TW533202B - Integrin receptor antagonists - Google Patents

Abstract

Compounds of the formula (IV): wherein A1 is C or N; X1-X2 is CHR1-CH, CR1=CH or NR1-CH; X3 is CR5R5', NR5, S(O)u or O; R2 is -OR', -NR'R"", -NR'SO2R""', -NR'OR', -OCR'2C(O)OR', -OCR'2OC(O)-R', -OCR'2C(O)NR'2 or CF3; R3 is H, halo, -OR12, -SR12, -CN, -NR'R12, -NO2, -CF3, CF3S(O)r-, -CO2R', -CONR'2, R14-C0-6alkyl-, R14-C1-6oxoalkyl-, R14-C2-6alkenyl-, R14-C2-6alkynyl-, R14-C0-6alkyloxy-, R14-C0-6alkylamino- or R14-C0-6alkyl-S(O)r-; R6 is W-(CR'2)q-Z-(CR'R10)r-U-(CR'2)s-V- or W'-(CR'2)q-U-(CR'2)s-U and V are absent or CO, CR'2, C(=CR152), S(O)n, O, NR15, CR15'OR15, CR'(OR"")CR'2, CR'2CR'(OR""), C(O)CR'2, CR152C(O), CONR15, NR15CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR15, NR15C(S), SO2NR15, NR15SO2, N=N, NR15NR15, NR15CR152, CR152O, OCR152, C=C, CR15=CR15, Het, or Ar, provided that U and V are not simultaneously absent; and W and W' are a nitrogen-containing substituent, ane integrin receptor antagonists.

Description

533202 A7 B7 V. Description of the invention (i) The title of the integrin receptor antagonist printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 'Invention category' The present invention relates to integrins, such as the receptor for vitronectin and fibrin Proto-receptor 'bound pharmaceutically active compound. These compounds are useful for inhibiting platelet aggregation and osteoclast attachment to bone. BACKGROUND OF THE INVENTION Integrins are a family of heterodimer proteins, which generally reside in regulating cell attachment. Representative of these proteins are the receptor for vitronectin (which is an ανρ3 heterodimer) and the receptor for fibrinogen (which is an απΐ) β3 heteromer; a polymer). The ligands of these receptors (such as vitronectin and fibrinogen) have been found to share the -Arg_Gly_Asp · common amino acid sequence, which is considered to be decisive in terms of binding. In fact, many integrin receptors appear to cross-react with ligands with such amino acid sequences. For example, the anbP3 receptor reacts with fibronectin and vitror ctin, thrombospondin and von willebrand factor, and fibrinogen. Functionally, the fibrinogen has a dimer with two binding sites for anbP3) that can react with activated receptors on the surface of platelets. Cross-linking caused by the binding of albP3 on adjacent platelets with prohelin is considered to be the main factor for platelet aggregation. Compounds that bind the anbP3 receptor to fibrinogen-inhibited compounds have been shown to inhibit platelet aggregation in vitro and in vivo

This paper size applies to Chinese National Standard (CNS) A4 specification (21〇'〆297mm) --------- ^ Package-- (Please read the precautions on the back before filling this page) Order 533202 A7 B7 V. Description of Invention (2) The formation of printed blood clots by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. See, for example, EP_A0 341 915. Vitronectin is found in various cell types, such as vascularized osteoclasts and endothelial cells. Recent studies have pointed out that the attachment of osteoclasts to the bone matrix is regulated by attachment receptors on the surface of these cells. For example, Davies, et al. Disclosed in the Journal of Cell Biology (J.CW/You>/·) '1989, Chuan 9, 1817, osteoclasts involved in regulating bone resorption Functional antigens are biochemically related to the receptors of vitronectin. It is known that vitronectin f is bound to bone matrix proteins including the tripeptide Arg-Gly-Asp (or RGD) motif, such as osteopontin, sialoprotein and platelet allele. Therefore, Horton, et al. (Ce /// fes ·), 19, ^, 368 in experimental cell research revealed that RGD peptide and antibody to vitronectin receptor 03C6) , Inhibits the absorption of ivory and cell dispersion caused by osteoclasts. Bertolini et al. Have confirmed the ring-S, S_Na-ethenyl- Cysteine, spermine, glycinyl, glycinyl, asparagine, and penicillamine inhibit osteoclast attachment to bone. In addition, Sato, et al., Published in the Journal of Cell Biology (/ Ce // from), 1990 '// i, 1713, revealed that the guanosine hemostatic cyclopeptide, a snake venom containing RGD sequence, Peptide, a potent inhibitor of bone resorption in tissue culture 'and inhibits osteoclast attachment to bone. Fisher, et al., In Endocrinology (5, 1993, / 32, 1411) have further shown that Suppressive Cyclopeptide inhibits bone resorption in vivo in rats. EP 528 587 and 528 586 reports, inhibiting

I ------- 0 ^-(Please read the notes on the back before filling in this page) The size of the paper is applicable to China National Standard (CNS) A4 (210X297 mm) 533202 A7 B7 V. Invention Description (Substituted by the Central Bureau of Standards for Consumers to replace substituted phenyl derivatives dominated by bone resorption by cooperatives. Bondinell, et al. In WO 93/00095 (PCT / US92 / 05463) It is disclosed in WO 94/14776 (PCT / US93A2436) that specific 6-7 bicyclic systems that are truly substituted are receptors for inhibiting fibrinogen (aUbP3). Others inhibit fibrinogen Receptor compounds of the 6.7 bicyclic system are disclosed by BUckbum et al. In WO93 / 08174 (PCT / US92 / 08788). Blackburn et al. Also in WO 95/04057 ( PCT / US94 / 07989) discloses that it has a fused compound that is fused to these 6-7 bicyclic rings through 5 or 6 member rings to form a three-disc system, and is used as an antagonist to inhibit fibrinogen. Other 6-6 bicyclic compounds that selectively inhibit vitronectin receptors are described in WO 96/00730 (PCT / US95 / 083 06) and WO 96 / 0〇574 (PCT / US95 / G8146). It has been found that a specific novel tricyclic system is a useful template when preparing an integrin receptor antagonist. It is also based on the discovery Such a ring system can be used as a template, which can be used to prepare compounds that are selective for the receptors of fibrinogen or fibrinogen after being appropriately substituted. SUMMARY OF THE INVENTION The object of the present invention is to To provide a compound of formula ① as described below, which has pharmacological activity in the inhibition of integrin receptors. The object of the present invention is also to provide a template which, after being appropriately substituted, is specific to a specific integrin receptor, Receptors and other integrins that are related to the receptors of hemoglobin (ailbp3) or the receptors of vitronectin (ανβ3) are subject to the Chinese National Standard (CNS) A4 specification (210X297 mm) on this paper standard [ Please read the notes on the back first to fill in the original text.), Νφ. 533202 A7 B7 Five 'Invention Note (5) X3 is printed as CR5R5', nr5, s (0) u Or 0; R ' Η, Ck alkynyl, C3-7 cyclofluorenyl-C〇-4 alkynyl or cardio; Cq_4 fluorenyl, R " is R ', -C (0) R' or -C (0) 0R5; · " C6 alkyl, C3-7 cycloalkyl-Qm alkyl, or Ai ^ Qm alkyl; R1 is fluorene, C-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl, or At-C0 -4 alkyl group; R2 is 视, 服 ,,,,,,,,,,,,,,,,,,,,,,,,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-, -C0CR, 2R2 ,; R2 'is -OR ,, -CN, -S (0) rRf, _S (0) 2 NR, 2, -C (〇) R, C (0) NR, 2 or -CO2R, R5 and R5 are fluorene, C6-6 alkyl, C3-7 cycloalkyl_C0-4 alkyl or At-C0_4 alkyl; < cr'2vu- (cr, 2) s-; R3, R4 and R7 are independently fluorene, halo, -OR12, -SRl2, -CN, -NR, R12, -N〇2, -CF3, CF3S (0) r, -CO2R ,, -CONR丨 2, Rl4-C0-6 alkyl-, R14_Ck carbonylalkyl (〇x〇alkyl), R14_C2-6 alkenyl ", R14_C2-6 alkynyl, R14-C〇-6 alkoxy-, RHQx Qi Ji or Rl4-C0- < 5 alkyl-S (0) r; R8 is R ,, C (0) R ,, CN, No2, SO2R, or C (0) 0R5; R9 is R ,, -CF3, -SR, or -OR ,; 7

(Please read the notes on the back before filling this page)

、 TT This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 533202 A7 B7

t is 0, 1 or 2; V is 0, I or 2; v is 0 or 1; and w is 0 or 1; or a pharmaceutically acceptable salt thereof. The present invention also includes pharmaceutically acceptable addition salts, complexes, compounds or prodrugs of the compounds of the present invention. A prodrug is considered to be any covalently bound carrier that releases an active parent drug according to formula (J) in a living body. Xu Feijing pointed out that the present invention, in the case where the compound of the present invention may have r or more centers of symmetry, includes each unique non-racemic compound, which can be synthesized and resolved by the known techniques. Under the suspicion that the compound has a residue and a double carbon bond, both cis (z) (cis (z)) and trans (E) (trans (E)) isomers are within the scope of the present invention. In which the compounds are in the form of tautomers, such as keto-enol tautomers, such as X and OR ·, and the mutual mX RR.N NR, X-NR · Λ ---- ---- ------ Crack-- (Please read the notes on the back before filling in this page} The Ministry of Economic Affairs t Central Quarantine Bureau, Consumers, Cooperatives Printed Mutant Isomers, such as RRN Eight NR · * and FTRWX ·, Existing In the circumstances, each tautomeric form is expected to be included in the scope of the present invention whether it is in an equilibrium state or locked in a certain form with an appropriate substitution of R ', unless otherwise stated The lack of meaning of any substitution in the circumstances of any occurrence is not relevant to the meaning of the substitution of the basic body, or the meaning of other substitutions of the basic body in any other situation ^ € This paper standard applies Chinese national standards ( CNS) A4 specification (210X 297 mm) 533202 A7 B7 V. Description of the invention (9 More specifically, the compound has the general formula (II) or (III) R4 A2, A3 n XR4 (II) (III) where Al and R1-R12 are as described in formula (I), AyA5 is selected from CH, CR3, CR4 and selected CR3, CR4, 〇y N and S, as long as the obtained E ring is stable and can be easily obtained by a routine preparation method. In a specific embodiment, the invention is a carbon according to formula (IV) Ring compound:

COR2 (IV) (Please read the precautions on the back before filling out this page) Printed by the Central Standards Bureau Member X of the Ministry of Economic Affairs, printed by the Consumer Agency. In particular, this donor can have formulas (V-1) to (Vr9):

11 This paper uses China National Standards (CNS> A4 size (210X297mm) 533202 A7 B7 V. Description of invention () 10 R5

R5

and

(Please read the notes on the back before filling this page.) In other specific examples, the compound of Benfenmin includes a 6.7 carbocyclic ring system connected by a heteroaromatic ring, such as formula (vi) or ( VII) Compounds:

Printed by the Consumers' House of the Central Standards Bureau of the Ministry of Economic Affairs

R6-

In further specific embodiments, the invention includes a benzoazabenzene compound of formula (VIII) or (IX):

VN χ1 〇COR2 (IX) 19 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 A7 B7 5. Description of the invention (suitable, local, A! Is C., preferably, χΐχ2 is cHRl-QH $ NE: 1-CH. Suitably, X3 is CR5CR5 '. Preferably, X3 is CH2. Suitably, Rl is Η. Suitably, length 2 is (like. Suitably, R3 and R4 For convenience, u is C0NR15, nr15C0, CH2ch2, or CH20, where R15 is a C (M ^ group, if necessary, via 2, CN, CG2R'RHc-6 alkyl or R14-C0-6 alkyl Substituted by an amine group. Generally, when U is Ar, it is a benzene ring, which is relatively substituted by ι, 3. Suitably R15 is R,-more suitably, a 15 alkyl group, Most preferably is fluorene or methyl. Conveniently, when the compound of formula (I) requires selective reactivity for fibrinogen receptors, it is W- (CR, 2) qZ- (CR, R1 〇) rU- (CR'2) s_V-, and R6 is preferably replaced as follows: ___... 一. · -— 一 '· .— ·· ———— One ... One--One acquisition, magnetic- -------- Install-(Please read the precautions on the back before filling in this page) Employees of the Central Bureau of Standards of the Ministry of Economic Affairs; if the cooperative prints that fibrin 4 antagonist activity is required, suitable substituents for R6 are: ___________ _____ ____________________________ ----------- " ―--- .......-. +. (CH2) 2-3 * U ^^ (CH ^ U (CH2) 2-U R'NL J Re-N ^ J N.

'v- 13 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533202 A7 B7 V. Description of the invention (l2)

Re-HN r〇 ^ U NR ·

FT-HN ar · R, xru cr, R-HNC (= _ NH- (CH2) 3 (CHR10) -U, and R " HN- (CH2) 5-U, where G is N or CH (RlO is hydrogen , Amine, mono or oxo; amine, hydroxy or Cm alkyl, and U is NR ^ CO, CONR ,, (CH: 2) CO, CIt = CH, OC, CH2, 0CH2 and ( CH2) 2-Particularly good substituents for promoting antagonistic activity of selective fibrinogen are:

R-HN

(j ^ yC0NR · ^ ynr, co ΜΗ NH NR.CO · (Please read the notes on the back before filling this page)-Binding

, (CH2) 2NROO R-N, J R-N

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

R • Cr (ch2) 3nr.co

I'M

Μ

f (CH2) 2C = C

R " f. J N

(CH2) 2NR4CO o, C〇 14 This paper size applies the Chinese National Standard (CNS) A4 specification (21 × M7 mm) 13533202 A7 Dissimilar, Invention Description

(ch2) 2nftco (CHA · γ (〇Η2) 3. FTN, J FTfll, ·

NR. ^ R-HN human N ^ R, R10, where R 'is H or Ck alkyl. Preferably R 'is methyl and r " is h. These particularly preferred groups for R6 are:

H-N

(CH2) 2N (CH3) CO (please read the precautions on the back before filling this page) Binding · When the formula (1) dipper compound needs to be selective for the receptor of vitronectin In the case of Heli, R6 is WHCRe2) 4-U-, and R6 is preferably replaced as follows :; · The preferred substituents are:

15 This paper size applies to the Chinese National Standard (CNS) A4 specification (2 丨 mm) 533202 A7 B7 V. Description of the invention (14)

Where Q is NH. Preferably, and RC is joined to form a cyclohexyl, benzyl or pyridyl ring-suitably, the sand is Ck alkyl ^ Ci_6 alkoxyfluorene or WNH 〇 suitably,-(CR »qU- is (CH2) q-NR'CO, (CHjq-CH2〇 ^ (CH2) q-CH2CH2 〇 [The particularly preferred R6 substituent for enhancing vitronectin activity is (please read the precautions on the back before filling this page)) ·

, 〇

Ra jf N, (ch2) 3-o n " ^ V ^ nr * co

Ra Orders ^ -ch2nroo

Rc <

• N

R.HN, JM, a 八 NHCO y-CHRNRCO

Employees of the Central Bureau of Standards of the Ministry of Economic Affairs. ¾% printed by cooperatives CX / · ch2nroo ·

When CHR'NROO and 〇Cf are on the 6-7 cyclic benzyl ring, through proper selection of the intervals of the substituents w and / or W ', one of the following can be obtained for vitronectin and fibrinogen: The receptor has selective activity, or has double lacquer for both winter receptors. 16 Coat > · This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 A7 B7 V. Description of invention (15) The Central Standards Bureau staff of the Ministry of Economic Affairs consumes printed compounds in cooperatives. Generally, the antagonist activity of fibrinogen is preferred to the intramolecular distance between the oxygen attached to the seven-membered ring carbonyl moiety and the basic nitrogen moiety of w or w 'is about 16 angstroms; however, The antagonist activity of the protein is preferably about 14 angstroms between the respective acidic and basic centers. The specific compounds lacking in this invention are: (±) -10,11_dihydro-3-[[[((1Qinbenzimidazole "2-fluorene > Shenyl] Residyl] carbonyl]-/ 5H-dibenzo [a, d] cycloheptene-10, acetic acid; (±) -1, 0,11-dihydro each [〖[(4 · Ga-5-methyl-1H-benzene, imidazole · 2-yl) methyl [Methyl] methylamino] carbonyl] · 5Η-dibenzo [a, d] cycloheptene-10-ethylfluorene; (±) -10,11-digas-3 · [[((1Η-benzimidazole Alkyl) methyl] methylamino] carbonyl] -5'-dibenzyl [a, d] cycloheptene'10 · acetic acid; and (Earth) -10,11-dihydrogen each [1-4,4 ' -Dihexahydropyridyl) carbonyl] -511_dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-dihydro-3 · [3- (2-benzimidazolyl) ) -1-propyl] -5H-dibenzo [a, d] cycloheptan-10-acetic acid; (±) -10,11-dihydro each [[[2- (2-4pyridinylamino) Ethyl] amino] carbonyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (Earth) -10,11 · difluoren-3- [3- (2-4pyridinylamino) ) -1-propoxy] -5Η-dibenzo [a, d] cycloheptene-10 "acetic acid; and 2-[[ΐ (1Η_benzimidazol-2-yl) methyl] methylamine ] Carbonyl] -6,11-dihydro-5H-dibenzo [b, e] azepine-6-acetic acid. Abbreviations and symbols commonly used in peptides and chemical techniques are used herein to describe the compounds of the present invention. Ci-4 alkyl, as it should be meant here, contains, methyl, ethyl, n-propyl

This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling out this page)-Packing · Ordering 533202 A7 B7 V. Description of the invention (17) Zhongfu sample of the Ministry of Economic Affairs Substitutes such as R7 printed by quasi-laboratory consumer cooperatives can be attached to any carbon atom that results in a stable structure, and can be achieved by techniques of conventional synthesis. 14- < ^ _ 6 alkyl means <: 1-6 alkyl, in which any carbon-hydrogen position is replaced by a carbon-Rl4 bond. As far as C2 * 6 alkenyl ash C2-6 alkynyl is concerned, Rl4-C2-6 alkenyl and R14-C2-6 alkynyl have similar meanings. Ar, which is aromatic, if applied herein, means benzyl, or naphthyl, or one to three phenyl or naphthyl substituted by R7. In particular, R7 may be Ci-4alkyl, Ci-4alkyl, alkthio, trifluoro group 'QH'F, Cl, Br or I. Het, which is a heterocyclic ring, if used herein, means a substituted five or six negative monocyclic ring, or a nine or ten membered bicyclic ring, if required, containing one to three stable and can be obtained by general chemical synthesis Heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle used for illustration is stupid and sore, benzo-flavor sigma-benzo-benzoyl, benzothiophene, squean, imidazole, indole, difluoroindole, hexahydroeridine, hexahydro This spray, this brief, this Luo bite, tetrahydro this bite, this bite, sit, fennel, quinoline 'isoquinoline', and tetra- and perhydro-aqualine and isoquinine. For the part of Z, the six-membered heterocyclic ring contains one or two nitrogens, such as hexahydropyridine, hexahydro grasshopper, tetrahydropyridine and pyridine. It is possible to obtain up to three substituents on this I ^ t ring by chemical synthesis and which are stable. For example, a combination selected from R7 is within the scope of the present invention. C3-7 ring entertainment * means a ring system with three to seven carbon atoms optionally substituted, which may contain up to two unsaturated carbon wide carbon double bonds. Representative C3-7 cycloalkanes are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Can be obtained by chemical synthesis and is

(Please read the notes on the back before filling this page)

18533202 A7 B7 V. Description of the invention (Any iron iron that violates three substituents on this ring, for example, a combination selected from Han 7 is within the scope of the present invention. ® If used here, Represents a nitrogen heterocyclic ring, which may be saturated, or unsaturated, stable five-, six-, or seven-membered monocyclic rings, or seven- to ten-membered bicyclic rings, which may contain up to five nitrogen atoms or one A nitrogen atom and a heteroatom selected from oxygen and sulfur, and it can be substituted on any atom leading to a stable structure. The nitrogen in the ring can be substituted to lead to the result of a fourth-order nitrogen. Nitrogen heterocycle Any stable position can be substituted by R20, such as η, Cl.4 alkoxy, F, Cl, &, I, No2 ,, OH, Co2R ', CONHR ·, CF3, Rl4-d4 Alkyl-S (0) u (for example, where u is 0, 1 or 2) or (^ _4 alkyl can be replaced by any of the foregoing Θ (please read the precautions on the back before filling out this page). · Order _ Representative X of the Central Bureau of Standards of the Ministry of Economic Affairs, printed by X Xiao Zuosha replaced the β representative < this is slightly I #, this bite, imidazole taste seat, taste bite cough, ton seat, Bi, n Guilin, this sitting lake, hexa nitrogen bite, hexahydro this talk, Morin, 〇tb bite, this bite cation (pyridinimn〗, tetrahydro this mouth, tetrahydro · and hexahydro_ like miscellaneous, 嗝Pyridine, quinuclidinium, yin # '异 therapy &#;, and tetra- and perhydro- ° quelin and iso ° quine 4. In particular,' @ may be pyridyl, pyrrolidinyl, hexahydro This pyridyl, hexaoxoyl, trimethylenepentamine, methyridinyl or tetrahydropyridyl 9 Θ is preferably 4-this pyridyl, 4- (2-aminopyridyl), 4-tetra Hydropyrimidinyl, 'hexahydro this bite or 4-hexahydro this group.

