N ", 〇 Record (39) (Please read the precautions on the back before filling this page)

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.

1T .— ^ Central Ministry of Iodine and Consumers' Co-operation Private Printing -36- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 565560 A7 B7 V. Description of the invention (#

Process X T I I

(42) (43) HC = C-R9 (53) -1 Pd / Cu

Z (44) 丫 Ύ # (38) 〇 (Please read the notes on the back before filling in this page) The central Ministry of Economics > PJe-x Consumer Cooperation Private Printing Traditional Chinese Formula U) Heptane (or benzopyrene) is treated according to any of the above methods to appropriately substituted bromoarylfluorenyl (heteroarylfluorenyl) halide, which is officially represented by the formula (4 2) The tritiated intermediate product of formula (4 3) can be obtained. The intermediate product (43) is produced by the method of Martinez et al., J. Med. Chern ·, 5 2, 3 4 fH (〖9 8 7) in the presence of pyridine and bis (triphenylphosphonium) vaporized platinum (U ) And copper (I) catalyst, coupled to an organic base such as triethylamine as a solvent and a closed pressure tube at room temperature to 100 ° C to formula (5 3, where R 9 is Trimethylsilyl or Ci-6 lower alkyl) monosubstituted acetylene. The acetylene intermediate product of formula (44) is saturated with mercury sulfate (ϊ T) in an aprotic inert solvent such as tetrahydrofuran according to the method of Reed et al., J. Org. Chem ·, 5 2, 3 4 ίΠ U 9 8 7). The following treatment is 13; sulfuric acid is hydrated to obtain the target compound of formula (3 8), where W is 0 or NH, A, B, X, Y, and Z are defined as -3 7-This paper size applies Chinese national standards (€ can) Eight private sights (210 '/ 297 mm) 565560 A7 B7 V. Description of the invention (from), and R 9 is hydrogen or C 6 low alkyl. (Please read the notes on the back before filling this page.) In addition, compound (44) in which R9 is trimethylsilyl can be treated with ether solvent such as tetrahydrofuran to fluorinate n-butylamine to obtain compound (4 4) where R 9 is hydrogen. The preferred formula (42) amidines in Reaction Scheme XIII can be treated with a substituted formula (41) substituted aryl (heteroaryl) carboxylic acid at room temperature to the solvent reflux temperature with sulfonium gas, or in the presence of such as methylene chloride Or tetrahydrofuran is aprotic inert sol. It is prepared by treating with dimethylformamide and 0-40 ° C as catalyst. The acetylene intermediate (53) in Reaction Scheme XTII is commercially available or known in the literature, or can be prepared according to similar methods for compounds known in the literature. As shown in Reaction Scheme XIV, the preparation of the acetamidine intermediate (3 8) in Reaction Scheme XII is based on the method of Kosugi et al., Bull. Chem · Soc. Jpn ·, 60, 767 (1987), in the presence of catalyst amount The bis (triphenylphosphine) -flavored platinum (II) is coupled to the reaction formula (4 3) bromoaryl (heteroaryl) by SU 丨] e in an aprotic organic solvent such as toluene and at room temperature to the reflux temperature of the solvent. ) The compound is (α -alkanevinyl) trioxane in reaction scheme XTII, preferably 2 -vinyl) tributyltin of formula (45).

Process X I V

_ 3 8 _ This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

565560 A7 B7 _ 5. Description of the invention (M) The preparation of the acetamidine compound (38) can also be carried out according to the method of Cabri et al., Tetrahedro Lett., 32, 1753 (1991). The catalyst aromatization is obtained from the aromatic halide intermediate product of formula (43). The (α-alkanevinyl) trioxane intermediate (45) in Reaction Scheme XIV is commercially available or known in the literature, or can be prepared according to a similar method to compounds known in the literature.

Compounds in which ri contains three heteroatoms can be prepared according to Reaction Scheme XV. Process XV (Please read the notes on the back before filling this page)

The central part of the Ministry of Economic Affairs 4 *-&P; PJh, T consumer cooperation shirts are numerous. Y_iV nh2 (47) Mouth base (green, '〇green-^ (39)

Called Hyunyl) 2 R4NHNH2 (36) (or NH2OH) (-CC, -►

.39 · This paper size applies to China National Standard (CNS) A4 (210X297 mm) 565560 A7 B7

V. Description of the invention (W The formula (n Bitpyridine, phenylhydrazone, or phenylhydrazone) is treated according to any of the above methods to appropriately substituted cyanoarylene (heteroarylfluorenyl) dentate, preferably The formula (46) cyanoarylene (heteroarylfluorenyl) chloride can obtain the nitrile intermediate product of formula (54). The intermediate product (54) is treated at room temperature to 50 ° C, and the inorganic acid with sulfuric acid can be converted into formula ( 47) Intermediate amidine. (47) is treated with an aprotic inert organic solvent such as digasmethane or tetrahydrofuran at 0 to 80 ° C to a dialkylammonium dioxal acetal, such as formula (39, wherein the alkyl group is It is CH3 > dimethylamine dimethyl acetal to obtain the intermediate product of formula (4 8). (4 8) is treated at room temperature to the solvent reflux temperature to treat with the formula U6) hydroxylamine or acetic acid of the substituted well to obtain The target compound of the formula (I, wherein W is 0 or NH, A, BX, Y, Z, R2 and R4 are as defined above, and R1 is a heterocyclic group, as defined above, and the following heterocyclic groups e, i or k are specified ≫ R2

XR2 (Please read the precautions on the back before filling this page) The central standard of Department M and only the consumer cooperatives Ink (k) Another intermediate amine (47, of which A and B are master) In reaction scheme XVI. The intermediate formula (49, A and B as the master) has been replaced by Kantitzky et al., Synthesis, 949 (1 989) to hydrate dimethylarylene 6® with hydrogenated gaseous base in the method of Kartitzky et al. 5 0). The carboxylic acid intermediate can be obtained by partial hydrolysis of the ester, and then converted into the compound of formula (5 2) according to any of the above methods. ^ Use any of the above methods to treat the formula (1) pyridinium phenyl phenyl diheptin (or phenyl hydrazone) Because) (5 2) can obtain the target intermediate amidine (4 7, A and B are master). -40- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of invention (suppression)

Process X V I Λχ

(51) J = COOH, attack. NH2 (49) J = COOCH:

(Please read the notes on the back before filling in this page) (52) J = Hydrochemical part (47A, B = 0 = Master) Another method for preparing compound of formula (I) in reaction scheme XV, where W is 0 or NH R1 is a heterocyclic group, and the e or i group of the heterocyclic group is selected as described above, and R 4 is not hydrogen, as shown in reaction scheme XVII.

1T

Hr · Printed by the Consumers' Cooperatives through the Central Standard of the Ministry of Work. This paper ruler> 1 Applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 5. Description of the invention (_

Flooding process XVII

R2 r4nhnh] Coffee 2 (36) (50) J: COOCH3 (55) J = COOCH3 Τλ hydrolysis (Please read the precautions on the back before filling this page) (56) J = COOCH3

(57) J = COOH ΤΑ,

(1).

ζ Amorphization part (58) (1, WsOorNfiR ^ eiandR4 is not Ηi;. ^-^ H <t, but the private seal is not included (R1 = e, i and R 4 are not Η &gt; In the reaction scheme XVI, the formula (50) of the substituted fluorene is treated at 0 to 100 «c to be a dialkylhydrazine dialkyl acetal, such as the formula (39, wherein the alkyl group is CH3 &gt; dimethylfluorene Amine Dimethyl: An intermediate product of formula (55) is suspected. The solution of (55) at room temperature to the temperature of the dissolving stream is treated with acetone which has replaced the well with formula (30). The purpose of formula (56) is obtained. Intermediate triazole hydrolyzes _ (56) with the formula (57, of which R1 -42- this paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 565560 A7 B7

N

V. Description of the invention (Heart is a heterocyclic group, and the e or i group is selected as above and R4 is not hydrogen). The citric acid is converted into a halogenating agent according to the above method, which is preferably a hydrazone or mixed anhydride of formula (58). The compound of formula (I) can be obtained by using a halogenated compound (5 8) to convert the formula (1) to pyridine, phenylhydrazine, or phenylhydrazone, wherein W is 0 or NH, A, B, X , Υ, Z, and R2 are heterocyclic groups. The above are shown above and the e and i groups of the heterocyclic group are shown below, and R 4 is not hydrogen. (i) Another method for preparing a compound of formula (I) in reaction scheme XV, in which W is 0 or NH, R1 is a heterocyclic group, and the e or i group of the heterocyclic group is as described above. Head R. 4 is not hydrogen, This is shown in Reaction Scheme XVIII. (Please read the precautions on the back before filling this page) Central Standards of the Ministry of Economics and Industry of China Cooperative Printing Co., Ltd. Printing paper size Applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 (Heart »s χνπι

νη2νη2 (36, R4 = Η)

Η (59) J = COOCH3

Base》 -R2 N (6¾) J = COOCH3

(Please read the precautions on the back before filling out this page) Printed by the Women's T Consumer Cooperatives of the Intermediate Standards Bureau, Ministry of Economic Affairs ¥

44- This paper size is applicable to the Chinese national standard (rNS) Λ4 specification (210X 297mm) 565560 Α7 B7 V. Description of the invention (w) The formula (55 &gt; intermediate ester) in reaction scheme XVII is processed at room temperature to the reflux temperature of the solvent The intermediate triazole ester of formula (59) can be obtained by using acetic acid of unsubstituted well (36, where R4 is H). At this time, the heterocyclic nitrogen can be alkylated or tritiated to obtain substituted triazole of formula (60). The ester (6 0) is hydrolyzed with a carboxylic acid of the formula (6 1), and then converted into a halogenating agent according to the above method, preferably a gas or a mixed anhydride of the formula (6 2). The halogenating agent (6 2) is used to The target compound of formula U) can be obtained by deuterating the formula (1) pyrimidine, phenylhydrazine (or phenylhydrazine), wherein W is 0 or N, X, Y, Z, A, B and R 2 are defined As described above, R 1 is the e and i groups defined as the above fluorene ring group, and R 4 is not fluorene. In addition, the compound of the formula (I) in the reaction scheme XV, wherein W is 0 or NH, A, B, X, Y, Z and R2 are defined as above, R1 is a heterocyclic group, as defined above, the heterocyclic group e is shown below. Or an i group, and R4 is hydrogen, and can be represented by reaction scheme XVIII of the compound of formula (I), where R4 is an optionally substituted aralkyl group, preferably p-chlorobenzyl, according to Buckle-A, J. Cheffi. Soc · Perkin Trans., 6 27 (1982) is prepared using a series of hydrogenolysis or treatment at 0-reflux temperature with a strong acid such as trifluoroacetic acid.

N—N, I printed by the central sample of the Ministry of Work and Consumers ’Cooperatives (read the precautions on the back before filling out this page) e (R4 = H) i (R4 = H) preferably compound of formula U) , Where R1 contains 4 heteroatoms, "is 0 or N Η, and R 4 is 氤. The preparation method is shown in reaction scheme XIX. -45- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7

R1 V. Description of the invention (44

Process X I X

NaN3, NH4CI DMF

The intermediate product of formula (54) in reaction scheme XV is treated in an aprotic organic solvent such as dimethylformamide at room temperature to the solvent reflux temperature to obtain sodium azide and ammonium chloride to obtain the objective of formula (I). Compounds in which W is 0 or N ，, A, BX, Υ, and Z are as defined above, R1 is a heterocyclic group, and the above-mentioned heterocyclic group is defined as above, and SR4 is hydrogen.