20 This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533202 A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy When Rc is attached to a five- or six-membered aromatic or non-aromatic ring, the formed ring is usually selected from the five- or six-membered heterocycles listed above for Het, or Phenyl, cyclohexyl or cyclopentyl ring. The preferred parts and components suitable for W ′ are benzozolyl, 4-nitrobenzoxazolyl, 5-nitrobenzimidazolyl, and substituted derivatives thereof. Specific groups are abbreviated herein. t-Bii means tertiary butyl, Boc means tertiary-butoxycarbonyl, Fmoc means fluorenylmethoxycarbonyl, Ph means phenyl 'Cb? means benzyloxycarbonyl, and BrZ means o-mobenzyl Oxocarbonyl, C1Z means o-benzyloxycarbonyl, Bn means o-benzyl, 4-MBzl means 4-methylfluorenyl, ke means methyl, Et means ethyl, Ac means ethenyl, Aik means Means Ci_4 alkyl, Nph means 1- or 2-naphthyl and cHex means cyclohexyl. MeArg is Nα-metaarginine. Tet means 5.4 tetramethyl. Specific reagents are abbreviated herein. DCC means dicyclohexamethylenediimide, DMAP means dimethylamine pyrimidine, DIEA means diisopropylethylamine, EDC means N-ethyl (dimethylaminepropyl) carbonyldiimide, HOBt Means 1-Hydroxybenzotriazole, THF means tetrahydrofuran, DMF means dimethylformamide, NBS means N-bromo-perhydroimine, Pd / C means palladium on carbon For catalysts, DPPA means diphenylphosphinoyl azide, BOP means benzotriazine " small oxo-ginseng (dimethylamine) hexafluorophosphate, W means hydrofluoric acid 'PPA means Refers to polyphosphoric acid, TEA to tri-6 amine, TFA to trifluoroacetic acid, and PCC to pyridinium aerochromate. 9 An intermediate that is particularly useful when preparing compounds of formula (I) is a compound of formula (X): 21 -This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇297mm) ------, 玎 ----- 'Please read the precautions on the back before filling this page) 20533202 A7 B7 V. Description of Invention (

The central standard of the Ministry of Economic Affairs f employee printing f cooperatives where X, X2, X3, R2, R3, r4, Ai & e are as described in formula (I), and L1 is a meta for the ring junction and is CHO, C 〇2R ,, βγ, I, OH, CF3SO3, CH2-T or NR, R15, and τ are OH, NHR15, Cl, Br or I. Compared with her, L1 is OH, CF3SO3, C02R 'or NR, R ", and R1 is H,' Ci_4 alkyl, alkoxy, R2 is C1-6 alkyl, or benzyl, R4 is fluorene or alkyl And R5 / R51 is Η, Η 0 preferably, Ai and E ring 俾 together form a fused phenyl ring, XhX2 is CHRl-CH or NR1-CH, and X3 is CHR5. Generally, compounds of formula (I) are via It is prepared by coupling an intermediate of formula (X) with a compound of formula (XI): R ^ L2 (XI), where R6 'is (CR, 2) S: L2 or W,-(CR, 2) q-L2, Wherein W, W ·, R ·, Z, r10, U, 屮, r and s are as described in formula (I), and l2 is 0H, NHR15, CC, CHO »CO #, Br '^ or 01. Under certain circumstances, 1 may need to further introduce the g-energy base through appropriate reactions. 22 This paper size applies the Chinese National Standard (CNS) A4 specification (2 l0x297 male thin) (Please read the note on the back first) Please fill in this page for matters) Binding Binding 533202 A7 ___B7 V. Description of the invention () 21 or remove the protective group to modify W or W, the group is explained in another article here. Generally, coupling will result in the formation of U or V groups, and methods for this coupling reaction are well known in the art. 93/08174 (PCT / US92 / 08788; Genentech), WO 93/08174 (PCT / US92 / 08788; Genitech), WO 96/00730 (PCT / US95 / 08306; SmithKline Beecl ^ am), WO 96/00574 (PCT / US95 / 08146; SmithKline Beech named 1)), WO 93 / 00095XPCT / US92 / 0M63; Smith Kline (SmithKIine Beecham)) and WO 94/14766 (PCT / US93 / 12436; SmithKline Beecham) broadly disclose these reactions and incorporate them herein as references. A compound of formula (X), in which Al is c and a2_a4 is CH, is prepared by obsessing with the method of flow chart 1: (Please read the precautions on the back before filling this page) 1

This paper size is applicable to China National Standard (CNS) A4 specification (21 × 2 $ mm) 22533202 A7 B7 V. Description of the invention (Process Min1 (碛)

(Please read the precautions on the back before filling this page) Employees of the Central Bureau of Standards, Ministry of Economic Affairs «• Printed by Mouth Cooperatives a) Tf2 0,2, Cardiac Dimethylpyridine, CH ^ Cl2; b) Allyl Trizheng Tin Tin,

LiQ, (Ph3P) 2PdCl2, DMF; c) RuCl3, H5IO6, Ctl4, CH3CN ^ H2O: d) PPA; e) EtoAc / LiHMDS »THF; f) H2, 10% Pd / C, concentrated HC1, AcOH; g ) EtSH, AICI3, CH2CI2; h) Tf2〇, 2,6r dimethylpyridine, CH2CI2 ·, i} CO, Pd (OAc) 2, KQAc, DMSO 〇 2_benzyl 4-methoxyphenol (US In this period, the Chinese Academy of Sciences will do the following from the diaphragm: &1949; 7i, 64) in the presence of a suitable base, such as 2,6-dimethylpyridine, in an inert solvent, usually CH2a2, by With trifluoromethanesulfonate 24 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

533202 Α7 Β7 V. Description of the invention (23) The reaction of printed acid anhydride (Tf20) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs converts it into the corresponding trifluorocarboxmate, compound 2 of the flowchart i (for example, 1- 2 ). By the method described by Tilley in (Org · Chem ·) 1990, 55, 9Q6, LiCl and palladium catalysts, such as gasified bis (tribenzylphosphine) palladium In the presence of (Π) ((Ph3P) 2P4Cl2), 1-2 allyltri-n-butyltin was reacted to obtain 1.3. The olefins in 3-Scheme 1 are tritiated and cleaved to provide a carboxylic acid 1 »4, which can be used in a suitable aqueous solvent, such as aqueous acetone or aqueous acetic acid. KM4 reaction was reached. However, preferably, the dilute hydrocarbons of 1-3 are oxidatively cleaved to directly provide carboxylic acids 1-4, which can be based on the general method I guided by Sharpies I. Journal of Organic Chemistry {J, Org.Chem , \ 9% \, 46, 36, Park 36, Organic Yunsai Street f / (J · 0 sigh CAem ·) 1985, 50, 1560, footnote 4), where Ru〇4 is appropriate CCI4, CH3CN and H2〇 In a mixed solvent, RuCl3 or Ru〇2 is reacted with NaI04 or H5K> 6 to generate in situ. Alternatively, this oxidation can be performed by two operations, including the first stage of oxidatively breaking olefins into corresponding aldehydes, which is achieved by procedures familiar to those skilled in the art, and subsequently used, for example, Described in Pinnick (4 sides 1981, 37, 2091) or Dalcanale or Montanari (Journal of Opportunity Chemistry {J.〇r & Chem :) Y)% 6 , 51,56Ί) NaClO2, this aldehydes are oxidized to carboxylic acids. The cyclic effects of 1-4 to 1_5 can be based on Proctor, Renfrew, and Sava (J. Am. Chem · Soc) ( C) The method described in 1969'1000) is achieved using polyphosphoric acid. Replace (Please read the notes on the back before filling out this page)-Pack. 、 11

__25 This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 533202 ΑΊ

The printed place of the Central Industry Bureau of the Ministry of Economic Affairs, the Project Industrial Cooperative, converts 14 to i_5 through the acid corresponding to 1-4, which is prepared by a method familiar to those skilled in the art. This acidic gasified compound is treated in an inert solvent such as CH2CI2 or CS2 with a suitable Friedel-Crafts catalyst such as AICI3 or SnCl4 'to obtain a cyclic ketone 1-5. The reaction of aldehyde_5 and acetol acetate with aldol type reaction can expose acetic acid to ammonium acetate, such as diisopropylamine (LDA) or bis (trimethylsilyl) It is produced in the presence of lithium amidated lithium (UHMDS) to perform the reaction to obtain ι_6. Although THF in various additives such as HMPA or TMEDA is often used, THF is usually selected as the solvent for the methanol reaction. Reduction of κ to 1-7 is achieved by hydrogenolysis of a suitable solvent, such as acetic acid, in the presence of a mineral acid, such as HC1, on a suitable catalyst, such as a saturated metal (PWC) on activated carbon. . Alternatively, in the presence of the boron trifluoride ethyl bond, by Orph and Opoulos and Smonu in (synthetic Tongli (do not ///? · (^ 所 所(Hungry) 1988, 833) The general method in 1-6 is treated with triethylsilane to achieve this reduction. Diethyl ether of 1-7 is removed to obtain 1-8 series by storing in an inert solvent, such as ΒΓ3 in CH2C12, It is achieved by reacting with ethyl mercaptan and A1C13 in an inert solvent, preferably CH2CI2. Other useful methods that can be used to remove methyl ether are, for example, Greene and John Wiley. and Sons) as described in "Protective Groups in Organic Synthesis". The 1,8 trifluoromethanesulfonate, 1-9, was used as described above for the 1 The method of -1 to 1.2, according to Cacchi and Lupi in (tetrahedral letter (2 ^. / ^ /.) 1922, ϋ,

This paper size applies Chinese National Standard (CNS) M specifications (210 × 297 mm) (Please read the precautions on the back before filling out this page) Binding and binding 533202 A7 B7 5. General methods described in the description of the invention (25 3939) Ze, in potassium acetate, ι, ι'-bis (dibenzylphosphino) bis (cyclopentadiene) ferrous (dppQ), and in the presence of the catalyst in a suitable solvent, such as DMSO, and carbon monoxide Obtained from the above description. It is clear that if compounds 1-6 are dehydrated, instead of performing argonization, compounds of general formula (V-2) can be obtained. 4-methoxyanilino), or 2- (phenoxy), or 2, (benzyl), substituted by benzene 4 acid, where X3 is Compounds of formula ① of NR5, q or S (0) are prepared by using the general method of Scheme 1. A compound of formula (X), where X1-X2 is NR1-CH and X3 is CR5CR5 ', NR', 0 or S (0) 〇-2, is prepared by the general method described in Scheme 2: Flow chart 2

This paper size applies to China National Standard (CNS) A4 specification (2 丨 〇 < 297 mm) 533202. Α7 Β7 Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs- ^ Printed by Qiaozhuosha V. Invention Description (26) Process Min 2 (continued)

5 a) HC〇2il ·, Ac2〇, △; b) PQCI3, PPA, △; c) CH = C (OCH3) Si (CH3) 2-third-Bu, TMSCN, [Rh (C〇D) Cl ] 2, CH2CI2; d) CX), Pd (0Ac) 2, KOAc, dppf, DMSO 0 Compound 1 (for example, 2-1) of Scheme 2 is synthesized by methods familiar to the art for. Zandai (ground, Li radicals can be replaced by cleavage groups, tris: fluoromethanesulfonyl groups or groups which can be converted to bromo, iodo or trifluoromethanesulfonyl groups) ^ With suitable reagents, : For example, formic acid, formate, or formic anhydride, at a suitable temperature of 3 $ in a solvent, convert compound 2_1 to N · phosphonic acid compound 2_2. With a suitable reagent, such as polyscale The mixture of tritium and -phosphorus oxygenate is treated at a suitable temperature to convert compound 2-2 into cyclic imine 2_3. Using 名 名 必 # 会 会 会 断 (仇 /.C/^zw. Order "·) 1990, general procedures in β, 3122-3131, Wei Wei suitable reagents, such as methyl acetate tertiary butadimethicone acetal, in the presence of trimethylsilyl cyanate and suitable < catalyst, For example, di_ # qi-jian (I, 5-cyclooctane dilute), a suitable solvent for iron (pih (cod) a] 2) rF, such as digas methane, to convert compound 2-J Into ethyl, acid ester 2. · 4.

--------- ^-Pack-(Please read the precautions on the back before filling in this page) Order »Line · 28 This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) 533202 A7 B7 V. Description of the invention (27) Printed on behalf of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, using the courtesy of the Fayuan Yunxue Society (Qi // Fen c, C / i / w Price) 1973, For general procedures in 1668, Reformmask reagents can be used. Instead of it, when using the general procedures in the Journal of the American Chemical Society (J. Am. Chem. Soc.) 19, 0, 72, 3874, it can be stored in the 6 anhydride of acetic acid. Compound 2-4 is converted to carboxylic acid 2-5 according to the general method described in Scheme 1. The general procedure in J.Org. Chem. WH, 3 $, 332Ί, by using CO, primary or secondary amine, and palladium to catalyze a compound immediately after treatment, where U is NRfCO can also be obtained directly from compounds 1-9 or 2-5. Simple trisubstituted benzene starting materials are either commercially available or prepared by routine methods familiar to those skilled in the art. The method of coupling to form an amidine bond is well known to those skilled in the art. The method of peptide synthesis is usually started by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer Verlag, Berlin, 1984. Ali et al. (J Med'Chem), T9, 9 from {IMQA Journal of Medicinal Chemistry Q Med. C7i⑽ ·), 30, 2291 (19 $ 7) are general Illustrative of this technique is incorporated herein by reference. The coupling reagents used herein represent reagents that can be used to form amidine bonds. Representative coupling methods utilize carbodiimide, activated anhydrides and esters, and dentate. Representative reagents are EDC, DCC, DPPA, BQP pilot, HOBt, N-

(Please read the notes on the back before filling this page)

UF Packing_ This paper size is applicable to China National Standard (CNS) 8-4 specification (2. 00 '297 mm) 533202 A7 B7 V. Description of the invention (28) Hydrazine and grass gas. Typically, a suitable carbodiimide coupling agent, such as' dicyclohexylcarbonyldiimide (DCC), is used, if necessary, on a catalyst, such as 1 · hydroxybenzotriazine (HOBt) and two In the presence of methylaminopyridine (DMAP), an amine or aniline is coupled via its free amine group to form a suitable carboxylic acid substrate. Other methods, such as the formation of activated carboxylic esters, anhydrides or fluorenyl radicals, or free carboxyl groups of suitable protected acids, and subsequent free amines with appropriately protected amines, It is also suitable to react in the presence of a base if necessary. For example, in a non-aqueous solvent, such as digasmethane or tetrahydrofuran (THF), protected Boc-amino acid or Cbz-formamidine is present in the presence of a test such as N-methylmorphine 1 PMAP or trialkylamine. The benzyl group is treated with isobutyl formate to form "activated anhydrides" which are then reacted with a second protected amine or a free amine of aniline. A compound, such as 1 * 10, is converted to a compound of formula (I) by a coupling reaction, such as the amidine coupling pong reaction in Scheme 3. Central Ministry of Economic Affairs

Printing company printing process circle 3

30

This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 533202

&) 1790,4'-dihexahydropyridine [1〇]], £ 0 (:, 11 € ^ -112, 0, Pr) 2NEt; b) 10NWOH, THF, H2O; c) 0, lNHa, H2O; d) TFA, CH2Cl2 [R = H4, cardiohexahydropyridine)]. Employees of the Central Bureau of Standards of the Ordering Department: printed and used by cooperatives, such as EDC and HOBt, or SOCI2 will be prepared as described in flow chart 1 (H0, ll-dihydro-3-carboxy-5H-dibenzo [a, d] Cyclopeptene-10-ethyl acetate (1-10) is converted to an activated form of a carboxylic acid, and this activated form is then combined with a suitable amine, such as 1-B0 04,4'-26 Hydropyridine or 2- (methylamino) methyldibenzotriazole dihydrochloride is reacted in a suitable solvent, such as DMF 1 CH2CI2 or CH3CN to provide compound 2 of Scheme 3 (for example, 3-2) Depending on whether acid neutralization is required, the added base can be used, such as diisopropylethylamine ((i-Pr) 2NEt) or pyridine β. Many other methods for converting carboxylic acids to amidines It is known and can be explained in standard reference books, such as "Outline of Organic Synthesis Methods" 31 This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 〇X π? Mm) Line 533202 A7 B7 V. Description of the invention ( 30 “Compendium of Organic Synthetic Methods” printed by Employee Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Volume I-IV (Willie One Published by Wiley_Interscience). Hydrolyze ethyl acetate 5_2 with an aqueous base, such as LiOH in aqueous THF or NaOH in aqueous methanol, and carboxylate the intermediate with a suitable acid. For example, TFA or HC1 is acidified to provide carboxylic acids 1-3. Alternatively, if desired, the intermediate carboxylate can be isolated, or the free carboxylic acid can be prepared by methods well known to those skilled in the art Carboxylic acid salt. If the amine moiety in the amine bond reaction (M0 to 3 · 2) is formed with a protective group, use a method suitable for removing the protective effect of the specific protective group used to hydrolyze the ester. This protective group is removed before or after the steps. These methods are described in the book "Organic Synthesis" (published by Wiley-Issue International) in Green Organic Synthesis. For example, if The nitrogen oxide contained in the serving is protected by a fourth_butyryl (BOC), for example, when used in compound 3-3, such as 4 N HC1 in dioxane or tetrafluoroacetic acid in (TFA), under acidic conditions, remove this BQC group to give 3-4 ammonium If necessary, this ammonium salt can be neutralized by methods familiar to the art. Flowchart 4 is used to illustrate the coupling method of carbon-carbon bond formation. A reducing agent (for example, in step b), which allows the method to be used to introduce carbon-bonded bonds, double bonds, or single bonds. Process Flow 4

(Please read the notes on the back before filling this page)

1T 32 533202 A7 B7 V. Description of the invention (3))

This paper size applies to China National Standard (CNS) A4 (210X297 mm) 533202 A7 B7 V. Description of the invention (34) Layoff circle 5 (continued)

(Please read the precautions on the back before filling in this page)-Binding and binding ) Cyclohexene, 100 / 0Pd / c, 2-propanol; c) 10NNaOH, EtOH 'and then acidification. Reaction of Compound 1 (S4) of Scheme 5 with 2. [(3-hydroxy-1-propyl) amino] wt pyridine oxide in a Mitsimobu-type coupling reaction (Organic Reactions) 092 , 42,335_656; I belong to you 7? Bo ^ 5 but 981 '1 · 28) and provide S »2. This reaction is dominated by the complex formed between diethyl azoformate and triphenylphosphine, and is performed in an aprotic solvent such as THF, CH2CI2 or DMF. Use a palladium catalyst for the pyridine oxide part of 5-2, preferably palladium gold wire on activated carbon.

One paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533202 A7 B7 V. Description of the invention (35) belongs to the reduction of the corresponding pyridine in an inert solvent such as methanol, ethanol or 2.propanol 5-3. In this type of reaction, cyclohexene, cyclohexyl, formic acid and formate such as potassium formate or ammonium formate are usually used as hydrogen transfer reagents. Saponification of the ethyl ester of 5-3 as described in the flow chart 丨 always provides the core 4. The acid addition salt of the compound is based on a standard method in a suitable solvent. Excess acid such as hydrogen acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, dish acid, acetate trifluoroacetic acid, maleic acid 4 Succinic acid or formic acid is prepared. Certain compounds form acceptable internal salts or two: salts. Cationic salts are prepared by treating the parent compound with an excess of analytical reagents, such as hydroxides, carbonates or alkoxides containing appropriate cations; or by treating with appropriate organic amines. Cations such as Li +, Na +, K: +, Ca ++, and NH4 + are specific examples present in pharmaceutically acceptable salts. The Central Standards Bureau of the Ministry of Economic Affairs makes a social seal for the labor and consumption orders? The invention also provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. Therefore, the compound of formula (I) can be used for the manufacture of pharmaceuticals. The pharmaceutical composition of the compound of formula (I) prepared as described herein can be formulated as a solution or lyophilized powder for non-vigilant administration. The powder can be reconstituted before use by adding suitable diluents or other pharmaceutically acceptable carriers. The liquid blend may be a buffered, isotonic aqueous solution. Examples of suitable diluents are normal isotonic saline, standard 5% dextrose in water or buffered sodium acetate or ammonium solution. Such blends are particularly suitable for parenteral administration, but can also be used for oral administration or included in a metered-dose inhaler or nebulizer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, gum arabic, polyethylene glycol, mannitol, sodium gasification, or sodium citrate.

37 This paper is compliant with the Chinese National Standard (CNS) M specification (210X297 mm) 533202 A7 ______B7 V. Description of the invention (36) Offset consumption by the Central Standards Bureau of the Ministry of Economic Affairs > Such compounds can be enclosed in capsules, made into lozenges or prepared in emulsions or syrups for oral administration. Pharmaceutically acceptable solid or liquid carriers can be incorporated to enhance or stabilize the composition, or to assist in the preparation of the composition. Solid carriers include starch'lactose ^ calcium sulfate dihydrate, bleaching earth, magnesium or stearic acid, vermiculite, pectin, slabrubber, clay or gelatin. Liquid carriers include syrup, peanut oil, olive oil, sonic water and water. The carrier may also include a sustained release substance such as glyceryl monostearate or glyceryl monostearate (alone or in combination with moth) ^ However, the amount of solid carrier is preferably between about 20 mg to about 1 Grams vary between dosage units. Pharmaceutical preparations are prepared according to conventional pharmaceutical technology and include grinding, mixing, granulating and compression (if needed) in the form of tablets; or grinding, mixing and filling in the form of hard gelatin capsules. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such liquid blends can be administered directly orally or filled into soft gelatin capsules. For direct administration, the compounds of the present invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol, and used as a suppository in a mold. The compounds described herein as vitronectin receptors can be used for the treatment of diseases in which the major diseases and systems are caused by the interaction of ligands or cells with the vitronectin receptor. For example, these compounds are useful in treating diseases in which pathology is caused by bone loss. Therefore, urgently needed compounds can be used for the treatment of osteoporosis, hyperparathyroidism, Berger's disease, malignant hypercalcemia, osteolytic damage due to bone metastasis, or lack of brake or sex hormone Bone loss. The compounds of the invention are also believed to be

Applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page)-Packing. Thread 533202 A7 B7 V. Description of the invention (37) Off-line consumption by the Central Standards Bureau of the Ministry of Economic Affairs The cooperative seal is used as an antitumor, anti-inflammatory, anti-angiogenesis and anti-metastatic agent, and can be used to treat cancer, atherosclerosis and restenosis. In particular, the compounds of the present invention are useful for inhibiting restenosis after angioplasty. The present invention also inhibits the binding of fibrinogen, and provides a method for inhibiting platelet aggregation and blood clot formation in mammals (especially humans), which comprises internally administering a compound of formula ① and a pharmaceutically acceptable Carrier. Indications for such treatments include acute myocardial infarction, deep venous thromboembolism, pulmonary embolism, segmental aneurysm, transient episode (TIA), stroke, and other conditions associated with donkey, and unstable colic β Chronic or acute conditions of excessive collectability, such as disseminated intravascular coagulation (DIC), septicemia, surgical or infectious bursts, trauma after surgery and childbirth, cardiopulmonary bypass surgery, intolerant umbrella transfer, placenta Exfoliation prematurely, thromboblastic primary thrombocytopenia (TTP), snake venom and immune diseases seem to be suitable for such treatments * 1 In addition, the compounds of the present invention can also be used to prevent metastatic conditions and prevent or treat fungal or bacterial infections To induce immune stimulating effects, to treat sickle cell disease, and to prevent or treat diseases in which bone resorption is a causative factor. The present invention further provides a compound of formula (I) and a fibrinolytic agent for inhibiting the reocclusion of arteries or veins after fibrinolytic therapy. Administration of a compound of formula (I) in fibrinolytic therapy can completely prevent relapse or prolong the duration of reocclusion. As used herein, the term fibrinolytic agent means any compound (natural or synthetic product) that directly or indirectly causes fibrin clot dissolution. Cytolysin activators are one of the known groups of fibrinolytic agents. Useful cytosolic original activity (please read the precautions on the back before filling this page).

39 scales Shizhou Chinese National Standard (CNS) A4 specification (210 × 297 mm) 533202 A7 ----- ----- B7 V. Description of the invention (38) Chemical agents include, for example, anistreplase, urokinase ( UK), pro-bed kinase (pUK), streptokinase (SK), histoplasminogen activator (tPA), and mutants or variants thereof. The compounds of the present invention can also be used to inhibit platelet aggregation in blood and blood products in vitro, for example for storage, or for use in living procedures such as for diagnostic or research winter applications. Zuosha printed compounds are administered to patients by oral or parenteral means sufficient to inhibit bone resorption 'or to inhibit platelet aggregation or other such indicated pharmaceutical concentrations. The pharmaceutical composition containing the compound is an oral dose of α ranging from about 0j to about 50 mg / kg, and is administered in a manner consistent with the condition of the patient. Preferably, the oral dosage is about 5 to about 20 mg / kg. For acute therapy ', parenteral administration is preferred. Intravenous injection of this compound in 5% dextrose in water or normal saline, or similar formulations with suitable excipients is most effective, but intramuscular bolus injections can also be used. Typically, the parenteral dose is from about 0.01 to about 100 mg / kg; preferably between 0.1 to 20 mg / kg. The compound is administered from # to four times daily to achieve a total dose of about 0.4 to about 400 mg / kg / day per dose. The exact concentration and method of compound administration are determined by those skilled in the art by comparing the concentration of the drug in the blood with the concentration required to achieve therapeutic efficacy. Compounds can be tested in one or more bioassays to determine the concentration required to administer pharmaceutical efficacy. Inhibition of vitronectin binding This paper is sized to the Chinese National Standard (CNS) Α4 (210 × 297 mm)

533202 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (39 Solid phase [3HJ-SK & F10726〇 Combined with aVJ33 · · Existing liquid Ί (containing imMCaQ2 and 1% octyl sugar bud) Human placenta or human platelet αγβ3 (〇 · 1_〇 · 3 mg / ml), so that there is 1 mMCaCl2, 1 mM MnCl2, 1 mM MgCl2 (Flush A) and 0. 05% · NaN3 T dilution, and then Immediately add 0.1 ml per well to a 96-well ELISA plate (Coming, New York, NY). Add 0 · 1-0 · 2 · μg ανβ3 to each well. Place the plate at 4 ° Incubate overnight at C. During the experiment, each tank was washed once with Washing A and incubated with 0_1 ml of bovine serum albumin in the same buffer at 3: 5% for 1 hour at room temperature. After incubation, The gas in each tank was completely evacuated and washed twice with 2 ml of Washing Solution A. The compound was dissolved in 100% DMSO to obtain a 2 mM storage solution, which was combined with a binding buffer (15010 ^ 1 ^ -lean (: 1 ( ? 117.4), 10〇111] ^ 1 KaCl, 1 mM Ca〇2, 1 mM MnCl ", 1 mM MgCl2) diluted to a final concentration of 100 μM. Then this solution was diluted to all The required final compound concentration. Uncalibrated antagonists of various concentrations (〇_〇〇〇Ι-ΙΟΟμΜ) were added to each well in three replicates, and then {3Η] -SK & F-107260 ( 65-86 Curie / millimolar). Incubate the plate at room temperature for 1 hour. After incubation, the gas in each tank is completely extracted, and washed twice with 0.2 ml of frozen rinsing solution A in a tank-to-tank manner. 6. The receptor was decomposed with 01 ml of 1% SDS, and the bound [3HJ-] was measured in a Beckman LS liquid scintillation counter (with 40% efficiency) by a liquid scintillation counting method with 3 ml of Ready Safe. SK & F-107260. The non-specific binding of [3H] -SK & F-107260 was determined in the presence of 2 μM SK & F-107260 'and was consistently less than the total radioactive coordination. 41 This paper applies to China National Standard (CNS) Α4 Specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

.JL equipment, line 533202 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____B7 V. Description of the invention (40) 1% of the child input. IC50 (concentration that the antagonist inhibits 50% [3H] -SK & F-107260 binding) is determined by a non-linear, least squares fitting procedure (which is modified from the LUNDON-2 program). Ki (including the dissociation constant of the antagonist) is calculated according to the equation: Ki = IC50 / (l + L / ^ d), where L and Kd are the concentration and dissociation constant of [3H] -SK & F-1070, respectively. The compound of the present invention inhibits the binding of vitronectin to SK & F-107260 at a concentration of fe 匍 from 0.1 to 25 micromoles. A preferred compound inhibits vitronectin binding at a concentration of less than 1 micromolar. The compounds of the present invention are also used in the art to evaluate the standard analytical method for inhibiting bone formation. For example, as disclosed in EP 528 587, the nest formation assay is used to test bone resorption in vitro and in vivo. Human osteoclasts can also be used. Replaces the osteoclasts of rats described by Wronski et al., Xu Mindian #Stored (Ce / Zs⑽d Maier M / y 1991, Sup. 1, 69-74, and the rat model of ovarian resection. Parathyroidectomy rats Chess Each experimental group consists of 5-6 male Spraue-Dawley rats. The rats were subjected to parathyroidectomy 7 days before use (From the seller, TacpnicFarms). Twenty-four hours before use, the blood was measured for circulating ionized calcium concentration in the whole blood immediately after the blood was drawn into the heparin-treated tube by tail vein puncture. Select the ionized calcium The concentration (measured with a Ciba-Coming model 634 oblique pH analyzer) was' 1.2 mM / L. Then a calcium-free chewing diet and deionized water for the rats were provided. At the beginning of the experiment, the rat weight Approx. 100 g. Measure the baseline of calcium concentration, and make money. ≫ _ 42 /----, ·, This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 meal) (Please read the precautions on the back before filling this page)-Binding · Order 533202 A7 --- ------- ---------- B7 V. Description of the invention (41) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, rats were injected with a single intravenous (tail vein) bolus, The control group (saline solution) or compound (dissolved in saline solution) was administered to the control group, and then a single subcutaneous injection of human parathyroid hormone 1-34 peptide < hPTH 1-34 was performed at a dose of 0.2 mg / kg. Stored in saline / bovine serum white peony, Bach, Ca) or I > TH vector. The approximate blood response to ρχΗ (and any effect of the compound on this response) was measured 2 hours after the compound / PXH administration. Rat ulna drift chess game Each experimental group was composed of 8-10 male Sprague-Dawley or Wistar rats with a solid weight of about 30-40 grams at the beginning of the experiment. The test drug is administered in a single or multiple daily doses for seven days by an appropriate route. Before the first dose is administered, a single dose is given to the rat—a fluorescent mark that can mark the position of the bone formation surface at a fixed time ( Tetracycline 25 mg / kg, or Calcein 10 mg / kg). After the compound dose is complete, the rats are killed and the two forelimbs are excised from the elbows, the feet are excised from the limbs, and the flesh is removed. The samples were frozen and mounted sadly on the microtome. Cut out the middle section of the ulna in the cryostat. The rate of bone resorption was measured morphologically in the intra-dorsal region of the bone cortex. The measurement is performed as follows: the bone mass reabsorbed on the periosteal surface is equal to the distance between the periosteal surface and the osseous bone-forming surface that was incorporated at day zero; the distance is determined by the calibration and Calculated by subtracting the bone width between the periosteal surfaces on day 7; the reabsorption rate in micrometers per day is calculated by dividing #result by 7. (Please read the notes on the back before filling out this page) Binding

This paper scale applies the Chinese National Standard (CNS) from the specifications (2 × 0 × 297 mm) 533202 A7 B7 V. Description of the invention (42) Human osteoclast reabsorption analysis printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ("lowercase analysis" ") Call for an equal amount of the osteoclast-derived cell suspension to be removed from the liquid nitrogen storage, quickly warmed at 37 ° C, and centrifuged (1,000 rpm, 5 minutes at 4 ° C) at RPMI- Wash once in 1640 medium. • The medium was withdrawn and replaced with mouse anti-HLA-DR antibody (diluted 1: 3 in RPMI-1640 medium). Incubate on top for one minute, and often mix cell suspensions. Call for washing the cells with RPMI-1640 medium twice by centrifugation (1000 rpm, 5 minutes at 4 ° C), and transfer the cells to a sterilized 15 ml centrifuge tube, and place them in a modified Neubauer counter Calculate the number of mononuclear cells. • Take a sufficient amount of goat anti-mouse Ig0 coated magnetic beads (5 / monocytes) from its storage bottle and place in 5 ml of fresh medium (this step removes the toxic azo nitride preservatives ) 6 The medium was removed by fixing the beads to a magnet and replaced with fresh medium. • Mix beads with cells, and incubate the suspension on ice for 30 minutes. The suspension is often mixed. * Fix the bead-coated cells to a magnet, and carefully pour the remaining cells (the osteoclast-rich portion) into a sterilized 50-millimeter centrifuge tube. ♦ Add fresh medium to the beads-coated cells to release any trapped osteoclasts. Repeat this cleaning procedure ten times. The beads-coated cells were discarded. It is recommended to use a large-caliber disposable plastic culture orphan loaded with a counter containing samples to calculate osteoclasts in the counter.

* Public 7 9 2 X (Please read the precautions on the back before filling in this page). Binding · Thread 533202 Α7 Β7 V. Description of the invention (43) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs • Centrifuging the cells into pills Granules, and the density of osteoclasts was adjusted to 1.5 × 104 / ml in EMEM medium (supplemented with 10% fetal bovine serum and 1.7 g / l sodium bicarbonate). Pour 3 ml of an equal volume of cell suspension (per treatment) into a 15 ml centrifuge tube. The cells were centrifuged into pellets. \ Call on each tube to add 3 ml of appropriate treatment (dilute to 50 μM in EMEki medium). Rhenium includes an appropriate vehicle control group, a positive control group (87MEM1 diluted to 100 micrograms / ml) to the isotype confrontation group (IgG2a diluted to 100 micrograms / ml). Incubate at 37 ° C for 30 minutes. ❶ Call for 0.5 ml of an equal amount of cells to be plated on 48-well plate sterilized dentine slides and incubate at 37 ° C for 2 hours. Each treatment was screened in four replicates. For reference, wash the slides in warm-to-warm BS (10 ml / slot in a 6-slot flat dish) six times and place them in a fresh treatment or control group. Incubate at 37 ° C for 48 hours. Wine-resistant salt acid phosphatase (trap) method (selective strain for osteoclast lineage cells). * The slides were washed in sodium chloride buffered saline and fixed in 2% glutaraldehyde (stored in 0.2 M sodium dimethylformate) for 5 minutes. * Wash it in water and incubate in TRAP buffer at 37 ° C for 5 minutes. ♦ After washing in ice water, incubate it in frozen acetate buffer / solid red garnet at 4. (: Incubate for 5 minutes. Φ The excess buffer is withdrawn, and the slide is dried after washing with water.

(Please read the precautions on the back before filling this page)-Installed, 1T thread paper ^^ Applicable to China National Standard (CNS) Α4 threat (210 X 297 Gongchu) 533202 A7 _______ B7 V. Description of the invention (44) Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards * The TRAP positive osteoclasts were counted with an optical microscope, and then removed from the dentin surface by ultrasonic vibration. Chun used a Nikon / Lasertec ILM21W confocal microscope to determine the Pit volume. Inhibition of RGD-dominated aiIbp3 binding < Purification of mbP3 Ten units of outdated, washed human platelets (from Red Cross) were obtained with 3% octyl glycoside, 20mM Tris-HCl (pH7.4), MOmMNaCl, 2mMCaCl2 Dissolve with gentle stirring at 4 ° for 2 hours. The lysate was centrifuged at 10,000 g for 1 hour. The obtained supernatant was applied to 5 ml of lentin lectin agar 4B column soil previously equilibrated with 20 mM Tris-HCl (pH 7.4), 100 mM NaCl, 2 mMCaa2, 1% octyl sugar (buffer A). After 2 hours of incubation, the column was washed with 50 ml of freezing buffer a. The aiIbP3 retained by Jiang with lectins was eluted with buffer A containing 10% dextrose. All steps are done at 4 ° C. The purity of the obtained αΐβ) β3 was > 95% when displayed by SDS-polyacrylamide gel electrophoresis. Incorporation into microlipids A mixture containing phospholipids serine (70%) and phospholipids choline (30%) (Avanti polar lipids) was dried under nitrogen vapor to the glass tube wall. The purified anbp3 was diluted to a final concentration of 0.5 mg / ml, and mixed with the scale lipid in a ratio of protein: squamlipid to 1: 3 (w: w). Resuspend the mixture (please read the notes on the back before filling this page) • Binding-Thread _

This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 533202 A7 __B7 V. Description of the invention (45) Printed and floated by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy Ultrasonic shock for 5 minutes. The mixture was then dialyzed against a 1000-fold excess of 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 2 mM CaCl2 overnight (replaced twice in between) using a 12,000-14,000 molecular weight truncated dialysis tube. The microlipids containing Jiang anbP3 were centrifuged at 12,000 g for 15 minutes, and resuspended in dialysis buffer at a final protein concentration of about 1 mg / ml. Store microlipids at -70 ° C until needed. The competitive binding with the fibrinogen receptor (anbP3) was analyzed by the indirect competitive binding method by using [3η] · SK & 3F407260 as the RGD type ligand. The binding analysis was based on This was done using a 0.22-micron hydrophilic solid-resistant membrane-resistant 96-slot filter pan (Millipore, Bedford, iVlA). Each trough was pre-treated with 10 μg / ml polylysine (Sigma Chemical) Co., Inc., St. Louis, MO.) At room temperature for 1 hour to block non-specific binding. Uncalibrated benzodiazepines of various concentrations were added to each tank in four replicates. [3H] _SiC & F · 1Θ7260 was added to each tank at a final concentration of 4.5 nM, followed by the addition of 1 microgram of liposomes containing purified platelet anbp3. The mixture was incubated at room temperature for 1 hour. Anbp3 was bound [3H〗 -SK & F-107260 was separated from unbound by filtering with a Millipore filtration manifold, followed by washing with frozen buffer (2 times, each 0.2 ml). The binding remaining on the filter Radioactivity in 1.5 ml of Ready Solve (Fullerton, CA), Beckman liquid scintillation counting (LS6800) (with

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This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 public envy) 533202 A7 B7 V. Description of the invention (46) Central brown standard of the Ministry of Economic Affairs—Industrial and Cooperative Cooperative Printing 40% efficiency) count. Non-specific binding was measured in the presence of 2pMSK & F-107260 and was consistently less than 0.14% of the total radioactivity added to the sample. All data points are the average of western repeated determinations. The competitive binding data was analyzed by a non-linear, minimum > square curve fitting program. This method provides iC50 of the antagonist (antagonist concentration that inhibits 50% [3H] -SK & F-107260 binding at equilibrium). Based on the equations of Cheng and Prusofif Ki = IC50 / (l + L / K (0) and the dissociation constant of the antagonist (K0, where L is used in competitive binding analysis The concentration of [3H] -SK & F-107260 (4 · 5 nM >, and Kd is the dissociation constant of [3H] -SK & F-J07260 when measured by Scatchard analysis as 4.5 · M. The inhibitory effect can be measured by the method described in W093 / 00095 (PCT / US / 92/05463). The thrombus-forming member in vivo can be determined by Aiken et al., Kang Zhe, 19,620 ( The method described in 1980) is documented by documenting the systemic and hemodynamic effects of injecting peptides into anesthetized dogs. Preferred compounds of the present invention have affinity for the vitronectin receptor relative to the fibrinogen receptor, Or the affinity for fibrinogen relative to the vitronectin receptor is greater than 5: 1. The better compound has an activity ratio of greater than 10: 1. The best compound has a selectivity greater than 100: 1 Competitive results of compounds of the present invention with fibrinogen receptors and increased binding to vitronectin receptors, formula Table 1 below: 48 Paper-scale hog applicable Chinese national standard (CNS) A4 size (210X297 public shame)

533202 A7 B7 V. Description of the invention (47) Compound printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Ex. #) Ki1 «IIbP3 (μΜ) Κ {/ αγββ (μΜ) 1 > 50 0.023 2 0.009 15 Mobility analysis The chemical compounds of the present invention were tested for their ability to inhibit the movement and proliferation of arterial or venous smooth muscle tissue, in order to analyze their ability to prevent arterial restenosis, such as typically occurring after vascular angioplasty. Use rat or human aortic smooth muscle cells. Cell movement was detected in a Transwell cell culture chamber by φ using a polycarbonate membrane (Costar) with 8 micron pores. Cover the lower surface of the filter with vitronectin. The cells were suspended at a concentration of 2.5-5.0 X 106 cells / ml in DMEM supplemented with 0.2% bovine serum albumin, and the test compounds at various concentrations were previously treated at 20 ° C for 20 minutes. Those using only solvents were used as the control group. 0.2 ml of the cell suspension was placed in the upper part of the chamber. The lower part contains 0.6 ml of DMEM supplemented with 0.2% bovine serum albumin. At 37. (:, Incubate under the atmosphere of 95% air / 5% CO2 for 24 hours. After incubation, the unmoved cells located on the upper surface of the filter are removed by gentle scraping. Then the filter is fixed in methanol and fixed in methanol. 〇〇〇 / 〇 Giemsa stain staining. Measured by a) counting the number of cell scales that have moved to the lower surface of the filter, or by b) extracting with 10% acetic acid and measuring the absorbance at t300 nM Got to move.