N-N (R4 = h &gt; compound of formula (I), wherein R1 is a fluorene ring group selected from e, f, g, h, i,

Or k, W is NR6 Ε Re is not hydrogen, the production method can be as in the reaction process XX (please read the precautions on the back before filling this page). The flow rate of goods and consumer cooperatives should be reversed by the central government department. 0 or 化 Η 院 ΝΗ is shown as the place, w

In the X type, V X and the resulting huge paper size are applicable to the Chinese National Standard (CNS) A4 specification (210'〆297 mm) 565560 A7 B7 V. Description of the invention (V)

Process XX

Alkylation or tritiation

Centralized by the Ministry of M &P; PJ Industrial Cooperative Cooperative I (from Flow VIII) (W = NH; A, B = sulphur; R 1 = g) (W = NR 6; A, B = sulphur; R 1 = g) or I (from process IX) (W = NH; A, B = sulphur; R 1 = f) or I (from process X) (W = NH; A, B = carbon; R 1 = h) (W = NR 6; A, B = sulphur; R 1 = h) or I (from process X11) (W = NH; A, B = C or N, R 1 = f, g, j) or I ( From Scheme XV) (W = NH; A, B = C or N, R1 = e, i, k), the compounds of formula (I, W = HH) in Schemes VIII, IX, X, XII and XV are treated as Methylformamide or tetrahydrofuran, an aprotic inert solvent, treated at 0-8G ° C with osmium such as NaH (or KH) and an alkylating agent such as an alkyl halide (preferably an alkane (bromide or iodine)) to Alkylation yields compounds of formula (I), where W is NR6 & R6 is alkyl, A, B, and R1 are defined as in Reaction Scheme XX and Lan-47- (W = NR 6; A, B = sulfo; R or (W = NR 6; A, B = sulphur; R 1 = f) or (W = NR 6; A, B = C or N; R 1 = f, g, j) or (W = NR 6; A, B = C or NjR1 = ek) (Please read the notes on the back before filling this page)

1T This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 5. The description of the invention (Park) is as follows. In addition, the compounds of formula (I, W = NH) in Reaction Schemes VIII, IX, X, XII and XV can be tested in the presence of amine ages such as pyridine or trialkylamines such as triethylamine, etc. An aprotic solvent (without using any solvent when pyridine is used), a carboxylic acid halide or a carboxylic anhydride can be obtained by halogenation at -4 ° C to room temperature to obtain formula (I, where W = NR6 and R6 is a fluorenyl group , A, B, and R 1 are defined as in Reaction Scheme XX and explained below).

⑴ (J) (k) Compounds of formula (I), where R1 is a heterofluorenyl group selected from e, i, k or n, W is NR6, and ER6 is not hydrogen. Β can be prepared as shown in Reaction Scheme XXI (read first read back) Please pay attention to this page, please fill in this page) im ',' ιτ Central Ministry of Economic Affairs and the goods and workers' consumer cooperatives _ 4 8-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 5 , Description of the invention (47

% η XXI

(54 W = Nil) alkylated or tritiated R6

Acid hydrolysis

R6

Economics, ¾—Ministry's final bid rate bureau GT-Consumer M press? Wooden 49 (Please read the notes on the back before filling this page)

This paper size is applicable to the Chinese S family crouching (rNS) Λ4 specification (210X 297 mm) 565560 A7 B7 V. Description of the invention (4

NaN3, NH4CI DMF

f N = x-cdT

r2P «* 1) (^) 2 ^ 0 ^ 39) 2) R4NHNH2 (36) (or NH2OH)

(Please read the precautions on the back before filling out this page.) According to the standards of the Ministry of Consumer Affairs and the Consumer Cooperatives, the printing process is xv. The formula (54, W = NH) is a compound such as dimethylformamide or tetrahydrofuran. Aprotic inert solvent, treated at 80 ° C with a base such as NaH (or KH) and an alkylating agent such as alkane (preferably an alkane gas (bromine or iodine)) by alkylation to obtain formula (6 3, W is NR 6 and R 6 is an alkyl) alkylated nitrile. (54) may be present in an amine base such as pyridine or trialkylamine in triethylamine, in an aprotic inert solvent such as digas methane (when used) Pyrimidine is not used in any solvent), at -4 (1 ° C to room temperature tritiated with carboxylic acid tumor or carboxylic anhydride to obtain a compound of formula (6 3, W is NR 6 and Re is fluorenyl)). By using a similar method to the above compound (54, W = NH), the compound (47, W = NH) in the reaction scheme XV can be alkylated or deuterated to obtain the formula (64, W = NR 6 and R 6 = Alkyl or fluorenyl) alkylation or halogenation intermediates. Reaction Scheme XXI Intermediate (6 3) and amine (6 4) can be converted into compounds of formula (I) in a similar manner, where W = NR 6 and R 6 is alkyl or fluorene ， R 1 -50- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 565560 Α7 B7 V. Description of the invention (to choose a custom group such as the reaction scheme XIX heterocyclic group), or convert to (I) A compound in which W = NReMR6 is an alkyl group or a fluorenyl group, and R1 is an e, I, or k group of a heterocyclic group as shown in the reaction scheme XV and the following is indicated.

or

N

II. Consumers 'cooperation, R4, R4 ^, R2, R4 /' ⑷, (K) (m) The target compound of the present invention can be tested for its biological activity according to the following method. Effect of vasopressin v 2 in normal awake and water-bearing rats on male or female normal blood pressure and sPrague ~ Dawley mice weighing 35-50-50 (Charles River Laboratories, Inc., Kingston, NY) Supplied with a standard rodent diet (Purina Rodent Lab. Chow 5001 and water. On the day of the test, rats were individually placed in a metabolic cage with facilities for separating feces and urine and a container for collecting urine. The test compound or reference agent was 10 fflg / kg oral dose and 10fflg / kg volume administration. The carrier used is 20¾ DMS0 pre-boiled corn flour. After 30 minutes of administration, the injection needle is used to inject 30 Big / kg water to the stomach. Test No rats were given any water or food. Urine was collected 4 hours after the test compound was administered. Urine volume was measured after 4 hours. ¾ F iske Οπ-Ten Osmio Hieter (Fiske Associates, Norwood, MA, 02062) or advanced The CRYOMATIC osmometer, model 3C2 (Advanced Instruments, Norwood, MA) measures urine permeability. The Na +, K +, and Cl- ions were measured using the ion-specific electrodes of the Beckman SYNCHRON EL-ISE Electrolyte strip analyzer. Urine permeability should increase proportionally. In the screening test, two mice were used for each compound. If the urine volume difference between the two rats is greater than 50%, the third mouse is used. The results are listed in Table I below. This paper size is applicable to Chinese National Standard (CNS) A4 specification (51¾¾¾7mm) (Please read the precautions on the back before filling this page) 565560 A7 B7 V. Description of the invention (β)

Table 1 Examples of decreased urine output U) a Difference in urine permeability b Rat type &quot; &quot; 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 12 -2 101 CD 13 6 106 CD 14 83 (1 mg / kg) 321 CD 15 98 (1 mg / kg) starch only 1363 CD 16 41 142 CD 17 72 262 CD 18 76 234 CD 20 10 89 CD 24 86 615 CD (Please read the notes on the back before filling this page) Order

Hr. The rate of entrapment in the zygomatic part and the consumption of the laboratories at the dose of 10 mg / kg, compared with the control group's percent decrease in urine output at the dose of 10 mg / kg, relative to the control group Permeability difference used mouse type: Sprague-Dawley (CD) -52- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 56556〇A7 B7 5. Description of the invention (θ) The following examples can be used to Ming Ming does not limit this issue August Fan®. li (Please read the notes on the back before filling this page)

Iz-ammonium __two 4 two (3 _ Shen 1 set _ two 1-some) cage one 1-(5 丄 U two steps A · 6,1 bu dihydro-5H-pyridine 骈 [2,3-b ] [l, 5] Benzene diheptene ~ 1: 1 with hydrofluoric acid, 1,2-phenylenediamine (52g, 4 8 0 · ϊβο1), and nicotinic acid (76g, 482 and mol Cyclohexanol (48flml) was refluxed under nitrogen for 2.5 hours. After heating, a precipitate was formed. The reaction temperature was carefully poured into ice-cold methane (1000ml) under vigorous stirring. The semi-solid was collected, and Washed in a courtyard and dried under vacuum to obtain 98.9 g (8350 of the title compound, which can be used in the next step without purification. Step 8.6, 1 dihydro-511-pyridine hydrazone [2, 3-1)] [1, 5 ] Benzene diheptane, the diborane dimethyl sulfide complex (3 5 in 1) was added from a syringe to cyanide containing step A-6, and the dihydro-5 Η-Btt pyridine [2, 3-b] 丨〗, 5] Benzene diheptain-5-one and hydrogen acid 1: 1 dioxane (2 3 0 hi 1). It was sonicated overnight at room temperature and dried under vacuum. The green residue was treated with cold 2 NHC 1 and ether. The cooling water layer was triturated with 5 (U NaO to pH 9), and then extracted with ethyl acetate to pass through the central part of the decoration department. Consumption cooperation, women's households. Dry the organic layer under anhydrous potassium sulfonate and steam (2 4 · 3 5 g, 61 · 4%). Crude the crude product with diethyl ether to purify. Collect the solid, wash and vacuum Dry. Combining different mother and liquid, # mix% (18. 5 g) by flash chromatography (silicone Merck-60, dissolving with 2 (UZ * acid ethyl acetate)), additional homogeneous material can be obtained by TLC ( Yellow solid, lld ° Step C · 2-Amo-4-Fluorobenzium Amo -53-This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 565560 A7 B7 — One-— — __________-- ---- V. Description of the invention (β) (Please read the precautions on the back before filling out this page} Will contain a few drops of dimethylformamide and 2-gas-4 -fluorobenzoic acid (1 3 · 6 1 g, 7 8 Mmol) of dichloromethane (85ml) under nitrogen was added dropwise to a 2M solution of grass methane gas (1.2 equivalents when the gas stopped generating, refluxed for another 25 minutes and dried under vacuum. Directly used in the next step. Step D · (2- -4--4-fluorophenyl)-(5,11-dihydro-pyridinepyrene [2, 3-b] [1,5] phenylhydrazine -6-yl) methanone will contain 6,11-di -511-pyrimidinidine [2,3-13] [1,5] benzidine diheptin (12.8g, 65mmol) in dimethylformamide (120ffll) under nitrogen and potassium sulfonate (1 9 · 7 6 g, 1 4 3 m hi ο 1). Cool and add dropwise dimethylformamide (5flml) of the crude 2-gas-4-fluorobenzylhydrazone gas (78mmol) in step C. Stir at room temperature for 75 minutes, dilute with water and extract with dichloromethane. The organic extract was dried over magnesium sulfate and dried under vacuum. The crude product was purified from a column (silicone Merck-60, hexane-ethyl acetate: 95: 5 to 80:20) to obtain the pure title compound U 4 · 2 5 g, 6 2 3;) and some of the impurities were less pure. (2 · 7 g). This pure was a white crystalline solid, which was used directly in the next step. NMR (DMSO-d6, 400 Μ 400ζ): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 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] +, 196 Μ '^ central sample rate and only consumer cooperatives India and India 骤 e. [2-ambient- 4- (3-methylpyrazole-1- Phenyl) phenylbenzene (5,11-dihydro_pyridine 骈 2,3-b] [1,5 1phenylbenzene diheptin-6-yl) methanone NaH (60 er oil, 1.8 g , 45 · 19 · ηιο1) washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (130 m)). Pure 3-methylpyridamidine (3 · 7 1 ϋ, 4 5 · 1 9 I »w ο 1). When gas generation ceased, remove the ice bath and stir at room temperature. Add once in step D (2 -Ga-54- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) 565560 A7 B7 V. Description of the invention (θ) -4 -fluorophenyl)-(5, 11-Ethylpyrene [2,3-b] [l, 5] Benzene diheptin _buki) A (8.11 layer, 2 2. 5 9 mniol), placed in an oil bath (preheated to 1 3 0 ° 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 methane gas and adsorbed to the silica Merck-60 column. The hexane-ethyl acetate (95: 5 ~ 3: 2) was used for 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, 68X) was obtained as a white solid by crystallization from hexane-ethanol supersonic oscillation, and the melting point was 2 07 ° C. NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3Η), 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, 1H , NH) MS (El, m / z): 415/417 [M] +; (+ FAB, m / z): 416/418 [M + H] + Calculated value for elemental analysis: C ^ HuClNp: C 66.43; H 4.36; N 16.84. Found: C 66.11; H 4.42; N 16.64