----------- (Please read the notes on the back before filling in this page), 11 533202 A7 ___ B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (48) General NMR The spectra were recorded at 250 or 400 MHz using a Bruker AM 25 or Bruker AC 400 spectrometer, respectively. CDCI3 is deuterated digas methane, DMSCM6 is hexadeuterated dimethanine, and CD3OD is tetragas methanol. Chemical shifts are reported in parts per million (δ) as a low magnetic field below the internal standard tetramethylsilane. The abbreviations of the data are as follows: s = single peak, d = double peak, t = three peak, q = four peak, m two multimodal 'dd — double peak of double peak' dt = double peak of multiple three bees, app = Obviously, br = broad. J means that the 桴 coupling constant is measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin_Elmer 3 infrared spectrometer, and Fourier transfer infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra are recorded in conductive mode, and band positions are reported in units of the reciprocal wave number (cnrl). Mass spectra were obtained on a VG 70 FE, PE Syx API III, or VG ZAB HF instrument using fast atomic collision (FAB) or electrospray (ES) ionization techniques. Elemental analysis was obtained using the Perkin_Elmer240C elemental analyzer. Melting points were obtained on a Thomas-Hoover melting point device and are uncorrected. All temperatures are reported in degrees Celsius. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin-layer plates were used for thin-layer chromatography. Both rapid and gravity tomography were performed on E. Merck Ki6selgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were performed on a Rainin or Beckman chromatograph. ODS means an octasilyl-derived silica gel

This paper size applies to China National Standard (CNS) A4 (210x297 mm) 0 Please read the notes on the back before filling this page) Pack. 533202 A7 B7 V. Description of Invention (49) Employees of the Central Bureau of Standards, Ministry of Economy Cooperative printed tomographic support. 5 gApex-ODS means a silica gel chromatography support derived from octadecylsilane with a normal particle size of 5 μ, which is based on Jones Chromatography, Littleton Made in Colorado. YMCODS-Human Q® is an ODS Analytical Support and is the registered name of YMCCo. Ltd., Kyoto, Japan. PRP-1⑧ is a one-product polymer (styrene-divinylene) method, and is a registered trademark of Hamilton Co., Reno, Nevada name. Celite® is a filter aid consisting of acid-washed diatomite, and is a registered trademark name of Manville Corp., Denver, Colorado. Preparation 1 Preparation of this Mo, l K dihydro-3-carboxydibenzylidenecycloheptene-10-ethyl acetate a) 3-amyl-4- (trifluoromethanesulfonyloxy) methoxybenzene in -78t: Add trifluoromethane hydrazine (10.0 mL, 60 mmol) to 2-benzyl * 4, methoxyphenol (10.71 g, 50 mmol) over 3 minutes under argon. Ear; according to the theory of iso-dart allowance (prepared by J. Jw · CTi · Soc. ≫ 1949, 7 /, 64) and 2,6-dimethylpyridine (12.0 ml, 100 mmol) were dissolved in anhydrous CH2Cl2 (250 ml) solution. Stir the reaction at -78 ° C for 0.5 hours, and then warm to room temperature. After 1 hour, the reaction is filled with (Please read the precautions on the back before filling this page). · Order—_ 51 This paper size is applicable to China National Standard Cars (CNs) M specifications (210 × 297 mm)

533202 A7 B7 V. Description of the invention (50) Diluted with hexane (250 ml) and sequentially with 1.0 NHC1 (2 X 100 ml), 1.0 N NaOH (2 X 50 ml), H2O (100 ml ) And brine (50 ml). Drying (Ka2S04), concentrating and subjecting to silica gel chromatography (10% EtOAc / hexanes), the title compound (16.65 g, 96 //) was obtained as a pale yellow solid:! 1 ^: 1 ^ 0.51 (10% £ 108 (: / hexane); 111 see ^ (250 MHz, CDCl3) 8 7′0-7.40 (m, 6H), 6.77 (cTd, J = 9.0, 3.1 Hz , 1H >, 6.66 (d, J = 3.1 Hz, 1H), 4.03 private, 2H), 3.37 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144 ， 1039，869 cm-1; M $ (ES) m / e 369 (l \ l + Na) +, 364.0 (M + NH4) +, 347.0 (M + H) + 〇b) 4-enediyl- 3-Benzyl methoxybenzene Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. LiCl (3.08 g, 72.8 mmol) in a bottom-adjusted flask was dried under flame under high vacuum and the system was placed under argon Cool to room temperature. 3-benzyl Fengbing (trifluoromethanesulfonyloxy) methoxybenzene (21.0 g, stone 0.6 mmol), gasified bis (triphenylphosphine), (11) (2.13 g, 3,0 mmol), anhydrous DMF (150 ml) and allyltributyltin (22.6 ml, 72.8 mmol) were added, and the mixture was purged with argon after three pumping / argon filling cycles . The mixture was preset at 95. (: Heated in an oil bath to obtain a yellow, homogeneous solution. After 1.5 hours, the dark mixture was concentrated in a rotary evaporator (high vacuum), and the residue was concentrated again from xylene. The resulting The residue was taken up in Et20 (120 ml) and stirred vigorously with 10% κ] ρ (120 ml) for 0.5 hours. The layers were separated and the aqueous layer was extracted with Et20 (2 x 120 ml). The combined organics were filtered through Celite (R) to remove insoluble solids, and the filtrate was sequentially ground (60 mL) and brine (60

---------- (Please read the precautions on the back before filling this page) Order 533202 A7 B7 Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (51 ml) Extraction and washing. Dry (Na2S04) and concentrated residual cloudy, yellow oil. After chromatography (silica gel, 5% EtOAc / hexane), the title compound (14.21 g, 98%) was obtained as a pale yellow oil. TLCRf (5% EtOAc / hexane) 0.51; 1HNMR (250 MHz, CDCl3) & 7.03-7.31 (m, 6H), 6.74 (dd, J = 8.3, 2.7 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H) , 5.79-5.98 (m, 1H), 4.89-5 · 0 · 7 (π, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 3.21-3.33 (m, 2H); FTIR (CCI4) 1610, 1496, 1256, 1046, 914 cm_l; MS (ES) m / e 239.2 (M + H) + 〇c) 2-Methyl-methoxybenzylacetic acid will be 50.06 (23.83 g, 104.5 milligrams) Mol) was dissolved in H20 (56 ml) and added to 4-allyl · 3-fluorenylmethoxybenzyl (5.30 g, 22 · 24 mmol) dissolved in CC14 (28 ml) and CH3CN (28 ml) Solution, and the fully stirred mixture was thoroughly cooled to 0 ° C. RuCl3 (231 mg, 1.11 mmol) was added and the reaction was stirred vigorously at 0 ° C for 4 hours, and then at room temperature for 45 minutes The mixture was filtered through Celite® and the filter was rinsed with CH2CI2 (120 mL) and then with H20 (120 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (3 X 120 mL). (Na2S04) and concentrated residual brown oil. This oil was partitioned between Et2O (90 ml) and 0.25 NNaOH (90 ml), and the layers were separated. The Et2O layer was divided into 0.25 N NaOH (2 X 10 ml) extraction—and the combined aqueous layer was acidified with concentrated HC1 (2). Extracted with CH2Cl2, dried (Na2S04) and concentrated to give the title compound as a yellow oil, which solidified to a yellow solid 53

--------- 0 — ^-(Please read the notes on the back before filling out this page) The size of the paper is applicable to China National Standard (CNS) A4 (210X 297 mm) 533202 A7 B7 Economy Printed by the Consumer Cooperatives of the Ministry of Standards of the People's Republic of China. 5. Description of Invention (52) (4.19 g, 74%): iHNMR (250 MHz, CDCI3) δ 7.05-7.35 (m, 6Η), 6.77 (dd, J = 8.3, 2.7 Hz, 1Η), 6.71 (d, J = 2.7 Hz, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 3.54 (s, 2H); FTIR (CCl4) 2300-3500 (wide); 1710 , 1611, 1502, 1496, 1285, 1257, 1045 cm-1; MS (ES) m / e 279.0 (M + Na) +, 274 0 (M + NH4) +, 257.G (3 ^ + H) + 〇d) 3-Methoxy-5H-diphenyliso {a, d] cycloheptan-10 (11H) -one at 100-110 ° C, the finely divided 2-benzyl-methoxy Phenylacetic acid (3.26 g, 12.72 mmol) was added to polyphosphoric acid (165 g), which was thoroughly stirred. After 15 minutes, the reaction was reacted on ice (330 g). Et20 (330 mL) was added, and the mixture was stirred vigorously for 15 minutes. The layers were separated, and the aqueous layer was extracted with Et20 (330 mL). The combined organic layers were washed with 5% NaHC03 (2 x 80 mL), then brine (80 mL), dried (Na2SO4) and concentrated. The residue was reconcentrated from toluene and then subjected to chromatography (silica gel, 20% EtOAc / hexane). The title compound (1,44 g, 48%) was obtained as a pale yellow solid: TLCRf (20% EtOAc / hexane) 0.46; also NMR (25t) MHz, CDCi3) δ 8.07-8.15 (m, 1H), 7.39- 7.49 (m, 1Η), 7.25-7.48 (m, 2Η), 7.19 (d, J = 8.3Hz, 1H), 6.86 (d, J = 2 · 6Ηζ, 1H), 6.71 (dd, J = 8.3, 2 6Ηζ, 1H), 4.21 (s, 2H), 4.11 (s, 2H), 3.77 (s, 3H); FTIR (CCl4) 1680, 1501, 1282, 1270 cm-1; MS (ES) m / e 261 (M + Na) +, 256 · 0 (M + NH4) +, 239.0 (M + H) + 〇

(Please read the precautions on the back before filling in this page) i # — The paper size of the binding and thread paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 533202 A7 _ B7 --------- 5 Description of the invention (53) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs e) (±) _1〇, 11-dihydro-10-hydroxy_3-methoxy_511_dibenzo [to] cycloheptene- 10-Ethyl acetate at -78 ° C under argon, EtOAc (8 mL, 6 shimmoles) was added dropwise to the bis (trimethylsilyl) sulfonium lithium amide present in a flame-dried flask. (1.0 from a solution stored in 11 ^, 6ml, 6mmol, and dried 11 ^ (24ml). The yellow solution was stirred at -7S ° C for 0.5 hours, and then 3-methoxy A solution of 5H-dibenzo [a, d] cycloheptene_10 (11 (), (7B3g, 3 mmol) in dry THF (3 ml) was added dropwise over 3 minutes. Additional drying THF (0.4 ml) was used for transfer. After 0.5 hours at -78 ° C, the reaction was quenched with saturated NH4C1 (15 ml), warmed to room temperature, and EtOAc (2 x 3 ml) Extraction. After drying (MgS04), concentration and chromatography (silica gel, 10% EtOAc / hex (400 ml), then 20% EtOAc / hexane), and recovered 3 "methoxy-5H-dibenzo [a, dlcycloheptene-10 (11Η > · ketone (305.4 mg, 43%), followed by the title compound (531.9 mg, 54%) as a pale yellow oil: TLCRf 0.37 (20% EtOAc / hexane); 1HNMR (250 MHz, CDCI3) δ 7 · 6 3 (d, J = 7 · 7 Hz, 1Η), 7.00-7.30 (m, 4Η), 6.80 (d, J = 2 · 6 Hz, 1H), 6.69 (dd, J = 8 · 2, 2 · 6 Hz, 1H), 3.95-4.35 (m, 2¾, 4.07 (s, 2H), 3.76 (s, 3H), 3.68 (s, 1H), 3.64 (d, J = 14 · Hz, 1H), 3.35 (d, J = 14 2Ηζ, 1H), 2.79 (d, J = 16.0 Hz, 1H), 2.66 (d, J = 16.0 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H); FTIR (C〇4) 3580 ( Obviously), 3509 (wide), 1735, 1715,

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297mm) (Please read the precautions on the back before filling this page)-Binding and binding 533202 A7 B7 V. Description of the invention (54) Central sample of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 1503, 1261, 1198, 1156, 1044 curl; MS (ES) m / e 675.2 < M + Na) + ^ 653.2 (2M + H) + 〇f) (± > 10,11 -Dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene 40-ethyl acetate 10% Pd / C (242 mg, 0.23 mmol) was added to (±) -10,11-dihydro-10-hydroxy-methoxy-5H-dibenzo [a, d] cycloheptene-10, ethyl acetate (74U mg, 2.27 mmol) and concentrated HC1 (019 ml, 2.27 mmol) dissolved in ice AcOH (3 ml), and the mixture was shaken on a Parr apparatus under chamber overflow under H2 (50 psi). After 6 hours, the reaction was filtered through Celite® and the filter was rinsed with EtOAc. The filtration was concentrated overnight, and the residue was reconcentrated from toluene. The resulting slightly yellow oily rice residue was subjected to chromatography (Dreamstone '20% EtOAc / hexane) to obtain the title compound (643.6 mg, 91%) as a colorless oil: TLCRf 0.57 (200 / 〇 EtOAc / hexane); iHNMR (250 MHz, CDCI3) δ 7.05-7,22 (m, 4H), 7.01 (d, J = 8.2 Hz, 1H), 6,76 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.2, 2.7 Hz, 1H), 4 · 30 (d, J = 15.0 Hz, 1H), 4.11-4.25 (m, 2H), 3.85 ( d, J = 15.0 Hz, 1H >, 3.70-3.90 (m, 1H), 3,77 (s, 3H), 3.31 (dd, J = 15.0, 4.1 Hz, 1H), 2.93 (dd, J = 15 · 0, 9.2 Hz, Iti), 2.64 (dd, J = 15.6, 5.0 Hz, 1H), 2.52 < dd, 15.6, 9.3 Hz, 1H), L27 (t, J = 7'l Hz, 3H); FTIR (CCU) 1734, 1611, 1504, 1285, 1263, 1155, 1044 cm-1; MS (ES) m / e333.0 (M + Na) +,

(Please read the precautions on the back before filling in this page) Binding 'Order P, this paper size applies Chinese National Standard (CNS) m specification (21 OX 297 mm) 533202 A7 B7 V. Description of invention (55) Central of Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Standards Bureau 328.0 (M + NH4) +, 311.0 (M + H) +, 265.0 (M + H-EtOH) + 〇g) < ±) -10, ll-dihydro_3 -Hydroxy_5H-dibenzo [a, d] cycloheptene-10 • Ethyl acetate was argon at 0 ° C. Anhydrous AlCl3 (1.38 g, 10.35 mmol) was known at one time. To (±) _1,11_dihydro-3-methoxy- · 5Η-dibenzo [a, d] cycloheptene_10_ ethyl acetate (643 · 6 mg, 2.07 mmol) was dissolved Anhydrous CH2CI2 (21 mL). The yellow solution was warmed to room temperature, stirred for 3 minus deformities, then cooled to 0 ° C, and quenched with frozen 3NHC1 (10 ml). The layers were separated and the aqueous layer was extracted with CH2CI2. The combined organic layers were dried (MgS04) and concentrated. Chromatography (silica gel, 25% EtOAc / hexane) gave the title compound as a colorless oil (611 · 7 mg, 100%): TLCRf 0.26 (20% EtOAc / hexane); 1HNMR (400 MHz, CDCI3) δ 7.03_7'22 (m, 4H), 6.93 ((1, J = 8.1 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.58 (dd, J = 8.1, 2.6 Hz , 1H), 5.00 (s, 1H), 4.25 (d, J = 14.9 Hz, 1H), 4.11-4.25 (m, 2H), 3.73-3.88 (m, 1H), 3.79 (d, J = 14 · 9 Hz, 1H) > 3.28 (dd, J = 15.0, 4.1 Hz, 1H), 2.91 (dd, J = 15.6, 9 · 3Ηζ, 1H), 2.65 (dd, J = 15.6 '4 · 0ίϊζ, 1H ), 2 * 53 (dd, J = 15i6, 9.5Ηζ, 1H), 1.27 (t, J = 7.2Hz, 3H); FTIR (CCl4) 3611 (obvious), 3447 (wide), 17M, 1504, 1291 , 1272, 1176, 1152 curl; MS (ES) m / e 314.2 (M + NH4) +, 297.2 (M + H) + 〇57

• Installation-(Please read the precautions on the back before filling this page) Order-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533202 A7 B7 V. Description of invention (56) Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau h) (±) -10J 1-dihydro-3- (trifluoromethanesulfonyloxy) -5Η-dibenzo [a, d] cycloheptene_10_acetic acid Ethyl acetate was added dropwise trifluoromethanesulfonic acid ^ (0.45 ml, 2.68 mmol) at -78 ° C under argon to (Earth) -10,11-dihydroquinone_5Η -Dibenzo [a, d] cycloheptene_10_ ethyl acetate (611.7 mg, 2.06 mmol) and 2,6-dimethylpyridine (0.48 ml, 442 mmol) are dissolved in anhydrous CH2CI2 ( 10.3 ml) of the solution, after 0.5 hours, the reaction was warmed to room temperature and stirred for 1 hour. The yellow solution was diluted with segment 20 (50 mL), and then sequentially washed with 1.0 N HC1 (5 mL), 5 ° / NaHC03 (5 mL), and brine (5 mL). Dry (MgS04), concentrate and subject to silica gel chromatography (20% EtOAc / hexane) to give the title compound (808.9 mg, 92%) as a colorless oil: TLCRf (20 ° / 〇EtOAc / Hexane) 0.58; ΐΉNMK (250 ΜΗ2ί, CDCl3) S 6.98_7.30 (m, 7H), 4.35 (d, 15 · 2Ηζ, 1H), 4.19 (q, J = 7.1 Hz, 2H) , 3.91 (d, J = 15.2 Hz, 1H), 3.78-3.95 (m, 1H), 3.37 (dd, J = 15.2, 4.1 Hz, 1H), 3.02 (dd, J = 15.2, 9.6 Hz, 1H), 2.70 (dd, J = 15.8, 4 · 8Ηζ, 1H), 2.53 (dd, J = 15.8, 9.6Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); FTIR (CCU) 1735, 1493 , 1427, 1250, 1215, 1144, 961, S56cm_1; MS (ES) m / e 45 U (M + Na) +, 4464 (M + NH4) +, 429.2 (M + H) + 〇i) ( Mo, ll-Difluoren-3-carboxy-5H-dibenzo [a, d] cycloheptan-10-ethyl

(Please read the precautions on the reverse side before filling out this page)-The size of the bound and bound paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 533202 A7 B7 V. Description of the invention (57) Central Bureau of Standards Ethyl acetate printed by employee consumer cooperatives will contain (earth) "10,11 · dihydro-3- (trifluoromethanesulfonyloxy) -5H-dibenzo [a, d] cycloheptene-10-ethyl Ethyl ethyl ester (808.9 mg, 1.89 mmol), KOAc (742 mg, 7.56 mmol), Pd (〇Ac) 2 (21.2 mg, 0.095 mmol), 1, Γ-bis (diphenyl) Phosphino) di (cyclopentene) ferrous (210 mg, 0.38 mmol), depleted with anhydrous DMSO (11 ml) with carbon monoxide (three pumps / CO charge cycle, followed by CO gas for 3 minutes ), And then heated under CO aeration in an oil bath set at 70 ° C. After 3.5 hours, the reaction was diluted with H20 (11 ml), cooled to 0 ° C, and 1.0 N HC1 (about 3 ml) ) Acidified. Extracted with C2Cl2, dried (Na2SO4), concentrated and re-concentrated from toluene, residual red color liquid (2-3 ml). Chromatography (silica gel, 3: 2: 0.1EtOAc / toluene) / AcOH; The mixed fractions were then mixed with 1: 1: 0.1 EtOAc / toluene / AcOH) to obtain the title compound (581.9 mg, 95%) as a viscous, yellow oil: TLCRf (3: 2: 0.1 EtOAc / toluene / AcOH) 0.60; lHNMR (250MHz, CDCl3) S 7.95 (d, J = 1.5Hz, 1H), 7.87 (dd, J = 7.8, 1.51ζ, 2H), 7.00_7.35 (m, 5H), 4.40 (d, J = 15 · 2Ηζ, 1H), 4.19 (q, J = 7.1 Hz, 2H), 197 (d, J = 15.2 Hz, 1H), 3 · 82-4 · 00 (π * 1H), 3.43 (d < !, J = 15.3, 4 0ttz, 1H), 3.07 (dd, J = 15 · 3, 9 · 5Ηζ, 1H), 2.69 (dd, J = 15.8, 4.8 Hz, Η), 2.53 (dd, J = 15.8 , 9.5 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); FTIR (CCl4) 2357-3378 (width), 1735, 1692, 1280 cm-1; MS (E; S) m / e 342.2 ( M + NH4) +, 325.2 (M + H) +, 307.2 (M + H- H2〇) +

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling out this page). Packing. 533202 A7 V. Description of Invention (58) Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Co-operative printing to prepare 2 2-carboxyl-10,11-dihydro-5 qindibenzyl (!) Preparation of Cyclofluorenyl-10-ethyl acetate a) 2-Benzylfluorenyl-5- Methoxyphenylacetate methyl 3-methoxy-phenylacetate, as described in Yun ## (Study on Sac), cold cut, 1991, 171, benzyl chloride and aluminum vaporization Treatment to obtain the title compound & b) 2-benzyl-5-methoxybenzyl 6-methyl ester. 2 制备 compounds will be prepared. According to the general procedure for the synthesis of 1978, 76 ，, boron hydride in methane gas. Treatment of sodium with trifluoroacetamidine gave the title compound. c) 2-Methenyl-5-methoxybenzylacetic acid The compound prepared in 2 (b) was treated with an aqueous solution of sodium hydroxide and methanol and stirred. The mixture was concentrated and treated with dilute hydrochloric acid to give the title compound. d) 5,11_dihydro-2-methoxy-10H-dibenzo [a, d] cycloheptene, ιο_one will prepare the compound of 2 (c), according to the general procedure of US patent 3,567,730, Add to a mixture containing phosphonic acid and p-oxidized phospholipid and heat to 80 ° c 'to give the title compound.

(Please read the precautions on the back before filling this page) Binding, binding-thread paper size application, Lai Jiazheng Standard (CNS) Conformance Inspection (21Gx297 public director) 533202 A7 B7 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of the invention (59) e) 5,11-dihydro-2-acryl-1011-dibenzo [3, (1) cycloheptan-10-one will prepare the compound of 2 (d), According to the general procedure of the tetrahedral letter L.) 1978, 5211, treatment with mercaptan ★ gasified aluminum to obtain the title compound. f) 5,11-Dihydro-2 · (trifluoromethylsulfanyl) oxy-10H-dibenzo [a, d] fluorhepten-10-one. 2 (e) compounds will be prepared. Xue Nayou 衿 / 6 # 叆 禊 (J. Chem. Sod. Chem. Commun) 1987, 9 (general cake order of H, treated with trifluoromethanesulfonic anhydride to obtain the title compound.) 5, 11 · 2 Hydrogen-2-methoxycarbonyl_10H_dibenzo [a, d] cycloheptene-10-fluorene will prepare 2 fluorene compounds, according to / 6 ## 会 游 Arsenic / fc 学 遥 禊 (A Chem. Soc. Chem. Co / w / w milk.) 1987, 904. General procedure in dimethylarsine treated with carbon monoxide, methanol, palladium acetate, and 1,3-bis (tetrabenzyl) propane to give the title compound. h) 5,11-Dihydro-2-carboxyl-10 benzodibenzo {&, (!) cycloheptene-10-one The compound prepared in 2 (g) was stirred with a dilute aqueous sodium hydroxide solution. The mixture was treated with dilute acid to give the title compound. 0 5,11-dihydro · 2-third-butoxycarbonyl-10H-dibenzo [a, cflcycloheptene-10 · one 61

(Please read the precautions on the back before filling this page)-Binding. The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 533202 Α7 Β7 V. Description of the invention (60) Central Standard of the Ministry of Economy Printed by the Bureau's Consumer Cooperative, the compound 2 (h) will be prepared and treated with N, N-dimethylformamide di-third-butyl acetal according to the general procedures of Hezheng 1983, 2,135. Title compound. j) 2-Third-fluorenyloxycarbonyl-5H-dibenzo [a, d] cycloheptenyl-10-ethyl acetate. The compound of 2 (i) will be prepared according to this machine and recommended "Og · 19H '1, \ and the journal of the Mercury Chemical Society qj Am. Chem · Soc) 1938, thre general procedure of 2947, treatment with zinc powder and ethyl bromoacetate to obtain the title compound. K > 2-carboxy-5H-di Benzo [Tun] cycloheptenyl-10-ethyl acetate will prepare a compound of 2 (j), which is treated with trifluoroacetic acid in digas methane and stirred. The mixture is concentrated to give the title compound. D 2_ 叛-10,11_dihydro-5H-dibenzo [a, d] cycloheptenyl-10-ethyl acetate was prepared using the general procedure of 1 (f), but substituted with the compound of 2 (k) Compound of 1 (e) to give the title compound. Preparation 3 Dihydro-4H-benzo [4,5] cycloheptane hydration 丨 2 7 1 | furan-1 107 ethyl

(Please read the notes on the back before filling this page) ip equipment-

, 1T 62, .., General Chinese National Standards (CNs) a4 specifications (21 × 297 mm) of the scale of the wave, 5. Description of the invention (61) The procedure of preparation 2 is used, but noon is replaced by 3_squeaming gas Gas to give the title compound. Preparation 4

(Please read the notes on the back and fill in this page first) Pack. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs a) 4- [N- (Third_butoxycarbonyl) Office (methoxycarbonyl) amine methyl] Potassium benzoate tert-butyl ester Dissolved potassium tert-butylmethyliminodicarboxylate c c, 1977, 1088-90) (1.56 g, 7.3 mmol) in dimethylformamide ( 20 ml) of the suspension was added to the tert-butyl 4-bromomethyl-3-sonylbenzoate (2.27 mM, 7.2 mmol) (lnf.j.peptideRes 1990, 36, 31) dissolved in two A solution of methylformamide (25 ml). The dark brown solution was stirred for 1 hour, poured into water (400 ml), extracted with ethyl acetate (3 X 100 ml), and the combined layer was extracted and washed with water (5 X 75 ml), and dried ( Sodium sulfate) and concentrated to give a pale orange oil, which was purified by flash chromatography on silica gel (20% ethyl acetate / hexane) to give the title compound (2.15 g, 73%): lHNMR (400MHz, CDCl3) 3 8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H) ob) 4_ [N- (Third · butoxycarbonyl) aminomethyl] -3-nitrobenzoic acid

The size of the paper on the 01T line is in accordance with the Chinese National Standard (CNS) A4 (210X297 mm) 533202 A7 ___________ B7 V. Description of the invention (62) The ester printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs will prepare 4⑻ of compound (2.15 g , 5.243 mmol) was dissolved in a mixture containing methanol (120 ml) and 0.95 N sodium hydroxide (15 ml). After 15 minutes, acetic acid (10 ml) was added and the mixture was concentrated. The residue was dissolved in ethyl acetate (300 ml) and extracted with water (3 x Na ml). The organic layer was washed with brine (nanoliter), dried (sodium gallate), and concentrated to give a yellow itch, which was subjected to flash chromatography on silica gel (20% ethyl acetate / hexane). Purify the title compound (10 g, 54%): Ipj NMR (400 MHz, CDCl3) 8 8.6 (s, 1H), 8.2 (d, 1H), 7.7 (d, 1H), 5.35 (m, 1H>) , 4.6 (d, 2H), 1.65 (s, 9H), 1.4 (s, 9H) 0c) 3-amino-4- [N- (third butoxycarbonyl) aminomethyl] benzoic acid Butyl ester The hydrogenation (40 psi) of the compound of Preparation 4 (b) (0.80 g, 2.27 mmol) was dissolved in a solution containing 10% palladium on carbon (0.5 g) in ethanol (100 ml). After 30 minutes, the mixture was filtered and concentrated to give the title compound (0.72 g, 1000 / ❶): lHNMR (400 MHz, CDCl3) S7.25 (m, 2H), 7.1 (d, 1H) , 4.9 (b, 1H), 4.25 (d, 2Ή), 1.6 (s, 9H), 1.45 (s, 9H), d) (E, Z) _4_ [N- (third-butoxycarbonyl) Aminomethyl] -3_ [2_ (l, 4-dimethoxy-1,4-dioxy_2_butenyl) amino] benzoic acid tert-butyl ester will prepare the compound of 4 (c) (〇 7 grams, 2,2 millimoles) and acetylene dimethyl

(Please read the precautions on the back before filling this page)-Binding-The size of the paper is applicable to the Chinese National Standard (CMS) A4 specification (210X297 mm) 533202 A7 B7 V. Description of the invention (63) Staff of the Central Bureau of Standards Consumer Cooperative printed a mixture of dimethyl acid (0.37 g, 2.6 mmol) in methanol (40 ml), heated to reflux for 30 minutes, cooled and concentrated. The residue was purified by flash chromatography (stone cutting gel '20% ethyl acetate / hexane) to give the title compound (0.77, 70%). LHNMR (40 °) ViH2, CDCl3) S9.6 (s, 1H), 7.7 (d, 1H), 7,35 (m, 2H), 3.5 (s, 1H), 5.0 (b, 1H), 4.4 (d, 2H), 3.75 (s, 3H) ,, 3.70, 3H), 1, 6 (s, 9H), 1.45 (s, 9H). e) '[N- (Third-butoxycarbonyl) aminomethyl] caloric dimethoxy, cardiac dioxo-2-butyl) amino] benzoic acid tert-butyl ester ^ will be prepared 4 ( d) The compound (0.68 g, 1.5 mmol) and 10% palladium (0.5 g) in methanol (70 ml) were shaken in a hydrogen atmosphere (40 psi) for ^ hours. The mixture was transitioned and concentrated to give the title compound (0 66 g, 95%): lHNlR (400MHZ, CDCl307.8 (d, 1H), 7 75 (s, 1H), 7.1 (d, 1H), 5.4 (b, 1H), 4.9 (b, 1H), 4.6 (m, 1H), 4.3 (m, 2H), 3.7 (s, 3H), 3e65 (s, 3H), 2.9 (m, 2H), 1.6 ( s, 9H), 1.45 (s, 9H). f) 4- (aminemethyl) -3- [2- (l, 4-dimethoxy-kdioxobutenyl) benzoic acid A 4⑷ compound (0,66 g,! 4 mmol) stored in methane (10 ml) and trifluoroacetic acid (10 ml) was kept at room temperature! Small and concentrated to obtain Title compound: This paper is in accordance with Chinese National Standard (CNS) M specifications (21〇'297 mm)

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LP binding-binding 533202 A7 B7 V. Description of the invention (64) g) (R, S) -8-carboxyl · 2,3,4,5_tetrahydro-1,1,4-benzodiazepine G-methyl 2-acetate 'The compound of Preparation 4 (f) was dissolved in methanol (60 ml) and treated with a 25% solution of sodium methoxide in methanol (0.73 ml, 3.2 mmol), and Warm to 50 ° C for 1 hour. The mixture was acidified with 1 n hydrogenated gas (15 ml) in diethyl ether and concentrated to give the title compound (0.44 g; 98%): iH NMR (400 MHz? DMSO-d6) S8.15 (t, 1H ), 7.2 (s, 1H) '7.1 (d, 1H), 7.05 (d, 1H), 5.0 (dd, 1H), 4.9 (m, 1H), 3.75 < < id, 3H), 3.6 (s, 3H), 2.8 (dd, 1H), 2.6 (dd, 1H). h) Speaking, 8) -8-tyl-10,11-dihydro-511-tetrapyre [551_sentence [1,4] benzodiazepine-11_methyl acetate will prepare 4 ( The compound of g) was treated with triphenylphosphine, diethyl azoformate and trimethylsilyl azide according to the general procedure of local permitting method 56,2395 to obtain the title compound. Preparation 5 --------- Pack — (Please read the precautions on the back before filling this page) Order Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (R, S) -8-Genji-l〇 , I 1_diaza-5H-miso 〖2, l_cyj ^ 4〗 Preparation of manganese diazepine_11_methyl acetate a) (R, S) -8-carboxy-2? 3, 4,5-tetrahydro-3-sulfide-1Η · 1,4-benzyl diazide leather · methyl 2-acetate 66 The paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 533202 A7 B7 V. Description of the invention (65) The compound of 4 (g) will be treated with Lawsonson's reagent (Lawessoon, s) according to the general procedure of the tetrahedral letter (巧 丨 仏 仏) 1980 2 / '4061' and The title compound was obtained. b) (R, S) _8_carboxy-2,5-dihydro-3_methylthio 4H-1,4-benzodiazepine-2-acetic acid methyl ester (7 ^ ra / ie is called 19 volumes, general sequence of 517, and treated with methyl iodide to obtain the title compound. C) (R, S) -8-carboxy-2,5-dihydro-3-[( 2,2-dimethoxyethyl) amino] -1H_1,4-benzodiazepine-2-methyl acetate. The compound of 5 (b) will be prepared according to the Journal of Heterocyclic Chemistry (j · / ^ im ) q; d / cC72e / w.) 1989, 26, 205. General procedure, treated with dimethylacetal, to give the title compound. (Please read the precautions on the back before filling out this page) • Packing. Order Du Yin 袈 d) (R, 3) _8 Carboxy-10,11-dihydro-5H-imidazolium [2,1-C] II, 4] Benzodiazepine-11-methyl acetate The compound of preparation 5 (c) was treated with an aqueous solution of trifluoroacetic acid to obtain the title compound. Preparation of 6 (R, S) _2-Amine-KUL · Dihydro-5Η-Difurylcycloheptene-10-Ethyl Acetate 67 This paper scale is applicable to China National Standard (CNS) A4 (210X297 mm) ) Line 533202 A7 B7 V. Description of the invention (66) Printed by the β Industrial Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a) 2-Benzyloxycarbonylamino_5H_dibenzo [a, d] cycloheptenyl-10- Ethyl acetate was used to heat a mixture containing the prepared 2 (k) depleted compound, triethylamine, and dibenzylphosphonium azide in toluene. The resulting mixture was treated with benzyl alcohol, stirred and concentrated. The residue was subjected to chromatography on a silica gel to obtain the title compound. # b) (R, S) -2 · Amine-1G, 11-dihydro-5H-dibenzo [a, d] cycloheptene ethyl acetate The compound prepared in 6⑻ was dissolved in methanol and α 10 Percent palladium and 1M hydrogenated hydrogen in ether were treated and the mixture was shaken in a hydrogen atmosphere. The mixture was purged and concentrated 'to give the title compound. Preparation 7 24HM (oxycarbonyl) hexahydro 4 phenyl] ΐ_N-methyl-ethylamine depletion preparation a) 2 _ [(noonoxycarbonyl) hexahydropyridyl]] Ethylamine will be 2- (1 · hexahydro Ethylamine is protected according to one of the procedures of the tetrahedral letter 1986, 27, 439. A solution of tertiary butyl diphenyl sulfite (7.8 ml, 3G millimolar) in acetonitrile (10 ml) was added dropwise to 2- (1-hexahydrofluorene 4) stirred at 10 ° C. Ii) Ethylamine (4.0 ml, 31 mmol) and phenethylamine (6.3 ml, 45 mmol) were dissolved in a solution of acetonitrile (20 ml). The mixture was stirred at room temperature for 2 hours and cooled

---------- Installation-(Please read the precautions on the back before filling this page) Threading Φ This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) 533202 A7 _______ _ B7 V. Description of the invention (67) The cooperation between the Ministry of Economic Affairs and the Central Bureau of Standards was printed to 10 C 'with diethylamine (6.3 ml, 45 mmol) and benzyl formate (4.3 ml, 30 Millimolar) was dissolved in a solution of methane (1 ml). The mixture was stirred at room temperature for 2 hours, filtered and filtered. The residue was stirred in 80% acetic acid (100 mL) overnight, poured into brine each time and extracted with ethyl acetate. The aqueous phase was basified with saturated sodium carbonate, extracted with ethyl acetate, and the organic phase was dried (magnesium sulphate), filtered and concentrated to give the title compound: (11 g, 14%): lHNMR (400MHz, CDCl3) S2.43 (6H'm), 2.80 (2Η, m), 3.52 (4Η, m), 5.14 (2Η, inclusive), 7.38 (5Η, s). b) 2- [1- [4- (benzyloxycarbonyl) hexahydrogenyl]] · N-methylethylamine at 10 C, add formic acid (0.5 ml, 12.2 mmol) dropwise via a syringe Into an acetic acid needle (1.0 ml, 9; & millimoles). The mixture was stirred for 10 minutes and heated to 50 ° c for 2 hours. The mixture was cooled to room temperature, tetrahydrofuran (10 ml) was added, and then a preparation 7 (a) compound (ΐ · g, 3.8 mmol) dissolved in tetrahydrofuran was added. The mixture was stirred at room temperature for 2.5 hours, concentrated, and the residue was dissolved in tetrahydrofuran (25 ml) and cooled to 10 ° C. 1.0 M of boron methyl sulfide G (10 ml) dissolved in tetrahydrofuran (10 ml), 10 mmol) was added dropwise at 10 $ ^ the mixture was stirred until the gas release stopped, and Heated to reflux? hour. The compound was cooled, carefully treated with a saturated vaporized argon methanol solution (20 mL), and heated to reflux for 1 hour. The mixture was concentrated to give the title compound; (400 mg, 40%) · MS (ES) m / e27 & 0 [M + H] +; (400 MHz, CDCI3) δ 2,6 «-3 · 92 ( 15Η, m), 5.15 (2H, (Please read the precautions on the back before filling this page)-Installation-Thread

This paper size applies to Chinese National Standard (CNS) A4 specification (21 × 297 mm 533202 A7 B7 V. Description of invention (68)

s) 5 7.37 (5H printed by the Central Standards Bureau of the Ministry of Standards and Consumers ’Cooperatives in India dkiJM: (benzyloxyjigyl methacryl-methyl))] the base of the base will be 4_ [Ν- (芊 oxycarbonyl Amidinoimine methyl)] benzenesulfonic acid (0 23 g, 10 mmol) and thiosulfur gas (3 ml) in digas methane (3 ml) was heated to reflux for 1 hour, concentrated, and Treated with toluene and concentrated several times to obtain the title compound. Preparation of 9 y- (Third · butoxycarbonyl W'-dicosadidin. Dihydrochloride 454, -dihexahydropyridine (2.5 g, 1.0 mmol) Mol) was dissolved in water (10 ml) and treated with SN sodium hydroxide to pH 8-9, diluted with ο alcohol to 120 ml, and stirred at room temperature. The resulting mixture was dissolved in ethanol (80 ml ) Di-tert-butyl diformate (2.4 g, 11 mmol) was treated with a portion and the mixture was stirred at room temperature. 5N sodium nitroxide was added periodically to maintain the pH at 8-9. After 5 After hours, the mixture was concentrated and the residue was muddy in a 1: 1 ether: water mixture (100 milliwells). The pH was adjusted to 12 with 5N sodium hydroxide. The aqueous phase was extracted with ether and the organic phase Extract sequentially with brine, dilute citric acid, and water. Adjust the pH of the aqueous phase to 12-13 with 5N sodium hydroxide and extract with ether. Extract and wash the organic phase with brine (dried (sodium sulfate)). Concentrated into clear oil and applied to the standard of China National Standards (CNS) A4 (210X297 mm) in true paper size (please read the precautions on the back before filling this page)

533202 A7 B7 V. Description of the invention (69) The work of the Central Standards Bureau of the Ministry of Economic Affairs, including the work of the company, ¾ dried in the air to obtain the title compound (1.7 g, 63%). TLC Rf0.4 (Kieselgel 60F254, 15: 3: 2.2 2-butanol: formic acid: water); MS (ES) m / e 268.3 [M + H] + 〇 Preparation of 10 M methylaminomethyl) benzimidazole di Preparation of the hydrochloride a) 2-((tertiary-butoxycarbonyl) carnitamine) Aminobenzidine will be phenylenediamine (100 g, 0.924 moles) and Boc-carnitine ( 175 g '0.924 mol) in DMF (10 ml), cooled to -10 ° C in argon, and DCC (190 · 8 g, 0.924 mmol) was dissolved in CH2CI2 (1750 ml) The solution was added slowly over a period of 1 hour. The temperature rise wing is 0 ° C when added. The reaction was stirred overnight while the temperature was allowed to rise to room temperature. The white precipitate was removed by transition, and the filtrate was diluted with H20 (35 liters) and saturated brine (1 liter). The CH2CI2 layer was separated and the aqueous phase was extracted with EtOAc (2 X 1 L). The combined organic phases were washed with H2Ol) and brine (0.5l) and then concentrated to a yellow residue (341 g). This material was dispersed in EtoAc to obtain the title compound (179.4 g, 70%) '. Melting point 134-136 ° C. b) ί [[N-Third-butoxycarbonylmethyl) aminemethyl] benzimidazole will be tertiary-butoxycarbonyl) carnitinamidyl] aminobenzylamine (178.4 g, 0.639 moles) Soluble in THF (900 mL) and AcOH (900 mL)

This paper is moderately sharp, county (please read the precautions on the back before filling this page)

L. Description of the invention (70) A7 B7 Central Standards Bureau of the Ministry of Economic Affairs: Only the consumer printing company's printing fluid 'heats JL under the silk and returns to the office; Remove most of the beauty. The silk solution was poured into iced water, and concentrated (just milliliter) was added to adjust the positive value to 1G. The formed oil crystallized at lion night. Gu Zhao was transitioned and dried at 5 ° C for two days under atmospheric pressure. The domain left yellow and white 13 bodies (167 g, 10G%): melting point 14G15G. Dagger. At room temperature and atmospheric pressure Dry under pressure to give the crude title compound (162 g, 97/0). C) 2- (methylaminomethyl) benzimidazine dihydrochloride A solution of mol) and methoxybenzene (134 ml, 1.23 mol) was cooled to 0 under argon. €, and a solution of 2 [[Third-butoxycarbonyl-N "methyl> aminomethyl] benzimidazole (161 g, 0.616 mmol) was dissolved in CH2Cl2 (800 ml) to Add slowly over 30 minutes. The temperature rises to 8 at the time of the addition and a white precipitate begins to form before the addition is complete. The reaction is stirred for 20 minutes and the title compound (66.6 g, 46%) is collected by filtration: melting point 250 -255 ° C (decomposed). Analytical calculated values for C9HUN3 · 2HC1: C, 46.17; H, 5.60; N, 17.95. Experimental values: C, 46.33; H, 5.68; N, 17.55. The filtrate was diluted with Et20, and the mixture was allowed to stand overnight. The title compound (62 g; total yield 128.6 g, 89%) was obtained as an additional pink solid by filtration: melting point 248-253 ° C (decomposition). Preparation 11 72