H 「2-氛 -4-(5-甲 _ _-ΐ-基） cage base 1-(5 · 1 1-two gas-Ult. 畦 骈「 2,3_bl 「L5l ^ gStf diheptene-6- A) The formazan via the central part of the stasis department *: The rate is only printed by the consumer cooperatives (please read the precautions on the back before filling out this page). The area obtained in step 1 of Example 1 contains the 3-methyl and 5-methylpyrazole regions. The isomeric fraction (0.543 g) was obtained from a flash column (Silica Merck-60, dissolved with toluene-ethyl acetate: 90:10 and then toluene-ethyl acetate-acetonitrile 90 ... 10: 5). Hexane supersonic salt can obtain 0.327 g of 3-methyl isomer in Example 1 and 0.105 g of the amorphous solid of the title compound. 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 -55- ^ The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 OX297 mm 1 565560 A7 B7 V. Description of the invention (β) Example 3 H 澳 -4 二 (3- 申 _ _ · · (A) Cage base 11-didipyridine hydrazone 12. ^ Step A. 2-Bromo-4 -fluorobenzyl chloride will contain a few drops of dimethylformamide and 2-bromo-4-fluorobenzoic acid (6.87g, 3 1.37fltmol) in Diqijiayuan (7〇 «* 1) Under radon gas, add a solution of grass methane gas hydrazone methane 2M (1. 16 equivalents). When the gas stops generating, reflux for 25 minutes and dry under vacuum. This crude radon gas can be used directly in the next step. Step B. [2-Bromo-4-fluorophenylb (5, 11-dihydro-pyridinepyrene [2, 3-b] [1,5] phenylpyridine-6-yl) methanone) The central part of the Ministry of Commerce only cooperates with the consumer and pulls the print (please read the precautions on the back before filling this page). It will contain the example 1, step B-6, 1 dihydropyridine [2, 3-b] 丨1,5] Phenylhydrazine (5.15g, 26.1inrool) in dimethylformamide (70ml) Under nitrogen, potassium sulfonate (7.95g, 57 · 51ιβμο1) was added, cooled and added dropwise to step 2 -Bromo-4-fluorobenzylhydrazone gas crude (31.37 wmol) dimethylformamide (30 ml). Stir at room temperature for 75 minutes, dilute with water and extract with dichloromethane. The organic extract was dried under magnesium sulfate and dried under vacuum to obtain a brown solid foam. The crude was dissolved in methane gas and attached to a silica Merck-60 spin column. Dissolve in hexane-ethyl acetate (95 ·· 5 ~ 75: 25) to obtain the pure title compound (6.18 g, 59.5 X) and some impurities (1.2 g). Milling from hexane gives a white solid foam which can be used directly in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.53 (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 -5 6-This paper size is applicable to Chinese National Standard (CNS) A4 (210X29 * 7mm) 565560 A 7 __B7____ 5. Description of the invention (lamp) Step C · [2-Bromo-Bu ( 3-methylpyridyl) phenylphenyl (5, 11-dihydro-pyridinepyridine [2,3-blf 1,5] phenylpyridine-6-yl) formyl _ NaH (6 (U oil 1.2g, 30 · 15ιπβιο1) washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide (1 1 0 1111). Pure 3-methylpyridamidine (2.47g , 3 (K15mmol). When the gas stops generating, remove the ice bath and stir at room temperature. Add (2-bromo-4-fluorophenyl)-(5,1,1-dihydro-pyridine) in step B in one portion [ 2,3-bl [l, 5] phenylhydrazone-6-yl) methanone (6g, 18.07πΐϊηο1). Place in an oil bath (preheated to 130 ° C) for 4 minutes, and cool in water. And ethyl acetate. The organic layer was dried over sodium sulfate. Dry in vacuum. Dissolve in methylene chloride and adsorb to silica gel Merck-60 column. Dissolve in hexane-ethyl acetate (9 5: 5 ~ 7 5: 2 5) to obtain the target compound with lower polarity (3.8 7 g) and 3-and 5 -methylpyrazole regioisomer mixtures (0.8 6 crystallized from hexane-ethanol supersonic oscillation to obtain the title compound (3.5 g, 51%), melting point 2 0 8-2 0 9 ° C (decomposition). NMR (DMSO-d6, 400 MHz): 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 [M] +, 265/263 Cooperatives India and China (please read the notes on the back before filling this page) Elemental analysis calculation value: C23Hi8BrN50 ·· C 60.01, H 3.94, N 15, 21. Measured 倌: C 59.92, H 4.05, N 15.01 M 4 (i , —11 22. Hydrogen-dipyridine—pyridine— 骈 — “2,3 ~ Μ「 1 · 51 Benzamidine di_in-bumou）-"4- (3dimethyl MLazole-1-mou)- 2-Mikasa Shen Cang 1-Shen Mian-Step A · 2-Trifluoromethyl-4-fluorobenzyl chloride-5 7-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 565560 A 7 B7 5. Description of the invention (妫) Will contain a few drops Dimethylformamide and 2-trifluoromethyl-4-fluoroarsinic acid (16.85g, 8 1 nim)] in dichloromethane (15 0 ηι 1) under nitrogen were added dropwise chloracetin ( 8.5ml, 97.4minol). When gas generation ceased, refluxed for another 10 minutes and dried under vacuum. This crude osmium chloride was used directly in the next step. step! } (5,1 dihydro-pyridine hydrazone [2,3-1)] [1,5] phenylhydrazine-6-yl)-(4-fluoro-2 -trifluorotolyl) -formyl The ketone will contain 6,1 1 -dihydro-5 Η-pyridine 骈 [2,3-b] 丨 1, 5] Benzene diheptin (1 0 · G g, 5 3 · 8 mm ο 1) of dimethylformamide (1 2 5 m 1) Under nitrogen, potassium sulfonate (2 2.4 g, 16 2 m in ο 1) was added. Cool and add dropwise to step A 2- Difluoromethaneamine (2 5 πΠ) of crude trifluoromethyl-4-fluorobenzylamine (81m mol). Stir at room temperature for 2 hours, dilute with water and extract with dichloromethane. Organic The extract was dried over magnesium sulfate and dried under vacuum. The crude was dissolved in dichloromethane and purified by flash chromatography (Silica Merck-(50, hexane-ethyl acetate (80:20)) to give the pure title Compound (6.9g, 3 3. U), which was crystallized from hexane-ethanol supersonic oscillation, melting point 183-185 ° 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 (m, 2H) , 8.12 (m, 1H), 9.59 (s, 1H, NH) MS (El, m / z): 387 [M] + Calculated by the central government of M Department «Mou Er Gong Consumer Cooperatives Co., Ltd. (Read the precautions on the back before filling in this page) Elemental analysis calculations · C2 () H13F4N30: C 62.02, H 3.38, N 10.85 .Measured values: C 62.06, H 3.22, N 10.67 Step C · (5, 1-Dipyridine-pyridine 骈 丨 2,》 3-b 1 [1,5] Phenyldiheptin-fi -yl)- [4- (3-methylpyrazole-butyl) -2-trifluorotolyl] -methanone NaH (G (U oil, fl.83g, 20.8nm, 1) was washed once with hexane, and then under nitrogen Dry and suspend in anhydrous dimethylformamide (60ιη1). Add -58 at a time. This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 565560 A7 B7 V. Description of the invention (θ) 3-Methylpyrazole (0.9 m), 1 1 · 2 mm ο 1). When the gas ceases to form, keep stirring at room temperature. Add step (5, 1 1 -dihydro-pyridine) in one step. [2,3-b] [l, 5] Phenyldiheptan-6-yl)-(4-fluoro-2-trifluorotolyl] -methanone (3.6g, 9.3βιβιο1), put in oil The bath (preheated to 130 ° C) for 30 minutes. After cooling, the layers were partitioned between water and ethyl acetate. The organic layer was dried under sodium sulfate and dried under vacuum. It was dissolved in dichloromethane and adsorbed on a silica_H e r k k-60 column. Dissolve 2 3 X ethyl acetate in hexane to obtain 3 · 3 g (7 9 X) of the target compound foam, and obtain the title compound by crystallization from hexane-ethanol ultrasonic vibration. Melting point 2 1 2-2 1 4 ° C . Redissolve in 30% ethyl acetate in hexane to obtain Example 6 with a more polar 5-methylpyrazole regioisomer. 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. Measured value: C 64.01, H 4.01, N 15.45 Example 5- (5,11 Didihydro. Difluoride_1 serving ......... (3 Erli Jit sniff :: 1 ..:. Base 1: 2-2 3. Fluorine-Li-Gai-yl. 1-Li_Chaotic Step A · 4-Fluoro-2-trifluoromethylbenzoic acid methyl ester is passed through the central part of the crotch-T-consumer cooperative seal (Please read the precautions on the back before filling this page) will contain a few drops of dimethylformamide and 4-fluoro-2-trifluoromethanebenzoic acid (25.6g, 123fflra〇U of digas methane (250ml) Chloramphenicol (1 1.3 m 1, 2 9 · 5 hi m ο 1) was added dropwise under nitrogen. When the gas ceased to form, reflux was continued for 15 minutes. Cool and add methanol (50 m 1). Stir 2 hours, concentrated and separated into dichloromethane and water. The organic layer was saturated with disulfonic acid. Washed with sodium solution, sulfuric acid-59- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A 7 ____ _B7 ^ _____ 5. Description of the invention (W) Drying under sodium and vacuum drying can get 1 8 G g (65. 9%) gold oil of the title compound. NMR (DMSO-d6, 400 MHz): δ 3.85 (s, 3Η), 7.67 (m, 1H), 7.80 (m, 1H), 7.95 ( m, 1H) MS (El, m / z): 222 [M] + Acidify the aqueous layer to 2N HC1, and filter the white solid to obtain 7.5g (29.3%) of 4-fluoro-2 -trifluorombenzyl acid. Step B. 4- (3-methylpyridinyl-methyl) -2-trifluoromethylbenzoic acid methyl ester NaH (f &gt; or oil, 3.85 g, 96 · 3η »ιηο1) was washed with hexane, It was dried under nitrogen and suspended in anhydrous dimethylformamide (150 in 1). Add dimethylformamide (7.5 0 m 1,9 6 · 3 mm ο 1) dimethylformamide (50 0 «I Π ^) dropwise at room temperature until the gas ceases to form, drop Add dimethylformamide (50 m 1) of methyl 4-fluoro-2-trifluoroformylbenzoate (〗 7.8 g, 80.1 mm) in step A. Stir 3 I at room temperature) After the separation, a saturated ammonium chloride solution was added to react for 1 h and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and dried under vacuum. Dissolved in dichloromethane and hexane (1) and adsorbed silicon_Merck-6 60 column ^ Dissolved with dichloromethane-hexane (1 ·· 1 ~ 4: 1) to obtain the title compound as a white solid (13.6g, 59.755), melting point 59-61 ° C. NMR (DMSO-d6, 400 MHz): δ 2.28 (s, 3H), 3.86 (s, 3H, C02CH3), 6.43 (m, 1H, Department of Surgery Printed by the Central Sample Rate Co-operative Consumer Cooperative (please read the notes on the back before filling this page) 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: C13HnF3N202: C 54.93, Η 3.90, N 9.86. Found: C 54.80, Η 3.73 N 9.81 Step C · 4- (3-methylpyridine-l-yl) -2-trifluoromethanebenzoic acid will contain 4- (3-methylpyridin-1-yl) -2-trifluoromethanecarboxylic acid in step B- 60- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 _B7__ V. Description of the invention (θ) (1.1? ^, 4.2 1 »1« 〇1) methanol (101 »1)) Add 2.5 Ke 1 ^ 011 (3.31 »], 8e3mino]). Heated to reflux for 90 minutes, cooled and concentrated. Separate between ethyl acetate and 1N HC. The organic layer was dried over sodium sulfate and evaporated to dryness to give the title compound (1. 4 g, amount) as a white solid, mp 192-194 ° C. NMR (DMSO-d6, 400 MHz): δ 2.28 (s, 3Η), 6.42 (m, 1H, 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, COOH) MS (+ FAB, m / z): 271 [M + H] + Elemental analysis and calculation 倌: C12K9F3N202: C 53.34, H 3.36, N 10.37. Measured letters: C 53 · 35, H 3.29, N 10.21 Printed by the Consumer Cooperative only through the central sample rate of the Ministry (please read the notes on the back before filling this page) Step I) (5, 〖b Dihydro-Itpyridinium f 2,3-b] f 1,5] phenylhydrazine-fi-yl)-丨 4-(3 -methylpyridinyl-1 -yl) -2 -trifluorotolyl In bupropion, 4- (3-methylpyrazol-1-yl) -2-trifluoromethanebenzoic acid (1.1 g, 4.1.1m! «Ο1) and triethylamine (0.57ηΠ, 4 · 1βϊβιο1) in methylene chloride (20ral) was added with 1,3,5-trifluorobenzylphosphonium chloride (0.63ml, 4.0ffflfl). After stirring for 5 · 5 hours, 6,1 dihydro-5Η-pyridine ， [2,3 -b] [1,5] phenylbenzodiheptaine (0.67g, 3.4βιβιο1) in step B of Example 1 was added. ) And 4-dimethylaminopyridine (0.42 g, 3.4 mm ο 1). After stirring for 18 hours, it was poured into a saturated sodium bisulfate solution. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. Dissolved in methane and adsorbed to silica gel M e r k-60 column. Dissolve in hexane-ethyl acetate (8: 2 ~ 7 ·· 3) to obtain the title compound foam (0.88 g, 5 8 · 2 rom), which was crystallized from hexane-ethanol by ultrasonic vibration. , Melting point 2 1 2-2 1 4 ° C. This compound is the same as the compound of Example 4. Example Γ). (—5, 11: Ξ ;. 氪 二! 骈 .. [2 ^ a.-bU 1.5. Ί 骈 庚 二 庚 因 二 LQ 二 -61- This paper size applies to Chinese national standards (CNS ) A4 specification (210X297 mm) 56556〇A7 _________B7____ V. Description of the invention (k) group "-U-(5 -Shen 蚍 _-1 -some) -2 -Three-parent Shenlaiji 1 two miles ^ 'ΜΑ- CL J) Θ Amphiphilic methane and 0.13 ethyl acetate solvate according to Example 4 to obtain the title foamy compound (0.3 50 g, 8¾), which was crystallized from the supersonic vibration of ethanol-hexane, melting point 2 3 8-2 4 0 X :. 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, 1H), 8.13 (m, 1H), 9.63 (s , 1H, NH) MS (+ FAB, m / z): 450 [M + H] + Calculated value for elemental analysis: C24H18F3N50 + 0.09 CH2C12 +0.13 C4H802: C 63.09, H 4.13, N 14.95. Found: C 63.39, H 4.23, N 14.89 Examples ... 1 (F) · 1 1-Diargon-pyridine 酣 f 2. 3-b 1 「1 · FH Cage 酣 Dinan 囡 -6-base） -Γ 2 -H Argon base _-4-(3-trifluorometidazole-l-fluorene) -phenyl 1 Shen-one__ Jingjing Department Central * ?: Zhuan Erji Consumer Cooperative Co., Ltd. (please read the precautions on the back first) (Fill in this page) NaH (G 0 Γ oil, 0 · 17 g, 4 · 2 5 ffl μ ο 1) was washed with hexane, dried under nitrogen and suspended in anhydrous dimethylformamide ( 1〇 »| 1). Add 3-trifluoromethylpyridine (0.34 g, 2.5 mm ο 1) at one time. After the gas is stopped, the ore is still stirred at room temperature after being generated. Example 4 is added at a time In step B, (5,1 1 -dihydro-pyridinepyrene [2,3-h] M, 5] benzopyrene-6- )-(4-fluoro-2-trifluorotolylbuprofen (0.75 g, 1.94 m in ο 1), put in an oil bath (preheated to 130 ° C) overnight. Cool Then the layers were separated between water and ethyl acetate. The organic layer was dried under sodium sulfate and dried under vacuum. The title compound (0.57g, 57.3%) was obtained by crystallization from ethanol as a white solid with a melting point of 1 2 7- 1 2 9 ° C. -62- This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) 565560 A7 B7 V. Description of invention (μ) NMR (DMSO-d6, 400 MHz): δ 4.19 and 5.46 (dd, 2H, CONCH2), 6.54 (m, 1H), 6.70 (m, IH), 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 [Calculated value of Mf element analysis: C24H15F6N50 ·· C 57.26, H 3.00, N 13.91. Found: C 57.07, H 2.97, N 13.58 Example 1 (ill cover_: „kib" 4 -(3-methyl-PH; _-hydrazone-a certain)-2-trimethylstilbene phenyl 1 -formamidine. NaH (60% oil, 0.12g, 3.0fflffl0l) was washed with hexane, and under nitrogen Dry and suspend Anhydrous dimethylformamide (20 M)). Pure 3-methylpiperidine (0 · 1 3 ffl 1, 1, · 6 1 and in ο 1) was added dropwise at room temperature. Generate lh, add (5, 11-difluorene-pyridinepyrene [2,3-b] U, 5 丨 phenylhydrazine-6-yl)-(4-fluoro-2- Trifluorotolyl] -methyl- (0.528, 1.34ηιαιο1). Put it in an oil bath (preheated to 130 ° C) for 30 minutes. Printed by the Central Ministry of Economic Affairs and the Consumer Cooperatives (Please read the precautions on the back before filling out this page). After cooling, add NaH (6 (in U oil, 0.08 g, 2.0 mrool, washed with hexane)) and methyl iodide (0.25 ^ 1, 4.0 mmol). Stir for another 15 minutes and partition between water and ethyl acetate The organic hydrazone was dried under sodium sulfate and evaporated to dryness. It was dissolved in dichloromethane and adsorbed on a silica_60 column. The title compound (0.28 g, 0.28 g, 45.1g) foam, crystallized by ethanol-hexane supersonic oscillation to obtain a white solid, melting point 1 88-190 ° C. NMR (DMSO-d6, 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 -6 3-This paper is applicable to China Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 A __ ---------- --............ ....... 11 &quot; 丨 闘 丨 · — — ~~ &quot; ―Summary _ &quot; &quot; V. Description of the Invention (with 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 (El, m / z): 463 [M] + (Read the first note on the back Matters then fill page) Elemental Analysis Calcd: C25H20F3N5O: C 64.79, Η 4 · 35, N 15.11 · Found: C 64.55, H 4.29, N 15.04 -