(Please read the precautions on the back before filling this page.) _ The size of the paper is applicable to the China National Standard (CNS) A4 (210X297 mm) 533202 A7 B7 5. Description of the invention (71 Aminoethyl) Amine Preparation of pyridine dihydrochloride a) Mono-Boc-1,2-ethylenediamine was dissolved at 0 ° C under argon to disodium dicarboxylic acid (10.91 g, 50 mmol). In a solution of CH2CI2 (50 ml), add dropwise over a period of 30 minutes a solution of 1,2-ethylenediamine (33 ml, 500 mol) dissolved in CH2CI2 (250 ml). Separate and kill when added. When the addition was complete, the reaction was warmed to room temperature, stirred for 1 hour, and concentrated on a rotary evaporator. The residue was taken up in H20 (100 ml) and filtered to remove a small amount of insoluble material. The mash was extracted with CH2CI2 (3 × 100 ml), and the combined organic phases were dried (MgS04) and concentrated to give the title compound (6.00 g, 75%) as a turbid liquid. LHNMR ( 250 MHz, CDCI3) δ 4.75 · 5 · 00 (ιη, 1H), 3.05-3.25 (m, 2Η), 2.65-2.85 (m, 2Η), 1.46 (s, 9Η), 1.12 〇 > rS, 2H). (Please read the precautions on the back before filling out this page} • Packing-Printed by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Ministry of Economic Affairs, and printed as a section b) -N-Oxide will contain mono-Boc_l> ethylenediamine (5.83 g, 36.39 mmol), 2-pyridine, oxide salt phosphonium salt (7:25 g, 43.67 mmol), A mixture of NaHC03 (I5 · 29 g, I82 mmol) and tertiary-pentanol (36 ml) was heated under reflux. After 47 hours, the dark brown mixture was cooled, diluted with CH2CI2 (100 ml), and filtered with suction to remove insoluble matter. The filtrate was concentrated and reconcentrated from toluene. After silica gel chromatography (10% MeOH / CHCl3), the impure title compound was obtained as a yellow solid (8.23 73 This paper is in accordance with the national standard (CNS) A4 size (210X297 mm) of the paper in Zhongzhou). Description of the invention (72) A7 B7 printed by the Central Standards Bureau of the Ministry of Economic Affairs, M Industrial Consumer Cooperative Co., Ltd. (7 89%), which were used without further purification. TLC (100 / 〇Me〇iL / CHCi3) Rf ^ .42 lHNMR (250MHz, CDCb) 3S.i6 (dd, J = 6.5, 1.3 3ζ, 1H), 7.05-7.30 (m, 2H), 6.68 (brd, J = 8.6Hz, 1H) , 6.50-0.65 («ι ·, 1H), 5.70 · 5.55 (m, 1H), 3.25-3.60 (m, 4H), 1.44 (s, 9H); MS (ES) m / e 254 (M + H) + 〇 · c) 2-[[2- (Boc-amino) ethyl] amino group batch 10% Pd / C (106 · 4 mg, 〇〇ι〇mmol) Mortar to 2-[[2 · (Booamino) ethyl] amino] This pyridine oxide (126.7 mg, 0.5 mmol) is dissolved with cyclohexene (0.25 ml, 0.255 mole) Green to EtOH (5 ml) and the mixture was heated to reflux. After 16_ hours, the reaction was filtered through Celite® and the filter was concentrated. The residue was prepared separately from another (0 · (5 millimolar rating) The residue was combined and the combined materials were purified by silica gel layer technique (5% MeOH / CHCI3). The title compound was obtained as a yellow oil (148.4 mg, 63%, 1 mol 2). -[[2 < Boc-amino) ethyl] amino] This pyridine oxide is used as a reference): TLC (5% MeOH / CHCl3) Rf0.43; lHNMR (400 Mftz, CDCI3) δ S.05-8.12 ( m, 1H), 7.37-7.46 (m, 1H), 6.53-6.61 (m, 1H), 6.41 (d, J = 8.3Hz, 1H), 5.12o > rs, 1H), 4.86 (br s, 1H), 3.26-3.51 (m, 4H), 1,44 (s, 9H); MS (ES) read 238 (M + H) + 〇d) 2-[(2-aminoethyl (Amino) amino] this bite dihydrochloride

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、 1T-line 74 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 A7 B7 V. Description of invention (73) The Central Bureau of Standardization of the Ministry of Economic Affairs ^^ Industrial Consumption is included as printed by the company. Under C, 4N HC1 (3.2 ml) in dioxane was added to 2-[[2- (Boc-amino) ethyl] amino] pyridine (148.4 mg, 0.63 mmol) in an inflow manner. The ear was dissolved in a solution of anhydrous CH2Ci2 (3.2 ml), and then the reaction was warmed to room temperature. After 2 hours, the mixture was suction-filtered to collect the precipitated solid, and it was treated with anhydrous Et2. Wash and dry to give the title compound as a yellow solid (132.8 g, quantitative value): · 1ΗNMK (400MHz, CD3OD) δ 7.99-8 · 07 (m, 1Η), 7.92_7 · 7, 1Η) , 7.19 ((!, J = 9.iHz, 1Η), 6.98-7.04 (m, 1Η), 3.76 (t, J = 6.2Hz, 2H), 3.27 (t, J = 6.2Hz, 2H, part Obscured by residual solvent signals); MS (ES) m / e 138 (M + H) + 〇 Preparation of 12-propyl) amino group pyridine-N-oxide by a) meso-1-propyl ) Amine] This bite oxide will contain 2-Gas 唆 · oxide (16.6 g, 0.1 mole), 3-amino-1-propanol (15.3 ml, 0.2 mole), NaHC A mixture of 〇3 (42 g, 0.05 mole), and second, pentanol (1 ml) was heated to reflux. After 21 hours', the reaction was cooled, diluted with CH2a2 (300 ml), and filtered with suction to remove insoluble materials. The filtrate was concentrated and reconcentrated from methylbenzate, leaving a yellow oil. Silica gel chromatography (200 / oMeOH / CHay) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20%

Dry -V A N- Μ (Please read the precautions on the back before filling this page)

• JL binding · Binding line 533202 Part X .a Paper ruler / meaning: A7 B7 74n

MeOH / CHCl3) Rf 0.48; 1HNMR (250MHz, CDCl3) S 8 〇7 (dd 'J = 6.6, 12 Hz, 1H), 7.34 (brt, 1H), 7.10-7.3〇 (m, m > , 6.64 (dd, J = 85, 14Hz, m), 6.40_6 · 60 (ιη '1H)' 4.49 (brs, ih); 3.65-3.90 (m, 2H) > 3.35-3.60 (m > 2H ). l.75.2.00 (m, 2H); MS (ES) m / e 169 (M + H) +. · Preparation of 13 dihydro-azepine-methyl acetate a) methoxy ( Methoxycarbonyl) Dimoxamine is prepared from 5-methylamino-2 phenyl) dibenzyl chloramine, as described in c /? Hungry Age, 2174-2190, in the presence of methanol gasification. Hydrogen treatment to give the title compound. $ 5,11-dihydro-3 · methoxy_5_methyl · dibenzyl and myosinone use the general procedure of NL 7011296, but replace 5-qi · 2_ with the compound of preparation 13 (a) (Methoxy county) diphenylamine to give the title compound. c) 3-side fluorene 11 · dihydrofluorene methyl. Dibenzo-deuterium heterogeneous. Formic acid acetate_ The general procedure of Example l (ei) is used, except that the compound Θ gas of 13 (b) is prepared ..: 76 SW 孓 sample standard ((, NS) Λ4 is now (210x297 mm > (Please read the precautions on the back before filling this page)

533202 A7 B7 V. Description of the invention (75) Substitute the compound printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to prepare the compound of 1 (d) to obtain the title compound. Preparation 14 > Carboxyl-10,11-dihydro-dibenzyl [1], £ 1 Benzene-1O-acetic acid methyl 8 | The generation borrowed a) 3-methoxy-dibenzo [b , F] oxafluorene-i〇 (iih) -one general procedure of Heierocyclic Chem. 19S6, 23, 265-9, except replacing 4-fluorophenol with phenol to get the title Compound. b) 3-Wingyl-10, l 1-dihydro-dibenzoxetan-10-acetic acid methyl ester The general procedure of Example l (e_i) was used, except that the compound of Preparation 14 was substituted to prepare 1 (d ) To give the title compound. Preparation of 15 i-carboxy-1 〇, 11 -dihydro-dibenzyl b, f | thiazepine-1 〇, methyl acetate The general procedure of Example 1 (ei) was used, except for 3-methoxy -Dibenzo [b, f] oxepine-10 (11H) -one 'was prepared as described in C from stream 0. (¾ concentrated w · 1979, #, 2108, 23, instead of preparation 1 ( d) compound to give the title compound.

(Please read the precautions on the back before filling this page) Binding and binding 77 This paper size is applicable to China National Standard (CNS) M specifications (210X297 mm) 533202 V. Description of invention (76) Employees of the Central Standards Bureau, Ministry of Economic Affairs Consumer Cooperatives Indo-A7 B7 2-Carboxy-6,11 · dihydro-5H_dibenzylb, el Aza-6-methyl acetate a) 2-Methyl-4-bromo (methylmethyl) Stupid amine 'Bennan Collect · Czech · Chem · Commun t96 preparation, $ 0, 1163-1172 general procedure, will be 2-pictyl_4 · mo-aniline (such as Lega. Dec /. &Amp; to fine. 1983, (Prepared as described in 3,411-414) and ethyl formate to give the title compound. b) 2-Bromo-11H_dibenzo [b, e] azabenzene will use the general procedure of CoHect · Czech · Chem. Commun. 196S 9 30, 1163-1172 to prepare a compound of 16⑻ in polyphosphoric acid and oxygen Heating in a phosphorous mixture gave the title compound. c) 2-Bromo-6,11-dihydro-5H-dibenzo [b, e] azepine [Bull. Chem. Soc. Jpn.] After methyl 6-acetate 1990, θ '3122 * 3131 general procedure, the compound of 16 (b) is prepared with 6-methyl tertiary-butyldimethylsilyl ketal, cyanotrimethylpyridinium and the catalytic amount of 2-μ- Gas · bis (1,5-cyclooctanedilute) -dioxoRh (COD) Cl] 2) was obtained in digas methane under the moraine to give the title compound. d) Weiji-6,11-difluorodibenzo [b〆] azepine-6-acetic acid methyl vinegar using the general procedure of Example 1①, except for preparing the compound of 16 (c). Applicable to China National Standard (CNS) A4 specification (210X29 * 7mm) (Please read the precautions on the back before filling this page)

Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs for consumer cooperation, instead of preparing the compound of 1 (h) to obtain the title compound. Li Bei 17 dihydrogen, 5-methyl-5H-difluorene, 1 ^〗 『1,41 diazepam, m · a) 2-aminomethyl bromide-N- (methyl) diphenylhydrazone The general procedure of Zwi · C / iew. 1898, 303, 322 was used for the amine, except that the aniline was replaced with methyl "benzylamine" to obtain 2-nitro-5-bromo-N- (methyl) diphenylamine '. Reduction from vaporized tin gives the title compound. B) 7-yan-5H-dibenzo [1 ^] [1,4] diazapyrene uses Z ^ / v.CT / ew.yicia 1964, 47 , 1163: 72 general procedure 'but replacing the 2-amine group with (II) diphenylhydrazine' to prepare the compound of Π⑻ 'to give the title compound. C) odor_10, ll-dihydro-5-methyl- The general procedure of 5H-dibenzo [b5e] [l, 4] diazine-l-acetic acid methyl ester was used in Example 16), except that the compound of Preparation 16 (b) was replaced by the preparation of φχ compound. Title compound: Φ 7fluorenyl-10, fluorene_dihydro-5-methyl-5H_dibenzo [Μί14] diazafluorene-11-methyl acetate Φ _ 79 (CNS) Cong Mi (210 × 297 mm) '(Please read the notes on the back before filling this page)

533202 A7 B7 V. Description of the invention (78) The printed bag of the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs uses the general procedure of Example 1 (0, but replaces the compound of preparation 1 (h) with the 彳 b compound of 17 (C) The title compound is obtained.? Difluorenyl-l, 10-ll-dihydro-5-methyl-5H-di-cage azabenzene-11-methyl acetate a) 4-bromo-N, methylamino-2 -(Phenoxy) dolamine, a journal of the Chemical Society of Japan (J. Chem. Soc.) T Pgrkin Trass I, I976, 127-1285, the general procedure of 4-Mo-2: (phenoxy) phenylhydrazone, Prepared as described in / 6 Academic Society Weng // (/C/iem.&c·), 1930, 1202-1208, and heated with formic acid to obtain the title compound. b) General procedures for 7-mo-dibenzo [1], 1,4] oxazepine back shoulder chemical society {J · Ch6m · Soc), Perkirt Trass I, 1976, 1279-12, 5 The compound of Preparation I8 (a) < was heated in a mixture of polyphosphoric acid and phosphorus oxyoxide to obtain the title compound. c) 7-bromo-10, ll-dihydro-5-methyl-5H-dibenzo [b, f] Il, 4] oxazepine-11-methyl acetate is used in Example 16 (c) General procedure, but substituting the compound of Preparation 18 (b) for the compound of Preparation 16 (b), the title compound is obtained.

〆Please read the precautions on the back before filling in this page). Binding · Binding-Thread-80 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 533202 A7 B7 V. Description of the invention (79) d) 7. Tetral-10, 11-dihydro; methyl-5 leudibenzo [1 ^ [1,4] oxazepine-11-methyl acetate The general procedure of Example 1 (0, but Substitute the compound of Preparation 18 (c) for the compound of Preparation 1 (h) to obtain the title compound ". Preparation 19 · 7 · Carboxy-1CU1-dihydronetylmethyldice # thioazepine-11-methyl acetate a ) 2-Phenylthio-4- (bromo) aniline is prepared from 3-bromo-n-nitrophenyl disulfide disulfide, as described by Yunxue Society (J. C / 2e / M., 1966, 963-72, Reduction with vaporized tin gives the title compound 々b) 7 · bromo-dibenzo [b, f] [l, 4] thiazepine The central consumer bureau of the Ministry of Economic Affairs, Consumer Cooperatives, printed use price / V. CT ^ mA ^ a 1964, 47, 1163-72 general procedure, except that 2- (benzylthio) aniline was replaced by the compound of 19⑻ to give the title compound. C) 7-Mo-10,11-dihydro -Dibenzo 0), phantom [1,4] thiazepine < 41-acetic acid methyl ester The general procedure of Example 16 (c), except that the compound of Preparation 16 (b) was replaced by the compound of Preparation 19 (b) to obtain the title compound. 81 'This paper size applies the Chinese National Standard (cNS) A4 specification (210X297)嫠) 533202 A7 B7 V. Description of the invention (8〇) Printed by the Consumers' Cooperatives of the Bureau of Standards in the Ministry of Economic Affairs d) 7_carboxyl-10, l 1_dihydro-dibenzo [b, f] [l , 4] Thiazepine-11-methyl acetate The general procedure of Example 1① was used, except that the compound of Preparation 1 (h) was replaced with a compound of 19 (c) to obtain the title compound. Preparation 20 -10J1- ; Hydroxy-dibenzyl ib, flfL4] Gaspyrene_10_methyl acetate a) 2-methoxydibenzo {b, f] oxapyrene-IO (IIH) -one using Journal of Heterocyclic Chemistry (/ · Ifeierocyc / ic CAe / w.) General procedure of 1986, 23, 265-9, except that 4-fluorophenol is replaced with phenol to obtain the title compound. B) 2 · carboxy-10,11-dihydro-di Benzo [b, f] oxapyrene-10-acetic acid methyl ester was used in the general procedure of Example 1 (ei), but the compound of Preparation 1 (d) was replaced by the compound of Preparation 20 to obtain the title compound. Compounds are used to illustrate Preparation of the intermediate compounds described in the 'method of preparing the biologically active compounds of the present invention. Example 1 Real brigade

----- II--Packing-- (Please read the precautions on the back before filling this page) Thread 82 This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) 533202 A7 ~ ~~~ ———— -_ V. Description of the invention (Si) Employees' Cooperatives of the Central Sample Rate Bureau of the Ministry of Economic Affairs, India, Fanfan 11 See 11-Dihydro-3 Training (1 Qinbenimidazol-2-yl) Methyl 1 Methylamine Preparation of kiwiyl IjH-dibenzo 丨 a, dl cycloheptan-1-ylacetate a) (Earth) -lO, ll-dihydro-3 _ [[[(1 苯 · Benzimido-2-2 Yl) f-yl] methylamino} kisyl] -5H-dibenzo [a, d] cycloheptane-10 ethyl acetate at room temperature, EDC (102. 4 mg, 1.06 ¾ Mo (Ear) add (soil) _10,11_dihydro-3_carboxy-5H-dibenzo [a, d] cycloheptene-10-acetic acid ethyl acetate (28S.6 mg, 0.88 mmol) in one portion. , 2- (methylamino) methylbenzimidazole dihydrochloride (247.2 mg, 1.06 mmol), HOBt · H2O (142 · 7 mg, 1.06 mmol), and diisopropylethylamine (0.16 ml, 3.52 mmol) was dissolved in a solution of anhydrous DMF (4.4 ml). The reaction was stirred at room temperature for 16.5 hours and then concentrated on a rotary evaporator (high vacuum). The residue was reconcentrated from xylene and then dissolved in Η20 (5 ml). Extracted with EtOAc x 5 ml), dried (MgS04), concentrated and chromatographed (silica gel, 5% MeOH in 1: 1 EtOAc / CHCl3) to give the title compound as a hazy yellow foam (389 2 millibeam, 95%): TLCRf (ΙΟνοΜθΟΗΚΙιΙΕίΟΑο / ΟΐαβΟΑΟ ^^ NMKβΟΟ MHz, CDC13) δ 7.70-7.80 (m, 1Η), 7.40-7.50 (m, 1H), 7.35 (s, 1H), 7.21- 7.32 (m, 3H), 7.04々 · 21 (m, 5H), 4.76-4.88 (m, 2M), 4.36 (d, J = 15.2 Hz, 1H), 3.90 (d, J = 15 · 2 Hz , 1H), 3.82, 3.95 (speaking, 1H), 3.38 (dd, J = 15.4, 4.0 &, 1H), 111 (s, 3H), 3.03 (dd, J = 15.4, 9.5 Hz, 3H) ; FTIR (Ca4) 2700-3470 (wide), 1735, 1629 (shoulder), 1617, 1484, 1454, 1422, 1397,

This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) (Please read the notes on the back before filling out this page)-Binding '533202 A7 B7 V. Description of the invention (82) Central standard of the Ministry of Economic Affairs Bureau ’s consumer cooperative prints 1271 '1180' 1157 cm-1; MS (ES) m / e468.2 (M + H) +. B) (Shi) -10,11 · Dihydro_3-[[[(( lH-benzimidazolyl) methyl] methylamine] quinyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid, & salt will be 1.0NLiOH (1.0 ml, 1.0 mmol) ) Added to (Earth) _1010-dihydrobenzimidazol-2-yl) methyl] methylamino] carbonyl · yl] -5H-dibenzo [a, d] cycloheptane-10-acetic acid ethyl Vinegar (389. 2 mg, 0.33 mmol) was dissolved in a solution of THF (4.2 ml) and thallium 20 (3.2 ml). The resulting yellow solution was stirred at room temperature for 2 hours and at 40 ° C for 15 hours. Hours, then 0.5 hours at reflux. It was then concentrated to dryness on a rotary evaporator. The residue was dissolved in H20 (4 mL). The solution was extracted with Et20 (2 X 4 ml), and the Et20 layer was discarded. Filter the water layer to remove particles? It was then neutralized with j 0 NHC1 (1.0 ml). The precipitated solid was collected by suction filtration, washed with a shaker, and then dissolved in hot i: i fcH3CN / H2O. The Ning solution was hot-filtered to remove insoluble color oil and allowed to cool to room temperature. Once the product oil had precipitated, the mixture was concentrated to dryness on a rotary evaporator. The residue was dissolved in MeGH (2 ml) and 5% NaHC03 (2 ml) was added. The return was warmed until a homogeneous solution was produced, then it was concentrated to remove MeOH. ODS chromatography (30% lVieOH / H2 (> then rechromatography with 1: 1 Me0H / H20)), concentrated, and lyophilized to give the title compound (187 · 5 mg, 45%) as a colorless powder: HPLCk , 1.47 (Hamiton PRP-1®, 35 / 0CH3CN / H2O-0.1% THF); 111 see 111 (400 circle 2, € 0300) geometrically heterogeneous mixture; 3 6.80-7 stone 5 (m, 11H), 4.64-5.05 (m, 2H), 3.68-4.41 (m, 3H),

(Please read the precautions on the back before filling this page). The binding and binding paper ifc standard is applicable to Chinese National Standard (CNS) A4 specification (210X297 gong) 533202 A7 B7 V. Description of invention (83) Central standard of Ministry of Economic Affairs Bureau Shellfish Consumer Cooperative Co., Ltd. printed 1?-2.87-3.46 (m, 5H), 2.30-2.58 (m, 2H); MS (ES) m / e 440.2 (M + H) +. Anal. Calculated values for C27H24N3O3Na2.25.20. C. 64:60; R. 5.72; N. 8.37. Experimental values: C, <34.52; Hf, 5.80; N, 8.27 〇 * Example 2 · (Earth) -10,11-dihydro-34H4,4f-dihexahydropyridyl) carbonyl 1-5Η- Second cage # fa, d〗 Preparation of cycloheptene_10_acetic acid a) (Earth) -10,11-dihydro-341- (1,004,4, -dihexahydropyridyl) carbonyl] -5H- Dibenzo [a, d] cycloheptene-10-ethyl acetate was added at room temperature with EDC (209.3 mg, 1.09 mmol) at a ratio of (±) -10,11-dihydro Each carboxy-5H, dibenzo [a, d] cycloheptene-10-ethyl acetate (296.3 mg, 0.91 mmol), l_BOC-4,4 · -bishexahydro 4b 唆 (293 mg, ί · 09 mol), HOBt Η20 (147 · 6 mg, 1.09 mmol), and a solution of diisopropylethylamine (0.32 ml, 1.82 ¾ mole) in anhydrous DMF (4.6 ml) in. The reaction was stirred at room temperature overnight and then concentrated on a rotary hair dryer (high vacuum). The residue was re-concentrated from xylene and then dissolved in H20 (5 mL). Extraction with EtOAc (2 X 5 mL), drying (MgS04), concentration, and silica gel chromatography (7.3 EtOAc / hexane) gave the title compound (463.4 mg, 89%): TLCRf (7: 3 EtOAc / hexane) 0.59; lHNMR (25 MHz, CDCI3) δ 6,94-7 · 46 (m, 7H), 4.58-4 · 88 (m,

85 This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

533202 A7 _____B7 V. Description of the invention (84) Sealing bags for consumer cooperation of shellers in the Central Standards Bureau of the Ministry of Economic Affairs 1H), 4.37 (d, J = 152Hz, 1H), 4.19 (q, J = 7.1Hz, 2H), 3.89 ( d, J = 15.2 ίζ, 1H), 3.68-4.30 (m, 4H), 3.38 (dd, J = 15.4, 4.1 Hz, 1H), 3.01 (dd, J = 15'3, 9.4 Hz, 1H ), 2.40-3.09 (m, 5H), 1.45 (s, 9H), 1.27 (t, J = 7.1Hz, 3H), 0.85_1.90 (m, 11H); FTIR (CCl4) 1734, 1694, 1637, 1426, 1171 cm_l; MS (ES) m / e 1149.8 (2M + H) +, 597.4 (M + Na) +, 575.4 519.4 (M + H-C4H8) + ° b) (soil) -HU1_ 二Hydrogen 3- [l- (4,4, · dihexahydropyridyl) carbonyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid will contain (earth dihydro_3, [17 (1 ^ 80〇454, -dihexahydro this pyridyl) carbonyl group] · 5Η-dibenzo [a, d] cycloheptaline-1Q · ethyl acetate g | (463.4 mg, 0.81 mmol), 1.0NLiOIJ (10 ml, ΐmmol), a homogeneous mixture of thF (4.1 ml) and Η20 (3.1 ml) was stirred at 40 ° C. After 17 hours, the homogeneous solution was dried at Cool in ice and acidify with 1 on HC1 (i · 5 mL). Extract with CH2a2 (3 X 10 mL) and dry (MgS (04) and concentrated, leaving a slightly off-white foam. This was dissolved in CH2CI2 (4.1 ml), and the solution was cooled to 0. TFA (202.4 mg, 1.06 mmol) was added all at once, and The reaction was warmed to room temperature. After 15 hours, the pale yellow solution was concentrated to dryness on a rotary evaporator, and the seed oil remained. ODS chromatography (30% MeOH / H2CMU% TFA) was performed, and the reaction was reduced. And freeze-dried to give the title compound (437.2 mg, 86%) as a colorless powder: HPLCk, 1.91 (Hamiton PRIM®, 35.0 /. ^ _ 86 This paper is in accordance with China National Standard (CNS) A4 specifications (210X297 males)

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533202 A7 B7 V. Description of the invention (85) Ink of CHFGN / H2 0-0.1% TFA, Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs; lHNMR (400MHz ^ CD3OD) δ 7.02-7.29 (m, 7H), 4.53 * 4) 3 (m, IH), 4.34 (d, J = 150 Hz, 1H), 3.99 (d, j = i50 Hz, 1H), 3.65-3.89 (m, 2H), 3.30-3.50 (m, 3H), 2.70-3.15 (m, 5H), 2.68 (dd, J = 16.0, 5.2 Hz, 1H), 2 52 (dd, j = 16 〇, 9.1Hz ^ 1H) »L06-2.09 (m, i〇fj) ； MS (ES) m / e 447.2 (M + H) + 〇C28H34N203 · UcF3C〇2ll Analytical calculation value: C, 59.00; Η, 5.91; M, 4.44ρ Real cockroach value: C , 58 ·%; Η, 6.00; Ν, 4,50. tlfe Example 3 Da) H [3- (2-Penyl benzazolyl) small propyl μ5Η-di-shang co [a, d] cycloheptene-10-acetic acid bis-a) 4- (2-tetrafluorene (Piperanyloxy) -1_tributyltinyl-butyne at 0 ° C under argon, a solution of n-butyllithium in hexane (1.6 M, 18.8 ml, 30 mmol) was flowed in Add to a solution of 2- (3 • butynyloxy) tetrahydro-2 // _ triple (4.7 ml, 30 mmol) in anhydrous THF (60 ml) over 2 minutes. After 0.5 hours, gaseous tributyltin (8.1 ml, 30 mmol) was added all at once, and the reaction was allowed to overflow to room temperature. After 3 hours, the reaction was diluted with hexane (300 mL), and then washed with H20 (2 X 60 mL), 10% KF (2 X 30 mL), and saturated brine (60 mL). After drying (MgS04), concentration and silica gel dissection (3%

(Please read the precautions on the back before filling in this page) Binding, binding-thread-This paper size is applicable to Chinese National Standard (cNS) a4 size (2i0X297 mm) 533202 A7 B7 V. Description of Invention (86) Central Standard of the Ministry of Economic Affairs Printed by Bureau Consumers Cooperative

After EtOAc / hexane *), the title compound was obtained as a nearly colorless oil, 27%) · TLC (5% EtOAc / hexane) Rf 〇37; 1h NMR (400 MHz, CDC1304.66 (narrow t, 1H >;, 3 75-3.96 (m, 2H), 3.49-3.62 (ni '2H)' 2.56 (appt, 2H), 1.76_1.91 (m, 1Η), 1.65-1.73 (η, 1Η) , 1.42-1 · 65 (ιη, ΐ〇Η), 1.22-1 · 4! Ί (m, 6H), 0.82-1.08 (m, 15H). · B) (±) -3- [ 4- (2, tetrahydropiperanyloxy) · ι · butyne + yl] -5 kg of dibenzo [a, d] cycloheptene-10-ethyl acetate 4 (() _ ιο, ιι-dihydro -Ηtrifluoromethanesulfonyloxy) _xyldibenzyl [a, d] cycloheptane-1. Ethyl acetate (1.34 g, 113 mmol), Φ < 2 ▲ Tetrahydro brigade oxygen Base) -1. Tributyltinyl 1-butadiene (1.66 g, 3.76 mmol), LiCl (398 mg, 9.39 mmol), vaporized bis (kingphenylphosphine) The mixture of Fang (110 mg, 0.094 mmol) and anhydrous' methane (31 ml) was heated under reflux under argon. After 1.5 hours, the reaction was rolled to remove most of the dioxane, The residue was taken up in Et20 × 100 ml). 10% KF (50 ml) was added and The mixture was stirred vigorously for 0.5 hours. The aqueous layer was removed and the Et> 0 layer was filtered through a celite mixture of Celite® and MgSQ <. The filtrate was condensed and the residue was chromatographed on a silica gel. (10% EtOAc / hexane) to give the title compound as a pale yellow oil (112 g, 83%): TLC (20% EtOAc / hexane) RfO.40; 1H, CDCI3) δ 721 (m, 1H ), 7.06-7.20 (m, 5H), 7.00 (d, J = 7.8 Hz, 1H), 4.69 (t, J = 36 Hz, 1H), 4.31 (d, J = 15JHZ, 1H), 4.11-4, 23 (tn, (Please read the precautions on the back before filling in this page)

This paper's ifc scale is applicable to China National Standard (CNS) A4 (210X297 mm) 533202 A7 B7 V. Description of the invention (87) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy 2H), 3.76-3.97 (m, 4H), 3.59_3.68 (m, 1H), 3.4S-3.57 (m, 1H), 3.34 ((M, J = 15.2, 4.1 Hz, 1H), 2.97 (dd, J = 15.2 , 9.5 Hz, 1H), 2.70 (t, J == 7.3 Hz, 2H), 2.65 (dd, J = 15.7, 4 · 8Ηζ, 1H), 2.51 (dd, J = 15.7, 9.5 Hz, 1H ), 1.78-1.92 (η, 1H), 1.68-1.78 (m, 1H), 1.44-1.68 (m, 4 lean), 1.27 (t, .J = 7.1 Hz, 3H); MS (ES) m / e 455 (M + Na) +. C) (±) 3- [4_ (2-tetrahydrobranyloxy) _1-butyl] -5H-dibenzo [a, d] Cycloheptene 40-ethyl acetate will contain (earth) -fluorene 4 · (2τ tetraarganepiperanyloxy)> 1-butynyl small group ρ5Η-dibenzo [a, d] cycloheptene-10 • ethyl acetate Ester (1.2 g, 2.77 mmol), 10% Pd / C (0.3 g, 0.2 $ mmol), and a mixture with EtoAc (28 mL) on a Parr device at room temperature at Shake under gas (50 psi). After 3 hours, filter the reaction through Celite (R) and concentrate the filtrate. Silica gel chromatography (10% EtOAp / hexane) to obtain the title compound as a colorless oil (1.06 g, 88%): TLC (20% EtOAAc / hexane) Rf0.51; iH NMR (400MHz »CDCI3) δ 7.05r7.20 (m ^ 4H) > 6.92-7.03 (m, 3H), 4.53-4.60 (m, 1H), 4.34 (d, J = 15.1Hz, 1H), 4.12-4.26 (m, 2H) , 3.80-3.90 (ιη, 3H), 3.71-3.80 (m, 1H), 3.44-3.51 (η, 1H), 3.35-3.44 (m, 1H), 3.33 (dd , J ==; 15 · 1, 4, 1 ttz, 1H), 2,95 (dd, i = 15 · 1 * 9 · 4Ηζ, 1H), 2j5 (d4, J = 115, 4 · 9Ηζ, 2H) , 2.49-2.61 (m, 3H), 1.77-L90 (m, 1H), 1.45 · 1 · 77 ^-(Please read the notes on the back before filling this page) Alignment-This paper size is applicable to China National Standards (CNS) A4 Specification (210X297)

533202 A7 B7 V. Description of the invention (88) Yin Fan, a consumer cooperative of employees of the Central Standards Bureau of the Ministry of Economic Affairs (m, 9H), l-27 (t, J = 7.1 Hz, 3H); MS (ES) m / e459 (M + Na) + ° d) (Ethyl) -3- [4-Cyclo-1-butyl] -5H-dibenzo [id] cycloheptane-l0_ethyl acetate -(2-tetrahydrolananyloxy) small butyl] -511-dibenzo [a, d] cycloheptene-10-ethyl acetate (456.0 mg, 1.04 mmol) and p-toluenesulfonic acid A solution of monohydrate (60 mg, 0.31 mmol) in absolute EtOH (10 ml), stirred at room temperature for 2 hours, and quenched the reaction with 5% NaHC03 (1 ml), and Concentrated to remove EtOH. The residue was diluted with H20 (2 pull-up) and extracted with CH2CI2. After drying (MgS04), concentration and silica gel layer folding (1: 1 EtOAc / hexane), the title compound (342 · 4 mg, 93%) was obtained as a colorless oil: TLC (1: 1 EtOAc / Hexane) Rf 0.49; 1HNMR (250MHz, CDCl3) 66.85-7.25 (m, 7H), 4.34 (d, J = 15.1Ηζ, 1H), 4.08-4.30 (m, 2H), 3 · 75-3 · 95 (m, 2H), 3.53-3.72 (m, 2H), 3.33 (dd, J = 15.1, 4 · 1Ηζ, 1H), 2.95 ((id, J = 15.1, 9.4Hz, 1H), 2.40-2.75 (m, 4H), 1.45-1.80 (π, 4H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) m / q 353 (M + H) +. E ) (±) -3 · [3-carboxy small propyl] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate will be (±) -3_ [4-hydroxy + butyl]- 5H-dibenzo [a, d] cycloheptene-10 • ethyl acetate (342.4 mg, 0.97 mmol) was dissolved in anhydrous CH2CI2 (19 mmol 90

(Please read the precautions on the back before filling this page)-Binding-Binding Line 'This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 cm) 533202 A7 ^ ------ El V. Description of the invention (89) The solution of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Co., Ltd.) was cooled to οχ: under argon, and the 2,2,6,6-tetramethoxyhexanoic acid I journal of organic chemistry (j.〇 rg. Chem.) (19, 50, 1332-1334; 260 mg, 1 36 mmol) were added in portions. The reaction was stirred at room temperature for 1 hour, then 2-methylbutene (1.2 ml, 11.64 mmol) was added, followed by NaciO2 (0.88 g, 7.76 mmol) and NaH2P. 4 (0.90 g, 6.50 mmol) in ice (0 ° C) was added in a solution of Η20 (26 ml). After 10 minutes, the reaction was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was sequentially washed with ice 1.0 NHC1 (10 mL) and saturated brine (20 mL), dried (MgS04) and concentrated. Silica gel chromatography (gradient: 1: 1 EtOAc / CHpi3, then 9: 9: 2 EtOAc / CHCl3 / EtOH) gave the impure title compound. Rechromatography on a silica gel (7: 3: 0.1 toluene / EtOAc / AcOH) gave the pure title compound (233.7 mg, 66%): TtC (1: 1 EtOAc / CHCl3) Rf 0.46; 1HNMR (400MHz ^ CDCI3) δ 7.05-7.22 (m ^ 4H), 6.92-7.05 (m, 3H), 4.34 ((1, J = 15.0 Hz, 1H), 4.10-4.25 (m, 2H), 3.80-3.90 ( m — 2H), 3.33 (dd, J = 15.1, 4.1 · ζ, 1H), 2.95 (dd, J = 15.1, 9.4 Hz, 1H), 2.48-2.60 (m, 4H), 2.48-2.60 (m, 4H ), 2.37 (t, J = 7.4 Hz, 2H), 1.87-2 · 00 (free, 2H), 1.27 (t, J; 7 · 1Ηζ, 3H); MS (ES) m / e389 (M + N3) +, 367 (M + H) + 〇f) (Earth) _10,11_dihydro-3-[[(2-aminophenyl) amino] carbonyl] propyl small butyl] -5H-diphenyl Benzene [a, d] cycloheptene-10-acetic acid ethyl SI ([]]-3- [3-carboxy small propyl] -5 fluorene-dibenzo [M] cycloheptene-10-ethyl

(Please read the notes on the back before filling out this page). Binding, binding-thread paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) 533202 A7 B7 V. Description of invention (90) Central Ministry of Economic Affairs Standard Bureau Shelley Consumer Cooperative printed ethyl acetate (233.7 mg, 0.64 mmol) dissolved in dry THF (6.4 ml). The solution was cooled to 0 ° C under argon, and 4-methyl Muffaloline (0.14 ml, 1.28 millimoles) was added. The solution was stirred at 0.1 ° C for several minutes, and then isobutyl formate (0.11 milliliters, 0.83 millimoles) was added dropwise. The turbid reaction was stirred at 0 ° C for 0.5 hours, and then a solution of 1,2 · phenylenediamine (138 mg, 1.28 mmol) in dry THF (0.6 iL) was added quickly. The reaction was warmed to room temperature and stirred for 3 hours, then diluted with H20 (2 mL) and extracted with EtOAc. Dryed < MgS04), concentrated and silica gel chromatography (3: 2 EtOAc / hexane) to give the title compound as a pale yellow foam (257.6 mg, 88%): TLC (3: 2 珙 OAc / hexane) Rf 0.40; lHNMR (25 MHz MHz CDC13) δ 6.90 ^ 7.23 (m > 10H), 6.72 · 6 · 80 (ιη, 2H), 4.33 (d, J = 15 · 0Ηζ, 1H), 410-4.25 (m, 2H), 3,71-3.91 (m, 4H), 3.32 (dd, J = i5.1, 4 · 0Ηζ, 1H), 2.95 (dd, J = 15.1, 9.5Hz, 1H), 2.59-2 72 (m, 3H), 2.54 (dd, J = 15.6, 9.5 Hz, 1H), 2.34 (t, J = 7.4 Hz, 2H), 1.9 ^ 2.09 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) m / e 457 (M + H) + 〇g) (Earth) -l0, ll-dihydro each [3- (2-benzimidyl) -1, stilbyl] dibenzo [M] cycloheptaene-10-acetic acid 6 The ester will be (±) -10,11-dihydro-3-[[(2- Mobenzyl) amino] carbonyl] propyl + butyl] -5'-dibenzo [a, d] cycloheptene-10 -A solution of ethyl acetate (257.6 mg, 0.56 mmol) in ice AcOH (2.8 L) and dry THF (2.8 mL) was heated under reflux under argon. After 3 hours, the reaction was Specifically concentrated, and

(Please read the precautions on the back before filling in this page). Loading ·, ιτ This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 533202 Α7 Β7 V. Description of Invention (91) Central Bureau of Standards, Ministry of Economic Affairs Printed by the Shellfish Consumer Cooperative

The residue was concentrated from dimethylbenzene and concentrated. The resulting residue was taken up in Et20 (30 ml), and extracted with i ONNaOH (2 ml), H20 (2 ml) and saturated brine (2 ml) in this order. After drying (MgS04), concentration, and silica gel chromatography (2% EtOH in 1: 1 EtOAc / hexanes), the title compound (236.3 mg, 96%) was obtained as a off-white foam: TLC ( 2% EtOH at 1: 1 EtOAc / hexane) Rf 0.34; 1 HKMR (400¾¾, CDC13) δ 7.30-7.80 (m, 2H), 7.03-7.24 (m, 6H), 6.80-6.95 (m, 3H) , 4.12-4.28 (m, 3H), 3.77-3.89 (to, 1H), 3.74 (d 'J = 15.1Ηζ, 1H), 3.28 (dd, J; 15.2, 4.0 Hz, 1H), 2, 90 (dd, J = 15.2, 9.5 Hz, 1H), 2.84 (t, J = 7 · 7Ηζ, 2H), 2.65 (dd, J = 15.7, 4 · 9Ηζ, 1H), 2.60 (t, J = 7.5Hz, 2H), 2.52 (dd, J = 15.7, 9.㈣, lH), 2.03-2.18 (m, 2H), 1.28 (t, J = 7.1Hz, 3H); MS (ES) m / e 439 (M + H) +. h) (Shidihydro-3- [3- (2-benzimidyl) -l_propyl] _5H_dibenzo [M] cycloheptene-10-acetic acid, the sodium salt will contain (earth) -10 , 11 -dihydro-3_ [3 «(2_benzimidazolyl) -μpropyl] _5Η_dibenzo [a, d] cycloheptene-10-ethyl acetate (236 · 3 mg, 0.54 Millimoles), 1.0NNaOH (0.65 milliliters, 0.65 millimoles) and absolute jEtoH (<4.8 milliliters) were warmed in an oil bath preset at 50 ° C. After 3 hours, the reaction was concentrated and the residue was subjected to 0JDS chromatography (gradient: 35% MeOH / H20, then 40 ° / 9Mρ0Η / Η20). Concentrated and then lyophilized to give the title compound (143 mg, 58%) as a colorless powder: HPLC