Inverted JJ (5 · 1 1 -di-pyridine-pyridinium pyrene "2 · 3-5 benzene-1 di-0 group" dione [2 -fluoro-4-(3 -Shen-HH. Favor -1 -Base) -Phenyl] -triamidine. 1 9 Hydrate Step A. 2, 4-Difluoro-benzylhydrazone will contain a few drops of dimethylformamide and 2,4-difluoro-benzyl acid (3.6 g , 2 2 · 8 mmo) methane (40 ml) was added dropwise human grass chloride (2 · 4ηϊ1, 27 · 5βιιηο]) under nitrogen. When the gas stopped generating, refluxed for 15 minutes and dried under vacuum. This crude Krypton gas can be used directly in the next step. Step B (2,4 difluorophenyl)-(5,1 1 -dihydro-% pyridine hydrazone [2,3-b] M, 5 1 phenylhydrazone diheptin -1 0 -based) -Ketone Museum, the central department of the Ministry of Commerce, but only the consumer cooperatives, India, will contain the example 1 step B-6,1 didihydro-5 毗 -pyridine 骈 [2,3-b] [ 1,5] Phenylhydrazine (3.08, 15.2111 «1〇1) dimethylformamide (351111) Under nitrogen, potassium carbonate (6.3g, 45.6romol) was added, and then added in step A Dimethylformamide (15 ml) of the crude 2,4-bis-chlorobenzene (22.8! «1» 〇1). Stir for 20 minutes at room temperature, wash with water and stir to collect a solid. Soluble in gas imitation 1 N NaO 洗 and brine. The organic layer was dried under sodium sulfate and dried under vacuum. The crude was dissolved in methane gas and attached to a silica_M e μ k-fi 0 column. Dissolved with 2 055 ethyl acetate Ethyl hexane can be used to obtain the title compound (2.6 g, 5 U) as a white foam, and then crystallized by hexane-ethanol supersonic oscillation. Melting point 1 6 1-1 6 3.0. -64- This paper size is applicable to China Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7___ V. Description of the invention (P) 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 (5,1 dihydro-pyridine hydrazone [2,3-b] [1, 5] Benzene diheptin-1 1 0 -yl)-丨 2-fluoro-4-(3- Methylpyrazole-1 -yl) -phenylbenzophenone 0.19 hydrate NaN (60% oil, 0.48 g, 1 2 · 0 m ro ο 1) was washed with hexane Under nitrogen Dry and suspended in anhydrous dimethyl amine _ (6 square «ι 1). Add pure 3-methylamine, azole ((1.48 m 1, 6 mm). Continue stirring until the gas ceases to form. Add (2, 4-difluorophenyl)-(5, 1b) in step B at a time. Dihydro-pyridine hydrazone [2,3-1) 1 [1,5] Benzene diheptan-10-yl) -methanone (2eup, 5.9a 11101). Place in oil bath (preheat to (130 ° C) for 60 minutes. After cooling, the layers were partitioned between water and ethyl acetate. The organic layer was dried under sodium sulfate and evaporated to dryness. It was dissolved in dioxane and adsorbed on a silica column. Hexane-ethyl acetate (9: 1-1 ·· 1) can be used to obtain the title compound and Example 1 the higher polarity 4-fluoro regioisomer. The title compound was obtained as a foam (0.30 g, 1 2 · 7%) Centralized by the Hexane Economics Department &gt;P; Ά, T Consumer Cooperative Co., Ltd. (Please read the notes on the back before filling this page)-Ethanol-Ultrasonic Oscillation Crystals, Melting Point 1 2 2-〗 2 5 ° C. NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3H, 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 , 2 H), 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 + 0.19 H20 ·· C 68.57, H 4.60, N 17 · 38 · Silanzhi ·· C 68.53, Η 4.68, N 17.56 -6 5- This paper size applies to the Chinese National Standard (CNS) A4 * 1 grid (210X297 mm) 565560 Α7 Β7 5. Invention Description U4)

Example 1 1Q (5 ill: di-hydro-pyridine hydrazine "2, 3-b 1" 1, 5 1 phenylhydrazone diheptin -1 0 -yl)-"4 difluorobis 2 bis (3: ri) r The title compound and its 2-fluoro regioisomer were obtained according to the method of Example 9 using phenylhydrazone-formamidine 0, 2 ethanol. From the preparation Η PLC (water silica gel column, dissolving with hexane-ethyl acetate _ (5 5: 4 5), at a flow rate of 150 ml / min, detected at 2 5 4 πϊπ), a foam of the pure title compound (0 · 2 5 g, 10 · 6 S;) can be obtained, and then crystallized by hexane-ethanol-ultrasonic vibration, Melting point 1 8 0-1 8 1 ° C 〇MS (El, m / z): 399 [M] + Calculated value for elemental analysis: C23H18FN50 + 0 · 20 C2H60: C 68.78, Η 4.74, N 17.14. Found: C 68.67, Η 4.76, Ν 16.97 Cases ... 11 [2 Dichlorodi 4: 丄 1 Erli 1 Ou Ling 骈 "2,3 2 11" Lv-51 stupid. Chaos show 2 1. Enterprise: _ 丄 丄 2A — 胤 — Step A (2 -Amino-4 -fluorophenyl)-(5methyl-5, ί 1-dihydro-pyridine hydrazone [2, 3-b 1 Μ, 5] phenylhydrazone diheptin-1 0-based) -methanone Na Na (β Π% in oil, 0.76 g, 19 · 0 mm 〇)) was washed once with hexane, and was consumed only at the central rate of the chin. Cooperatives in India (Please read the back Please fill in this page again if necessary) Dry under nitrogen and suspend in anhydrous dimethylformamide (10 m 1). Add to step 1) (1-Chloro-4-fluorophenyl) at 0 ° C dropwise. )-(5,1 1 -dihydro-pyridine 骈 丨 2,3-b] [l, 5] phenyl hydrazine-6-yl) methanone (6.12 g, 17.3 mm ο 1) dimethyl Formamidine (50 m 1). After the gas stops generating, remove the ice bath and hold the ore at room temperature and stir. Add methyl iodide (2.5 1 g, 17.1 in ffl ο 1) at a time. , Stir for another 1 hour. Separate between 20% sodium gaseous solution and dichloromethane. Dry the organic layer under magnesium sulfate and evaporate to dryness. Dissolve in methane-66- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7 V. Description of the invention (W) and adsorption to the silica gel Merck-6 60 The column was dissolved with hexane-ethyl acetate (9 5: 5-8 5:〗 5). The title compound was obtained as white crystals (4.55 g, 72%), melting point 2 2 2-2 2 3 ° C. NMR (DMSO-d6, 400 MHz): δ 3.46 (s, 3H, NCH3), 4.37 and 5.67 (2 broad m, 2H, CONCH2), 6.87-6.97 (m, 2H), 7.06-7.14 (m, 2H), 7.20-7.32 (m, 3H), 7.36 (m, 1H), 7.60 (m, 1H); 8.21 (m, 1H) MS (El, m / z): 367/369 [M] +; (+ FAB, m / z): 368/370 [ M + H] + Calculated value for elemental analysis C20H15ClFN3O: C 65.31, H 4.11, N 11.42. Measured values: C 65.04, H 4.14, N, 11.27 Step B (2 -Ga-4-(3 -Methylpyrazole- 1 -yl) -phenyl)-(5 _methyl-5, printed by the Central Consumers ’Cooperative, and printed by a consumer consumer cooperative (please read the precautions on the back before filling out this page) 1 1- 二 气-比Pyridine 骈 2,3-b] 丨 1,5] Benzene diheptin-1 0-yl) -methanone NaH (G0% oil, 0.2 6 4 g, 6. 6 ιηιηο1) was washed with hexane, and It was dried under nitrogen and suspended in anhydrous dimethylformamide (8 m 1). Add pure 3-methylpyrazole (0 · 5 4 1 g, 6 · fi m m ο 1) dropwise at fl ° C. After the gas stopped generating, remove the ice bath and stir the ore at room temperature. (2-Gas-4-fluorophenyl)-(5-methyl-5,1,4-dihydro-pyridine [2,3-b] [1,5] phenylhydrazine- 10-yl) -methanone (1.21 g, 3.3 nm). Place in an oil bath (preheated to 13 (TC) for 30 minutes. After cooling, separate between 20% sodium gaseous and digas methane. Dry the organic mash under magnesium sulfate and evaporate to dryness. Dissolve in digas methane and Adsorbed on a silica gel Merck-60 column. Dissolved in hexane-ethyl acetate (95: 5-70:30) to obtain the title compound with lower polarity (0.936 g, 66%) and 3- And 5-methylpyridine regioisomers (0.22 g). The title compound was obtained as a white solid by crystallization from hexane-ethanol supersonic oscillation. Melting point 2 1 8-2 19 ° C (decomposition). -6 7-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7_ V. Description of the invention (W) NMR (DMSO-d6, 400 MHz): δ 2.21 (s, 3Η, pyrazole C-CH3 ), 3.49 (s, 3H, NCH3), 4.39 and 5.69 (broad dd, 2H, CONCH2), 6.32 (m, 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 [Mf, 219, 195 Elemental analysis calculation 倌: C24H20ClN5O: C 67.05, H 4.69, N 16.29. Found: 0 67.26, 11 4.69, N 16.15 Example 12 (5, 1 1-2 氲-«LSign 骈 丄 2 ^ 3 二 k] 丄 Lil. 笨 — 骈-二 1.HF 2 -methyl-5-(3 -methylpyridine瞍 Di 1 diyl JL-U ″ Li®__one — Step A 5 -Fluoro-2 -methylbenzylhydrazone will contain a few drops of dimethylformamide and 5-fluoro-2-formylbenzoic acid (2.3) g, 15.0 phase and 0.1 ml of dichloromethane (Uflml) were added dropwise chlorochlorine (1.16 and 1, IR.SmmolU) when the gas was stopped, and then refluxed for 10 minutes and dried under vacuum. It can be used directly in the next step. Step B (5,1 Benzodihydro-pyridine hydrazine [2,3-b] [l, 5] Benzene diheptin-fi-jib (5-fluoro-2- Tolyl) -Methyl Ketone MM section is accurate and only J consumer cooperation pull India (please read the precautions on the back before filling this page) will contain Example 1 step B-6, 1 dihydro-5 Η- Pyridine hydrazone [2,3-b] [1,5] Benzamidine diheptaine (2.0 g, 10.1 mmol) in dimethylformamide (15 into 1) was added with potassium sulfonate (4. G, 29.7 mfflOl). The dimethylformamide (lOffil) of the crude 5-fluoro-2-methylbenzylhydrazone gas (15ramo]) in step A was added dropwise. Stir at the slaughter temperature T for 5 minutes, dilute with water and stir to collect solids by filtration. Dissolve in chloroform and wash with 1 N N a 0 Η and brine. The organic oil was dried over sodium sulfate and dried under vacuum to obtain purple oil. The crude product was dissolved in dichloromethane and attached to silica_Merek-G0. The column c was dissolved with 2 U ethyl acetate in hexane to obtain the title compound (1.88 g, 55.8 X) foam, and then crystallized by ethanol-hexane supersonic oscillation, melting point 138-140 ° C. -6 8-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7__ V. Description of the invention (W) 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] + Calculated value for elemental analysis: C20H16FN3O: C 72.06, Η 4.84, N 12.60. Found: C 71.88, hydrazone 4.78, N 12.67 Step C (5,1,1-dihydro-pyridine hydrazone [2,3-b] [5,5] phenylhydrazone diheptin-10 -yl)-丨 2-methyl-5- (3-Methylpyrazol-1-yl) -phenylbutanyl_ Wash NaH (60% oil, 0.25g, 6.25ηιιιο1) with hexane, dry under nitrogen and suspend in anhydrous dimethylformamide Phenamine (10 »1). Add pure 3-methylpyrazole (0.28ml, 3.5mn »ol) in one portion at room temperature. Hold the ore and stir until the gas stops generating. (5,1 1-dihydro-pyridinium [2,3-»)] [1,5] phenylhydrazine-6-yl)-(5-fluoro-2-tolyl) )-Ketone (0 · 7 5 g, 1 · 9 4 in ffi ο 1). Heat under reflux for 26 hours. After cooling, separate between water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness. It was dissolved in dichloromethane and adsorbed on a silica gel Merc fc-6 60 column. Dissolve in hexane-ethyl acetate (8: 2-7: 3) to obtain the title compound as a pale yellow foam (0.55g, 5 1. 550, and then crystallize by sonication with hexane-ethanol, with a melting point of 20-9-2 1 0 ° C 〇 The central ministry of the Ministry of Justice of the People's Republic of China only prints f (Please read the precautions on the back before filling this page) NMR (DMSO-d6, 400 MHz): δ 1.94 (s, 3H, CH3) , 2.23 (s, 3H, pyrazole CH3), 4.13 and 5.49 (dd, 2H, C0NCH2), 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. Found: C 72.57, H 5.49, N 17.46 -69- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 A7 _B7 __— One or five, the description of the invention (M) Example _ 1 3 L4 ^ _U-II Ξ._Τ JIL.M 1 M cover 丄 — ( Please read the precautions on the back before filling in this page) mm m 12., sb iii NaH (60% oil, 0.12g, 3.0 μm μ1) with hexane under nitrogen Dried and suspended in anhydrous dimethyl formate (10 m 1). 3-Third-butyprazole (0.20 g, 1.6 βιμο1) was added at room temperature at one time, and stirred while holding the ore until the gas stopped ih generation 0-times Add (5,1,4-Dihydro-pyridinium [2,3-b] [1,5] phenylhydrazine-6-yl)-(4-fluoro-2 -trifluorotolyl) in step B of Example 4 ] -Methyl ketone (0.50g, 1.3nm)]. 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. Dry under sodium sulfate and evaporate to dryness. Dissolve in dichloromethane and attach silica® «61 ^ b () (1 column. Dissolve in 25% ethyl acetate in hexane to obtain the title compound as a foam (0.2 3 g, 3 6 5S), crystallized by hexane-ethanol milling, melting point 1 36-1 4 Π ° C. NMR (DMSO-d6, 400 MHz): δ 1.26 (s, 9Η, 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, 1H), 8.47 (m, 1H, pyrazole CH), 9.62 (s, 1H, NH) MS (El, m / z): 491 [Mf elemental calculated value: C27H24F3N50 ·· C 65.98, H 4.92, N 14.25. Measured values: C 65.75, H 4.92, N 13.95 Example 14 d LI _ dipyridine-pyridine di bl "1,51 benzopyridine-fi-yl" 4- (3 -methyl 1azole-1 -yl)-2 Ί Zhi Liben _ _ "": · A_1 Huan. Formamylic acid dissolves Μ 0, 15. hexamethylene 1: 1 will contain Example 4 step C of (5, 11-Dihydro-0ft pyridine 骈 2, 3-b] [1,5] benzene-70- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 565560 A7 B7___ 5. Description of the invention (⑺ ) Diheptyl-6-yl)-[4- (3-methylpyrazol-1-yl) -2-trifluorotolyl] -methyl- (0.518, 1.13ffl®ol) in dichloromethane (10ml ) Add methanesulfonic acid (please read the notes on the back before filling this page) (0.074m], 1.14niffl0]). After stirring at room temperature overnight, hexane was added and the solid was collected by filtration to obtain the title salt as a white solid (0.54 g, 87.6%), melting point 2 5 6-2 5 7. . 〇MS (+ FAB, m / z): 450 [M + H] + Calculated value for elemental analysis: C24H18F3N50 + CH403S + 0.15 C6H14: C 55.70, Η 4.35, N 12.54. Actual I value: C 55.37, H 4.48, N 12.45 Example 15 (5, JAr ^ _ M rJli (a-¥ Jtt m -1Γ * —Μ Μ