(Please read the precautions on the back before filling this page)-Binding-Binding 93 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 A7 _B7 V. Description of the invention () Central Bureau of Standards, Ministry of Economic Affairs Industrial and Consumer Cooperatives India Fan (PRP_1®, 40% CH3CN / H2〇 containing 01〇 / 〇TFA) K, 2 1.5; lHNMR (400MHz, CD3OD) S7, 41-7.49 (m, 2Η), 6.86 · 7 · 27 (m, 9jH), 4 · 24 (d, J = 14.7 Hz, 1H), 3.73-3.85 (m, 1H), 3.23–3.25 (m, ΐίϊ), partially obscured by residual solvent signals ), 2.80-2.93 (m, 3H), 2.62 (t, J = 7.5 Hz, 2H), 2j6 (d4, J = 14.4, 5.1 Hz, 1H), 2.40 (dd, J = 14 · 4,9 · 7Ηζ, 1H), 2.05-2 · 17 (π, 2H); MS (ES) m / e 411 (M + H) +-C27H25N20 gNa · 1'5 H2〇 Value: C, 70 · 57; H, 6.14; N, 6.10. Experimental values: C, 70 · 65; hydrazone, 5.95; N, 5.95. Example 4 (Equation, dihydro-3-m2 "(2-this pyridylamine ethyl) amino 1 carbonyl Preparation of Benzo 丨 a, dl 瓖 heptene-10-acetic acid a) (±) -10,11-dihydro, 3 _ [[[2- (2-The pyridylamino) methyl] amino] carbonyl] _ 5H · Dibenz [a, d] cycloheptene-10-ethyl acetate, at room temperature, add E0C (112.7 mg, 0.59 mmol) in one portion at a time (Earth) -10,11-dihydro 4-carboxybenzo [a, d] fluoreneheptene · 10-ethyl acetate (157.8 mmol, 0.49 mmol), 2-[(2-aminoethyl) amino] pyridine dihydrochloride M (123 · 5 mg, 0.59 mmol, HOBt · H2Q (79.5 mg, 0.95 mmol), and diisopropylethylamine (0,43 ml, 2.45 mmol) in anhydrous DMF (2.5 ml) In solution. Will react

(Please read the precautions on the back before filling in this page)-Installation_line 94 paper sizes are applicable to Chinese National Standards (CNS) A4 specifications (210X297 gong) 533202 V. Description of invention (employees of Zhongli Bureau of the Ministry of Economic Affairs Cooperation, Du Yin 95 A7 B7 93 &gt; Stir at room temperature for 18 hours and then concentrate. The residue was re-concentrated from xylene and then released with Kao (5 ml) and sequentially with EtOAc (2 X 5 ml) Extract with CHCI3 (2 X 5 ml). Combine the base layer and treat with a small amount of MeOH to dissolve a small amount of insoluble material. Dry (MgS04), concentrate and silica gel chromatography (5% Meop) / CHCl3), the title compound was obtained as a yellow oil <199 · 1 mg, 92%): TLC (h / 〇MeOH / CHCl3) Rf42; lHNMR (400MHz, CDCl3) 6 8.10 (d, J = 3.5 Hz ★ 1H), 8.02 &lt; brs, 1H), 7.60_ · narrow d, 1H), 7.33 · 7.42 (m, 1H), 7.08-7.22 (m, 5¾, 6.57-6,65 (m, lH), 6.45 (d, J = 8JHz, lH), 4.79-4.90 (m, 1H), 4.36 (d, J = 15 · 1Ηζ, 1H), 4.11 «4 · 26 (m, 2H), 3.92 (d, J soil 15.1 Hz, 1H), 3.80-3.95 &lt; m, 1H), 3.55-3.72 (ηχ, 4H) , 3.38 (dd, J = 15.2, 4.1 Hz, 1H), 3.03 (dd, J = 15.2, 9.5 | iz, 1H), 2.66 (dd, J = 15.8, 4 · 8Ήζ, 1H), 2 05 (dd, J = 15.8, 9 · 6Ηζ, 1H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) m / e 444.2 (M + H) + 〇b) (±) -10, 11-dihydro each [[[2- (2-The pyridylamino) methyl] amino] carbonyl] -5H-dibenzo [a, d] cyclohepteneacetic acid, the sodium salt will be (±) -10 , 11-dihydro-H [[2 &lt; 2- * bpyridinylamino) methyl] amino] carbonyl] _5H-dibenzo [a, dlcycloheptane_10_acetate 6 ester (199 · 1 mg (U5 mmol) and 1.0 NNaOH (0.54 ml, 0.54 mmol) dissolved in absolute EtOH (4 ml), warm in an oil bath set at 45 ° C. After dreaming (please read first (Notes on the back then fill out this page)

This &quot; Zhongguanjia standard (;) 8 4 Lin (210X 297 mm 533202 A7 B7 V. Description of the invention (94) After 23 hours, the reaction was concentrated, and the residue was subjected to 0DS chromatography (gradient: 30% MeOH / H20, then 40% MeOH / H20). After concentration and lyophilization, the title compound (95.8 mg, 46%) was obtained as an almost colorless powder: HPLC (PRP_1®, 30 ° / 〇CH3C1 ^ / H2〇 contains 0.1% TFA) K, 2 · 0; 1HNMR (400MHz, CD30D) S7.92 (app. D, J = 4.21¾, 1H), 7.61 (d, J = 1.8Hz ·, 1H ), 7.53 (dd, J = 7.9, 1.8 Hz, 1H), 7.38-7.47 (m, 1H), 7.01-7.24 (m, 5H), 6.56 (d, J = 7.9Hz, m), 6.50- 6,60 (m, 1H), 4.34 (d, J = 14.9 Hz, 1H), 3.97 (d, J = 14.9 Hz, 1H), 3.78'3.89 (m, 1H), 3.44-3.61 (m, 4H) , 3.39 (dd, J = 15.4, 4.4H ?, 1H), 3.00 (dd, J = 15.4, 10.2Ηζ, 1H), 2.61 (dd, 14.9, 5.1Ηζ, 1H), 2.43 ( dd, J = 14.9, 9 · 5Ηζ, 1H); MS &lt; ES) m / e 411 (M + H) +. For C25H24N3O3Na · 1.33H2O: C, 65.07; Hf, 5.82; N, 9J1. Experimental values · C, 65 02; Η, 5'62; N, 9.17. Example 5 Printed by Fangong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs --------------- (Please read the precautions on the back before filling out this page) (Soil:)-1〇, 11 -Bi-1-343- (2 «amino) small propoxy 1-511-shib [[a, d] cycloheptene-10-acetic acid production a) (±) -10,11-dihydro- 3- [3- 〖2- (N_oxy4pyridyl) amino] small propoxy] -SH-dibenzy [a, d] cycloheptan-10-ethyl acetate

96 This paper size applies to China National Standard (CNS) A4 (21〇 &gt; &lt; 297mm) 533202 A7 B7

At room temperature under argon, 2-[(3-hydroxy · 1 · propyl) amino] pyridine ^ N-oxide (2 mmol) and diethyl azoformate (2 mmol) (Ear) dissolved in anhydrous DMF (10 ml), slowly added dropwise (soil H (Uι diqidongjingfeng-5H-yiben 弁〗 a, d) cycloheptin-10-acetic acid ethyl acetate ( 1 mmol) and triphenylphosphine (2.1 mmol) are dissolved in a solution of anhydrous DMF (10 ml). When the reaction is complete, the solvent is removed on a rotary # evaporator, and the residue It was reconcentrated from xylene to remove residual DMF. Silica gel chromatography was performed to obtain the title compound. B) (±) -1 〇, 11 -dihydro-3- [3_ (2-this 唆) Amine) _1-propoxy] _5H-dibenzo [M] cycloheptene, 10-ethyl acetate, (earth) -10,11-dihydro, 3- [3- [2-(^ oxy Pyridyl) amine 棊] _1-propoxy] -5H-dibenzyl [a, d] cycloheptene-10-ethyl acetate (1 mmol), cyclohexene (10 mmol) and 10 A mixture of% Pd / C (0.1 mmol) in isopropanol (10 ml) was heated at reflux. When the reaction was complete, the mixture was filtered through Celite® and the filtrate was concentrated on a rotary evaporator. will The residue was reconcentrated from toluene, and then subjected to chromatography on silica gel to obtain the title compound. (Please read the notes on the back before filling out this page) Cooperatives Yinfan c) (Ethyldihydro-3_ [3 &lt; 2-this pyridylamino) small propoxydibenzo [a, d] cycloheptene-10-acetic acid, the sodium salt will be (±) -10, 11_dihydro-343- (2-pyridinylamino) spropoxy] -5H-dibenzo [a, d] cyclomolar-10-ethyl acetate (1 mmol) and 10NNa. A solution of H (l. 2 mmol) in absolute EtOH (10 ml) was set at 50. (: Of

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 male thin) 533202 A7 V. Description of invention (%) The Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, India, and the oil bath are warm in the oil bath. When the reaction was complete, the solvent was removed on a rotary evaporator and the residue was purified by ODS chromatography. After concentration and lyophilization, the title compound was obtained. Example 6 Debenzimidazole 1yl) methyl 1 methylamine]] [6,11-dihydro-5H-one hydrazone X-acetic acid a) 2-[[[((1Η-benzimidazole) (Methyl) methyl] methylamino j carbonyl] _6 j 丨 _dihydro_ 5H-dibenzo [b, e] azepine "6-acetic acid series using the general procedure of Example 1 (a), except that The compound of Preparation 16 (d) was substituted for the compound of Preparation 1 (0 to give the title compound. B) 2-[[t (lH-benzimidazol-2-yl) methyl] methylamino jcarbonyl] -6,11- Dihydro · 5H-dibenz [b, e] azepine-6-acetic acid was used in the general order of Example Kb), but the compound of Preparation 1 was replaced by the compound of Preparation 6 (a) to obtain the title compound. The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the specific embodiments filled in above, but also includes changes within the scope of the following patent applications. Various references to journals, patents, and other articles cited in this article are included in the state of the art, and are still incorporated herein by reference in their entirety.

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

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 {Filled by the Bureau} The Central Standards Bureau of the Ministry of Economic Affairs X Consumer Cooperatives Printing Contractor Code: Supplementary Category: A6 B6 IPC Classification: This case has been Apply for a patent from the United States (region), date of application ... The relevant microorganisms have been deposited on: June 29, 1595 AD Date of deposit: 2-2-Case No. 6 (ΜΧ) 0? 665

Ef Yes No No. Priority deposit number: (Please read the notes on the back before filling in the columns on this page) Binding-The size of the paper is applicable to the Chinese National Standard (CNS) Α4 size (210 × 297 mm) 533202 Λ7 ___ R7 May 1 clearly stated CT) — _ allowable body, providing a combination of selectivity. The invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutical carrier. The present invention is also a method for treating a disease in which the condition is alleviated by binding to an integrin party, particularly to a receptor of vitronectin or fibrinogen. In a particular aspect, the compounds of the present invention are useful in the treatment of osteoporosis, atherosclerosis, restenosis, cancer, and situations where platelet aggregation needs to be suppressed, such as stroke, temporary ischemic attack, myocardial infarction, and lysis Re-embolization after thrombotherapy. Detailed description The invention includes compounds of formula (I): R4

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

Ai is C or N; E is a five- or six-membered heteroaromatic year-old six-membered aromatic ring, optionally substituted by R3 or Π2 is CHRkH, CRkH, NRLCH, s (〇v α O-CH; ϋ -6-

This paper size applies the Chinese National Standard (CNS) A4 specification (2I0X297 ^ tT 533202 ^ 7Γ · ^ 02. LJ: i-•• ·, "· 1: · Γ a j 5. Invention description (6 R1G is Η, Cm Alkyl or -NRir; R12 is R, -C (0) R ·, -QCONR ,, -C (0) 0R5, 4 (0), or s (o) 2nr, R14 is H, C3. 6 cycloalkyl, Het or Ar; R15 is H, &lt;: -alkyl, C3.7 cycloalkyl-CQ.8 alkyl or Ar-C0.8 alkyl; U and V are absent or CO, CRf2, C (= CR152), S (0) n, O, NR15, CR15'OR15, CR '(ORn) CR'2, CRiCRXOR ,,), C (0) CR, 2, CR152C (0), CONR15 , NR15CO, OC (O), c (o) o, C (S) 0, OC (S), C (S) NR15, N15C (S), S02NR15, NR15S02, N = N, NR15NR15, NR15CR152, CR1520, OCR152, 0C, CR15 = CR15, Het or Ar, the condition is that U and V do not exist at the same time; W is R, R &quot; N-, R, R &quot; NR, N-, R, R &quot; NR, NCO -, R, 2NR, NC (= NR,)-, R, ONR, C (= NR,)-, '^^ Clothing Aw (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative r * 2n r ^ n JJR &quot;… R9 Ν ·, R. 2N ν 'rS NR ·· · RR «N meaning y, Rm (meaning NPTT · X ·, rr'n person nr ·· Θ; xi Rb) [VV R. ~ Ra (O) w Ra NR4 NR or

N

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 533202 A7 V. Description of invention (7), 仏; Fu Chong

Q printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is NR ', 0 or S; 1 ^ is Η, CN6 alkyl, Ar-CV6 alkyl, Het-CV6 alkyl, or c3.6 cycloalkyl-C0_6 alkane Group, halogen, OR1, SR1, COR1, OH, N02, N (R!) 2 ^ CO (NR1) 2 ^ CHCNR1 ^; Rb and Rc are independently selected from H, CN6 alkyl, Ar-CV6 alkyl, Het-C0_6 alkyl, or C3_6 cycloalkyl-C0_6 alkyl, halogen, 〇Ri, SRI, COR1, OH, N02, NCR1)], CCKNR%, CI ^ NR%, or Rb and Re are joined together to Forms five or six-membered aromatic or non-aromatic rings, optionally via halogen, Cm alkyl, OR1, SR1, COR1, OH, N02, NOR%, CCKNR%, CH / NR,, CN, or R "R, NC (= NR,)-; X is N = CR ;, C (O) or O; Y is absent, s or o; Z is (CH2) t, Het, Ar or CV7 cycloalkyl;

Weiweiwei mnq Γ S or or or or or :: This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) kFFr ^,-口

It printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 533202 '! Λ /,., 1, t --- ~~-~ i # 〇 £ ia ^! L ： 3__ V. Description of the Invention (") ^ ~~ ^ ---, isopropyl, n-butyl, isobutyl, and tert-butyl. In addition, CM alkyl includes, pentyl, n-pentyl, isopentyl, neopentyl and hexyl, and simple lipids. Isomers. Unless otherwise specified, any C &quot; alkyl or alkyl group may be optionally substituted with R7. In addition, the term "alkyl" and "alkyl" means that no alkyl group is required (for example, a covalent bond is present) As used herein, C: 2-6 alkenyl means a 2 to 6 carbon alkyl group, in which a carbon-carbon single bond is replaced by a carbon-carbon double bond. Cm alkenyl contains ethylene, 1-propylene, 2- Propylene, 1-butene, 2-butene, isobutene, and several isomeric pentenes and hexenes. Both cis and trans isomers are included. Unless otherwise specified, any &lt; ^ · 6 alkenyl Optionally substituted by R7. CM alkynyl means an alkyl group of 2 to 6 carbons in which a carbon-carbon single bond is replaced by a carbon-carbon parameter bond. (: 2-6 alkynyl includes acetylene, 1-propyne, 2_ propyne, 1-butyne, 2-butyne, 3- The simple isomers of alkynes and pentynes and hexynes. The sp3 carbon atom in any CM fast group can be optionally substituted by R7. Cw carbonylcarbonyl means a carbonyl group of up to 4 carbons, of which the CH2 group is via C. O), or carbonyl. The substituted formamidine, acetamidine, ^ propionic acid, 2-acetone, 3-propanoic acid, 2-butyridine, 3-butanyl, 1- and 4-butanyl are Representative. In addition, Cw carbonylalkyl includes higher analogs and isomers of five and six carbons substituted by carbonyl. C3-6 carbonylalkenyl and &lt;: &gt; 6 carbonylalkynyl means a c3 &lt; alkenyl Or C3_6 alkynyl, where the CH2 group is substituted with C (O). C3-4 carbonylalkenyl contains 1-oxo-2-propenyl, 3-oxo-1-propenyl, 2-oxo-3-butenyl Etc. C1-6 alkynyl 'C2_6 fine group' C2-6 alkynyl or c1-6 alkynyl "18- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) --- --- 1T ------- 0 (Please read the notes on the back before filling out this page) 533202-仏, month __________ V. Description of the Invention (爻) ~ a) THPOCH2CH2Sn (Bu) 3, ( pph3) 2pdcl2, Lic dioxane; b) H2 '10% Pd / C' EtOAc; c) p-T5〇Η · Η20, Et. H; Sentence gasification of 2,2,6,6-tetrahydroxanthine 1-BOC-4,4'-dihexahydropyridine, CH2C12; e) NaC102 'Na2HP〇3, 2-methyl-2- Butylene, H20; f) isobutyl chloroarsinate, 4-amidinomorphine, and then phenylenediamine; g)

AcOH, THF; h) 1.0 N NaOH, EtOH and then acidification. The Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative Co., Ltd. printed Compound 1 ('I) of Flowchart 4 on aromatics and organotinane 5478-5486) in a Stille-type coupling reaction with 4- (2-tetrahydroanyloxy) -1-tributtinane butyne to provide 4-2. The reaction is catalyzed by a palladium salt, preferably bis (triphenylphosphine) palladium (11) ((PhsP) 2PdCl2), and in the presence of a chlorinated chain in a suitable inert solvent, usually DMF or Dioxane. The reduction of the acetamidine unit of 4-2 is performed under standard hydrogenation conditions familiar to those skilled in the art. The resulting compound (4_3) is deprotected under standard conditions used to remove the tetrahydrofuranyl (THP) ether, providing 4-4. Various conditions for the deprotection of THP ethers are described in standard reference books such as Greene, "Protective Groups for Organic Synthesis," (published by Wiley-Interscience). Will The first alcohol part of 4-4 is oxidized to the second-stage extraction method described by Wovkulich {Journal of Organic Chemistry {J. 〇rg. Chem) \ 9W, 58, 832-839). Corresponding carboxylic acid 4_5. Many methods have been described to choose from for the oxidation of the first alcohol to the corresponding carboxylic acid, and can be used in this paper. ^ Family ^ (CN ^ y ^ 格 (2丨 〇 &gt; &lt; 297 public ^ 53320 $ The profit case is requested / Yi Bizhi (the year of the Republic of China see the month β 迠 present)-Attachment r \ i em 1 ... 19 ^, τ 33 V. Description of the invention () Γ ^ Ά is found in such reference books. The conversion of 4-5 carboxylic acid to benzimidazole derivative 4_6 is in accordance with the general procedure described in Wo. Therefore, 4-5 was first used (for example ) Isobutyl chloroformate, in the presence of a suitable base, usually 4-methylmorphofluorene, triethylamine or diisopropylethylamine, in an inert solvent such as THF or CH2Cl2 Into an activated form of a carboxylic acid. The activated form is then reacted with an excess of an appropriate 2-diamino aromatic derivative, such as 1,2-phenylenediamine, to provide the corresponding mono- Ammonium. The mono-amidine is then framed under standard conditions, such as acetic acid in refluxing THF, to provide 4-6. The ethyl ester of 4-6 is used with an aqueous base, for example, in aqueous THF. LiOH or NaOH present in aqueous methanol or ethanol is hydrolyzed and the intermediate carboxylate is acidified with a suitable acid, for example, or HC1 to provide carboxylic acids 4-7. Alternatively, the intermediate carboxylate can be isolated, if It is hoped that the carboxylate salt of a free carboxylic acid can be prepared by a method familiar to those skilled in the art. Flow chart 5 is used to illustrate the coupling method for forming a bond between carbon and oxygen, which can be used for Formation of ether linkages. Similar coupling methods can also be used to form sulfide and amine linkages.

Claims (1)

533202 ΔΧ Α8 Β8 C8 D8 6. Scope of patent application j Patent Application No. 86106142 ROC Patent Appln. No. 86106142 Amended Claims Chinese Text-Attachment (II) —— Amended Claims in Chinese-Enel. (II) (February 2, 1992) (Submitted) on February 24, 2003) 1. A compound of formula (IV): Wherein X ^ χ2 is CH2-CH or NH-CH; X3 is CH2; R2 is OH; R3 is Η; and printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R6 is Benzene, Misoyl-Ci_4, and Ci_4. Aminoamino-pentyl 5 hexamidinepyridylcarbonyl, benzimidazolyl-Cm alkyl, pyridylamino-Cm alkylamino-carbonyl or pyridylamino-C ^ alkoxy; or pharmaceutically acceptable Accepted salts. 2. The compound according to item 1 of the scope of patent application, which is: (±) -10,11-dihydro-3-[[[((111-benzimidazol-2-yl) methyl] methylamino]] carbonyl ] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-dihydro-3-[[(4, cardiodihexahydropyridyl) carbonyl] -5H- Diphenyl-44-This paper is sized for China National Standard (CNS) A4 (210x297 mm) 85556B Apply for a patent, printed by a member of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by a consumer cooperative, d] cycloheptene-10-acetic acid; 丨: dilute (±), 10, 11 --- gas, Γ * ,, lice , 3-[[[2- (2-Pyridinylamino) ethyl] amino] carbonyl] -5Η_-Benkai [M] cycloheptan, acetic acid; aminooxy] • dibenzo = [[ (11 ^. Misal-2-yl) methyl] methylamine_dibenzo ~] azapyridine each acetic acid. Fei 3 :::! A pharmaceutical composition for making fibrinogen receptors, which contains the compound of the second item of the patent as the active ingredient. Medicine for inhibiting vitronectin receptor The compound according to item i of the patent application range is used as an active ingredient, and three compounds are used as an active ingredient for the treatment of osteoporosis, atherosclerosis, or angioplasty. According to application §_Scope No. 6: = stroke, temporary ischemic attack, myocardial infarction or a medical composition called treatment after re-embolization, the compound in the scope of patent application No. 1 is used as an active ingredient. ', Dagger 3 &lt; -45 ^ (210x297 ^