Os, —11: 1 m.ane-of ... 1 丄 11— will contain the steps of Example 4 (: (5,1 dihydro-pyridine [2,3-1)] [1,5] benzene骈 Diheptin-6 ~ yl)-[2-trifluoromethyl-4- (3-methylpyrazol-1-yl) -phenylpropanone (0.55g, 1.22rorool) in dichloromethane (l 0 ml) was added 1N HC1 in diethyl ether U · 2 2 w)). Stir for 1 hour and filter the solid to give the title salt as an amorphous white solid (0.5 g, 84.1X). MS (El, m / z): 449 [M] + Calculated value for elemental analysis: C24H18F3N50 + 1.04 HC1 + 0.10 CH2C12: C 58.38, H 3.91, N 14.12. Found 倌: C 58.23, H 4.07, N 14.03 Example li " 2: Chlorine: 丄: · (3: 1 defeat 2 1 2 11 PI— Step A 6 H -Pyridinidine 骈 [2,3-b] [1,5] Benzene diheptin-7 1- This paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 public director) 565560 A7 _____ B7 ___ 5. Description of the invention (&gt;) Lithium aluminum argon (0.258g, 6.877ιβιπο1) was added to the sample under nitrogen mixing 611-Pi_ 骈 丨 2,3-1)] [1,5] Phenylhydrazine-5--5- (0.636 莒, (Read the precautions on the back before filling in this page) 3 m 〇] &gt; 2 5 m 1 of tetrahydrofuran. Heat to reflux for 3 hours, add 0.3 ffl 1 water, IN NaOH, water and 3.8 g of sodium sulfate in order to decompose the excess lithium aluminum hydride. Collect the solid by filtration and wash with ethyl acetate. Evaporate under reduced pressure. The filtrate was removed to obtain a crude product (0.45 g), which was purified by flash chromatography (silicon-Merck-60, dichloromethane-ethyl acetate (19: U). The title compound was obtained as a yellow solid (0.1 g, 17%) 0 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-Gas-4-fluorophenyl] Ml 1H-5- 4, 10-diazodiphenylhydrazone [a, (Πcycloheptene-1 0 -yl) -methyl_ 2-chloro-4-fluorobenzoic acid (0.37g, 2.12ηιηο1) and grass gas (fl. 3 0 3 inl, 2.3ffl « 10mL of dichloromethane and the catalyst amount of dimethylformamide were stirred at room temperature until the gas stopped for 1h to form tritium. The crude cyanide was added to step A (5 Η-pyridine).骈 [2,3-b] 丨〗, 5] Benzamidine diheptain (0.45g, 2.1 2mmol) and triethylamine (0.35ml, 2.5inmol), a gas-methane machine-mixed solution 1 5 m 1. At room temperature Stir overnight, add water and dry under sodium sulfate. The solvent was evaporated to give the crude title compound as a gummy solid, which was used directly in the next step. NMR (DMSO-d6, 400 ΜΗζ): 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-1 -yl) phenyl]-(1 1 H HI-4 -72- paper size Applicable to China National Standard (CNS) A4 specification (21 × 297 mm) 565560 A7 B7 V. Description of the invention (), 10-Diazodiphenyl hydrazone U, d] cycloheptene-1 0-yl) methyl _ ( Please read the precautions on the back before filling this page.) Add 3-methylpyrazole (0 · 1 6 1 ® 1, 2 · 0 m BI0 u to KH (0.fl8g, 2.0 fflffl0l) of 5m] anhydrous dimethylformamide. Stir at room temperature until the gas ceases to form c. Add step B containing [2-chloro-4 -fluorophenyl]-(1111-5-Naruto- 4,10-Diazodiphenylhydrazone [&amp;, (!) Cyclohepten-10-yl) -methanone (0.79 g, 2.14 mffimol) in Offil dimethylformamide. Heat to 1 3 3.5 ° C at 0 ° C for 5 hours. After cooling, the layers were separated between ethyl acetate and brine. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness in vacuo. The crude product was purified by flash chromatography (silica gel Mer) ck-60, dichloromethane-ethyl acetate (9 ·· 1 ~ 9: 1)). The title compound was obtained as a white solid (0.88 g, 21%), melting point 2 2 0-2 2 2 ° C. NMR (DMSO-d6, 400 MHz): δ 2.218 (s, 3H, CH3), 5.106 (broad 2H, CH2N), 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 [ΜΓ, 219 Example 11 Γ 2 二 氲 -4: L3: 三 氲 — l 骈 .L2,3_: i] _LL · ^ After the central government ’s rate of M, only a consumer cooperative, India Fan, washed NaH (60% oil, 0.195 g) in hexane, dried under nitrogen and suspended in anhydrous dimethylformamidine Amine (〗 〇m 1). Add 3 * trifluoromeprazole (0.364 g) dropwise at 0 °. After the gas stops generating, it is warmed to room temperature. One-time addition example: step 丨) in (2- 氱 -4 -fluorophenyl)-(5,1 dihydro-pyridine hydrazone | 2,3-b 1 [1,5] phenylhydrazone diheptin-6- Base) Carmen I (〇. 7 7 7 g, 2 · 2 3 m in ο 1) and placed in an oil bath (preheated to 30 ° C) for 4.5 hours. Saturated gasification after cooling-7 3- This paper size applies Chinese national standard (milk) 8 4 ^ (210 乂 297 mm) 565560 A7 B7 V. Description of the invention (π) (Please read the notes on the back first Fill out this page again) Separate between sodium and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to dryness. Dissolved in dichloromethane and adsorbed on a silica_Merck-6o column. The title compound (0.727g, 69X) can be obtained by dissolving in hexane-ethyl acetate (95: 5-3: 2), and a white solid can be obtained by crystallization from hexane-ethanol supersonic vibration, melting point 183 -1 8 5 ° C 〇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, pyrazole 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: C23H15C1F3N50: C 58.80, H 3.22, N, 14.91 · Measured value: C 58.67, H 3.14, N 14.83 cases—18

Ml boat, "2,3-bl" 1.5l caged diheptin-10-a certain bupropionone step A · 2-Amino-4- (3-dimethylamine propyne-butyl) benzoic acid methyl ester Under nitrogen, 4-bromo-2-chlorobenzoic acid methyl ester (25.13g, lOlniBiol), the central part of the Ministry of Health * ?. Printed in the Industrial and Consumer Cooperatives ^ dimethylamine-2-propyne (16βι1, 150βιηιο1) , 100ml triethylamine of bis (triphenylene) gaseous lead (11) (1.0g) and copper iodide (1) (0.15g) was heated to (50 ° C for 2 hours. The reaction liquid was cooled, Filtered through S ο 1 kaf 1 0c and washed with ethyl acetate. The layers were separated in acetic acid and diluted sodium sulfate sulphate. Organic 1 was washed with water and brine, dried under sodium sulfate. Filtered through Merck-60 silica _Column, vacuum concentration to obtain orange oil of the title compound (23.8g, 95%), which can be fermented for the next step. -74- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) 565560 A7 B7 V. Description of the invention (9) 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 B · 2-Gas-4- (3-dimethylamine-2-propen-1-yl) benzoic acid methyl ester M-chloroperbenzoic acid (16g, 93m «ol &gt;, at -100T!) Under nitrogen to the ester containing 2-chloro-4- (3-dimethylaminepropyn-1-yl) in step A A solution of methyl benzate (2 3 · 5 g, 9 3 · 4 mm ο 1) in methane (2 0 0 a 1 &gt;) was stirred. After the addition was completed, the mixture was stirred at a lower temperature for 30 minutes and filtered through An aluminum column filled with two gas methane-methanol v / v) (400 g, Brockman activity I). The intermediate N-gas is dissolved from the above system. The dichloromethane is carefully replaced by evaporation at room temperature or lower. Methanol, being careful not to evaporate to dryness. Heat to fi0 ° C overnight, and dry in vacuo. Less pure 1 can be obtained by flash chromatography (Merck-60 silica gel column, hexane-ethyl acetate (1: 1)). 2 · 1 g. Milling with ether afforded the pure title compound as an orange solid (6.15 g, 483ί). NMR (DMSO-d6, 300 MHz): δ 2.98 (s, 3Η, NCH3), 3.2 (s , 3Η, NCH3), 3.83 (s, 3H, OCH3), 5.85 (d, 1H, vinyl H), 7.75-8.0 (m, 4H, vinyl H + ArH). Step C · 2-Amo-4- (1 H -pyrazol-3 -yl) benzyl methyl ester will be 2-methyl-4-(3 -dimethylamine-2 -propenyl) benzyl methyl ester in step B 22.9mniol) Anhydrous (U.44ffl), 45.8mmol) of ice was printed by the center of the Ministry and printed at -T Consumer Cooperatives (please read the precautions on the back before filling this page) acetic acid 1 5 m] heating to 9 fl ° C 3 0 points. Concentrated in vacuo and partitioned between ethyl acetate and water. The organic tincture was washed with water and brine, and dried under sodium sulfate. The solvent was distilled off and triturated with ether-hexane to give the title compound as an orange solid (5.11 g, 9 U). 0 NMR (DMSO-d6, 300 ΜΗζ): δ 3.85 (s, 3H, OCH3), 6.9 (d, 1H), 7.9 (m, 3H), 8.0 (d, 1H), 13.15 (broad, 1H, NH). -75- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 565560 A7 B7 ------_____________-------------- --------------------------- --------------------- -------------------------- 5. Description of the invention (&Gt;) Φβ 2-chloro-4-((methyl-1H-pyrazol-3-yl) benzyl methyl ester under 2-cyanocyanine 3-() methyl benzate (5.0 g, 21.2 βιϊβο1) of anhydrous dishenyl formamide 5 (ml) was added dropwise to a solution of NaH (0.51 g, 21.2 «im〇l) washed with hexane. 5 ml of anhydrous dimethylformamide was stirred at room temperature for 30 minutes, and methyl iodide (2.7 μm 1,42.2 mw 〇1) 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. The solvent was distilled off to obtain 4.8 g of an orange oil. By flash chromatography (Merck-60 silica gel column, hexane-ethyl acetate (4:])), 2.9 g (55SJ) of the target propeptazole isomer was obtained. NMR (DMSO-d6, 300 ΜΗζ): 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). Step E · 2-Gas-4- (1-methyl-1H-pyrazol-3-yl) benzoic acid -Pyrazol-3-yl) methyl benzate (2.9g, 20ml of 5ml of 2.5N NaOH in methanol and stir at room temperature overnight. Add 2 · 0 m] 2 · 5 NN a 0 Η and gently heat for 30 minutes . Concentrated in vacuo, diluted with water and acidified with 2 M HC 1. The precipitate was collected by filtration and dried to give 2.55 g (9) of the title compound.-Τ through the central rate of M Department. Read the notes on the back before filling this page) NMR (DMSO-d6, 300 MHz): δ 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 -pyrazole-3 -yl) -phenyl) _ (5 J 二 dihydro- Pyrimidine 骈 2, 3-b] [1,5] Benzene diheptin-10-yl &gt; -methyl m 2-Ga-4- (1-methyl-1H- Pyrazol-3-yl) -76- This paper size applies to China National Standard (CNS) Α4 (210X297) ) 565560 A7 B7__ V. Description of the invention (K) Benzoic acid (2.1g, 8.88ηιηο1) and triethylamine (1.3ml, 9.2ιη®ο1) in 75ml of dichloromethane treated with 2,4,6 -three gases Benzamidine chloride (1.48 and 1,9 · 2 in ο 1) and intended to stir for 2 hours at room temperature. Add 6,1 bu difluorene_5} 1- batch pyridine [2] , 3-1)] [1,5] Phenylhydrazine (1.748, 8.9111 «101) and stirred for 18 hours ^ washed sequentially with a saturated sodium bisulfate solution and brine. After drying under a sulfuric acid pin, it was concentrated and adsorbed to the silica Mercfc-60. Dissolve in ethyl acetate-hexane (4: 3-2: 2) to obtain a slurry of the pure title compound, and then crystallize from ether. This white solid (0.78 g, 2 3 X yield based on recovered raw materials) has a melting point of 1 9 fi-ί 9 7 ° 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, H 4.36, N 16.84. Found: C 66.20, H 4.49, N 16.59. Example 丄 9_

LZ-M _ Defeated late [21 Central Ministry of Economic Affairs and the only consumer cooperation cooperation to print India (read the precautions on the back before filling in this page) Example 1 2-chloro-4 in step 8 without water -(1 -Methyl-1 H-Bftazole-3 -yl) Arthroic acid (1.9g, 8.05mmol), grass gas (0 · 79ιη1, 9. ··· ππ〇1) and catalyst-containing dimethyl 20 ml of diammonium dimethylformamide were stirred at room temperature for 1 hour. The solvent was distilled off, and the solid tritium gas was dissolved in 5 I »1 dimethylformamide and added directly to the example. [Step B] 6, 1 dioxane-5 dipyridine [2, 3-b I | 1 , 5] Benzamidine diheptaine (1.59g, 8.05ιπηιο1) and potassium sulfonate (1.25g, -77- This paper size applies to Chinese National Standard (CNS) A4 specifications (2 丨 0X297 mm) 565560 A 7 B7_ V. Description of the invention (outside) 9 · 0 «I 〇1). After stirring at room temperature for 2 hours, the layers were partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. Slurry was obtained by flash chromatography (Mercfc-60 silica gel column, ethyl acetate-hexane (4: 3 ~ 2: 1)), and white solid was obtained by crystallization from ether (1.88, 6 131 yield 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 can be determined by the difference scanner at 202 ° C. MS (+ FAB, m / z): 416/418 (M + H) +. Calculated value for elemental analysis: C23H18C1N50: C 66.42, Η 4.36, N 16.84. Found: C 66.20, Η 4.42, Ν 16.80. Example ία 12 dichloride: Α di (二二二, _ hydrogen-dihydrazine-pyridinium [2 J · brewing-· Example 1 9 丨 2-气 -4-(1 -methyl- BuΗ _pyrazole-3 -yl) -phenylbu (5, Η-dihydro-pyridine 骈 [2,3-b] [1,5] phenyl phenyl diheptin-1 0 -yl) -methanone (〇 · 382β, 0.92mrool) lOrol tetrahydrofuran was added dropwise to the tetrahydrofuran 2 of NaH (0.025g, 1.02 »1 twisted 0)) which had been washed with hexane to supply 10 gas, and then methyl iodide (1.π» 1 was added. ) And stirred for 2 hours. The layers were separated in ethyl acetate and water. The organic hydrazone was washed with brine and dried over sodium sulfate. The solvent was evaporated and the product was subjected to flash chromatography (Merck-60 silica column, methane-acetic acid). Ethyl ester (2: 1)) can be obtained as the title compound (Π.18g, 47%. It is printed by the central government standard of the Ministry of Economic Affairs and printed by the consumer cooperative (please read the precautions on the back before filling this page) Crystals can be obtained as a pale yellow solid (0.16 g), melting point 2 49-250 ° C. NMR (DMSO-d6, 400 MHz): 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. -78- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 56556〇Α7 Β7 i 'Description of the invention (Π) Grade 1 [2 ~ 气 — 二 4 二 13 1_ 清 _ 一 1 -yl) phenyl 1-(5 · 1 ΐ-digas-attached 1 骈 U-U hH] Μ. 5 1 cage骈 Diheptin-6-yl) -methyl abuse step A 2 -Ga-4-(3 -methyl-1 Η-Uftazole-1 -yl) benzyl methyl ester washed in hexane without water KH (〇.424i ?, 10.6mrool) of 5 ® 1 dimethylformamide stirring solution was added at a time 3-methylpyridin (0 · 8 5 ffi 1, 10.6ffifflOlU gas was added to stop adding 2-Gas-4-fluoroarthroic acid methyl ester (2.0 g, 10.6 wi η »ο 1). It was heated to 130 ° C for 15 minutes, and after cooling, the layers were separated in ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Distilling off the solvent gave 2.2 g of butter containing 3-methyl and 5-methylpyrazole regioisomers. In addition, it can be determined from N M R that the hydrolysis of the ester yields about 203; acid. A white solid (1.5 5 g from 3-methylpyrazole isomer) was separated from the 5-methyl isomer by flash chromatography (Merck-60 silica column, dichloromethane-hexane (2: 1)). , 56%) NMR (DMSO-d6, 400 MHz): δ 2.264 (s, 3H, 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 (El, m / z): 250/252 [M] +, 219 Printed by the Central Ministry of Economic Affairs and printed by the β Industrial Consumer Cooperative (Please read the precautions on the back before filling this page) Step B 2-氱 -4-(3-methyl-1H-pyrazole-boxy) benzyl acid Methyl-l-fluorene-l-azol-1-yl) acetic acid methyl ester (K42g, 5.6mrao]) and tetrahydrofuran (20ml) containing 6.1 1M lithium hydride were stirred overnight at room temperature. The layers were separated in ethyl acetate and IN HC1. The organic layer was washed with water and brine, and dried under sodium sulfate. The solvent was distilled off to obtain the title compound (1.05 g, 7 8 X), melting point 192-193 ° C. -79- &gt; Paper size applies Chinese National Standard (CNS) A4 specification (21〇 × 297 mm) 565560 A7 B7 V. Description of the invention (#) 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 · Measured value: C 55.79, H 3.98, N 11.73 Step C 丨 2 -Chlorine- 4-(3 -methylpyridin-1 -yl) phenylphenyl (5,1 1 -dihydro-pyridine 骈 丨 2,3-b] [l, 5] phenylpyrene-6-yl)- The method of step D of the methanone simulation example 5 uses 2-ammo-4-(3-methyl-1H-pyrazol-1-yl) benzyl acid (0.971 g, 4.1 ββ1β1), triethylamine ( Class 0.57 1,4 · 1βιι »ο1), 1,3,5-trichlorobenzene tritium gas (fl.6 3inl, 4.0mffl0l), Example 1 Step 6 in step B, 〖1 -Diargon-5 Η- Pyridine [2,3-b] 丨 1,5] Phenylpyridine (0 _ (5 7 g, 3 · 4 Β »m ο 1) and 4 -dimethylamine pyridine (0 · 4 2 g, 3 · 4 IB m ο 1) of methane (2 0 m 1) to obtain the same compound as in Example 1. Example—22—

2 diargon 2 4 2 5 2 S-based-: fluorenyl dicaptofluorenyl diyl "... I The method of step A of Example 21 was followed, and the 3-methylpyridinium isomer in Example 21 was subjected to flash chromatography (Merck -6 silica gel column, dichloromethane) to isolate the title compound. It was a white solid (η · 20 g, 7.5 ×). NMR (DMSO-d6, 400 Mhz): δ 2.425 (s, 3H, CCH3), 3.875 (s, 3H, OCH3), 6.33 (s) Please fill in this page again) 1H), 7.65 (m, 2H), 7.79 (s, 1H), 7.95 (d, 1H). MS (El, m / z): 250/252 [M] +, 219 Example 2 L2L :. Chlorine di JL · Fluorine ·· 繁 —i: 丄 LL: Di .. Nitrogen dimonium ^ 骈 —Diheptyl and didione and ketone-will contain the case 〖Step B in 6, Π -二 氲 -5 Η -benzene 骈 [b mt 骈 骈 丨 2,3-e] -80 A paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 565560 Α7 Β7 V. Description of the invention ()丨 1,4〗 Diheptane (〇 · 〖g, 0.5 · ffl m ο 1) in tetrahydrofuran (5 ffl 1) was added with dimethylamine (0 · 19. HSSfflfflol) and 2-chloro-4- Fluoxetine (0 · 1 crude 1, 0 e76 mm). Stir at room temperature overnight and evaporate to dryness. The layers were separated in saturated gasified ammonium 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 12r Αζ, L5 ^? · 41 Three _-3_ radicals) _ ϋ —] di · Ι_5 — H -J =: M-Jit ^ IZ. ^ Step A 2-氱 -methyl terephthalate

Dimethylphosphine (4 0 m) of methyl 2-gas-4-gas benzyl acid (12.4 g, 63.4βιιβο1) and potassium sulfonate (1.3 g, 9.4 m, and ο 1) Under cooling, add 3 OX degassed plutonium (7.6 m). After warming to room temperature, stir overnight. Water was added to react for 1 h and the precipitate was collected by filtration. Dissolved in methane and attached to a silica gel M e r k k -G o column. The title compound was obtained as a white solid (10 g, 74%) by melting with dichloromethane-methanol (98: 2 ~ 9 0 ·· 10), melting point 154-156 ° C. NMR (DMSO-d6, 400 MHz): δ 3.87 (s, 3H), 7.67 (s, 1H, NH), 7.86-7.91 (m, 2H), 8.00-8.01 (m, 1Η), 8.20 (s , 1H, NH) MS (El, m / z): 213 [M] + Calculated value for elemental analysis: C9H8C1N03: C 50.60, Η 3.77, N 6.56. Found: C 50.36, H 3.66, N 6.44 Qingji Printed by the Ministry of Economic Affairs and Consumer Cooperatives (please read the precautions on the back before filling this page) Step 2-Chloro-N-(1 -dimethylamine ethylene)-methyl terephthalate Medium 2-chloro-methyl terephthalate (1.02g, 4.8rorool) and N, N-dimethylacetamidodimethylacetal (3.5 m 1, 2 3 · 9 mm ο 1) in radon gas Heat to 9 n ° c 3 ο min. Palm oil can be obtained by cooling and evaporating the solvent under vacuum, which can be directly used in the next step ^ -8 1-This paper size applies Chinese National Standard (CNS) Α4Λ lattice (210 × 297 mm). Industrial and Consumer Cooperatives Co., Ltd. 565560 A7 B7 V. Description of the invention (p) NMR (DMSO-d6, 400 MHz): δ 2.29 (s, 3Η), 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] triazol-3-yl) benzoic acid methyl ester was charged from a syringe to the middle containing step B under a nitrogen-free trap (Π. 30 ro 1,9. Mm ο 1) under nitrogen. The product (4 · 8 πm m ο 1) was glacial acetic acid (6 hi 1). Heating to 90 ° C for 30 minutes, cooling and concentrating in vacuo gave a light brown solid. Dissolved in methanol and neutralized with saturated sodium bisulfate solution. It was extracted with dichloromethane and ethyl acetate, and the combined solution was taken and dried over sodium sulfate. The solvent was distilled off to obtain a solid, and the title compound was mixed with a white solid (0.81 g, 6755), and the melting point was 19 (5-1 98. 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 (EI, m / z): 251 [M] + Elemental analysis value: CnH1QClN302: C 52.50 , H 4.01, N, 16.70. Found: C 52.68, H 3.83, N 16.50 Step 1) · 2-Chloro-4-丨 1-(4-methylbenzyl) -5 -methyl-1 H-[ 1,2,4] Difluoren-3-yl] benzoic acid methyl ester with digas methane 0.03 solvate NaHUO% oil, 0.3g, 7.5ηιιο 1) washed with hexane, suspended in nitrogen Anhydrous dimethylformamide (20 m 1). The triazole intermediate product U · 36 g, 5 m Βΐ ο 1) of step C was added and stirred for 1 hour. After stirring for 3 hours, p-methoxybenzyl chloride (0 „7 5 m 1, 5 · 5 m in ο 1) was added, and water was added to stop the reaction and extracted with ethyl acetate. The extract was combined, dried under anhydrous sodium sulfate and Concentrate in vacuum. Dissolve in dichloromethane and adsorb to the silica gel Merck-60 Column 8 2-This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page ) Order 565560 A7 B7 V. Description of the invention (heart). The title compound (1.23g, 6 6 fi. 2%) is obtained by dissolving 3% ethyl acetate in dichloromethane to give a white solid, melting point 10-2-1 fl 4 ° C. NMR (DMSO-d6, 400 MHz): δ 2.48 (s, 3H), 3.72 (s, 3H), 3.86 (s, 3H), 5.35 (s, 2H), 6.90-6.92 (m, 2H) , 7.23-7.25 (m, 2H), 7.89-8.02 (m, 3H) MS (EI, m / z): 371 [M] + Calculated value for elemental analysis: C19Hi8C1N303 + 0.03 CH2C12: C 61.05, H 4.86, N 11.22 · Measured values: C 60.83, H 4.96, N, 11.18 Step E · 2-Ga-4 _ [1-(4-methylchlorobenzyl) -5 -methyl-1 H-[1,2,4] Azole-3-yl] acetic acid and ethyl acetate 〇 ″ hydrate 〇 04 solvate will be step 1) _ Intermediate product (1. Gg, 4.3 mmol) in methanol (15 ml) was treated under nitrogen to 2.5 N N a 0 Η (3. 5 ffl 1, 8 · 8 m 1). Reflux for 2 hours, cool and concentrate in vacuo. The layers were separated in ethyl acetate and water. The aqueous layer was acidified with 1 N H C 丨. The precipitate was collected by filtration to obtain the title compound U · 25 g, 8 1 · 2 X &gt; white solid, melting point 1 5 4-1 5 fi ° C. NMR (DMSO-d6, 400 MHz): δ 2.47 (s, 3H), 3.72 (s, 3H), 5.34 (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 (El, m / z): 357 [M] + Calculated value for elemental analysisC18H16C1N303 + 0.10 H20 + 0.04 C4H802: C 60.07, H 4.59, N 11.57. Actual measurement: C 59.75, H 4.41, N 11.43 Printed by the Central Ministry of Economic Affairs and the Zhenggong Consumer Cooperative (Please read the precautions on the back before filling this page) Step F t 2 -Chloro-4-[1- (4-methylamino group) -5-methyl-1H- [1,2,4] three ton-3-yl] chloro chloride will be step E acid (1 g, 2.8 mm ο 1) and A few drops of dimethylformamide digas methane were added dropwise chlorchloride (0.3 m 1, 3.4 m η »ο 1) under nitrogen. When the gas was stopped for 1 h, refluxed for 15 minutes and dried under vacuum to obtain the title compound, which was used in the next step. -8 3 A paper size applies to the Chinese national standard (CNS &gt; A4 size (210 X297 mm) 565560 A7 B7 —_________ ______-----------—— 丨 丨 丨: 5. Description of the invention (A) Step G · 丨 2-chloro-4-[1-(4-methoxybenzyl 5 -methyl-1 Η-[1, 2, 4] = · _-3 -yl) phenyl (5,1 b dihydro-pyridine hydrazone f 2,3-b Η 1,5] phenylhydrazone diheptin-6-yl) -formaldehyde I 0 · 0 6 dichloromethane solvate will contain the procedure of Example 1 B of Γ), 1 bis dihydro-5 Η -pyridine 骈 [2,3-b] [1,5] Benzene diheptane (0.55 g, 2 · 8 m η 〇)) Methylformamide (10 m 1) was added potassium arsenate (0.39 g, 2.8 mm ο 1) under nitrogen. Dimethyl formaldehyde (2.8 fflmol) of crude tritium gas in step F was added dropwise. Amidine (10 ml). Stir for 90 minutes at room temperature, dilute with water and extract with ethyl acetate. Combine the extracts and wash with 1 NN a 0, dry under sodium sulfate and evaporate to dryness. Gas methane is adsorbed on the silica Merc-0 column. Dissolve with ethyl acetate ·· hexane (1: Impurities with lower polarity can be obtained. Re-dissolve with 2 X methanol-digas. Alkanes give the title compound (0.57 g, 38%) as a white solid with a melting point of 2 1-8-2 1 ° C. 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 + H] + Calculated value for elemental analysis: C30H25ClO2 + 0.06 CH2C12: C 66.60, Η 4.67, N 15.50. Measured value: C 66.24, H 4.85, N 15.23 Through the central #rate of the Ministry of Yiyi, the cooperation between goods and workers has been printed. (Please read the precautions on the back before filling this page) Step H · 丨 2-Chloro-4-(5-methyl-1-H-[1,2,4] tris -3 -yl) -phenyl BU (5,1 BU digas-pyridine 骈 2,3-b] U, iH phenyl hydrazine diheptin-6-yl) -methanone Step G triazole intermediate (0.54 g, 1 · 〇 J 0 1) trifluoroacetic acid (1 5 π »1) was heated to reflux under nitrogen for 7 days. Cool and evaporate the trifluoroacetic acid σ in water and neutralize to a saturated sodium bisulfate solution. Ethyl acetate-8 4-This paper size applies Chinese national standard (CNS &gt; Α4 size (21 × 297mm) 565560 Α7 Β7 V. Description of the invention (imitation) National intermediates and 3-E-sodium salt according to the law The reaction can be obtained by the method of Step 16 C. Example—21 [2 Difluoro-4-(3 -methylpyrazole-1 -yl) phenyl hydrazone-(11 Η-5 -free -4 · 1 0 -di TΓ Death .... —— [_ ..4..1 .. (1 ...]. _ 丽 _Q 基 __ ”. Example 1 2-chloro analogue method in fi, from step 1 of 6 The 6 Η -pyridine hydrazone [2, 3-h] 丨 1,5] benzene diheptane in A is obtained by reacting the 2,4-difluorobenzylhydrazone gas in step 9 of Example 9 to obtain the title compound. (2,4 -Difluorophenyl) &gt; (1 1 Η-5-P; f-4,] 0-diazodiphenyl hydrazone [a, d] fluorene heptene-1 0 -yl) _methanone intermediate with 3 -Pyridazole pin salt can be reacted according to the method of Step 6 of Example 16 to obtain the title compound. Example 28 [2: Chlorine :: _ 4 di_ (1 diridyl-1H -episo-3-yl) phenyl 1- (11 [1-5-Turn_4 · 10 222! Ϊ́. Diphenyl hydrazone "a, cH cycloheptyl-10-yl) -A .. 嗣 Analog method similar to that in Example 1 9 from Example 1 9 2 -Chloro-4-(1 -methyl-1 fluorene-hydrazone-3 -yl> benzyl The title compound can be obtained by reacting chlorine with 6 Η-pyridine 骈 U, 3-b] Μ, Μ in Example A 6 step A. (Please read the precautions on the back before filling this page). 、 1Τ Printed by the Ministry of Economic Affairs and the Central Government and the Consumers' Cooperatives. 80- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

565560 Announcement 6. The scope of patent application No. 87 1 1 2 3 54 "Tricyclic vasopressin agent ㈠" patent case (Amended in October 2012) (I) wherein W is 0 or NH; A and B are each a carbon atom; R1 is selected from the following groups: 565560 6. The scope of patent application: R2 is hydrogen, CV4 straight chain alkyl, C3.7 branched chain alkyl, or CF3; R3 and R5 are each hydrogen, straight chain alkyl, or C3.7 branched chain alkyl; R4 is Hydrogen, or straight-chain alkyl; X is hydrogen or alkyl; Y is hydrogen, halogen, (^ .4 alkyl or CF3; Z is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof. Compounds, Where R1 is selected from the group R2 is hydrogen, Ch linear alkyl, C3_7 branched alkyl, or CF3; R3 and R5 are each hydrogen, (^ .4 linear alkyl, or C3.7 branched alkyl; R4 is X 'or Cb4 straight bond; X is hydrogen or Ci-4 alkyl; Y is hydrogen, halogen, q.4 alkyl, or CF3; z is hydrogen or Ch4 alkyl; or a pharmaceutically acceptable salt thereof. 3 · The compound as described in the first item of the scope of patent application, which is [2-chloro-4- (3-methyl-pyrazol-1 · yl) phenyl]-(5,1 1 -dihydro-pyridine hydrazone [2 , 3 work] [1,5] Benzamidine diheptin-6-yl) -methanone 4. As the compound in the scope of application for the first item, it is [2-bromo · 4- (3-methyl- Pyrazolyl) yl) phenyl] diazine = phenylhydrazone [a, d] cycloheptene-10-yl) -methanone. 5. The compound according to item 1 of the scope of patent application, which is [4-(3-methyl-pyrazol-1-yl) -2 -trifluoromethyl-phenyl]-(11Η · 5-噚 -6 · As the compound in the first item of the patent application scope, which is [2-fluoro-4-(3-methyl-pyrazol-1-yl) -phenyl] _ (1 丨 ^ 5- 噚 -4,10- Diaz-diphenylhydrazone [a, d] cycloheptene · 10-yl) -methanone. 7. The compound according to item 1 of the scope of patent application, which is [2-chloro-4-(1-methyl -111-pyrazol-3-yl) -phenyl]-(1111-5-fluorene-4,10-diazepine-diphenylfluorene [, _ d] cycloheptene-10-yl) -methanone. 8. —A pharmaceutical composition for treating mammalian diseases that can be cured or relieved by vasopressin, which contains the compound as the active ingredient in the first patent application scope or a pharmaceutically acceptable salt thereof, 565560 6. The scope of patent application And a suitable pharmaceutical carrier. 9. The pharmaceutical composition according to item 8 of the patent application, wherein the condition cured or relieved by vasopressin is selected from the group consisting of diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and Abnormal coagulation, or temporarily urinating. -4-